Progress in Heterocyclic Chemistry. Volume 7

PROGRESS IN HETEROCYCLIC CHEMISTRY Volume 7 PROGRESS IN HETEROCYCLIC CHEMISTRY Volume 7 Related Titles of Inte...

Author: Suschitzky H. | Scriven E.F.V.

176 downloads 1680 Views 13MB 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 7

PROGRESS IN

HETEROCYCLIC

CHEMISTRY

Volume 7

Related Titles of Interest from Elsevier Science Ltd Books

Organic Chemistry Series CARRUTHERS: Cycloaddition Reactions in Organic Synthesis DEROME: Modern NMR Techniques for Chemistry Research GAWLEY & AUB~: Asymmetric Synthesis* HASSNER & STUMER: Organic Syntheses Based on Name Reactions & Unnamed Reactions PAULMIER: Selenium Reagents and Intermediates in Organic Synthesis PERLMUTTER: Conjugate Addition Reactions in Organic Synthesis SIMPKINS: Sulphones in Organic Synthesis TANG & LEVY: Chemistry of C-Glycosides* WILLIAMS: Synthesis of Opticallly Active (z-Amino Acids WONG & WHITESIDES: Enzymes in Synthetic Organic Chemistry Major Works of Reference ABEL, STONE & WILKINSON: Comprehensive Organometallic Chemistry I1" ALLEN & BEVINGTON: Comprehensive Polymer Science BARTON & OLLIS: Comprehensive Organic Chemistry HANSCH et aL: Comprehensive Medicinal Chemistry KATRITZKY, REES & SCRIVEN: Comprehensive Heterocyclic Chemistry I1" KATRITZKY, METH-COHN & REES: Comprehensive Organic Functional Group Transformations* TROST & FLEMING: Comprehensive Organic Synthesis * in preparation Journals

TETRAHEDRON (rapid publication primary research journal for organic chemistry) TETRAHEDRON: ASYMMETRY (international journal for rapid publication on all aspects of asymmetry in organic, inorganic, organometallic, physical chemistry and bio-organic chemistry) TETRAHEDRON LETTERS (rapid publication preliminary communications journal for organic chemistry) BIO-ORGANIC & MEDICINAL CHEMISTRY LETTERS BIO-ORGANIC & MEDICINAL CHEMISTRY CARBOHYDRATE RESEARCH HETEROCYCLES Full details of all Elsevier Science publications, and a free specimen copy of any Elsevier Science joumal, are available on request from your nearest Elsevier Science office

PROGRESS IN

HETEROCYCLIC CHEMISTRY Volume 7 A critical review of the 1994 literature preceded by two chapters on current

heterocyclic topics Editors

H. SUSCHITZKY

Department of Chemistry and Applied Chemistry, University of Salford, UK and

E. F. V. SCRIVEN

Reilly Industries Inc., Indianapolis, Indiana, USA

PERGAMON

U.K.

Elsevier Science Ltd, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB. U.K.

U.S.A.

Elsevier Science Inc., 660 White Plains Road, Tarrytown, New York 10591-5153, U.S.A.

JAPAN

Elsevier Science Japan, Tsunashima Building Annex, 3-20-12 Yushima, Bunkyo-ku, Tokyo 113, Japan Copyright 91995 Elsevier Science Ltd All rights reserved. No part of ~is publica#on may be reproduced, stored in a re~ievalsys ternor ~ransmittedin any form or by any means: electronic, electrostatic, magneto tape, mechanical, photocopying, recording or o~erwise, w#houtpermission in w~'ng from ~e publishers.

First Edition 1995 Library of Congress Cataloging In Publication Data

A catalog record for this serial is available from the Ubrary of Congress British Library Cataloguing In Publication Data

A catalogue record for this book is available from the British Ubrary ISBN 0 08 042090 7

Printed in Great Britain by Biddies Ltd, Guildford and King's Lynn

Contents Foreword

vii

Advisory Editorial Board Members

viii

Chapter I:

Polyfunctlonallzed Pyrroles and Pyrazoles from Conjugated Azoalkenes

O. A. Attanasi, P. Filippone and F. Serra-Zanetti, Istituto di Chimica Organ|ca della Facoltk di Scienze, Universitd di Urbino, Piazza della Repubblica 13, 61029 Urbino, Italy

Chapter 2: Application of D|els-Alder Cycloaddltlon Chemistry for Heterocycllc Synthesis 21 A. Padwa, Emory University, Atlanta, GA, USA

Chapter 3: Three-Membered Ring Systems

43

A. Padwa, Emory University, Atlanta, CA, USA and S. S. Murphree, Miles Inc.,

Charleston, SC, USA

Chapter 4: Four-Membered Ring Systems

64

J. Patrick and L. K. Mehta, Brunel University, Uxbridge, UK

Chapter 5: Five-Membered Ring Systems Part 1. Thiophenes & Se, Te Analogs R. K. Russell, The R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA and J. B. Press, Emisphere Technologies Inc., Hawthorne, NY, USA

82

Part 2. Pyrroles and Benzo Derivatives R. J. Sundberg, University of Virginia, Charlottesville, VA, USA

106

Part 3. Furans and Benzo Derivatives W. Friedrichsen and K. Pagel, Institute of Organic Chemistry, University of Kiel, Germany

130

Part 4. With More than One N Atom S. A. Lang, Jr, American Cyanamid Company, Pearl River, NY, USA and V. J. Lee, Microcide Pharmaceuticals Inc., Mountain I/iew, CA, USA

148

Part 5. With N & S (Se) Atoms not submitted

164

Contents

vi

Part 6. With O & S (Se, Te) Atoms R. A. Aitken and L. Hill, University of St Amtrews, UK

165

Part 7. With O & N Atoms G. V. Boyd, The Hebrew University, Jerusalem, Israel

179

Chapter 6: Six-MemberedRing Systems Part 1. Pyridine and Benzo Derivatives J. E. Toomey and R. Murugan, Reilly Industries Inc., Indianapolis, IN, USA

195

Part 2. Diazines and Benzo Derivatives G. Heinisch and B. Matuszczak, Institute of Pharmaceutical Chemistry, University of Imzsbruck, Austria

226

Part 3. Triazines, Tetrazines, and Fused Ring Polyaza Systems D. T. Hurst, Kingston University, Kingston upon Thames, UK

244

Part 4. With O and/or S Atoms 268 J. D. Hepworth and B. M. Heron, University of Central Lancashire, Preston, UK

Chapter 7: Seven-MemberedRings

294

D. J. LeCount, Formerly of Zeneca Pharmaceuticals, UK

I, Vernon Avenue, Congleton, Cheshire, UK

Chapter 8: Eight-Memberedand Larger Rings

315

G. R. Newkome, University of South Florida, Tampa, FL, USA

Subject Index

329

Foreword Progress in Heterocyclic Chemistry (PHC) Volume 7 reviews critically the heterocyclic literature published mainly in 1994. The first two chapters are traditionally review articles. Chapter 1 surveys useful synthetic routes to "Polyfunctional Pyrroles and Pyrazoles" starting from conjugated azoalkenes. This review is based on the researches of O.A. Attanasi and his school in Urbino (Italy). As last year the second review is unconventional, comprising a compilation of the "Application of Diels-Alder Cycloaddition Chemistry for Heterocyclic Synthesis". It is written by our president A. Padwa and is in an unusual format with a pertinent list of references dating back forty years in some cases. We were encouraged to include this review because of favourable comments received from readers about this type of survey in PHC Volume 6. The remaining chapters deal with advances in the heterocyclic field, arranged in ascending order of ring size. The reference system in the text is as usual modelled on that used in ComprehensiveHeterocyclic Chemistry(Pergamon, 1984). We much regret that Chapter 5 Part 5 on Five-Membered Ring Systems with N & S (Se) Atoms was not submitted through unforeseen circumstances. This omission will be rectified in the next volume. Again we had a number of unsolicited approaches from our readers offering review articles for publication in future issues, for which we are grateful. This highlights the importance attributed to PHC as a publication in the heterocyclic field. We thank all authors for providing camera-ready scripts with clear diagrams. We ask for forbearance for lack of uniformity in the technical presentation, which is unavoidable with authors from so many countries. We are much indebted to David Claridge of Elsevier Science for his invaluable help with the presentation of chapters. We hope that our readers will find that PHC offers information and inspiration in a pleasurable way, helped by an index and numerous diagrams. H. StJscnrI~rV E. F. V. SCRIVEN

vii

Editorial Advisory Board Members Progress in Heterocyclic Chemistry 1995--1996 PROFESSORA. PADWA(CHAIRMAN)

Emory University, Atlanta, GA, USA DR D. BELLUS**

PROFESSORK. MORI**

PROFESSOR J. BERGMAN

PROFESSORS. F. MARTIN

Science University of Tokyo Tokyo, Japan

Ciba Geigy Ltd Basel, Switzerland Royal Institute of Technology Stockholm, Sweden

University of Texas Austin, TX, USA

PROFESSORT. GILCHRIST**

PROFESSORL. E. OVERMAN

PROFESSORT. HINO

DR P. ORNSTEIN**

PROFESSORP. A. JACOBa

PROFESSORV. SNIECKUS

PROFESSORA. R. KATRITZKY

PROFESSORB. STANOVNIK**

University of California Irvine, CA, USA

University of Liverpool Liverpool UK

ELI LILLYCO INDIANAPOLIS,IN, USA

Chiba University Japan

University of Waterloo Ontario, Canada

Wesleyan University Middletown, CT, USA

University of Ljubljana Ljubljana, Slovenia

University of Florida Gainesville, FL, USA

PROFESSORH. MOORE

University of California Irvine, CA, USA

** New member

viii

The International Society of Heterocyclic Chemistry is pleased to announce the establishment of its home page on the World Wide Web. Access can be gained from the following locations" for USA, Americas, Japan" h ttp :lie uc h 6 f. c hem. em ory. ed u/ishc, h tml for Europe" h ttp ://www. ch. ic. ac. uk/ishc/

This Page Intentionally Left Blank

Chapter 1 Polyfunctionalized Pyrroles and Pyrazoles from Conjugated Azoalkenes ORAZIO A. ATTANASI, PAOLINO FILIPPONE and FRANCO SERRA-ZANETTI

Istituto di Chimica Organica della Facolt& di Scienze, Universit& di Urbino, Piazza della Repubblica 13, 61029 Urbino, Italy

1.1 I n t r o d u c t i o n Conjugated azoalkenes, also named conjugated azo61efins or more rarely 1,2-diaza-l,3-butadienes, have been demonstrated to be valuable tools in organic synthesis both as acceptors in Michael additions and as partners in cycloaddition reactions [86OPP2991. In general, the >C=C< double bond in the heterodiene system of these substrates has been shown to be particularly reactive towards nucleophilic reagents because of the activating effect of the-N=N- group. In view of their versatility, we have frequently turned our attention to the synthesis of unknown conjugated azoalkenes [83CJC2665, 84S671, 84S873, 84S874, 85OPP385, 85JHC1341,85H867, 87SC555, 88OPP408]. Some differences related to the presence of electron-rich (electron releasing) and electron-poor (electron withdrawing) substituents, mainly located on the terminal carbon and nitrogen atoms of conjugated azoalkenes, have been described in reference to the reactivity of these compounds 191JCS(PI)3361 ]. The azo-ene system of conjugated azoalkenes undergoes various nucleophilic attacks, frequently with high yield and under very mild reaction conditions, producing hydrazone derivatives by 1,4-conjugated addition (Michael-type). It is noteworthy that the hydrazones generated are often useful intermediates, giving rise to spontaneous reactions (i.e. eliminations, substitutions, internal nucleophilic attack with or without further elimination, heterocyclizations). In fact, in the presence of a good leaving group on the nucleophilic agents we have observed olefination

2

Polyfunctionalized Pyrroles and Pyrazoles

processes of the hydrazonic intermediate adducts, giving functionalized cx,l~-unsaturated hydrazones |88TL5787, 90T5685, 91JCR(S)252, 93T7027, 94S372, 94OPP485|. Based on our studies of conjugated azoalkenes over nearly twenty years, these starting materials have been shown to represent useful building blocks for the construction of uncommon polyfunctionally substituted pyrrole |93MI461] or pyrazole heterocycles. Using the above-mentioned hydrazone intermediates, derived from attack of nucleophilic species bearing carbonyl, cyano or carboxylate functions in a-position, many widely functionalized 1-aminopyrroles have been obtained (i.e. 3-substituted-l-aminopyrroles, 1-amino-2,3dihydropyrrol-2-ols, 1,2-diaminopyrroles, pyrroloi2,3-blpyrroles, 1amino-lH-pyrrol-2(3H)-ones, and 3-unsubstituted-l-aminopyrroles). The reaction pathway indicates an intramolecular interaction between the >C=N_-NH- nitrogen atom and one of the above-mentioned functional groups followed by an appropriate molecular rearrangement and/or elimination, leading to the heterocyclization process. Scheme 1 shows the type of new pyrroles synthesized in our laboratory.

--•N--

NH--

N--NH--

O

o

Nm ~m

It

~N--

N-- NH---

Nil-NHz New l-aminopyrroles Scheme 1

Polyfunctionalized Pyrroles and Pyrazoles

3

In the case of the hydrazone intermediates from the nucleophilic attack of reagents possessing none of the above functions, the closure to give highly substituted pyrazole rings becomes possible. This is due to the internal attack by the >C=N-NH- nitrogen atom on the carboxylate group present in the azoalkene residue with loss of a suitable molecule yielding interesting 4-phosphoranylidene- IH-pyrazol-5(4H) - o n e s, 5alkoxypyrazoles, and 1H-pyrazol-5(2H)-ones. 5-Substituted-pyrazoles derive from a slightly different reaction pathway. Schemes 2 shows the type of new pyrazoles synthesized in our laboratory. \/

~N~N~

O

RO

I New pyrazoles Scheme 2

1.2 Pyrroles The synthetic strategy elaborated by us for the polysubstituted title heterocycles from conjugated azoalkenes has made possible the direct preparation of pyrroles with four or five substituents, dihydropyrroles containing up to seven substituents, and fused pyrroles bearing eight substituents. In the case of pyrroles and dihydropyrroles, three substituents (one on the nitrogen and two on the ring) are from the azoolefinic substrates and the rest are derived from the nucleophilic reagents. In fused pyrroles, conjugated azoalkenes supply two equal or different substituents onto the nitrogen heteroatoms and four substituents onto the ring, while the other two substituents derive from the nucleophile

4

Polyfunctionalized Pyrroles and Pyrazoles

agents employed. In accordance with the general pathway of the reaction, these facts permit to program the substituents of the final molecules. The mechanism of these reactions requires the presence of at least one hydrogen atom on the terminal carbon atom of the azo-ene system, to give 3-substituted-l-aminopyrroles, while the presence of two hydrogen atoms on the same carbon atom should produce 3-unsubstituted-l-aminopyrroles |90T395, 93JCS(P 1) 1391 I. It is noteworthy that in pyrrole derivatives obtained from conjugated azoalkenes prepared by reaction of carbonyl compounds and several hydrazine derivatives (i.e. tert-butylcarbazate, benzoylhydrazine, p-toluenesulfonylhydrazine, p-methoxybenzensulfonyl-hydrazine, 2,4,6trimethylbenzensulfonylhydrazine), the amino function on the nitrogen heteroatom possesses a protective group (i.e. Boc, Bz, Ts, Mbs, Mts) which is removable by well known procedures [91M12771. In general, easier reactions are observed when methylene or methine groups in a-position to carbonyl, cyano or carboxylate functions are further activated by directly linked strong electron withdrawing groups (i.e. ketonic, ester, amidic, sulphonic, nitrilic, nitric, phosphoranic, phosponic). However, even remote activation has been found to be sufficient in some cases to bring about the expected reactions. Frequently these reactions occur with high yield in one-flask at room temperature, often without isolation of the intermediates, sometimes by metal ion or base catalysis.

1.2.1 3-Substituted- l-aminopyrroles The activated methylene group of 13-diketones or lS-ketoesters [82JOC684, 83JHC1077, 85S157, 85H867, 86SC343, 86JHC25, 87I"4249, 88H149, 95UP1], 13-ketoamides [83S742, 84S671, 84S873, 84S874, 86OPPI, 86SC1411, 88G5331, 15-ketosulphones [86BCJ3332, 87S381, 88JHC 1263], 13-ketonitriles [92JCS(PI) 1009], and I~-ketophosphonates [94S 181] readily attacks the heterodiene system of conjugated azoalkenes, yielding the hydrazonic 1,4-adduct intermediates followed by the lamino-2,3-dihydropyrrol-2-ol owing to five-membered ring formation. In this cyclization the ketonic group is clearly favoured in respect of the ester, amidic, and nitrilic groups, with preference for the aliphatic rather than aromatic carbonyl. The loss of a water molecule gives the final 3substituted-l-aminopyrrole derivatives, as the more stable heteroaromatic rings (Scheme 3). The reaction between conjugated azoalkenes and

Polyfunctionalized Pyrroles and Pyrazoles

5

compounds containing a remotely activated methylene group in c~-position to a keto-group proceeds in an analogous way |93JCS(PI)3151. H

R2

R2

R 3 ~

N~.N~

RI

H a4

N----. NH-- Rt

O

a.r R3

\

~4

/

R2

R3~

~

/

"lilO

H---- NH-- RI

R2

Nllm RI

~ R4

R"r

RI=H, Ph, 4-NO2C6H4,4-CIC6H4,MeOCO, EtOCO, Me3COCO, NHaCO, PhNHCO, PhSOa, 4-MeC6H4SO2, 2,4,6-Me3C6H2SO2,4-CIC6H4SO2,4-OMeC6H4SO2, MeCO, PhCO, 3-CIC6H4CO,3-MeC6H4CO, PhCHaCO, 3-NO2-2-Pyridyl,2-Pyrimidyl, 2Benzothiazolyl, PhaPO, (EtO)aPO, (PhO)EPO. R2=ph, PhCH2, Me, 4-NO2C6H4. R3=ph, MeOCO, EtOCO, PhCH2OCO. R2,R3=-(CH2)4-. R4=Me MeCO,Me3CCO, PhCO, 4-BrC6H4CO, MeOCO, EtOCO, Me3COCO, PhCHzOCO, NHaCO, EtaNCO, PhNHCO, 4-OMeC6H4NHCO, 4-CIC6H4NHCO. MeSO2, PhSO2, 4-MeC6H4SO2, CN, 4-NO2C6H4, 2-FC6H4,(MeO)2PO. RS=Me, Et, Pr, Ph, MeOCOCH2, Me3C, 4-NO2C6H4. R4 Rs=-(CH2)3CO. Scheme

3

An exception to this general reaction pathway is represented by some pyrroles derived from the reaction between conjugated azoalkenes and compounds containing active methinic groups. In this case. the molecule, yields the pyrrole ring, as terminal reaction product 189G631 I. All the intermediates mentioned have been isolated, characterized. and then converted into subsequent intermediates or products. Particular difficulties were encountered in the isolation and characterization of the supposed l-amino-2,3-dihydropyrrol-2-ol intermediate which was isolated for the first time after many years of investigations [87T42491. These difficulties were ascribed to the poor stability of this intermediate due to the facile loss of water, as well as methanol or acetic acid 189G631 I, with

6

Polyfunctionalized Pyrroles and Pyrazoles

production of a five-membered aromatic heterocycle. Therefore, these reactions often occur with high yields in one-flask at room temperature, in the presence of catalytic amounts of copper(ll) chloride. The relatively little-known and quite controversial 13C-NMR chemical shift assignments for several of these compounds have been studied in detail [85MRC383, 88MRC714, 88G533]. In view of the wrong structural assignment by previous authors, the crystal structure of some of these molecules was unambiguously determined by X-ray diffraction studies 182JOC684, 85AX(C)450, 87T4249, 88G533]. 1.2.2

1-Amino-2,3-dihydropyrrol-2-ois l-Amino-2,3-dihydropyrrol-2-ols, having an hydrogen atom on the carbon atom in position 3, were isolated for the first time during the synthesis of some 3-substituted-l-aminopyrroles, as moderately stable intermediates because of the elimination of a water molecule with consequent aromatization of the pyrrole ring [87T4249]. The structure of one of these intermediates was unequivocally confirmed by X-ray diffraction investigation [87T4249]. Several derivatives of this type have been produced by treatment of conjugated azoalkenes with CH-substituted [$-diketones, [~-ketoesters, [~ketolactones, fl~-ketonitriles or [~-nitroketones containing an activated methinic group [89G631,92JCS(PI)3099, 93T70271. It has been observed that the heterocyclization process of the hydrazonic 1,4-adduct occurs selectively on the keto group and the absence of a proton on the carbon atom in a-position allows the preparation of unknown stable l-amino-2,3-dihydropyrrol-2-ols in good H

R1 + R 3 ~

R5 O

R2

N-

Nil" RI --~

.-. Nil- R I

R4f " ~ O

Rs

a s`"

"OH

RI=MeOCO,MeaCOCO, NH2CO, PhNHCO, PhCO, 3-CIC6H4CO,3-MeC6H4CO, PhCH2CO. R2=MeOCO,EtOCO. R3=Me MeCO, PhCO, EtOCO, CN, NO2. R4=H, Me, Ph. R 3 R4=-(CH2)2OCO.

RS=Me, Ph, 4-NO2C6H4. R4,RS=-(CH2)3-, -(CH2)3CO,2-C6H4CO. Scheme 4

Polyfunctionalized Pyrroles and Pyrazoles

7

yields (Scheme 4).

1.2.3 1,2-Diaminopyrroles The ready reaction of conjugated azoalkenes with a molar excess of nitriles containing activated methylene groups (e.g. malononitrile, 13cyanoamides, lS-phosphononitriles or remotely activated nitriles) has been examined. This reaction afforded the preliminary equimolecular conjugate adducts by nucleophilic attack of these reagents on the azo-ene system of the azoOlefin substrates. An intramolecular nucleophilic attack from the >C=N-NH- nitrogen atom on the carbon atom of the cyano group brings about the five-membered ring closure leading to the 2-iminopyrroline intermediates that readily tautomerize into novel 1,2-diaminopyrroles (Scheme 5). H

R z ~ N~f'N~Rt

+

n3~

c.n

/

H..~

~N----Nll--

RI

'

-'~

.c':----,N !1[2

\

\

R2

/

/ Nil--- R I

--.- NIt--- R I

NH~

R I=H, MeOCO, EtOCO, Me3CO, CONH2CO, PhNHCO. R2=MeOCO, EtOCO. R3=CN, 4-NO2C6H4, 2-Benzoimidazolyl, PiperidineNCO, (EtO)2PO.

Scheme 5

These reactions often proceed with good yields in one flask at room temperature I90JCS(PI) 1669, 92JCS(P 1) 1009, 93JCS(PI)315, 94S 1811. 1.2.4 Pyrrolo[2,3-b]pyrroles A molar excess of conjugated azoalkenes reacts with nitriles containing activated methylene groups (e.g. malononitrile, 13-

8

Polyfunctionalized Pyrroles and Pyrazoles

cyanoketones, 13-cyanoesters, 13-cyanoamides or 13-phosphononitriles) to give at first 1"1, and then 2:1 conjugate adducts. At times, these bisadducts have been obtained either starting with a molar excess of the same conjugated azoalkene, or by addition of a further amount of a different conjugated azoalkene molecule to the 1" 1 adducts formed. H R2~,~

~N ~

N ~ RI + R 3 ~ C N C

R s ~

R2 N~N~ R4 p. R3 Rs I

]-~ f ~ N - - N H - - R n ]

~C~

R2 ~

N

NH--R4

N

~N___

NH---Rn

R3 RS

R I and R4=MeOCO, EtOCO, Me3COCO, NH2CO, PhNHCO. R2 and RS=MeOCO, EtOCO. R3=MeOCO, EtOCO, Me3COCO, PhCO, CN, PiperidineNCO, (EtO)2PO.

Scheme 6

The 2" 1 conjugate adduct intermediates undergo a double concerted ring formation in which one nitrile group is twice operative, most probably due to the greater reactivity of the imino function produced after the first ring closure rather than to that of other cyano or different groups present in the molecular residue. For this reason fused-type, rather than spiro-like, five-membered heterocycles have been obtained by these reactions, providing new polyfunctionally substituted 1,3a,6,6atetrahydropyrroloi2,3-blpyrroles (Scheme 6). Frequently, these reactions take place smoothly with good yields at room temperature without isolation and purification of the intermediates 190JCS(PI)1669, 92JCS(PI)I009, 94S 181 I. The complicated molecular structure of one of these compounds has been unequivocally established by X-ray diffraction study 190JCS(P1)16691.

Polyfunctionalized Pyrroles and Pyrazoles

9

1.2.5 1-Amino- l H - p y r r o l - 2 ( 3 H ) - o n e s Many widely substituted l-amino-lH-pyrrol-2(3H)-ones, which cannot be easily prepared by other procedures, have been recently prepared by treatment of conjugated azoalkenes with various activated esters or Meldrum's acid derivatives. During many years of our investigation, only cyano or ketonic carbonyl groups proved to be operative in the pyrrole ring production from 1,4-adduct intermediates. A qualitative examination of the comparative reactivity order between these two functional groups in the closing step may be summarized as follows: CO>CN [92JCS(PI)I009, 92JCS(PI)30991. Other activating groups, including the ester group, present in the nucleophilic agents were found to be ineffective in the cyclization process. This is mainly due to the spontaneous ability of the cyano and keto groups to undergo ring formation under very mild conditions, while the ester group generally requires more drastic conditions (i.e. strong bases). In fact, activated esters with one active hydrogen atom (i.e. CHsubstituted 13-cyanoesters, [~-diesters, [~-esterphosphoranes or 13esterphosphonates) react rapidly with conjugated azoalkenes to produce the corresponding hydrazonic adduct intermediates, from which the required l-amino-lH-pyrrol-2(3H)-ones are formed by ring closure onto the carboxylate group, with loss of a molecule of alcohol (Scheme 7, path A). However, in the case of the 1,4-adduct intermediates derived from the treatment of conjugated azoalkenes with CH-substituted 13-cyanoesters, the ring closure onto the cyano group is more difficult because of the lower stability of the 2-iminopyrroline compared to the final 1-amino-lHpyrrol-2(3H)-one originating from the ring closure on the ester function 190T5685, 92JCS(PI)3099, 94SC453, 94CJC23051. The treatment of conjugated azoalkenes with 13-diesters or 13esterphosphonates possessing two active hydrogen atoms produces, by means of the usual preliminary hydrazone intermediates, the unusual 3monosubstituted l-amino-lH-pyrrol-2(3H)-ones, as discussed above 194SC453, 94CJC2305 I. These findings appear to be consistent with the following qualitative reactivity order in the closure of the heteroring: CO>CN>COOR. The reaction between conjugated azo61efins and Meldrum's acid or its 5-substituted derivatives leads, via 1,4-conjugate addition, to the

10

Polyfunctionalized Pyrroles and Pyrazoles

corresponding hydrazones which undergo decarboxylative alcoholysis and simultaneous cyclization to new 3-unsubstituted or 3-monosubstituted lamino- 1H-pyrrol-2(3H)-ones (Scheme 7, path B) [94S6051.

OR 2H R 3 ~ O ~,,,m, R3~--~ N-NHRI ~ A R4RO~~O ~

R2 R3~

R 2 ~ N-.N,,RI I~~B

~,~0,~0 " ~

o

- NilRI o

~0 ""8382 -M~I" _.~ /-CO2

O,~R 3 o

R

H ON

RI=MeOCO,EtOCO,Me3COCO,NH2CO,PhNHCO. R2=MeOCO,EtOCO. R3=H,Me, Me2CH,Ph(CH2)2,MeCO(CH2)2,MeOCO,EtOCO,PhCH2OCO,CN, CN(CH2)2,(EtO)2PO. R4=H,Me, Ph. R3,R4=Ph3P. Scheme 7

3-Unsubstituted- or 3-monosubstituted-l-amino-lH-pyrrol-2(3H)ones in solution exhibit an enol-keto tautomeric equilibrium. In order to assign the structure, the X-ray crystal structure of one of these compounds has been determined I94CJC2305] and used for the interpretation of the relevant spectroscopicai data of IH- and IaC-NMR [90T5685, 94SC453, 94S605, 94CJC23051. These reactions furnish a convenient and expeditious access to new highly functionalized l-amino- 1H-pyrrol-2(3H)-ones. 1.2.6 3-Unsubstituted-l-aminopyrroles Phosphorus ylides of a-oxotriphenylphosphoranes readily add to the azo-ene system of conjugated azoalkenes to yield the 1,6-zwitterionic intermediates. These intermediates generate the pyrrole ring by the usual intramolecular nucleophilic attack and simultaneously a phosphonium

11

Polyfunctionalized Pyrroles and Pyrazoles

betaine which cyclises to a four-centre 1,2-oxaphosphetane intermediate. The loss of a triphenylphosphine oxide molecule from this intermediate leads to a 3-unsubstituted-l-aminopyrrole, in accordance with the classic Wittig mechanism (Scheme 8). -

Rz~

H

N~N~ o

R3 O"

R2

\

NIt-- RI ...-.-~ H ' ~ ~ N - . . - -

R2

/ NIl- R

. P h3PO '- []

rh~'".O/\H 3

NH- R1

R3

R l=MeOCO, EtOCO, Me3COCO. R2=MeOCO, EtOCO. R3=Me, Ph.

Scheme 8 However, this reaction is in competition with a triphenylphosphine elimination from the common 1,6-zwitterionic intermediates that results in a carbonyl-olefination of the starting materials. This occurs particularly when a good leaving group is present on the nucleophilic agent 188TL5787, 90T5685, 93T7027, 94S372, 94OPP4851, and clearly reduces the yields of 3-unsubstituted- 1-aminopyrroles [91JCR(S)252]. 1.3

Pyrazoles

As already mentioned, variously substituted title compounds, with the exception of some 5-substituted-pyrazoles, have been obtained when conjugated azoalkenes possessing an ester function on the terminal carbon atom of the azo-alkene were reacted with nucleophilic species without functional groups able to undergo a nucleophilic internal attack on the >C=N-NH- nitrogen atom of the preliminary Michael adduct. In this case, an internal nucleophilic attack from the >C=N-NH- nitrogen atom of the intermediate on the carboxylate group has been shown under appropriate reaction conditions to give pyrazole-type rings. However, in the course of

12

Polyfunctionalized Pyrroles and Pyrazoles

our research in this field, variations in the general pathway have been noticed. Our synthetic procedure assures a versatile entry to pyrazoles bearing several substituents, some of which are particularly interesting as products in organic or pharmaceutical chemistry and as intermediates for further structural modifications by cleavage of their respective protective groups (i.e. Boc, thioesters, thioethers, sulfonylamino) [91M12771. Furthermore, unlike the general pathway for the synthesis of pyrrole derivatives from conjugated azoalkenes that need at least one hydrogen atom on the terminal carbon the preparation of the pyrazole derivatives from the same reagents is compatible with the presence of a different function on the above-mentioned carbon atom, providing multi-substituted pyrazoles. Therefore, this synthetic procedure is suitable to give pyrazoles with four or five substituents. Three or four of which are supplied by the conjugated azoalkenes and one from the nucleophilic species. The reactions usually proceed with good yields under mild conditions and can often be carried out in one pot reactions without isolation and purification of the intermediates. To date we have studied the synthesis of pyrazole rings with four substituents. However, our investigations are directed towards the design of new multi-substituted pyrazole derivatives from conjugated azoalkenes.

1.3.1 4-Phosphoranylidene- 1H-pyrazol-5(4H)-ones Phenyl-, alkyl-, and phenyl-alkyl phosphines add promptly in a 1,4conjugate way to the azo-ene system of conjugated azoalkenes to supply stable and isolable 1,5-zwitterionic species that tautomerize into corresponding ct-alkoxycarbonyl-~t'-hydrazonotriphenylphosphorane intermediates. By progressive replacement of phenyl with alkyl groups, the phosphines become more reactive due to enhanced electron-donation. In methanol under reflux these intermediates produce betaines by internal nucleophilic attack of the nitrogen anion on the ester group. From them derive unknown 4-phosphoranylidene-lH-pyrazol-5(4H)-ones by elimination of an alcohol molecule (Scheme 9). These compounds are useful both as products and as tools in organic chemistry 192T1707. 94OPP321]. In some cases, the concomitant cleavage of the bond between the nitrogen heteroatom in position I and the substituent has been observed.

13

Polyfunctionalized Pyrroles and Pyrazoles

N~N~ Rt + R~P---~Rz

1120~

N" 1~I~Rt ~

Ns NH.ld ---t.

R20

n3~,,9

n~ +H

§

",' 7 , , o - ~ o ~-, ,

.- ~.o>/,,oN;~

~.o.

O~

N~,N

~,

RI =H, EtOCO, Me3COCO, NH2CO, PhNHCO. R2=Me, Et. R3=Me3, n-Bu3, Me2Ph, MePh2, Ph3.

Scheme 9

1.3.2 $ - A l k o x y p y r a z o l e s The zwitterionic phosphorus betaine intermediates from the reaction of conjugated azoalkenes with triphenylphosphine selectively undergo cyclization to four-membered 1,2-oxaphosphetane intermediates. From them 4-unsubstituted-5-alkoxypyrazoles have been obtained through loss of a triphenylphosphine oxide molecule [92T1707]. This behaviour is in full agreement with a typical Wittig reaction (Scheme 10). H

O

R20~ +

H

~'~'0

Rt

H

N

Nj

!,

RZO -

.

N/N

!, Rt=H, EtOCO, Me3COCO, PhNHCO. R2=Me, Et. S c h e m e 10

I

Rt

14

Polyfunctionalized Pyrroles and Pyrazoles

Recently, 4-acylthio-5-alkoxypyrazoles have been prepared by the reaction of conjugated azoalkenes with thiocarboxylic acids [95UP2]. The preliminary hydrazone intermediates which arise from the normal 1,4addition of thioacids to the azo-ene system of conjugated azoalkenes in the presence of trifluoroacetic acid, have provided the above-mentioned derivatives. The reaction pathway proceeds through steps already described in the general presentation of this section. They lead to closure of the heteroring with elimination of a water molecule to give the pyrazole heterocycles (Scheme 11).

il20

N J J ' N ~ RI

+

R3COSH

N I Nil 9 R 1

Rz

SCOR a -3

H

-

a3~

/

- H20

RzO

./ N

I

1

RI

R t=MeOCO,EtOCO, Me3COCO, NH2CO, PhNHCO. R2=Me, Et. Ra=Me, Ph.

Scheme 11

1.3.3 lH-Pyrazoi-S(2H)-ones Hcteroarylthiols react quickly with conjugated azo61efins to afford ct-hctcroarylthiohydrazoncs by the usual 1,4-addition of the thiol to the hcterodiene system. The treatment of the latter compounds with sodium methoxide, and then with trifluoroacetic acid provides mainly rcgioisomeric 4-hetcroarylthio-lH-pyrazol-5(2H)-oncs in good yields by an hcterocyclization process with the loss of an alcohol molecule. These reactions can be succesfully executed in a one-pot procedure (Scheme 12). A detailed I H- and 13C-NMR study of these compounds in DMSO-d6 shows a solvent effect on the r tautomerism, often with conversion of the kcto into the enol form. X-Ray diffraction determination demonstrates unambiguously that these compounds exist in

Polyfunctionalized Pyrroles and Pyrazoles

15

the solid state in the keto form. This tautomeric equilibrium has been found to be extraordinarily slow, requiring in some cases 720 h at 25 ~ to attain it with a value of AG#=25+30 kcal mo1-1. The average value for an analogous phenomenon is about AG#-~5 kcal mol-I. This unusual occurrence was ascribed to the presence of intramolecular and intermolecular hydrogen bonds revealed by X-ray diffraction [95JOC 149]. Similarly, the r derivatives, obtained as above, when treated with sodium hydride produce 4-acylthio-lH-pyrazol-5(2H)ones that show a similar enol-keto tautomerism [95UP2]. A more exact kinetic investigation by 1H-NMR spectroscopy has determined the rate constants k to range between 10.6 and 10-7 s -I corresponding to AG # values varying between 25 and 26 kcal mol-]. These data are in agreement with our initial observations of a AG# value for the enol-keto tautomeric equilibrium of these compounds to be nearly 5 times greater than that measured in similar circumstances [95JOC149].

r~o

n~

R3XH

r~

.3x\

/

n3x

t---~n-~u n~ R3X

\

/

- RZOH N/N

!,

I

RI

RI=H, MeOCO, EtOCO, Me3COCO, NH2CO, PhNHCO. R2=Me, Et. R3=Me, Et, Ph, MeCO, PhCO, 2-Pyrimidyl, l-Me-2-1midazolyl,4-Me-1,2,4-Triazol-3yl, 5-Me-1,3,4-Thiadiazol-2-yl,2-Benzoxazolyl,2-Benzothiazolyl. X=O,S.

Scheme 12 Thus, r r prepared in accordance with our previous procedures 179SC465, 81JOC4471, under analogous reaction conditions give 4-alkoxy- or 4-phenoxy-lH-pyrazol-5(2H)-ones

16

Polyfunctionalized Pyrroles and Pyrazoles

[95UP3l. These compounds also manifest a remarkable tendency to enolketo tautomerism at present under investigation by integrated 1H-NMR and UV techniques. All these reactions may be represented as shown in Scheme 12.

1.3.4 5-Substituted-pyrazoles The synthesis of these compounds is little different from that shown above. In fact, 3-hydrazono-2-triphenylphosphoranylidenebutanoates, prepared as equilibrium mixtures with the related 1,5-zwitterionic species according to the methodology described [92T1707], have produced 5substituted-pyrazoles with acyl chloride or anhydrides [94JCR(S)I92]. These reactions take place by nucleophilic attack of the nitrogen on the acyl group, affording the N-acyl intermediate with loss of hydrochloric or carboxylic acid. This intermediate undergoes internal cyclization, providing a phosphonium betaine via a nucleophilic attack by the alkylidene phosphorane in its ylide form on the carbonyl group. The formation of a P-O bond leads to the 1,2-oxaphosphetane intermediate which gives rise to triphenylphosphine oxide and 5-substituted-pyrazole derivatives, in a typical Wittig reaction (Scheme 13).

R ~

Nfj'

N~

Rl

+phsP R 2 ~ J.-

~ I ~ R 1 +RaCOX N -HX ~

Ph3P+

+ R~ Ph3P,~

N

R

Nt

1

I

\\

R3 R]1 R2 Ph1~ "

/

)

~

N

R

N/

E

. PhaPO

\ .

/ / n3

'

R!

Ri=H, EtOCO, Me3COCO, PhNHCO. R2=MeOCO,EtOCO. R3=Me, CICH2,EtOCOCH2, HOOCCHEOCH2,Ph, 2-Thienyl.

Scheme 13

/

R2

/

N Nj

Polyfunctionalized Pyrroles and Pyrazoles 1.4

17

Conclusions

The reported findings demonstrate the versatility of conjugated azoalkenes as useful intermediates in the synthesis of heterocyclic systems. This ability must also be considered in the wider context of these compounds undergoing other I3+21, I4+21, and rarely 12+21 cycloaddition reactions 186OPP2991. Further research is at present in progress in our laboratories aimed to widen the application of these compounds in organic synthesis. This work was supported by financial assistance from the Ministero dell'Universith e della Ricerca Scientifica e Tecnologica (MURST - Roma) and Consiglio Nazionale delle Ricerche (CNR - Roma). Interest in biological activity by National Cancer Institute, Cyanamid, and DuPont is also gratefully acknowledged. One of the authors (OAA) is particularly indebted to Prof. L. Caglioti and G. Rosini for their contribution to this chemistry. The authors gratefully acknowledge all those who took active part in these investigations, and in particular L. De Crescentini, E. Foresti (X-ray diffraction), D. Giovagnoli, M. Grossi, Z. Liao, A. Mei, F. R. Perrulli and S. Santeusanio. Helpful suggestions regarding some aspects of these researches from Prof. A. McKillop, as well as the kind assistance in this review of Prof. H. Suschitzky are gratefully acknowledged. Acknowledgements

-

References

79SC465 81 JOC447 82JOC684 83JHC1077 83CJC2665 83S742 84S671

Attanasi, O. A.; Battistoni, P.; Fava, G. Synth. Commun. 1979, 9, 465. Attanasi, O. A.; Battistoni, P.; Fava, G. J. Org. Chem. 1981, 46, 447. Attanasi, O. A.; Bonifazi, P.; Foresti, E.; Pradella, G. J. Org. Chem. 1982, 47, 684. Attanasi, O. A.; Bonifazi, P.; Buiani, F. J. Heterocycl. Chem. 1983, 20, 1077. Attanasi, O. A.; Battistoni, P.; Fava, G. Can. J. Chem. 1983,61, 2665. Attanasi, O. A.; Santeusanio, S. Synthesis 1983, 742. Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S. Synthesis 1984, 671.

18 84S873 84S874 85OPP385 85JHC1341 85MRC383 85AX(C)450 85S157 85H867 86OPP1 86SC343 86JHC25 86SC 1411 86BCJ3332 86OPP299 87S381 87SC555 87T4249 88H149 880PP408

Polyfunctionalized Pyrroles and Pyrazoles Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S. Synthesis 1984, 873. Attanasi, O. A.; Perrulli, F. R. Synthesis 1984, 874. Attanasi, O. A.; Grossi, M.; Serra-Zanetti, F. Org. Prep. Proced. Int. 1985, 17, 385. Attanasi, O. A.; Filippone, P.; Mei, A.; Serra-Zanetti, F. J. Heterocycl. Chem. 1985, 22, 1341. Attanasi, O. A.; Santeusanio, S.; Barbarella, G.; Tugnoli, V. Magn. Res. Chem. 1985, 23, 383. Giuseppetti, G.; Tadini, C.; Attanasi, O. A.; Grossi, M.; Serra-Zanetti, F. Acta Cryst. 1985, C41,450. Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S.; Serra-Zanetti, F. Synthesis 1985, 157. Attanasi, O. A.; Perrulli, F. R.; Serra-Zanetti, F. Hetrocycles 1985, 23, 867. Attanasi, O. A.; Grossi, M.; Serra-Zanetti, F. Org. Prep. Proced. Int. 1986, 18, 1. Attanasi, O. A.; Filippone, P.; Mei, A.; Serra-Zanetti, F. Synth. Commun. 1986, 16, 343. Attanasi, O. A. ; Filippone, P.; Mei, A.; Serra-Zanetti, F. J. Heterocycl. Chem. 1986, 23, 25. Attanasi, O. A.; Filippone, P.; Mei, A.; Perrulli, F. R.; Serra-Zanetti, F. Synth. Commun. 1986, 16, 1411. Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S.; Serra-Zanetti, F. Bull. Chem. Soc. Jpn. 1986, 59, 3332. Attanasi, O. A.; Caglioti, L. Org. Prep. Proced. Int. 1986, 18, 299; and references cited therein. Attanasi, O. A.; Filippone, P.; Santeusanio, S.; SerraZanetti, F. Synthesis 1987, 381. Attanasi, O. A.; Filippone, P.; Guerra, P.; SerraZanetti, F. Synth. Commun. 1987, 17, 555. Attanasi, O. A.; Grossi, M.; Serra-Zanetti, F.; Foresti, E. Tetrahedron 1987, 43, 4249. Attanasi, O. A.; Filippone, P.; Guerra, P.; SerraZanetti, F. Hetrocycles 1988, 27, 149. Attanasi, O. A.; Grossi, M.; Mei, A.; Serra-Zanetti, F. Org. Prep. Proced. Int. 1988, 20, 408.

Polyfunctionalized Pyrroles and Pyrazoles

88MRC714

88G533

88JHC1263 88TL5787 89G631 90JCS(P1)1669

90T395 90T5685 91JCS(P1)3361

91M1277

91JCR(S)252 92T1707 92JCS(P1)lO09

92JCS(Pl)3099

93JCS(P1)315

19

Attanasi, O. A.; Grossi, M.; Perrulli, F. R.; Santeusanio, S.; Serra-Zanetti, F.; Bongini, A.; Tugnoli, V. Magn. Res. Chem. 1988, 26, 714. Attanasi, O. A.; Filippone, P.; Guerra, P.; SerraZanetti, F.; Foresti, E.; Tugnoli, V. Gazz. Chim. ltal. 1988, 118, 533. Attanasi, O. A.; Grossi, M.; Serra-Zanetti, F. J. Heterocycl. Chem. 1988, 25, 1263. Attanasi, O. A.; Filippone P.; Santeusanio S. Tetrahedron Lett. 1988, 29, 5787. Attanasi, O. A.; Santeusanio, S.; Serra-Zanetti, F. Gazz. Chim. Ital. 1989, 119, 631. Attanasi, O. A.; Santeusanio, S.; Serra-Zanetti, F.; Foresti, E.; McKillop, A. J. Chem. Soc. Perkin Trans. 1 1990, 1669. Schantl, J. G.; Hebeisen, P. Tetrahedron 1990, 46, 395; and the references cited therein. Attanasi, O. A.; Filippone, P.; Mei, A.; Bongini, A.; Foresti, E. Tetrahedron 1990, 46, 5685. Ferguson, G.; Lough, A. J.; Mackay, D.; Weeratunga,, G. J. Chem. Soc. Perkin Trans. 1 1991, 3361; and references cited therein. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis John Wiley & Sons, 2nd ed., New York 1991, pp 277-405. Attanasi, O. A.; Filippone, P.; Mei, A. J. Chem. Res. (S) 1991, 252. Attanasi, O. A.; Filippone, P.; Mei, A. Tetrahedron 1992, 48, 1707. Attanasi, O. A.; De Crescentini, L.; Santeusanio, S.; Serra-Zanetti, F.; McKillop, A.; Liao, Z. J. Chem. Soc. Perkin Trans. 1 1992, 1009. Attanasi, O. A.; De Crescentini, L.; McKillop, A; Santeusanio, S.; Serra-Zanetti, F. J. Chem. Soc. Perkin Trans. 1 1992, 3099. Attanasi, O. A.; Liao, Z.; McKillop, A.; Santeusanio, S.; Serra-Zanetti, F. J. Chem. Soc. Perkin Trans. 1 1993, 315.

20

Polyfunctionalized Pyrroles and Pyrazoles

93JCS(PI)1391 Gilchrist, T. L.; Lemos, A. J. Chem. Soc. Perkin Trans. 1 1993, 1391; and the references cited therein. Attanasi, O. A.; Ballini, R.; Z. Liao; Santeusanio, S.; 93T7027 Serra-Zanetti, F. Tetrahedron 1993, 49, 7027. Attanasi, O. A.; Filippone, P.; Serra-Zanetti, F. Trends 93M1461 Heterocycl. Chem. 1993, 3, 461. Attanasi, O. A.; Filippone, P.; Giovagnoli, D.; Mei, A. 94S181 Synthesis 1994, 181. Attanasi, O. A.; Filippone, P.; Giovagnoli, D.; Mei, A. 94SC453 Synth. Commun. 1994, 24, 453. 94OPP321 Attanasi, O. A.; Filippone, P.; Giovagnoli, D. Org. Prep. Proced. Int. 1994, 26, 321. Attanasi, O. A.; Santeusanio, S.; Serra-Zanetti, F. 94S372 Synthesis 1994, 372. 94OPP485 Attanasi, O. A.; Santeusanio, S.; Serra-Zanetti, F. Org. Prep. Proced. Int. 1994, 26, 485. Arcadi, A.; Attanasi, O. A.; Liao, Z.; Serra-Zanetti, F. 94S605 Synthesis 1994, 605. 94JCR(S)192 Attanasi, O. A.; Buratti, S.; Filippone, P.; Giovagnoli, D. J. Chem. Res. (S) 1994, 192. 94CJC2305 Attanasi, O. A.; De Crescentini, L.; Foresti, E.; SerraZanetti, F. Can. J. Chem. 1994, 72, 2305. Attanasi, O. A.; Foresti, E.; Liao, Z.; Serra-Zanetti, F. 95JOC149 J. Org. Chem. 199 5, 60, 149. 95UPI Attanasi, O. A.; Perrulli, F. R.; Santeusanio, S.; SerraZanetti, F. in preparation. 95UP2 Attanasi, O. A.; Buratti, S.; Filippone, P." Giovagnoli, D. in preparation. Attanasi, O. A.; De Crescentini, L.; Serra-Zanetti, F. in 95UP3 preparation.

Chapter 2 Application of Diels-Alder Cycloaddition Chemistry for

Heterocyclic Synthesis

ALBERT PADWA Emory University, Atlanta, GA, USA 2.1

INTRODUCTION

The importance of the Diels-Alder reaction in organic synthesis derives in large part from its ability to generate six-membered rings containing several contiguous stereogenic centers in one synthetic operation. In recent years the Diels-Alder reaction of heterosubstituted 1,3-dienes and dienophiles has emerged as a powerful method for preparing highly functionalized heterocyclic ring systems. The aim of this chapter is to provide an indication of the wide assortment of Diels-Alder chemistry that has been used for heterocyclic synthesis. Although some older references are mentioned, the coverage has been selected from the last fifteen years, including new applications and modifications of older reactions and innovations. The organization of the review is according to structural type and represents an extension of an approach used earlier in Volume 6 of PHC. Each synthetic sequence is accompanied by references to the original literature. We hope that you find this unusual format to be useful. The following reaction sequences provide a sampling of some noteworthy transformations in this area of heterocyclic chemistry.

2.2

Reaction Schemes I Imino Die/s-Aider Reactions I

Reviews: Boger [87M1001] Weinreb [82TET3087, 79HET949]

Imines as Dienophiles [81TL4607] 1) benzene OMe/ A, 15 h O O Ph3P=NCO 2tBu NCO2tBu ]~ 2) H3O+ ,,J~N/~I H~ " "COOEt '~ HjjI-,COOEt + J ' ~ 84 % ;. tBuO OSIMe3 EtO2C O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Lewis Acid Catalyzed Reactions of Imines

Danishefsky [82TL3739]

OMe ,~~ Me3SiO

+

'NCH2Ph ' U. ~.

H- y

21

1.0 eq ZnCI2,THF rt, 36-38h 69 %

IP

~ O

P

h

Application of Diels-Alder Cycloaddition Chemistry

22

Danishefsky - Application of the aldimine diene-cyclocondensation reaction for total synthesis [86JOC3915] H EtOyOSiEt3 ~ ./',~C02Me

IJ, ,

+

N

ZnCI2

50 %

OMe

OMe

Holmes- Synthesis of piperidine alkaloids using a tosyl imine [87TL813] 0 HyCO2Me ~]1OSiMe3 Lewisacid Tos~N

+

1) MeCO3H.

2) LiAIH4 H3O+ " TosN~ CO2Me

OH

I" OH

Grieco - Diels-Alder reaction of iminium salts generated under Mannich conditions in aqueous solution [85JACS1768] 1.3 eq PhCH2NH2-HCI 1.3 eq HCHO H2O, 55 ~ 96 h 62 %

~N

~-

1.3 eq PhCH2NH2-HCI 1.3 eq HCHO rt, 23 h 45 %

t ~

I.,,

CH2Ph

N CH2Ph

A chiral amine as an imino precursor

O

+

Me~,,,,H

H2Nq "Ph

HCHO/H20 86 % =

ON

Ph

Me_ H

4

91

Grieco- Cyclocondensation of C-acyl iminium ions with cyclopentadiene [86TL1975] O +

Me-NH2 HCI

H20, rt, 22 h

O

Me

82 %

4.2

91

23

Application of Diels-Alder Cycloaddition Chemistry Grieco - Iminium ions derived from aryl amines and aldehydes function as heterodienes [88TL5855] i~

H20 +

5equiv

=

MeCN rt, l h 98%

NH2" TFA

+ H

H

3.7 ' 1

H

H

Grieco - Intramolecular imino Diels-Alder reaction [85JACS1768, 86JOC3553]

NH3CI"

HCHO/H20 ,

v

50 ~ 48 h

"H

95 %

CHO

PhCH2NH2, HCI EtOH-H20 70 ~ 63 %

=

CI

H,,,

H sa e

NH

N H h

h 2.5 ' 1

"~CHO

MeNH2HCI

H20/EtOH (1" 1) 70 ~ 66 %

MeN Dihydrocannivonine

Vollhardt - Oxime ethers as dienophiles [80JACS5245]

CpCo(CO)2 SiMe3

~

N,,OMe

45 %

O H Me3Si~.~~

MeaSi~

N'OMe

Me3Si ~..,"L~..,'~",~ N,,OMe

24

Application of Diels-Alder Cycloaddition Chemistry

Boger- Vinyl sulfonylimines as azadienes - preparation from the corresponding oximes or unsaturated aldehydes [91JACS1713] OH|

Mean

M

PhSOCI.

S(O)Ph

S02Ph

M

-20tO 0 ~

25~

SO2Ph I

H.~O

PhSO2NH2MgS04

H~

Ph

Ph

Reaction with electron-rich dienophiles

$O2Ph I N~,,.Ph

SO2Ph i EtO,~" i -Ph +

CH2

H

OCH2Ph CH2CI2 12 kbar

H" Me

M

SO2Ph

OCH2Ph

28%

H,,,~OMe +

o

100 ~ dioxane 89 %

C II CH2

CH2CI2 12 kbar 54 %

~

L,j

"Me

I =

OMe CH2

25

Application of Diels-Alder Cycloaddition Chemistry

Weinreb - Intramolecular Die/s-Aider reactions of N-acyl azadienes [85ACR16, 79JACS5073, 81JACS6387, 82JACS7065] 650~ ll~s

c~

CH2~,~ I~/N~ O

-HOAc

O

73'0

,co-- ,co 73 %

~ O

=

~N~ O

"~176I Q

1

1) H2,Pd 2) B2H8 6-Coniceine

Weinreb - Acylimines as key intermediates for alkaloid synthesis [83JOC3661]

OBn

r'~Y

AcO

~__~._.~ OBn

o-dichloro- --N H /~ benzene .--i./

178~

O

o//-"

.~

930/.

,,OBn

,,OH

=

O

epi-Lupinine

Rigby - [4+2]-Cycloadditions of vinyl isocyanates [84JOC4569, 86JOC1374, 89JOC224, 89JOC4019, 89JOC5852, 89SC2699, 91JACS8975]

[~

~C~0

0

MeO

NCO

OMe

MeO" ~

H2/ Pd (C) 73 %

v

~ +

~

34 %

=-

MeO

0

v OMe

MeO" ~ I

Application of Diels-Alder Cycloaddition Chemistry

26

4+2-Cycloaddition reaction of vinyl isocyanates with benzyne

9

+

58% !

NCO

NH2

O

good synthon for ben~ne

Magnus - Indole 2,3-quinodimethane strategy for synthesis of indole alkaloids [84ACR35] 1'~ ~:~/'~ E"N E+

NI~CH2 R

N

J R

SiMe3

=

CH2

H

N R

O

~ ~ , ,H,,..~,,,J ~

,3,00

N

I.L IJ.. CH2 C'3CCH20COC' ~"~"/"~Nf'Me 46 % I R

"''~Et

L~

N~ S P h

I

R

33"---~/0 R

CH2 I Acvlationl

O

~~

"=

Me ~,,.~ CycllzationlI

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

~ . . . . . . . . . . . . . . .

~N'~ I

R

jJlN e ~ M

""Et

NI R

o

,Cl1-C12]-........~,, bond L,= ~1~,, .''~?E' " ~ "N R

f

PhS~

O O

!

I(+)- Aspidospermidine ]

.

Kopsanone and Tabersonine

" ~L~~'N ~'~'~'"Et R

. . . . . . .

~ . . . . . . . . . . . . . . . .

E"N"~'I H,,.

c,~oCH~OCOC," ~,

~~'"~

i-PrNEt,120~

CI

PhCI

~ ' ~ N J I~ " C I R

27

Application of Diels-Alder Cycloaddition Chemistry Die/s-Aider reactions with inverse electron demand Bradsher -Azonia polycyclic aromatic compounds as dienes [55JACS4812,

58JACS933, 68JOC390, 73CC156]

2R~R 1 Br"

R ..R1

+

heat = 66-100 %

R2.~H

(~+N~~

Br-

mixture of stereoisomers C104" r ~ +N

CH2=C(OEt)2 .= 25 ~ 1 h 89 %

H EtQ ~.....H -- +'~20Et ~'~N+.~~

C104"

Regioselective-- ethoxygroups are nonadjacentto quaternarynitrogen Cycloaddition of isoquinolinium salts Franck- Use of vinyl sulfides for synthesis of 1-naphthaldehydes [89JOC1097]

,~ts

R'

RtR~ ./~--"H

R 1 = R2= H

.~r

CHO

R1

1)H+, H20

2) K2CO3, MeOH, H20

overall 91% .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

o

Kahn.- Oxidative intramolecular cycloaddition of an azodicarbonyl system [88JACS1638]

NHBn COC'

O O

O

exo-adduct

Application of Diels-Alder Cycloaddition Chemistry

28

Die/s-Aider reaction of nitroso compounds [84JOC4741, 86JACS1306,78TL4767,

80JACS3632, 85JACS5534] t-BuMe2SiO,,

N

~ r OMe

jT"OMe

CsF MecN"20 oC

r

83% _ ,,0..,,,OMe

Note: dihydroxazinering adopts a boat-like conformation to take advantage of anomeric effect

_,,0,..,OMe

70" 13

Kibayashi- Stereospecific total synthesis of GTX 223AB [86TL5513] 4"

H

-"

Pr4N104= CHCI3 O

~

H

1) Zn, HOAc 2) BnOCOCI Na2CO3/CHCI3 MsCI, Et3N 31H2,Pd/C,MeOH

H

several steps

H

I=,

Gephyyrotoxin 223AB

Weinreb - Intramolecular N-sulfinyl carbamate cycloaddition [84JOC3243, 85TET1173]

pyridine

0 .,~.x.R

/

S"

=

N"~O "-"'~ =H~

,.~o .oc,,; .-~~ ] "~176o,,.~o

P"CH'~176

O~h

L~

Me~l~ OH

co~oonon, o, aminoglycoside antibiotic 66.40-D

29

Application of Diels-Alder Cycloaddition Chemistry Weinreb - Use of N-sulfinyl cycloadducts for synthesis of homoallylic amines [83TL987, 84JACS7861, 84JOC3243, 85TET1173] Me

Me O" Me. / O Mev'L~4/' 1)NaOH Me,,~,,~l~leS; -SO2 TosN=S=O= . ~ , Me~H. ~ 85%= Me PhMe,0 ~ NTos 2) HaO,= Me ."" NHTos overall Me Me H

Me Me

Me NHTos "_- Me Me

Weinreb - N-Sulfinyl compounds as heterodienophiles [84JACS7861, 84JOC3243, 85TET1173]

.o, ~. -

o NH2

SOCI2 pyridine"

i

r

n-C13H27

Ba(OH)2

n-C13H27~ ~ O "

1) PhMgBr 2) (MeO)3P 85 %

85 %

'~n .C13(~27

"15~

13H27

N

Ii=

_NH2 n-C13H27~ O H

OH

OH

threo-Sphingosin

E.threo .carbamate

Weinreb - Stereochemica/contro/[84JACS7867] Me +

§ .oS" II NCO2Bn

Me

Me PhMe 25 oC95 %

,oCO2Bn

PhMgBr

Me

H.,,,I~::~Me 2,3-eigmatropic

Me,~Ix. " "OSPh H NHCO2Bn

I[~ ~

~ sMe" r+" . = /"1

Me'~NI~I~O2Bn ]

P(OMe)3

OH

MeOH = Mei~~,,,~Me 85 %

NHCO2Bn

threo.hydroxy carbamate Note: Only E-isomerdue to reversible [2,3]-sigmatropic rearrangement

Application of Diels-Alder Cycloaddition Chemistry

30

Weinreb -

Diels-Alder adducts of sulfur dioxide bis(imides) Me

S ~'NR II NR

[84JACS7867]

Me

benzene "' 25 oc

+

Me R = Tos, C02Me

i RN

1) PhMgBr

I

Me

=

2) P(OMe)3

NHR .,,~ .,~ . Me NHR

83-92 %

Me

T P(OMe)3

PhMgBr

Me

Me

2,3-

H'~i~-Sp h

shift

I-I" "NHR

Intermolecular [4+2]-Cycloadditions employing a-pyrones as dienes Moody

3-Pyridyne as a dienophile

NH2,,v,,,% N HO2C i ~ / ,

1) HNO2 2) Me2NH

72%-

[88JCS(P1)247]

Me2N_N=N~

M6

N

H02C] ~ ~ '' Me E//ipticine

M6

MeCN Me

OH

H

KOH, &

BF3-Et20 T Ac20 44 %

N" H

Me

A

-

+

Me

Me Isoellipticine 40 % (1 1) 9

31

Application of Diels-Alder Cycloaddition Chemistry Boger [84JOC4045] r MeO

MeO2C -

2.2 eq Nail, THF

O

H"C=C(C02Me)2 ~,'

Me

7 steps from 4-benzyloxycyclohexanone

81%

MeO

Me

MeO2C 10 eq H2C=C(OMe)2 toluene,140 ~

Me

~OH

.OMe 7 steps

21 h

75 %

17%

MeO

.,, MeO

Me

Me

Juncusol

Intramolecular 4+2-Cycloadditions of a-pyrones

Martin - Azatriene gives hydroisoquinoline [85JACS4072] BN n ~0

an N

O

xylene ID reflux 93 %

H

RO

~l o

RO OMe

(:/:)-Reserpine Hetero Die/s-Aider Reactions Reviews: Boger and Weinreb [87MI001, 91MI402, 91MI451] Intramolecular Cycloadditions Involving Oxabutadienes Tietze -in situ generation of heterodiene via Knoevenagel condensation [87ACIE 1295, 82ACIE221]

~CHO

o

o~o ~ io~~.~o

0_.~ O ~

"T

OMe + ~ , . 0 I I

(S)-Citronellal

0

.

L ~176

exo.E-anti

preferential 5,6-cis-fused cycloadduct from endo. E-syn transition state = 52 %

0~.,,.0,~ H

~,~ 0 O

i-de 998 %

endo-E-syn

H .C02Me 6 steps

Osugar

Deoxyloganin

Application of Diels-Alder Cycloaddition Chemistry

32

Tietze - Asymmetric induction effected by remote stereogenic center[82ACIE221] O DMF

+

O (R)-Citronellal

R R=

100 ~

O

preferential 6,6-trans-fused cycloadduct 65 %

R

w

C5Hll

1) LDA, PhSeCI 2) mCPBA -40 ~ to rt w

46 %

R

R

(-)-(9R)-Hexahydrocannabinol

i-de 998 %

Talley o-Quinone methide cycloaddition controlled by remote chiral center [85JOC1695]

HO

CF3CO2H CHCI3

Me

87 %

OH

Danishefsky- Lanthanide catalysis [84TL721]

~CHO 0.05 eq Yb(fod)3,. rt, 80 h ~

EtO~/u~"

80 %

EtO~l

endo product only

==~CHO 0.05 eq Yb(fod)3, rt, 80 h 60-80 %

EIO mixture endo + exo

33

Application of Diels-Alder Cycloaddition Chemistry

I"`'`r~176

I

Thioketones are generally readily available to undergo thermal or photochemical cycloadditions RIJR1 +

hv =

R R1

Vedejs - Unstable thioaldehydes can be generated and trapped in situ by a photochemical method[80JOC2601, 83JACS6999, 82JACS1445, 83JACS1683, 86JOC1556, 88JOC2226, 88JACS5452]

o ~~

[ o

h~

..~

C

~ Y

Vedejs - Intramolecularthioaldehyde cycloaddition shows only moderate stereoselectivity [88JOC2220] H hv

phi

"

~

+

H

0

H

12" 1)

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

Vedejs - Trapping of thioaldehyde by both Die/s-Aiderand ene reactions [88JOC2220] c.O2Et

Ph.~

O

hv =

O

S

i,

O

R

CH2

R1

O2Et

F.. R=RI=H 1 R=Me, R =2-methylpropenyl

O M~.~y..SH EtO2C" L ~

=

89 %

intrarnolecular EtO2C, H ene reaction , eo . ~ S 62 % M

=

retro A Diels-Alder

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

Baldwin - New thermal method for generating thioaldehydes from alkyl thiosu/finates [82CC 1029]

~

S.

'40

(1.1)

34

Application of Diels-Alder Cycloaddition Chemistry

New tactics for effecting Diels-Alder reactions Dauben- Cycloadditions at high pressure [80JACS7126, 85JOC2567] ~CO2Me S~ ~ _j,,~O

1)liq HCN 2) H3PO4

3) HCI, AcOH-H20 =

~ s~.~o

4) SOCI2, A 50 % O

O O~o

+

0

Ra-Ni, EtOAc ,%3 h _.~ 51% overall (+8 % epimer)

O

O

~

~0

7 kbar, i1, 24 h

(10 g scale) "

O

~ ~ O Canthat~din

Knight - Vinyl furan Diels-Alder reactions [88TL2107]

MeO2C'~"~

290 ~ 100 %

v

MeO2C'~~'~ 290 ~ 97 %

MeOjC/~/,~

Keay - High pressure intramolecular Diels-Alder reaction of furan as a diene [89TL1045] O 12 kbar R

R2

25 ~ R, R1, R2 = H, Me 43-65 %

McCulloch - Diels-Alder reactions of pyrroles [70CJC1472]

R2

R1 +

i CO2Me

R 1 = H; R2 = Me

CO2Me C AlCla III = Ci CH2CI2 COiMe 75 %

N,CO2Me R~~ COiMe R2 \ CO2Me

R1 AICI3

~

CO2Me

85 % R2f..,,,~n,~CO2 Me

H"N'cojMe

Application of Diels-Alder Cycloaddition Chemistry

35

Kozikowski - Diels-Alder reaction of pyrrole with allene [78JOC2083]

,r.CO,Et

o

N"~

0

+ ~

0

/i~N

70 %" "COjEt

CO2Et 75 ~

/~=N

CO2Et

CO2Et

O2Et

J~"\CO2Et

CO2Et

CO2Et

Murase - Vinyl pyrroles as dienes for Die/s-Aider reactions [91CPB489] S /JL'Me

SCH2Ph

.SCH2Ph = ~ /~"CH2 1) 0 BnCI

i Me

0

2) DDQ

THF

I Me

21% overall

Wuonola - Intramolecular [4+2]-cycloaddition of imidazoles [92TL5697]

i~)

Me"N~N

Me

0 Me Me"N~"N"

A 220 ~

N

Me ,~

- HCN 7O%

0

Liotta - Tandem Diels-Alderlretro Die/s-Aider reaction of oxazoles [83TL2473] N~

Ph

O + ---

\

OAc

= PhC=N + O ~ 90 %

Oxazole cycloadditions - Synthetic equivalent of 2-aza-1,3-dienes

Firestone [67TET943] Me~'~ O + MeSO2~o N~/

~ ~ 130 75 %

MSO2Me . U ~ O - MeSOiH

-

OH MeN ~ ~ O

OAc

Application of Diels-Alder Cycloaddition Chemistry

36

Jacobi- Intramolecular cycloadditions with oxazoles [84TL4859,92MI001, 81JOC2065, 78JACS7748,90JOC202] C:

Me

Me 0 60

Me

H* ==~ 98% = 0

%~

O

Gnididione o

o 94

%

~ ' ~ 0/'~0 Paniculide-A

OMe

OMe

N

0

S I Retro Oiels-Alder of Oxazoles

(-) Norsecurinine

I

Jacobi -Synthesis of furans or functionality derived from a s u ~ u r a n [87TET5475] ~ O~o ~ ,,,,~~N)J~OMe

PhEt _ reflux-

Me

1) NaBH4 ,.

- MeCN

2) pH5

94 %

OH..~ O

O H

PaniculideA

H

Application of Diels-Alder Cycloaddition Chemistry

37

Diels-Alder of Thiazole Derivatives Jacobi - Formation of fused ring thiophenes [84HET281, 88TET3327, 87TL2937] Me~OEt

~

OEt

N~ ,S

I

R

-MeCN

O

57 %

H Me~~O ~

"

R = CH2OMe

Me

i ~

H

Ra-Ni_ 85 % -

74%

Me

~en~U~

Me Me

1'1 Intramolecular Kondrat'eva Pyridine Synthesis [57MI666, 59MI484] Weinreb - Addition of DBN is helpful to intramolecular cycloadditions [89JO05580]

~~1'~ N,,Ac

.,Ac

A o-DCB DBN

OTBS

A -H20

[

~NAc

OTBS

OTBS

NOTE: oxazolesbearingan EWG at C4are unreactivein cycloadditions.

I Heter~

cti~ I

Cycloadditions involving heteroaromatic azadienes. Review: Boger [86CR781] Sauer [69TL5171]

49--*7./o CO2Me

'pyrrolidine CO2Me

38

Application of Diels-Alder Cycloaddition Chemistry

Boger - Die/s-Aider reactions of heterocyclic azadienes for the total synthesis of complex molecules [87JACS2717] NH CO2Me dioxane 1) H2S,Et2NH ~~~'SMe 80 ~ 22 h NO2 dioxane _- NO2 N + || | 2) Mel, MeCN 82 % MeO" ~'~ 42 % MeO" ~ MeO2C

N)~-N N.,~N

R2N",~M e 4 eq

~OBn " ~ "OMe OMe

CH2CI2, 6.2 Kbar rt, 120 h ,

ID,

65 %

(2.8" 1)

0

M e O ~ IN.< CO2Me

10 steps

I=

0

[~OBn

NH2~Me

~r~ "OMe OMe

Streptonigrin OMe

Indole as a dienophile in inverse electron demand Die/s-Aider reaction

Snyder [90JOC3257]

R

CO2Me

CO2Me

COtMe

CO2Me

R=Bz Inverse electron demand 4+2 reactions of pyridazines

Neunhoeffer [73LAC1955] R1 R21 R i ~ / N I~1

+

Me2N~CH2 1110Me

R2"~

91

x

X = NMe2,OMe 57-93 %

NOTE: Dimethylanilinederivative formedpredominantly.

39

Application of Diels-Alder Cycloaddition Chemistry Neunhoeffer - Reaction of dimethyl pyridazine 4,5-dicarboxylic acid dimethyl ester with an ynamine [72TL1517, 73LAC437]

.C02Me

N~"~CO2 Me MeC_=CNEt2 MeO2CN.~ NEt2 N~,,,,'~CO2Me

-N2

MeO2C,,~~ NEt2 MeO2C" ~

Me

"Me

Inverse electron demand 4+2 reactions of 1,2,4,5-tetrazines [84MI550,

78MI1095] Sauer [66TL4979] R N"~N N~"N

R1CH=CHR 1

,,sN R N . I ~ ..R1 1~"TL'..~H N

=

"N2

R

~RR 1 N .

R

.,

Die/s-Aider reactions of electron deficient heteroaromatic dienes

Roffey [69JHC497], Seitz [79AP452], Sauer [84TL2541, 83TL1481, 75TL2897]

EtO,,,ll/Ph r /

NH

,N I~1/CO2Me

LMeO2C Ph

CO2Me

"N2

CO2Me N~I',,N

27 %

CO2Me

N-J~N N~IN I

II

CO2Me

"'y"

r

=- "

R = alkyl, Ph

~,bCO~M,, " 1

N.=-~N..NMe2 /

,

j

CO2Me

"N2 =

N~,,N.NMe2

56-81%

CO2Me

Taylor - Route to condensed pyrazines via internal cycloadditions using nitriles as dienophiles [89JOC1245, 86JOC1967] CN Ph,,,,,~N,,N L x

X = O, NCOCF3

225.235oc

Ph,. N,. ~ X

40

Application of Diels-Alder Cycloaddition Chemistry

2.3 References 55JACS4812 57MI666 58JACS933 59MI484 66TL4979 67TET943 68JOC390 69JHC497 69TL5171 70CJC1472 72TL1517 73CC156 73LAC437 73LAC1955 75TL2897 78JACS7748 78JOC2083 78MI1095 78TL4767 79AP452 79JACS5073 79HET949 80JACS3632 80JACS5245 80JACS7126 80JOC2601 81JACS6387 81JOC2065 82ACIE221 82CC1029 82JACS 1445 82JACS7065 82TET3087 82TL3739

C. K. Bradshaw, L. E. Beavers, J. Am. Chem. Soc. 1955, 77, 4812. G. Y. Kondrat'eva Khim. Prom. (Moscow) 1957, 2, 666. C. K. Bradsher, T. W. G. Solomons, J. Am. Chem. Soc. 1958, 80, 933. G. Y. Kondrat'eva Izv. Akad. Nauk. SSSR, Ser. Khim. 1959, 484. J. Sauer, G. Heinrichs, Tetrahedron Lett. 1966, 4979. R. A. Firestone, E. E. Harris, W. Reuter, Tetrahedron 1967, 23, 943. D. L. Fields, T. H. Regan, J. C. Dignan, J. Org. Chem. 1968, 33, 390. P. Roffey, J. P. Verge, J. Heterocycl. Chem. 1969, 6, 497. W. Dittmar, J. Sauer, A. Steigel Tetrahedron Lett. 1969, 5171. R. C. Bansal, A. W. McCulloch, A. G. McInnes, Can. J. Chem. 1970, 48, 1472. H. Neunhoeffer, G. Werner, Tetrahedron Lett. 1972, 1517. C. K. Bradsher, F. H. Day, A. T. McPhail, P. S. Wong, J. Chem. Soc., Chem. Commun. 1973, 156. H. Neunhoeffer, G. Werner, Liebigs Ann. Chem. 1973, 437. H. Neunhoeffer, G. Werner, Liebigs Ann. Chem. 1973, 1955. . Burg, W. Dittmar, H. Reim, A. Steigel, J. Sauer, Tetrahedron Lett. 1975, 2897. P. A. Jacobi, T. Craig, J. Am. Chem. Soc. 1978, I00, 7748. A. P. Kozikowski, M. P. Kuniak, J. Org. Chem. 1978, 43, 2083. H. Neunhoeffer, Chemistry of Heterocyclic Compounds; Wiley: New York, 1978; Vol. 33 pp 1095-1097. G. E. Keck, Tetrahedron Lett. 1978, 4767. G. Seitz, W. Overheu, Arch. Pharm. 1979, 312, 452. S. M. Weinreb, N. A. Khatri, H. Shringarpure, J. Am. Chem. Soc. 1979, 101, 5073. S. M. Weinreb, J. I. Levin, Heterocycles 1979, 12, 949. G. E. Keck, D. G. Nickell, J. Am. Chem. Soc. 1980, 102, 3632. K. P. C. Vollhardt, R. L. Funk, J. Am. Chem. Soc. 1980, 102, 5245. W. G. Dauben, C. R. Kessel, K. H. Takemura, J. Am. Chem. Soc. 1980, 102, 7126. E. Vedejs, M. J. Amost, M. Dolphin, J. Eustache, J. Org. Chem. 1980, 45, 2601. N. A. Khatri, H. F. Schmitthener, J. Schringarpure, S. M. Weinreb, J. Am. Chem. Soc. 1981, 103, 6387. P. A. Jacobi, D. G. Walker, I. M. A. Odeh, J. Org. Chem. 1981, 46, 2065. L. F. Tietze, G. von Kiedrowski, B. Berger, Angew. Chem. Int. Ed. 1982, 21, 221. J. E. Baldwin, R. C. G. Lopez, J. Chem. Soc., Chem. Commun. 1982, 1029. E. Vedejs, T. H. Eberlein, D. L. Vanle, J. Am. Chem. Soc. 1982, 104, 1445. R. A. Gobao, M. L. Bremmer, S. M. Weinreb, J. Am. Chem. Soc. 1982, 104, 7065. S. M. Weinreb, R. R. Staib, Tetrahedron 1982, 38, 3087. J. F. Kerwin, S. J. Danishefsky Tetrahedron Lett. 1982, 23,

Application of Diels-Alder Cycloaddition Chemistry

83JACS1683 83JACS6999 83JOC3661 83TL987 83TL1481 83TL2473 84ACR35 84HET281 84JACS7861 84JACS7867 84JOC3243 84JOC4045 84JOC4569 84JOC4741 84MI550 84TL721 84TL2541 84TL4859 85ACR16 85JACS1768 85JACS4072 85JACS5534 85JOC1695 85JOC2567 85TET1173 86CR781 86JACS1306 86JOC1374 86JOC1556 86JOC1967 86JOC3553 86JOC3915 86TL1975

41

3739. E. Vedejs, D. A. Perry, J. Am. Chem. Soc. 1983, 105, 1683. E. Vedejs, D. A. Perry, K. N. Houk, N. G. Rondan, J. Am. Chem. Soc. 1983, 105, 6999. M. L. Bremmer, N. A. Khatri, S. M. Weinreb, J. Org. Chem. 1983, 48, 3661. R. S. Garigipati, J. A. Morton, S. M. Weinreb, Tetrahedron Lett. 1983, 24, 987. J. Balcar, G. Chrismam, F. X. Huber, J. Sauer, Tetrahedron Lett. 1983, 1481. D. Liotta, M. Saindane, W. Ott, Tetrahedron Lett. 1983, 24, 2473. P. Magnus, T. Gallagher, P. Brown, P. Pappalarado, Acc. Chem. Res. 1984, 17, 35. P. A. Jacobi, K. Weiss, M. Egbertson, Heterocycles 1984, 22, 281. R. S. Garigipati, A. J. Freyer, R. R. Whittle, S. M. Weinreb, J. Am. Chem. Soc. 1984, 106, 7861. H. Natsugari, R. R. Whittle, S. M. Weinreb, J. Am. Chem. Soc. 1984, 106, 7867. S. W. Remiszewski, R. R. Whittle, S. M. Weinreb, J. Org. Chem. 1984, 49, 3243. D. L. Bo~er, M. D. Mullican, J. Org. Chem. 1984, 49, 4045. J. H. Rigoy, N. Balasubramanian, J. Org. Chem. 1984, 49, 4569. S. E. Denmark, M. S. Dappen, J. A. Sternberg, J. Org. Chem. 1984, 49, 4741. H. Neunhoeffer, Comprehensive Heterocyclic Chemistry; Pergamon: London, 1984; Vol. 3, p 550. S. Danishefsky, M. Bednarski, Tetrahedron Lett. 1984, 25, 721. K. MUller, J. Sauer, Tetrahedron Lett. 1984, 2541. P. A. Jacobi, C. S. R. Kaczmarek, U. E. Udodong, Tetrahedron Lett. 1984, 4859. S. M. Weinreb, Acc. Chem. Res. 1985, 18, 16. S. D. Larsen, P. A. Grieco, J. Am. Chem. Soc. 1985, 107, 1768. S. F. Martin, S. Grzejszczak, H. Rtieger, S. A. Williamson, J. Am. Chem. Soc. 1985, 107, 4072. H. Iida, Y. Watanabe, C. Kibayashi, J. Am. Chem. Soc. 1985, 107, 5534. J. J. Talley, J. Org. Chem. 1985, 50, 1695. W. G. Dauben, J. M. Gerdes, D. B. Smith, J. Org. Chem. 1985, 50, 2576. S. W. Remiszewski, T. R. Stouch, S. M. Weinreb, Tetrahedron 1985, 41, 1173. D. L. Boger, Chem. Rev. 1986, 86, 781. S. E. Denmark, M. S. Dappen, C. J. Cramer, J. Am. Chem. Soc. 1986, 108, 1306. J. H. Risby, F. Burkhardt, J. Org. Chem. 1986, 51, 1374. E. Vedejs, T. H. Eberlein, D. J. Mazur, C. K. McClure, D. A. Perry, R. Rugged, E. Schwartz, J. S. Stults, D. L. Varie, R. G.Wilde, S. Wittenberger, J. Org. Chem. 1986, 51, 1556. E. C. Taylor, L. G. French, J. Org. Chem. 1986, 51, 1967. P. A. Grieco, S. D. Larsen, J. Org. Chem. 1986, 51, 3553. S. J. Danishefsky, C. Vogel, J. Org. Chem. 1986, 51, 3915. P. A. Grieco, S. D. Larsen, W. F. Fobare, Tetrahedron Lett. 1986, 27, 1975.

42 86TL5513 87ACIE1295 87JACS2717 87MI001 87TET5475 87TL813 87TL2937 88JACS1638 88JACS5452 88JCS(P1)247 88JOC2220 88JOC2226 88TET3327 88TL2107 88TL5855 89JOC224 89JOC1097 89JOC1245 89JOC4019 89JOC5580 89JOC5852 89SC2699 89TL1045 90JOC202 90JOC3257 91CPB489 91JACS1713 91JACS8975 91MI402 91MI451 92MI001 92TL5697

Application of Diels-Alder Cycloaddition Chemistry H. Iida, Y. Watanabe, C. Kibayashi, Tetrahedron Lett. 1986, 27, 5513. L. F. Tietze, H. Denzcr, X. Holdgrfin, M. Neumann, Angew. Chem. Int. Ed. 1987, 26, 1295. D. L. Boger, R. S. Coleman, J. Am. Chem. Soc. 1987, 109, 2717. D. L. Bogcr, S. M. Wcinrcb, Hetero Diels-Alder Methodology in Organic Synthesis; Academic Press: San Diego, 1987. P. A. Jacobi, C. S. R. Kaczmarek, U. E. Udodong, Tetrahedron 1987, 43, 5475. T. N. B irkinshaw, A. B. Holmes, Tetrahedron Lett. 1987, 813. P. A. Jacobi, R. F. Frcchette, Tetrahedron Lett. 1987, 2937. M. Kahn, S. Wilke, B. Chcn, K. Fujita, J. Am. Chem. Soc. 1988, 110, 1638. E. Vedejs, J. S. Stults, R. G. Wilde, J. Am. Chem. Soc. 1988, 110, 5452. C. May, C. J. Moody, J. Chem. Soc., Perkin Trans. 1 1988, 247. E. Vedejs, T. H. Eberlein, R. G. Wilde, J. Org. Chem. 1988, 53, 2220. E. Vedcjs, J. S. Stults, J. Org. Chem. 1988, 53, 2226. P. A. Jacobi, M. Egbcrtson, R. F. Frcchcttc, C. K. Miao, K. T. Weiss, Tetrahedron 1988, 44, 3327. J. A. Cooper, P. CornwaU, C. P. Dell, D. W. Knight, Tetrahedron Lett. 1988, 29, 2107. P. A. Grieco, A. Bahsas, Tetrahedron Lett. 1988, 29, 5855. J. H. Rigby, N. Balasubramanian, J. Org. Chem. 1989, 54, 224. R. B. Gupta, R. W. Franck, K. D. Onan, C. E. Soll, J. Org. Chem. 1989, 54, 1097. E. C. Taylor, L. G. French, J. Org. Chem. 1989, 54, 1245. J. H. Rigby, J. Holswort, J. Org. Chem. 1989, 54, 4019. C. Bubramanyam, M. Noguchi, S. M. Weinrcb, J. Org. Chem. 1989, 54, 5580. J. H. Rigby, M. Qabar, J. Org. Chem. 1989, 54, 5852. J. H. Rigby, M. Qabar, Synth. Commun. 1989, 20, 2699. B. A. Keay, P. W. Dibble, Tetrahedron Lett. 1989, 30, 1045. P. A. Jacobi, H. G. Selnick, J. Org. Chem. 1990, 55, 202. S. C. Benson, J. L. Gross, J. K. Snydcr, J. Org. Chem. 1990, 55, 3257. M. Murase, S. Yoshida, T. HOsaka, S. Tobinaga, Chem. Pharm. Bull 1991, 39, 489. D. L. Boger, W. L. Corbett, T. T. Curran, A. M. Kasper, J. Am. Chem. Soc. 1991, 113, 1713. J. H. Rigby, M. Qabar, J. Am. Chem. Soc. 1991, 113, 8975. S. M. Weinreb in Comprehensive Organic Synthesis; B. M. Trost, I. Fleming, Eds.; Pergamon: Oxford, 1991; Vol. 5, Ch. 4.2, pp 402-450. D. L. Boger in Comprehensive Organic Synthesis; B. M. Trost, I. Fleming, Eds.; Pergamon: Oxford, 1991; Vol. 5, Ch. 4.3, pp451-510. P. A. Jacobi in Advances in Heterocyclic Natural Product Synthesis; W. H. Pearson, ed.; JAI Press: Greenwich, 1992. M. A. Wuonala, J. M. Smallheer, Tetrahedron Lett. 1992, 34, 5697.

Chapter 3 Three-Membered Ring Systems ALBERT PADWA Emory University, Atlanta, GA, USA and

S. SHAUN MURPHREE Miles Inc., Charleston, SC, USA 3.1

INTRODUCTION

Thrce-membered ring systems encompass the smallest of heterocycles, but by no means the least active. Indeed, these compounds are extremely valuable substrates for the organic chemist, as versatile synthetic intermediates or as reagents with unique selectivity. A yearly review chapter in PHC clearly can not be comprehensive in covering the progress in this highly active field. The following pages are meant to provide a sampling of highlights extracted from the year's literature representing significant and novel transformations, particularly those of interest to heterocyclic chemists. The organization of the review follows that of previous years.

3.2 3.2.1

EPOXIDES Preparation of Epoxides

Since epoxides are valuable intermediates for the synthesis of natural products and other bioactive compounds, recent literature shows a strong emphasis on general methods for the preparation of optically active epoxides. The asymmetric approaches used can be generally divided into "Sharpless" and "non-Sharpless" methodology. The former, firmly entrenched and thoroughly characterized, is a basis upon which continuing innovation takes place. For example, Ko and co-workers [94JOC2570] have added a twist to the Sharpless asymmetric dihydroxylation reaction to access erythro-diols. TBDMS-protected allyl alcohols (e.g., 1) are dihydroxylated to give threo-diols (e.g., 2). Once activated (cyclic sulfate) and deprotected, these substrates undergo quasi-Payne rearrangement (providing the requisite inversion) to give terminal epoxides (e.g., 5). Treatment with a nucleophile results in attack at the least substituted epoxide carbon, providing erythro-diols (e.g., 7). ,,OTBDMS OH TBAF AD ~S~O BnO"'~'~'OTBDMS ~ B n O " ~ ~SOTBDMS 1. S0Cl2 2. RuGI3 BnO = NalO4 2 1 OH B n O " ~ . ~" ~

T~-s'o~ 4

_ BnO'~,t,~

~so~" S

OH ~,t,~,,SPh H SPh H+ ----P" BnO OH ~so~"

PhSNa ~ BnO~

43

6

7

44

Three-Membered Ring Systems

This methodology [94TL3601] was used to construct the optically active erythro-diol 8, which was then stereospecifically converted to (+)- disparlure (9), the sex attractant pheromone of the female gypsy moth. This transformation represents a formal asymmetric epoxidation across a nonfunctionalized olefin, not a direct option with traditional Sharpless asymmetric epoxidation technology. This clever variation using initial Sharpless dihydroxylation (applicable to nonfunctionalized olefins) and subsequent epoxide formation is starting to be recognized as a useful indirect method for asymmetric epoxidation. I. MeC(OMe),3 2. AcBr 3. K2CO3/MeOH 8

9; (+)-Disparlure

Chiral (salen)Mn(III) catalysts have also emerged as useful reagents to help fill the lacuna among unfunctionalized alkene epoxidations. In their recent review on the chemical and biological synthesis of chiral epoxides, Besse and Veschambre [94TET8885] declared that the "use of metalloporphyrins and related salen complexes..." is undoubtedly the method of the future. Which is not to say that this methodology is without limitations. However, Jacobsen and coworkers, whose pioneering work brought chiral (salen)Mn(III) mediated epoxidations to the fore, have in the past year examined some of the thorny problems commonly associated with these catalysts in an effort to broaden the scope of such asymmetric epoxidations. With an eye toward industrial applications, Jacobsen recently published a practical method for the large-scale preparation of the di-tert-butyl (salen)Mn(III) catalyst 10a [94JOC1939]. This addresses the question concerning the ready availability of the catalyst, but the mechanistic details of this reaction have thus far evaded a completely unified picture. H~'IIH

~t-Bu CI t-B/ lOe: R = t-Bu 10b:

R = (i-Pr)3SiO

Generally speaking, (salen)Mn(III) catalyzed epoxidations are believed to proceed via a stepwise mechanism in which initial attack of the substrate forms a radical intermediate, the configuration of which is determined by the facial selectivity of the catalyst. This intermediate can either collapse directly to the epoxide or undergo rotation and subsequent collapse, an event whose fate is determined by the diastereoselectivity of the catalyst toward ring closure and/or the relative lifetime of the radical intermediate. Thus, the product distribution is determined by the influence of at least two independent factors [94JA425]. These parameters were probed in an in-depth study dealing with the epoxidation of cis-cinnamate esters 11, a protocol Jacobsen has used for the enantioselective synthesis of diltiazem (13), a commercial anti-hypertensive agent [94TET4323]. Surprisingly, electronic and steric factors on the phenyl moiety exercise practically no influence on the enantioselectivity (lst step) of the reaction, whereas increasing steric

Three-Membered Ring Systems

45 R1

c~

R2 A.,,~R1

R2

trans

O'S, R2

+ O II LM

LM-O_ I

minor

I

' R2

IIR2

R1

trans

O~e/R2

bulk about the ester group results in a profound improvement ( l l b vs. lld). Where electronic effects did come into play was in the cis/trans selectivity (2nd step). A strong correlation was observed between the Hammett sigma values and the cis/trans ratio, with electron withdrawing groups favoring trans formation ( l l a vs. lie). This latter effect is probably due to an increased lifetime of the intermediate radical, which is then able to partition to the trans-isomer before collapsing to the product. tOMe

O ' ~ ~ X"

CO=R

v

(R,R)-I 0a

COp

_

NaOCi 4-MeCeH4NO

r

X

12

v

11a: X = OMe; R = I-Pr 11b: X = H; R = Me

- .N...~O

13; Dlltlazem L,~ NMe2 HCI 9

11 9X = NO2;R =Me 11d: X= H; R =i-Pr

Considering these and other results, Jacobsen formulated that the following substrate properties are important for high enantioselectivity: (1) an aryl, alkenyl, or alkynyl group be conjugated to the alkene, (2) a cis double bond linkage is necessary as well as a bulky R group, and (3) the presence of an allylic oxygen substituent. An ideal substrate is one that possesses at least three of the aforementioned characteristics. In light of the observed insensitivity of the enantioselectivity towards steric bulk on the phenyl ring, a new model for initial substrate-catalyst binding was proposed in which the substrate approaches in a skewed manner where the aromatic portion is turned away from the catalyst and the R group is poised to exert significant steric influence. Mechanistically, this scenario is rationalized as being a "least-motion" path, since the initially formed radical is not far from a stable conformation. The proposed transition state is consistent with the observation that trans-alkenes are notoriously difficult to epoxidize using these reagents (slow reaction rates, low ee's), since the position of the Ar

~

R 0 ii

,m~Mnm

I

Three-Membered Ring Systems

46

Ar group in these substrates would be expected to encounter considerable steric hindrance. It is somewhat unusual that certain trisubstituted olefins (e.g., 14), have been found to undergo smooth reaction at low temperatures to give epoxides (e.g., 15) with high enantioselectivity [94JOC4378]. Interestingly, the asymmetric induction in these cases occurs in an opposite sense than that observed for the disubstituted olefins. [ ~

NaOCI Ph

catalyst

14

Ph 15

Pyridine N-oxide derivatives were found to produce a remarkable rate enhancement. It is not believed that they function as an axial ligand on the active catalyst species, since product ee's and cis/trans epoxide ratios are insensitive to the presence of these additives. Current theory suggests that the active Mn(V) oxo complex exists in equilibrium with an inactive dimer with the Mn(III) complex (see below). By binding to the latter, pyridine N-oxide derivatives shift the equilibrium toward the free active catalyst and thus enhance the reaction rates. It has also been observed that in dichloromethane, N-methylmorpholine N-oxide (NMO) and mchloroperbenzoic acid (MCPBA) produce a 1:1 salt which is unreactive toward olefins yet which is very efficient in oxidizing the (salen)Mn catalyst. This is significant in preserving the enantioselectivity of the process, as it prevents uncatalyzed racemic side-oxidation of the substrate [94JA9333]. CI-Mn Iv , O---MnlV--ci

0 II Mnv + I CI

.~._.._~y

L Mn"l I CI

_

_

0 II Mnv I CI

+

PyO MnllI I CI

As previously noted, optically active trans-epoxides are not easily available through the (salen)Mn-catalyzed epoxidation of trans-olefins. However, a modification in the conditions for cis-alkene epoxidation can provide access to trans-epoxides [94JA6937]. Addition of an cinchona alkaloid derivative such as 18 promotes a remarkable crossover in diastereoselectivity, such that the trans-epoxide 17 can be prepared in 90% de from cis-B-methylstyrene (16). It is not yet clear whether these chiral quaternary ammonium salts fundamentally change the nature of the manganesebased oxidant, or rather somehow prolong the lifetime of the radical intermediate, allowing rotation before collapse.

h/=~cHa P 16

lOb

N.oc,_ PhCI 18

J P~

OMe Cl- ~

z~ CH3 17

18

In the case of terminal olefins, asymmetric epoxidation typically results in relatively low enantiomeric excess. For (salen)Mn(III) catalysis, it is not clear whether the low degree of asymmetric induction is due to poor enantiofacial selectivity during

47

Three-Membered Ring Systems

the first discrete step, or more facile rotation of the intermediate radical, which is unencumbered by alpha-substitution. Since both of these are thermodynamic events, it would be expected that selectivity would be improved by lowering the reaction temperature. Indeed, when styrene (19) is epoxidized at-78oc, a slightly improved enantiomeric excess is observed compared to the room temperature reaction [94JA9333]. The asymmetric induction may be further improved by modifying the catalyst. Replacing the tert-butyl group with the triisopropylsiloxy group affords a catalyst (i.e., 10b) which is not only sterically more defined but also electronically attenuated, thus presumably milder and more selective [94TL669]. Using this catalyst at low temperatures, a dramatic increase in the enantiomeric excess was observed. 10b

MCPBA

Ph

NMO

19

O

20

This catalyst also resulted in a somewhat higher selectivity in the epoxidation of cyclic 1,3-dienes (e.g., 21-o22) when compared to the tert-butyl derivative lOa [94TL669].

[~ 21

OAo

lOb

~

OAc

NaOCI 22

Catalysts of type 10 have also been examined in the epoxidation of unfunctionalized cis- and trans-alkenes using hydrogen peroxide as a terminal oxidant [94TL941]. The Katsuki group have focused their attention on (salen)Mn(III) catalysts of a slightly different configuration (e.g., 23 and 2,4), which are characterized as having chiral residues at the aromatic 3,3'-positions. Recent studies into the epoxidation of conjugated cis-olefins [94SL356], including chromene derivatives such as 25 [94SL255], have led to the hypothesis of a flanking substrate attack which is steered by both steric interactions (e.g., the cyclohexyl residue) as well as n-n repulsive forces. The latter directing parameter was invoked to explain the apparent reversal of facial selectivity in the epoxidation of enyne 27 [94SL479], although it is not entirely clear which outcome would be predicted on the basis of sterics alone. Furthermore, the enantiofacial selection ofcis-olefins in these catalyst systems appears to be influenced mainly by the chirality at the C 1" and C2" positions (e.g., cyclohexyl), whereas transolefin epoxidation seems to be directed more by the C3 and C3' substituents [94TET4311].

HII',~H

%o" 'o-4 ~h

E~" n

23

24

48

Three-Membered Ring Systems

o2.

. AcNH"

v

v

H202

AcNH 26

25

23

---/ 27

,..

PhlO v CH3CN

28

k

Mukaiyama's work with the related 6-ketoiminato Mn(III) complex 29 has revealed that this catalytic system induces the aerobic epoxidation ofunfunctionalized cis-olefins with good enantiofacial selectivity, albeit in moderate yield and with significant trans-epoxide formation [94CL1259].

PW"

0 29

29, 02

_

(CH3)3CCHO 30

31

Although chiral catalysts continue to dominate the literature in this arena, there are a number of novel achiral alternatives. Examples of the latter are a manganese porphyrin/tetrabutylammonium periodate system, useful for neutral homogeneous conditions [94TL945], as well as a polybenzimidazole-supported molybdenum(VI) catalyst suitable for industrial application in the Halcon process for propene epoxidation [94CC55]. Chiral catalysts are not de rigueur for the preparation of optically active cpoxides. Given that the substratc olefin can itself be chiral, there are often structural features which allow for stereoselective functionalization. In their study on the epoxidation of partial ergot alkaloids and conformationally-fixed styrenes (e.g., 32), Martinclli and co-workers found that these reactions exhibit remarkable facial selectivity which could not be satisfactorily rationalized by steric arguments. Force-field modeling indicates that torsional steering is most likely responsible for the observed effects. Thus, treatment of 32 with MCPBA results in the formation of the anti epoxide 33 in excellent yield and with high stereoselectivity (98:2). The analogous syn epoxide (34) was prepared indirectly via the bromohydrin, since bromine attack also occurs in an en fashion [94JOC2204].

49

Three-Membered Ring @stems

R

R

~

R

MCPBA~,

1. NBS/H20. 2. NaOH

kl___.#.,,,H

B~

33

32

. ~ H 34

Often, the diastereoselectivity may be attributed to the presence of one or more discrete functional groups, as in the epoxidation ofchiral (E)-crotylsilanes which represents a key step for the asymmetric synthesis of substituted tetrahydrofurans (i.e., 35--->37). Both catalyzed and uncatalyzed peracid oxidation conditions result in high anti selectivity, a phenomenon which is associated with the phenyldimethylsilyl and free hydroxyl groups. Epoxidation of the O-protected species gives a 1"1 mixture of syn and anti isomers [94TL6453]. B

s SiMo2Ph 35

I

ArCO3H I

0

~

OH 1 SiMo2Ph 36

PhM~o'~R HO

37

Similarly, enone 38 has been shown to undergo ketone-directed epoxidation when treated with MCPBA to give exclusively the syn epoxyketone 40. As for the mechanism, hydrogen bonding effects were discounted on the basis of solvent insensitivity. Intramolecular attack by some oxidized form of the ketone moiety could be operative, although 180 labelling studies have ruled out a dioxirane intermediate as the active epoxidizing species. Thus, the observed stereoselectivity was rationalized on the basis of intramolecular epoxidation by an alpha-hydroxy peroxide (i.e., 39) or possibly by a carbonyl oxide intermediate [94TL6155 180

le O

MCPBA

O 39

38

40

During the past year, Adam and his group have added some fine tuning in their direct synthesis of epoxy alcohols from olefins [94ACR57]. The photooxygenation of alkenes in the presence of transition-metal catalysts typically suffers from low regioselectivity during the initial singlet oxygen enr reaction (Schenck reaction). However, the use of vinylsilanes as substrates significantly improves the overall selectivity of the method. The silyl group directs the photooxygenation by favoring geminal hydrogen abstraction (cf. 41--->42). Steric requirements also help direct the metal-catalyzed epoxidation, providing silyl epoxy alcohols 43 in fair yields and with

SiMe3 R

R 41

1. 102 ~

HOy ~

2. NaBH4

R

SiMe3 R 42

tBuOOH =

MeaSi~O HO

VO(acac)2

R R 43

Three-Membered Ring Systems

50

excellent diastereomeric ratios [94JOC3341]. Vinylstannanes give similar results [94CB 1441]. A novel synthesis of epoxides from aldehydes and sulfur ylides has been reported this past year [94JA5973]. This reaction, which gives predominantly trans epoxides, proceeds through an interesting catalytic cycle in which the sulfur ylide is generated in situ from a diazo precursor, which is slowly added into a reaction medium containing catalytic rhodium(II) acetate and substoichiometric amounts of dimethyl sulfide. The use of a chiral sulfide produced observable (11%) enantioselectivity. RCHO

R 4 ~ ,R'

3.2.2

R2S=CHR'[Rh2(OAc)4]

[R2S]

N2CHR'

N2

Rh=CHR'

Reactions of Epoxides

A quintessential epoxide reaction is the addition of nucleophiles to give ringopened products. The broad range of usable nucleophiles lends an enviable flexibility to the protocol, while continuing advances in regio- and stereoselection expand its applicability. For example, synthetically useful halohydrins are available directly from olefins through hydrohalo addition, although the application of this approach to asymmetric synthesis sometimes proves problematic. On the other hand, the cleavage of epoxides with metal halides, a subject recently reviewed by Bonini and Righi [94SYN225], provides a regio- and chemoselective preparation of halohydrins, a method which is easily carried over to chiral substrates as demonstrated in the synthesis of the marine natural product 2-bromo-B-chamigrene (46).

THF HO~~ Br 44

46

2-bromo-l]-chamlgrene

4S

The regiochemist~ of the ring opening reaction can sometimes be controlled by means of chelation. For example, the complete C-4 selectivity observed in the ring opening of pyran epoxide 47 by organometallic reagents such as Me2CuLi and AIMe3 has been rationalized on the basis of a bidentate chelate intermediate (i.e., 48). This hypothesis is supported by the observation of lower selectivity when crown ethers are added to the reaction medium [94TET1261 ].

0 0

47

[ 48

]

o

Me"

Me 49

Three-Membered Ring Systems

51

In a related observation, Guanti and coworkers [94 TET2219] observed that both the rate and regiosclectivity in the rcductivc ring opening ofchiral epoxide 49 can be enhanced by Lewis acids. The efficiency ofregioselection is highly dependent upon a variety of reaction parameters, such as the choice of Lewis acid and hydride donor, as well as of the O-protecting groups. Thus, a tfibutyltin hydride/magnesium iodide system mediated the regioselectivc ring-opening of chiral epoxy dio150.

/OTIPS ~OPMP

/OTIPS [H]

~ O P M-~P OH 51

50

Regioselectivity may also be controlled by g-interaction, as seen in the aluminum hydride reduction of unsaturated cyclic epoxides (e.g., 52). The observed rcgiochemical outcome was explained by an intermediate g-complex (53) in which the substrate is essentially planar. This model, which is supported by semiempirical calculations, minimizes axial-attack effects and emphasizes subtle electronic factors as well as hydride donor-carbon distances [94TL6647].

H~.I--H

52

53

54

Many epoxides undergo efficient ring-opening by oxygen nucleophiles in the presence of tris[trinitratocerium(IV)]paraperiodate, a heterogeneous catalyst [94SC1959]. In this case, the regiochemistry is presumed to depend upon the fate of a proposed epoxide radical cation (55). \ /

/N /x 55

Carbon nucleophiles may also serve as epoxide ring-opening agents, providing a particularly useful method for preparing long chain secondary alcohols. For example, terlmnal epoxides react with 2-(trialkylsilyl)allyl organometallics (e.g., 57) to give good yields of 1-substituted 4-(trimethylsilyl)-4-penten-1-ol products (e.g., 58). a-Haloepoxides proceed in a similar manner giving long-chain halohydrins (e.g., 59-->60). Depending upon the reagent and substrate, Lewis acid additives are sometimes needed for optimal conversion [94JOC4138].

.SIMe2Ph ( ~Cu(CN)Li2 29 S7

Or ~ ~

56

57 .78oc

81Me2Ph 58 OH $1Me2Ph

59

--40~

60

OH

CI

Three-Membered Ring Systems

52

A similar protocol provides for the formal alkylation of alkenes via the organolithium reductive alkylation of epoxides. For example, treatment of epoxide 61 with excess tert-butyllithium results in the direct formation of the disubstituted alkene 63 in excellent yield. Variously substituted epoxides may serve as substrates, although the study was limited to the readily available alkyllithium reagents. A preference for the formation of trans-olefins was observed, which became more pronounced with bulkier bases (e.g., tert-BuLi). The proposed mechanism proceeds via metallation at the primary carbon atom from the less hindered side, giving a chelated lithioepoxide (62) which undergoes anti-addition of the alkyl group and subsequent syn-elimination of Li20 to give trans-substituted olefins [94TL7943].

0

sec-BuLi,,. ,,O:

H ~ H9 RL......~i 2 H/ ~ C 4 H 9 61

H~C4H9 --C4H9 ~

ecBu~ H ~C4H9

,/ i.,i

S

C4H9

-

63

62

Epoxide ring opening can occur with concomitant elimination, as seen in the above example, or with subsequent oxidation. For example, a novel copper-catalyzed tandem ring opening and oxidation of optically active (trifluoromethyl)-epoxide (64) was the basis for a recent synthesis of optically pure trifluoropropionic acid (65). The method appears to be applicable to substrates with electron-withdrawing substituents, since electron-rich epoxides undergo degradation under the reaction conditions [94SL507]. OH

F3C~,~

1. HNO3,Cacat_ o. o0oc

-

,~

64

coo.

65

Such nucleophilic ring opening reactions can also take place in an intramolecular fashion, forming other ring systems. Thus, optically active oligo(tetrahydrofurans) have been prepared using an epoxide cascade reaction. Diepoxide 66 underwentp-toluenesulfonic acid-catalyzed rearrangement to form the THF-trimer 67 [94TL7629]. p-TsOH

m,,.-

P O ~ O H

66

67

Upon treatment with cobalt octacarbonyl, acetylenic epoxy alcohols (e.g., 68) form Nicolas-type complexes which undergo Lewis acid-catalyzed rearrangement to give tetrahydropyranol derivatives 69. It is interesting to note that the cyclization proceeds exclusively via a 6-endo process and with exclusive retention of configuration at the propynyl position. Both cis- and trans-2-ethynyl-3-hydroxytetrahydropyran derivatives can be prepared stereospecifically [94TL2179].

1. Co2(CO)8 ~ 2. BF3.OEt2

O Ph

68

HO~,~ M ~ O ') Ph 69

(96%)

Three-Membered Ring Systems

53

When the attacking nucleophile is carbon-centered, intramolecular epoxide ring-opening reactions provide an entry into carbocyclic systems. For example, epoxy allylsilane 70 cyclizes in an overwhelmingly 5-exo fashion under Lewis acid catalysis to form a putative silyl-stabilized carbocation intermediate (71) which then undergoes B-elimination and lactonization to give the alpha-methylene-f)-lactone 72. A side product (73) arises from the internal capture of the intermediate carbocation 71. This procedure has been applied to the synthesis of (-)-teucriumlactone (74) [94TL7809].

:•0

LA J

EtOOC"+.&'T~

5-exo

EtOOC ~

H

71

70

It

EtOOC~

~

72

3 ~ _

.~

74;teucrlumlactone 73

Benedetti and coworkers have examined the intramolecular ring opening of epoxides by bis-activated carbanions, a process exemplified by the rearrangement of phenylsulfonyl epoxide 75 in a sodium ethoxide-ethanol medium to the phenylsulfonyl cyclopentano176. This quantitative study on the effect of ring size in such cyclizations revealed similarities to the intramolecular radical addition onto alkenes [94JOC 1518]. H

PhSO2~~~]

O

NaOEt

CN 75

PhS~

CNIN" ~OH 76

More complex heterocycles can be obtained by a type of double addition or cycloaddition onto epoxidcs. Insertion ofisocyanates was found to be catalyzed by late rare earth chlorides [94SL129] producing oxazolidinones, as seen in the high yield conversion of epoxidr 77 to oxazolidinone 78. This protocol appears to be general, although cyclic epoxides give poorer yields. A similar transformation involves the insertion of carbon dioxide, a reaction which has been carded out enantioselectively by using chirally modified Zr- and Ti-complexes as catalysts. In this way enantiomericaUy enriched 1,3-dioxolanones (e.g., 80) were prepared [94SL69].

/0• CICH2/ 77

n.C3H7NCO YCI3 (10%)

/~CH2CI n-C3H7--N~O O 78

Three-Membered Ring Systems

54

CO2 1,,. Ti(OI-Pri4/Binol

R'~ O

R-~O O.~o

79

80

The Lewis-acid catalyzed rearrangementofepoxides to carbonyl compounds has been studied and it has been found that either ketones or aldehydes can be selectively obtained by the proper selection of reaction conditions. For example, spiroepoxide 81 undergoes rearrangement to aldehyde 82 upon treatment with methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide), or MABR, whereas ketone 83 is formed predominantly when antimony pentafluoride is used [94TET3663]. Bu

Lewisacid 82

81

Bu CHO

Bu 83

O

This rearrangement has been used to prepare the interesting triol I]6. Thus, optically active ketoepoxide 84 undergoes acyl migration in the presence of boron trifluoride etherate with inversion of configuration to give the unstable ketoaldehyde 85, which is directly reduced to give 86 in 75% overall yield [94CL157]. Similarly, treatment of epoxy alkynols 87 with boron trifluoride etherate gave a mixture of cumulenals 88 and hydroxyallenes 89 [94TL6977]. O

Me O Me~CO2Me

~'-

84

O Me~ ~ J ~ ~'ICO2Me M~ "CHO

v

8S

OH

87

CH3

86

OH

BF3- Et20

2

OH Me--OH Me I

R2

88

CHO

H

CHO 89

Dittmer and coworkers have published a catalytic variation on their method of allylic hydroxyl group transposition mediated by tellurium. The process calls for the epoxidation of an allylic alcohol (e.g., 90), usually with Sharpless conditions, followed by protection of the alcohol to give epoxide 91. These compounds then undergo rearrangement and elimination in the presence oftellurium(II) to produce new allylic alcohols 92 which are formally the products of a 1,3-allylic isomerization. The recent modification allows for the use of catalytic amounts (0.1 equiv) of tellurium which is regenerated in situ by the presence of rongalite as a terminal reductant [94TL5583]. This protocol has been used in the synthesis of (-)-boivinose (93), the unnatural isomer of a stroboside constituent [94JOC4311 ]. t-BuL

1.TBHP,Ti(Oi-Pr)4,(+)-DET OH 90

t-BuL

Te2-

2. TsCI

t-Bu~ H

Ts 91

92

Three-Membered Ring Systems

55

OH 93

Replacing rongalite with a more active reducing agent, such as lithium triethylborohydride, and using a less electronegative protecting group, such as acetate, results in a crossover in reactivity. Thus, glycidyl acetates 94 undergo deoxygenation and deacetylation to provide allylic alcohols 95 in yields of 70% or greater with retention of configuration at the carbinol center [94JOC1004].

Rs,,~H Te = R3,~H R2,~ OAc UE6BHY R2~'~ OH R1

R1

94

95

Another extremely mild epoxide deoxygenation protocol involves the use of bis(cyclopentadienyl)titanium(III)chloride, which promotes homolytic cleavage of the epoxide C-O bond. The mildness of this reagent is showcased in the deoxygenation of epoxide 96 which gives the highly sensitive methoxydihydrofuran derivative 97 in 66% yield. While the deoxygenation is in itself quite useful, this general method of epoxide-based radical generation lends itself to a variety of applications. Significantly, the regioselectivity of the epoxide cleavage is often quite high, itself being determined by the stability of the resultant radical, and sometimes opposite to what is expected for a classical SN2 epoxide ring opening. For example, treatment of the spiroepoxide 98 with Cp2TiCI leads to an intermediate carbon radical which can be trapped by a H-atom donor, in this case cyclohexadiene, to give the secondary alcohol 99. By comparison, a "classical" reductive ring opening with lithium triethylborohydride gives only the tertiary alcohol 100. Finally, the intermediate radical can be trapped intramolecularly by, for example, an olefinic residue to give carbocyclic products. This is nicely illustrated by the preparation of the bicyclooctanemethanol derivative 102 in 88% yield from epoxide 101 [94JA986].

TrO~U,j-,~OMe ..'"~'~OTr O

(66~176 TrO~~1 O' ~ ~ s OTr "~ / ~OMe

96

97

OH

(91%)

(>95%) 11111

98

99

Three-Membered Ring Systems

56

o6 " lol

3.3 3.3.1

H 102

DIOXIRANES Preparation of Dioxiranes

Sander and co-workers [94ACIE2212] have reported the first preparativescale synthesis of a dioxirane via carbene oxidation. Thus, the relatively stable dimesityldioxirane 106 was prepared by the low-temperature 02 oxidation of carbene 104 in matrix isolation in CFCI3; an intermediate carbonyl oxide (105) was observed spectroscopically.

A r ~ =N2 Ar

hv

~--

103

3.3.2

At, r>: A

02

A-

104

Ar~ sO" Ar/3"~O+

hV =

Ar,= 0 ArX( ~

105

R = Mesityl

106

Reactions of Dioxiranes

This field is heavily dominated by the chemistry of dimethyldioxirane (DMD, 107) which, because of its ready availability and unique reactivity, has become a useful oxidant in the organic chemist's repertoire of reagents. The utility of DMD lies in its mildness and consequent ability to provide labile products which are not available by other methods. For example, substituted benzofurans 108 [94SYN111 ] as well as N-acylindoles 110 [94JOC2733] are converted to the labile epoxides 109 and 111, respectively, in excellent yields upon treatment with DMD. R"

R=

e

.R

~

108

CH2R2 Ra~CH2R1

~"-CH3 O 110

~ R

3

Me 109

DMD

CH2R2 Ra'~~t,~'/O r

U ..L 7 "-c"'R' ~CH3 O 111

Three-Membered Ring Systems

57

Even though DMD is by far the most common of the dioxirane oxidants, other members of this family occasionally offer advantage. This can be seen from the epoxidation of 1,3-dimethylcyclohexene (112). Under normal DMD conditions, the corresponding epoxide (114) is produced in 56% yield and with a cisltrans ratio of 14:86. On the other hand, using the dioxirane 113, itself easily prepared by treatment of2-chlorocyclohexanone with Oxone, results in the quantitative formation ofepoxide 114 with a cisltrans ratio of 4:96 [94TL1577].

113

=..

O

112

cis/trans = 4:96

114

Aside from the epoxidation reactions, DMD is also a useful reagent for other interesting oxidative transformations. For example, Murray and Gu have studied the DMD-mediated hydroxylation of alkenes (e.g., 115--->116)and found that the reaction is facilitated by solvents with hydrogen bond donor properties. This pronounced effect led the authors to propose that site selectivity could be directed by pendant hydrogen bond donor groups on the substrate [94JCS(P2)451 ]. Another handy application of DMD is the very high yield preparation of vicinal triketones and related compounds (119) starting from 1,3-dicarbonyl compounds [94SC695]. 1tS~ H3H CH3

DMD = "-

/ ' ~ . . . ~ OC'H3 H ~~~CH3 CI 116 H

O

O

R'~~R,

TsN3

R~y" N2

117

3.4

,,,,O O

100

R'

o

o

R"~R' O

118

119

OXAZIRIDINES

Among this interesting class of heterocycles, perfluorodialkyloxaziridines (i.e., 120) have been shown to be versatile oxidizing agents for certain types of reaction. For example, 56-steroids 121 are hydroxylated in good yields with complete regio- and stereoselectivity to the corresponding 56-hydroxy derivatives lZZ [94JOC5511 ]. In addition, these reagents are useful for the enantioselective conversion of silanes (123) to silanols (124) [94TL6329] as well as for the controlled stepwise oxidation of sulfides 125 to sulfoxides 126 or sulfones 127 [94JOC2762]. 3

R1

I .R6

pO C3F7 ,, F,C4~'N : "'" ~'F =

~

120

H O ~ RI

.R3 S

I R.8 -4

Three-Membered Ring Systems

58

R1 R2'"~Si--H R3

120 ~

RI~ ~, R2'"~Si--uH R3

123

124

120 RISER '

~ 2.2 eq

125

0~_/I0 RI~R'

o

120 <

R~ ~R'

1.0 eq

127

126

Oxaziridines as substrates undergo an interesting photolytic rearrangement to ring expanded lactams, a transformation which appears to be accelerated by the presence of an aromatic ring within the substrate or by the addition of an external sensitizer [94JA6439]. This rearrangement has been used as a key step (i.e., 128--->129) in the total synthesis of yohimbine alkaloids [94JA9009]. CO2CH3

CO2CH3

H

H

O~ ~ ~ I P H

129

128

3.5

AZIRIDINES

3.5.1

Preparation of Aziridines

Tanner has recently published several important review articles dealing with the synthesis of chiral aziridines and their use as chiral auxilliaries and ligands [94ACIE599, 94TET9797, 94TL4631 ]. In addition, Evans has issued a retrospective on the very useful copper-catalyzed olefin aziridination reaction, in which electronrich and electron-deficient olefins undergo efficient aziridination using the nitrene precursor (N-(p-tolylsulfonyl)imino)phenyliodinane in the presence of soluble Cu(I) and Cu(II) salts [94JA2742]. R2 R1

Ts R3

PhI="NTs

M1

R3

Aziridine-2-carboxylic acid derivatives 133 may be prepared in a stereochemically predictable method by using the Oppolzer camphor sultam as a chiral auxilliary. The standard protocol of amine addition onto an alpha-bromoacrylate is imbued with stereodifferentiation by the face-selective alpha-protonation of enolate 131, a step which the chiral auxilliary dictates to occur in a si-fashion [94TL 1653].

59

Three-Membered Ring @stems

O

RNH2

H. ,H"O,:

si-protonation

=,..-

130

131

O

SN2

RHN'-'~

H

(~ "O 132

133

A method has been reported this past year for the direct synthesis of Ndiphenylphosphinyl (DPP) protected aziridines 135 from 2-aminoalcohols 134. The DPP group combines the advantanges of (1) activation of the aziridine ring towards nucleophilic attack and (2) subsequent ease of removal [94SL 145]. 1. DPPCI, Et3N, CH2CI2 R • O H .........

NH2

2. TsCI, Et3N, DMAP

Nail, THF "-

R~-- 7 N I

135

134

DPP

In a similar vein, Davis and co-workers have found the p-toluenesulfinyl group to be useful for such purposes. Aziridine-2-carboxylic acid derivatives 138 are prepared in high diastereomeric purity by a Darzens-type reaction of the lithium enolate of methyl bromoacetate (137) with enantiopure sulfinimines (e.g., 136) [94JOC3243]. These compounds have been employed as intermediates in the asymmetric synthesis of the antibiotic (+)-thiamphenicol (139) [94TL7525].

p: H p-Tolyl~S.,,N~.~Ar 136

3.5.2

OMo Br~OLi

,\

,co M.

H/~N4f~H

137 138

o 0H3SO2'~1~ I H'-~,,'~ CHCl2 OH

139;thlamphenicol

Reactions of Aziridines

Aziridines can be N-alkylated using a variety of base systems. A particularly mild environment is obtained by using potassium carbonate in the presence of 18crown-6, a mixture which avoids proton-catalyzed ring-opening sometimes observed under other conditions. For example, alkylation of aziridine 140 with benzyl bromide in triethylamine/tetrahydrofuran gives only 19% of the alkylated aziridine along with significant amounts of ring-opened product 142. Changing the base to K2CO3 (with 18-crown-6) increased the yield of intact 141 to 84% [94SC1121].

Three-Membered Ring Systems

60

BnBr N~'Bn OTBDPS ~ ~OTBDPS 140

Br + ~[,~~OTBDPSNBn2

141

142

As in the analogous epoxide reactions, ring-opening is often the desired transformation, especially when it occurs with concomitant C-C bond formation. These reactions often occur with high regioselectivity, although predicting the outcome is not always so easy. For example, the rigid aziridine 143 undergoes ring opening at C-2 by the soft nucleophile N-methylindole, even though this same nucleophile is known to react with other aziridine-2-carboxylic esters at C-3 under similar conditions. The observed regioselectivity in this orbital-controlled ring opening was rationalized on the basis of LUMO coefficients [94JOC434]. Alkylative ring opening can also be carried out using copper(I)-modified Grignard reagents. Thus, the DPP activated aziridine 146 underwent ring-opening without deprotection to give the phosphinyl amine 147 in 73% yield. This protocol could not be extended to aziridine-2-carboxylic esters, as attack at the carbonyl group competed [94TL2739].

CH30

~_.j

o

NI Ac

,•

c.,o

Me 144 BF3.Et20 ~

0 4

AcHN

7'

0

$

~

~ I Me

143

145

Ph~.~O ph~

/N\

EtMgBrCuBr.Et2S _

ar~~"

Ph.~p , ,HN ~ Ph II '" O Bn

146

147

The ring-opening reaction is not limited to carbon-based nucleophiles. For example, 1,2-diamines 150 may be prepared by the ytterbium triflate-catalyzed addition of amines to N-protected aziridines 148 [94TL7395]. In addition, certain Naryl and N-alkyl azifidines undergo reductive ring cleavage upon treatment with lithium powder in the presence of naphthalene to give dilithiates (e.g., 152) which can be subsequently alkylated with various electrophiles [94JOC3210]. R iI I

/N~R' + R/ 148

NR1R2NH

cat. Yb(OTf)3 ---

NHR" R'~~

R'

NR1R2

149 150

Three-Membered Ring Systems

Ph I /N\

Li, CloH6cat.

NPhLi

R/

61

E+ ,,.._

NHPh

152

151

153

With functionalized aziridines, eliminative ring-opening becomes a possibility. For example, 2-bromomethylaziridines 154 can be made to undergo radical induced opening either by treatment with tributyltin hydride in refluxing benzene [94SL287] or by reduction with a zinc-copper couple in methanol at room temperature under sonochemical conditions [94CC 1221 ]. The usual products are allylamines 156.

R1y R 2 /NN~.

R1yR2

n-Bu3SnH AIBN I--

R2

/N

154

156

155

N-Functionalized vinyl aziridines 157 undergo an interesting aza-[2,3]Wittig rearrangement upon treatment with LDA to form exclusively cis-2,6-disubstituted tetrahydropyridines 159. The observed results are rationalized by proposing a transition state conformation represented by structure 158, in which the tert-butyl acetate group and the alkene moiety are in a cis-like alignment while the vinylic group adopts an endo orientation [94JA9781 ].

R~.N'~/CO2t'Bu ~LDA

R J'J.LiL"O.....,,"~1~1.! 1

R1 157

~ R~N,~CO2t-Bu

._~

v

Ot-Bu

-- R1

159

158

Finally, Alper has reported the preparation of imidazolidinethiones 162 by the palladium(II)-catalyzed cyclization ofaziridines 160 and sulfur diimides. Through a mechanism not yet fully elucidated, the methylene carbon of the aziridine is incorporated into both the thiocarbonyl and methylene positions of the product in this fascinating palladium catalyzed reaction [94JA1220].

R / ~ R'

+

ArN=S=NAr 161

160

PdCI2(PhCN)2

flH s

t~ =R' 162

3.6

References

94ACIE599 94ACIE2212

D. Tanner, Angew. Chem., Int. Ed. Engl. 1994, 33, 599. A. Kirschfeld, S. Muthusamy, W. Sander, Angew. Chem., Int. Ed.

62

94ACR57 94CB 1441 94CC55 94CC1221 94CL157 94CL1259 94JA425 94JA986 94JA1220 94JA2742 94JA5973 94JA6439 94JA6937 94JA9009 94JA9333 94JA9781 94JCS(P2)451 94JOC434 94JOC1004 94JOC1518 94JOC1939 94JOC2204 94JOC2570 94JOC2733 94JOC2762 94JOC3210 94JOC3243 94JOC3341 94JOC4138 94JOC4311 94JOC4378 94JOC5511 94SC695 94SC 1121

Three-Membered Ring Systems

Engl. 1994, 33, 2212. W. Adam, M. J. Richter, Acc. Chem. Res. 1994, 27, 57. W. Adam, P. Klug, Chem. Ber. 1994, 127, 1441. M. M. Miller, D. C. Sherrington, J. Chem. Soc., Chem. Commun. 1994, 55. N. De Kimpe, R. Jolie, D. De Smaele, J. Chem. Soc., Chem. Commun. 1994, 1221. K. Okada, T. Katsura, H. Tanino, H. Kakoi, S. Inoue, Chem. Lett. 1994, 157. T. Nagata, K. Imagawa, T. Yamada, T. Mukaiyama, Chem. Lett. 1994, 1259. W. Zhang, N. H. Lee, E. N. Jacobsen, J. Am. Chem. Soc. 1994, 116, 425. T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116, 986. J. -O. Baeg, H. Alper, J. Am. Chem. Soc. 1994, 116, 1220. D. A. Evans, M. M. Faul, M. T. Bilodeau, J. Am. Chem. Soc. 1994, 116, 2742. V. K. Aggarwal, H. Abdel-Rahman, R. V. H. Jones, H. Y. Lee, B. D. Reid, J. Am. Chem. Soc. 1994, 116, 5973. A. J. Post, S. Nwaukwa, H. Morrison, J. Am. Chem. Soc. 1994, 116, 6439. S. Chang, J. M. Galvin, E. N. Jacobsen, J. Am. Chem. Soc. 1994, 116, 6937. J. Aub6, S. Ghosh, M. Tanol, J. Am. Chem. Soc. 1994, 116, 9009. M. Palucki, P. J. Pospisil, W. Zhang, E. N. Jacobsen, J. Am. Chem. Soc. 1994, 116, 9333. J. Ahman, P. Somfai, J. Am. Chem. Soc. 1994, 116, 9781. R. W. Murray, D. Gu, J. Chem. Soc., Perkin Trans. 2 1994, 451. L. Dubois, A. Mehta, E. Tourette, R. H. Dodd, J. Org. Chem. 1994,59, 434. D. C. Dittmer, Y. Zhang, R. P. Discordia, J. Org. Chem. 1994, 59, 1004. F. Benedetti, F. Berti, S. Fabrissin, T. Gianferrara, J. Org. Chem. 1994, 59, 1518. J. F. Larrow, E. N. Jacobsen, J. Org. Chem. 1994, 59, 1939. M. Martinelli, B. C. Peterson, V. V. Khau, D. Hutchison, M. R. Leanna, J. E. Audia, J. J. Droste, J. Org. Chem. 1994, 59, 2204. S. Y. Ko, M. Malik, A. F. Dickinson, J. Org. Chem. 1994, 59, 2570. W. Adam, M. Ahrweiler, K. Peters, B. Schmiedeskamp, J. Org. Chem. 1994, 59, 2733. D. D. DesMarteau, V. A. Petrov, V. Montanari, M. Pregnolato, G. Resnati, J. Org. Chem. 1994, 59, 2762. J. Almena, F. Foubelo, M. Yus, J. Org. Chem. 1994, 59, 3210. F. A. Davis, P. Zhou, G. V. Reddy, J. Org. Chem. 1994, 59, 3243. W. Adam, M. J. Richter, J. Org. Chem. 1994, 59, 3341. L. E. Overman, P. A. Renhowe, J. Org. Chem. 1994, 59, 4138. A. S. Pepito, D. C. Dittmer, J. Org. Chem. 1994, 59, 4311. B. D. Brandes, E. N. Jacobsen, J. Org. Chem. 1994, 59, 4378. A. Arnone, M. Cavicchioli, V. Montanari, G. Resnati, J. Org. Chem. 1994, 59, 5511. A..Saba, Synth. Commun. 1994, 24, 695. J. Ahman, P. Somfai, Synth. Commun. 1994, 24, 1121.

Three-Membered Ring @stems 94SC1959 94SL69 94SL129 94SL145 94SL255 94SL287 94SL356 94SL479 94SL507 94SYN111 94SYN225 94TET1261 94TET2219 94TET3663 94TET4311 94TET4323 94TET7629 94TET7809 94TET7943 94TET8885 94TET9797 94TL669 94TL941 94TL945 94TL1577 94TL1653 94TL2179 94TL2739 94TL3601 94TL4631 94TL5583 94TL6155 94TL6329 94TL6453 94TL6647 94TL6977 94TL7525

63

N. Iranpoor, F. Sh. Zasrdaloo, Synth. Commun. 1994, 24, 1959. M. Brunner, L. Mu6mann, D. Vogt, Synlett 1994, 69. C. Qian, D. Zhu, Synlett 1994, 129. H. M. I. Osborn, J. B. Sweeney, Synlett 1994, 145. R. Irie, N. Hosoya, T. Katsuki, Synlett. 1994, 255. N. De Kimpe, D. De Smaele, P. Bogaert, Synlett 1994, 287. H. Sasaki, R. Irie, T. Katsuki, Synlett. 1994, 356. T. Hamada, R. Irie, T. Katsuki, Synlett. 1994, 479. T. Katagiri, F. Obara, S. Toda, K. Furuhashi, Synlett 1994, 507. W. Adam, K. Peters, M. Sauter, Synthesis, 1994, 111. C. Bonini, G. Righi, Synthesis 1994, 225. M. Chini, P. Crotti, C. Gardelli, F. Macchia, Tetrahedron 1994, 50, 1261. G. Guanti, L. Banff, V. Merlo, E. Nadsano, Tetrahedron 1994, 50, 2219. K. Maruoka, N. Murase, R. Bureau, T. Ooi, H. Yamamoto, Tetrahedron 1994, 50, 3663. N. Hosoya, A. Hatayama, R. Irie, H. Sasaki, T. Katsuki, Tetrahedron 1994,50, 4311. E. N. Jacobsen, L. Deng, Y. Furukawa, L. E. Martinez, Tetrahedron 1994, 50, 4323. U. Koert, H. Wagner, M. Stein, Tetrahedron 1994, 50, 7629. K. Nishitani, Y. Harada, Y. Nakamura, K. Yokoo, K. Yamakawa, Tetrahedron 1994, 50, 7809. E. Doris, L. Dechoux, C. Mioskowski, Tetrahedron 1994, 50, 7943. P. Besse, H. Veschambre, Tetrahedron 1994, 50, 8885. D. Tanner, C. Birgersson, A. Gogoll, Tetrahedron 1994, 50, 9797. S. Chang, R. M. Heid, E. N. Jacobsen, Tetrahedron Lett. 1994, 35, 669. P. Pietik~iinen, Tetrahedron Lett. 1994, 35, 941. D. Mohajer, S. Tangestaninejad, Tetrahedron Lett. 1994, 35, 945. M. Kurihara, S. Ito, N. Tsutsumi, N. Miyata, Tetrahedron Lett. 1994, 35, 1577. P. Garner, O. Dogan, S. Pillai, Tetrahedron Lett. 1994, 35, 1653. C. Mukai, Y. Ikeda, Y. Sugimoto, M. Hanaoka, Tetrahedron 1994, 50, 2179. H. M. I. Osborn, J. B. Sweeney, Tetrahedron Lett. 1994, 35, 2739. S. Y. Ko, Tetrahedron Lett. 1994, 35, 3601. D. Tanner, P. G. Andersson, A. Harden and P. Somfal, M. Kurihara, S. Ito, N. Tsutsumi, N. Miyata, Tetrahedron Lett. 1994, 35, 4631 A. Kumar, D. C. Dittmer, Tetrahedron Lett. 1994, 35, 5583. A. Armstrong, P. A. Barsanti, P. A. Clarke, Tetrahedron Lett. 1994, 35, 6155. M. Cavicchioli, V. Montanari, G. Resnati, Tetrahedron Lett. 1994, 35, 6329. J. S. Panek, R. M. Garbaccio, N. F. Jain, Tetrahedron Lett. 1994, 35, 6453. E. F. Healy, J. D. Lewis, A. B. Minniear, Tetrahedron Lett. 1994, 35, 6647. X. Wang, B. Ramos, A. Rodriguez, Tetrahedron Lett. 1994, 35, 6977. F. A. Davis, P. Zhou, Tetrahedron Lett. 1994, 35, 7525.

Chapter 4 Four-Membered Ring Systems J. PARRICK and L. K. MEHTA Brunel University, Uxbridge, UK

4.1 INTRODUCTION This very selective review is drawn from a large number of papers describing four-membered ring heterocycles. The organisation of the review is similar to that of previous years with a special section devoted to 13-1actams at the end of the chapter. Books (92MI10000, 93M120000) devoted to the chemistry of this ring system have been published. In other areas, it is encouraging to find signs of more interest in azetidines, perhaps stimulated by the discovery of the explosive (1), and in oxetane and thietane chemistry. 4.2 AZETINES AND AZETIDINES

1-Azetin-4-one chemistry is reviewed (93AHC 171). 1,3,3-Trinitroazetidine (TNAZ) (1) has physical properties which are desirable if the compound is to be used as an explosive (93TL6677), though care is necessary in its preparation. TNAZ is obtained (30-50% yield) from N-tosyl-3-azetidinone oxime (2) (93TL6677, 94JHC271) and routes to this oxime are available from epichlorohydrin (94JHC271). 3-Amino-l,2-propanediol is readily converted into 3-ethyl- 1-azabicyclo[ 1.1.0]butane (3) (94JOC 1608) and its treatment with dinitrogen tetroxide, ethyl chloroformate and methanesulfonic acid anhydride gives (4), (5) and (6) respectively, but trifluoromethane sulfonic acid provides (7) (72%) and ozonolysis of (7) affords the ketone (8). Derivative (9) is known (94JOC1608). The reactions of (4) separately with nitrous acid, hydrazoic acid and tetrabutylammonium nitrate in the presence of 64

Four-Membered Ring Systems

65

triflic anhydride are known (94JOC5499). Novel fused systems include the bicyclic phosphonic acid esters (10) (93ZOB 1906) and the tricyclic azetidine (11, R = Boc and R = COAr) (93T5047). R2

NO2 O2N-~N_NO 2 HON~N--Tos (1)

~ N

(2)

//~N--R (3)

1

(4) R 1 = NO, R2 = ONO2 (5) R 1 = CO2Et, R2 = CI (6) R1 Mes,R2 = OMes I

MeHCk_~

O

NI----Tf (7)

-- Tf

q~N (8)

N ~ N - - NO2 (9) H

CO2Me .~ Ar

R--N Ph

O=P(OEt)2 (lO)

I

(ll)

Tos

Cyclic voltammetry of N-aryl diphenylketene imines (ArN:C:CPh2) gives a variety of products including (12) (93T6285). 2-Methyleneazetidines, readily obtainable form 4-chloro-3,3-dimethylbutan-2-one, undergo [3+2]cycloaddition of an azide (RN3) to yield the spiro-compounds (13). The triazoline (13) loses diazomethane readily to give the cyclic amidine (14) (94JOC5189). Other spiro-azetidines include (15) (94H 1879).

H

N

R Ph ~NAr ~ ~ N:mJ._ Ph rN I Ph - - N - A r U_.N_A R N-Ar Ph (13) (14) (12)

The

mechanism

of

I Me (15)

dealkoxycarbonylation

of

2-(3-

66

Four-Membered Ring @stems

azetidinyl)malonate (16, R = CO2Me) by chloride and cyanide ion has been studied (94TL3441). The chloride mediated process produces a 3-azabicyclo[3.1.0]hexan-2-one derivative while the azetidine ring is retained in the product (16, R = H) from the cyanide induced reaction. Investigations of the mechanism of nucleophilic attack on the 4-position of 1-protected 2-substituted-3azetidinols indicates that there is little carbocationic character at C-4 in the transition state when the 2-substituent is alkyl, but the cation character is more developed when the 2-substituent is phenyl (94JOC2172).

PhH2C -- Nr~~ j'~ CO2Me (16)

4.3 OXETANES AND THIETANES

The use of high pressure in the synthesis of oxetanes and thietanes is reviewed (92PJC 1535) and aspects of oxetane chemistry are discussed (94MI23). Photocycloaddition of silylenol ethers (RC(:CH2)OSiMe3) with benzaldehyde gives the 3-(silyloxy)oxetane (17) (45-72% yield) with excellent regiocontrol (except when R = Me) and a high degree of diastereoselectivity (93CB2457). The photocycloaddition of benzoquinone to 1-acetoxy-2-cyclohexylideneethane gives (90% yield) the oxetanes (18) and (19) in 9:1 ratio respectively (93TL3505). O

O

I Ph

,,, R OSiMe3 (17)

AcOH2C CH2OAc (18)

(19)

Ring opening of oxetanes with dinitrogen pentoxide gives dinitrates of 1,3-propanediol but 3-hydroxymethyl-3-methyloxetane gives the mononitrate (62%) (93T7051). Ring opening of 2-vinyloxetanes by tributylstannane involves a novel 1,6-butyltin group transfer from allylic carbon to alkoxy oxygen (93CC1152).

Four-MemberedRing @stems

67

(R)-4-Benzyloxy- and (R)-4-alkyloxycarbonyl-2-oxetanones are obtained in three steps from L-(S)-malic acid in high enantiomeric excess (>98%) (93TA1925). 4-Alkyl- and 4-phenyl2-oxetanones are obtained with up to 56% e.e. by asymmetric [2+2]cycloaddition of ketene to aldehydes catalysed by trimethylaluminium complexes of an axially chiral 1,1'-binaphthalene-2,2'diol derivative (94JCS(P1)1549). 2-Iminooxetanes are available from the ketene imines in a regiospecific reaction (93T4293). A one-pot preparation of 4-iodomethyloxetan-2-one is reported (93SL899). Electrochemically generated organometallic compounds react with ketones in a Reformatsky reaction to give esters or lactones (93AG1218) and the formation of 13-1actones is favoured when a sacrificial indium anode is used (94JOC3161). The stereoselective synthesis of spirolactones is achieved by [4+2]cycloaddition of 3-methylene-4-isopropyloxetan-2-one (21) with 1,3-dienes (93CB 1481). The addition of (21) to enantiomerically pure (20) gives the separable adducts (22) and (23) which, on separate thermolysis, undergo a retro-Diels-Alder process to yield the (S)- and (R)-forms of (21), respectively, each in 99% e.e. (93CB 1509). O Ph

U (20) :5

. (21) o

(23)

(22/

The rearrangement of 4-substituted oxetan-2-ones carrying an exocyclic ketone group (24) gives mainly cis-2,5-disubstituted tetrahydrofurans (93TL6997). However, the metal promoted rearrangement of spiro-ketone (25) gives 2(5H)-furanones and 2(3H)-furanones (94TL6737). Studies of the 2-oxetanones having inhibitory activity on 3hydroxy-3-methylglutaryl coenzyme A synthase (94CPB512) and investigations designed to probe factors affecting the hydrolytic stability of antibodies related to the naturally occurring (+)-

68

Four-Membered Ring Systems

obafluorin (26) are reported (94JOC3642).

0_~01 Ph

2,3 -(HO)2C6H3COHN~o O

0 O

0

(24)

(25)

4 -HOC6H4H2C (26)

(S)-2-Propylthietane (30) occurs as a natural secretion from the stoat. The Hofmann route to racemic (30) from the sulfone (27) by pyrolysis of the quaternary salt (28) gives the sulfone (29) (36%), whereas pyrolysis of the N-oxide (31) in the presence of Nhydroxypiperidine gives by Cope elimination the isomeric sulfone (32) (58%). The sulfone (29) is converted into (32) under the conditions use in the Cope reaction. The thietane (30) is obtained by reduction of the sulfones (93JHC873). Me !

C5HIoN~,"

7 C5H10N\

/Pr

(28)

Pr

(29)

/ Pr

Pr

L so I2

L SO (2

(27)

(30)

/

!

C5H10N~,.

/ Pr

L S0 I2 (31)

Pr

Uso2 (32)

Details of the diastereoselective synthesis of the bicyclic thietane (33) by solid-state photocyclization of an acyclic thioamide are available (94JOC3131). Photocycloaddition of 1,1-diphenylethene to 4-thioazetidin-2-one gives the adduct (34) which, on desulfurization, provides a route to 4-spirocyclopropyl fl-lactams (93TL5951) (see 4.7). Flash vacuum pyrolysis of vicinal substituted hydroxymethylbenzene thiols is used to obtain 2H,5H-benzo[1,2-b: 4,5-b]bisthiete (35) (60%) (94AG493). Similarly the thietes (36) and (37) are available from hydroxymethylnaphthalene thiols. Valence isomers of these thietes are thioquinone methides and examples of

69

Four-Membered Ring Systems

their cycloaddition products are given (94TL2161). H

Ph

Me X N

Ph

Ph S "-! LII I A I Ph N Ph 6" Pri (34)

S

I Me I [XMe (33)

(35)

(36)

(37)

4.4 DIAZETIDINES, DIOXETANES AND DITHIATANES

Phenyl isocyanate dimerises at high pressure in the presence of pyridine to give (38) in high yield (94NKK146). Singlet oxygenation of (39) at -78~ gives a useful yield of dioxetane (40, Ar = 3-MeOC6H 4) (94CC2449).

r> o,~Np

h

A r ~

(38)

Ar/~

(39)

(40)

The reaction of singlet oxygen with 2,3-disubstituted indoles yields labile dioxetanes but these are partially stabilized if the indole has an N-acyl substituent (93JOC47) and the products (e.g. 41, R 1 = Me, R 2 = Bu t) may then be isolated. Reduction of the dioxetane (41) with dimethyl sulfide gives the epoxide (42). The dioxetane (43) is photochemically decomposed with intense luminescence (93TL5247). R2

R2 o

I Ac (41)

Ac (42)

Ac (43)

Four-Membered Ring Systems

70

Tetrasubstitution of 1,3-dithietane 1,1,3,3-tetraoxide occurs in the presence of tetramethylammonium fluoride in acetonitrile by Michael addition of activated olefins (RCH=CH2, where R is electron withdrawing) (93ZOR574).

4.50XAZETIDINES, OXATHIETANES AND THIAZETIDINES A review of the chemistry of 1,2-oxazetidines containing 3or 4-oxo or 3- or 4-imino groups is published (93JHC579). The ring opening reactions of 2,4-disubstituted 1,2-oxazetidin-3-ones is utilized in the synthesis of acyclic and heterocyclic compounds (93PHA669). The spirosultones (e.g. 44) are produced by the addition of sulfur trioxide to the corresponding cycloalkylidenecycloalkene at low temperature (93RTC457). The addition of sulfur trioxide to perfluorovinylsulfonyl fluoride gives the 13-sultone (45) (94JFC101) and, in a similar way, perfluorovinylamines yield the bis(perfluoroalkyl)aminosultone (46) (94IC628). O- SO2

I I

II! (44)

F F

F F

O- SO2 (45)

O- SO2 (46)

The thiazetidine 1,1-dioxides (sultams) (47, R = OH, CI; n = 1 or 2) (93AP519) and the bicyclic systems (48, n = 1 or 2) are described (93AP437). The 4-methylene sultam (49) is also known (93MI18).

o s-NI-i X (CH2)R (47)

-(CH2)n H2C~'--IN ph (48) (49)

4.6 BORON, SILICON AND PHOSPHORUS HETEROCYCLES The naphtho[ 1,8-bc]borete (50) has been prepared, an X-ray crystal structure obtained and some of its reactions examined (94AG(E) 1247. The boretanes (51) have been obtained from olefins (94JOM25).

Four-Membered Ring Systems

NPr~ I

R1

\

/

R2

B[ - B [ Pr~N"

(51)

(50)

"NPr2i

71

S=~ [._ SiR2 (52)

The addition of silenes to styrene has been used to obtain silacyclobutenes (94ZN(B)831, 93CB2177) and also to produce a mixture of bicyclic silanonenes by the addition of a 1,1-dichlorosilene to cycloheptadiene through [2+2] and [4+2]cycloaddition processes (94AG(E)77). The flash vacuum pyrolysis of 1-vinylsilacyclobutanes gives siliranes (93ZN(B)l193). The results obtained from ab initio calculations of the conformation of (52, R = H) and electron diffraction experiments for (52, R = Me) have been compared (94MI853). Aryl isocyanides insert in the Si-Si bond in bicyclic 1,2-disilacyclobutanes (93JOM35). Macrocyclic compounds containing two 1-aza-3-silacyclobutane rings have been prepared and an X-ray crystal structure obtained (93CC1585). Ring expansion reactions of diazirines (94JA2159) and a phosphatriafulvene have been used to obtain the diaza-phosphetes (53) and imino-phosphetes (54), respectively (94TL1527). Highly stereoselective alkylation and halogenation of the carbanion from (54, R = H or Me) provide access to a wide range of optically pure cyclic phosphines of known stereochemistry (93T10291). Me

Bu t ~ But ]

NR 2 p~__R1

(53)

Me

P = menthyl Me O

(54) Thermolysis of (55) yields 1,2Z,5-azaphosphete (56), which undergoes reaction with boron trifluoride or methyl iodide with retention of the ring, while ring expansion reactions occur with isocyanates, isothiocyanates and acetylenedicarboxylates, and ring opening processes occur with water, carbon disulfide and pentafluorobenzonitrile. An X-ray crystal structure is available for (56, R = NPr2i) (94JA8087).

72

Four-Membered Ring Systems R

R.. oN-N~ R,P N MeO2C

(55)

!

R-P-N

.._

I--I

"-

MeO2C/

CO2Me

\CO2Me (56)

4.7 AZETIDINONES (I~-LACTAMS)

An important event in azetidin-2-one (13-1actam) chemistry is the publication of a book (93MI20000) containing reviews on novel methods for the construction of the 13-1actam ring (93MI257) and bicyclic 13-1actams (93MI121), the introduction and transformation of functional groups (93MI49) and on protective groups in 13-1actam chemistry (93MI1). In addition, a review of the preparation of 13lactams from sugars is available (941JC(B)913). The stereochemistry of products obtained from the addition of ketene to imines (the Staudinger reaction) depends upon a variety of factors (93MI295). 2-Aza-l,3-butadienes react with certain ketenes to provide excellent cis-stereoselectivity (93JOC5771). Enantiomerically pure 13-silyl substituted carboxylic acids are available and can provide precursors of ketenes (94JOC240). An efficient asymmetric synthesis of cis-4-formyl-3-substituted ~lactams from L-(+)-tartaric acid uses the diimine (57) to yield (58) (94JOC932). Microwave irradiation causes an increase in rate of Staudinger reactions (93BMC2363). The first asymmetric synthesis of 4-substituted azetidin-2,3-diones (59) uses the Evans-Sjoegren ketene (93TL6325).

>(O~ _ NRI R~, H ~ . = "" / R2 NR1

(57)

OJ

1~1

(58)

HO ~__~ .,,,,R O"

"C6H4OMe-4 (59)

The cycloaddition of ester enolates with imines is of continuing interest and potassium tert-butoxide may be used to generate the enolate (94S805) but more usually tin, titanium or zinc enolates are employed. When enolates are generated from 2pyridylthioesters, the stereochemistry of the tin enolate may be greater than and, in some cases, opposite to that for titanium enolates (94T5821). The effect of the lithium, zinc or titanium on the diastereoselectivity in addition reactions of the enolates of a-

73

Four-Membered Ring Systems

sulfenylacetates to a chiral imine has been reported (93BMC2343). Chlorozinc and zinc enolates are used in highly stereoselective routes to (60) (94T2939) and (61, R 2 = Ph, C=CPh, or C-CSiMe3), the last in a one-pot process (93BMC2351). The influence of the structure of the imine (94T2939) including the presence of chiral auxiliaries is explored (93TA 1441, 93TL6921). HO H2N

,,Ph Ph (60)

Et2N% CO2Me

.,,,

O~,__ I N "R1 (61)

Me SiMe3 (62)

An alternative use of imines in ~l-lactam formation is found in the catalyzed addition of an allyl phosphate (CH2=CHCH2OP(O)(OEt)2), an imine and carbon monoxide to give a 1,4-disubstituted-3-vinylazetidin-2-one (94JOC3040). An ab initio study of the alkene-isocyanate addition process predicts that the 13-1actam is formed through a concerted suprafacial mechanism (93CC1450). Chlorosulfonyl isocyanate adds to (allenylmethyl)silanes, e.g. ButMe2SiOCH2CMe=CH-CH2SiMe3, in a highly regioselective manner to give 3-methylene 13-1actams (62) (93BMC2405). The intramolecular cyclization route to a specific 13-1actam often depends on the availability of a 13-aminoester having the required stereochemistry. A review which considers the asymmetric synthesis of 13-aminoesters is available (94MI475). Ytterbium promoted addition of benzylamine to 2-alkenoic esters having a stereogenic centre at the )'-position (94CL827) and triphenyl borate mediated reaction of chiral imines with silylketene acetals have been utilised to give 13-aminoesters stereoselectively (93BMC2337). Cyclization of 13-aminoesters (93BMC2337) and 13-aminothioesters (93T10965) to 13-1actams is achieved with Grignard reagents. L-Aspartic acid esters undergo cyclization with titanium(IV) tetrabromide and provide (S)-4-alkoxycarbonyl 13lactams (94SC745). The tin(Ill) amide (Sn[N(SiMe3)2]2, prepared in situ, is a useful cyclizing agent for esters (93JA9417). Acids are activated and cyclized with N-[(chlorosulfinyl)oxy]methylene-Nmethylmethammonium chloride in the presence of base; the yields are better for secondary rather than primary amines (93BMC2419). In addition, (3-nitropyrid-2-yl)dialkylphosphates are useful cyclizing agents (93MI415). Mitsunobu cyclization of N-substituted 13-hydroxyamides

74

Four-Membered Ring Systems

has given 1,3-disubstituted (93BMC2423) and 1,3,4-tri-substituted 13-1actams, in the latter case the starting material was L-tartaric acid (93BMC2429). Hydroxamic acids carrying a 13-hydroxyl group and a hydroxylamine O-substituent are cyclized in a similar way to give, after N-deprotection, 3-substituted 13-1actams (93T7385). Sulfur controlled radical cyclization of N-ethenyl-tx-bromoalkanamides occurs in a 4-exo-trig manner to give the trans-3,4-disubstituted 13-1actam (93SL649). Rhodium catalyzed carbene insertion reactions are very useful for the preparation of bicyclic 13lactams but are little used to form monocyclic l~-lactams. High yields and exceptional stereocontrol are achieved when o~-diazoamides are decomposed in the presence of rhodium(lI) catalysts to give (63) (93BMC2409). O

O

O ]~N~CO2

~

N2

,•, ....[....~O Et 96% ,,~ EtO2C~

i~ut

N,But (63)

Further examples of ring expansion and ring contraction routes to 13-1actams are available. Regio- and stereo-selective carbonylation of an optically pure trans-2-vinylaziridine gives (64) (93BMC2415). ~ ' , ....~ O S i P h 2 B u t

" J ' ~ O / ~Nx R

N I R

OSiPh2But"

(64)

The cyclopropanone (65) on treatment with trimethylsilylazide, sodium azide and 15-crown-5 gives the azide (66), which is readily converted to the 13-1actam (67) in high yield (93JCS(P1)1553). O Me3Si q

~ SiMe3 (65)

Me3SiO

N3

Me3Si --

~,SiMe3 (66)

Me3Si ~ O"/

pSiMe3 ,, SiMe3 (67)

Photochemical ring contraction of the pyrazolidin-3-one (68) (93BMC2383) and the pyridone (70) (93CPB1885) gives the lactams (69) and (71) respectively.

Four-Membered Ring Systems

75

hv

0 :~N -NH

-- o~~, H,o

I

(69)

Ac (68)

MeO2C~ N ~ O hv

/ MeO2C

H

(7O)

Ill NH ~o (71)

Interest in spiro-13-1actams has increased. Compounds of the type (72, X = O, NR or S) are known (93T10229). Liquid phase thermolysis of (72, X = O, R = Ph) at 100~ in the presence of 4bromobutene gives the spiro-cyclopropane (73) (94JOC4090).

O

O R

R-

R N

N 'N-~ (72)

- N

R ~

Ph

- - - - ' ~ Br

(73)

Addition reactions of vinylazetidin-2-ones to give spiro compounds are known (93HCA2958). Other spiro compounds include (74) (94JHC565), some of which show promising activity as aldose reductase inhibitors and are of potential use in the prevention of secondary complications from diabetes (94JMC2059).

O R

NH O ~Me 0(74)

The utility of a 1-(p-nitrophenyl)-l,3-dihydroxy-2-propyl N-protecting group is described (93BMC2379). p-Methoxyphenyl N-protection is often employed but the deprotection reaction with

Four-Membered Ring Systems

76

ceric ammonium nitrate does not always proceed smoothly (94T4185) and (75) was unexpectedly obtained in one case (93T7803). Ac

HO

Ro R

..,

I

..,,V ~ S

N '~C6H4OMe- 4 OMe (75)

A 4-acetoxy substituent on a [3-1actam is replaced by thioacid salts in a zinc halide mediated reaction in non-protic medium (94TL3379) whereas copper salts and copper enolates are recommended for the replacement of a 4-phenylthio group (94TL5887). Intermolecular coupling reactions of 4-phenylseleno 13-1actams are used to prepare tribactams (94CC441). A CKNOWLEDGEMENTS We thank Drs. M. Porssa and C. J. G. Shaw for their helpful comments.

REFERENCES 92MI10000 92PJC1535 93AG1218 93AHC171 93AP437 93AP519 93BMC2337 93BMC2343 93BMC2351

'The Chemistry of 13-Lactams', ed. M. I. Page; Blackie Academic & Professional, Glasgow, 1992. D. Jenner; Pol. J. Chem., 1992, 66, 1535. H. Schick, R. Ludwig, K. H. Schwarz, K. Kleiner and A. Kunath;Angew. Chem., 1993, 105, 1218. A. M. Costero; Adv. Heterocycl. Chem., 1993, 58, 171. P. Schwenkkraus and H. H. Otto; Arch. Pharm. (Weinheim, Get.)., 1993,326, 437. P. Schwenkkraus and H. H. Otto; Arch. Pharm. (Weinheim, Get.)., 1993, 326, 519. Y. Hattori and H. Yamamoto; Bioorg. Med. Chem. Lett., 1993, 3, 2337. T. Fujisawa, D. Sato and M. Shimizu; Bioorg. Meal. Chem. Lett., 1993, 3, 2343. J. T. B. H. Jastrzebski and G. van Koten; Bioorg. Med. Chem. Lett., 1993, 3, 2351.

Four-Membered Ring Systems

77

93BMC2363

B. K. Banik, M. S. Manhas, S. N. Newaz and A. K. Bose;

93BMC2379

Bioorg. Med. Chem. Lett., 1993, 3, 2363. T. E. Gunda and F. Sztaricskai; Bioorg. Med. Chem. Lett.,

93BMC2383 93BMC2405 93BMC2409 93BMC2415 93BMC2419 93BMC2423 93BMC2429 93CB 1481 93CB 1509 93CB2177 93CB2457 93CC1152 93CC1450 93CC1585 93CPB 1885 93HCA2958 93JA9417 93JCS(P1)1553 93JHC579 93JHC873 93JOC47

1993, 3, 2379. J. D. White and S. G. Toske; Bioorg. Med. Chem. Lett., 1993, 3, 2383. E. W. Colvin, W. A. Koenig, M. A. Loreto, J. Y. Rowden and I. Tommasini; Bioorg. Med. Chem. Lett., 1993, 3, 2405. M. P. Doyle, S.-M. Oon, F. R. van der Heide and C. B. Brown; Bioorg. Med. Chem. Lett., 1993, 3, 2409. D. Tanner and P. Somfai; Bioorg. Med. Chem. Lett., 1993, 3, 2415. D. Prajapati and J. S. Sandhu; Bioorg. Med. Chem. Lett., 1993, 3, 2419. F. Farouz-Grant and M. J. Miller; Bioorg. Med. Chem. Lett., 1993, 3, 2423. M. Klich and G. Teutsch; Bioorg. Med. Chem. Lett., 1993, 3, 2429. W. Adam, S. Nava, O. Victor, E. M. Peters, K. Peters and H. G. yon Schnering; Chem. Ber., 1993, 126, 1481. W. Adam, V. O. Nava Salgado, B. Wegener and E. Winterfeldt; Chem. Ber., 1993, 126, 1509. N. Auner, C. R. Heikenwaelder and W. Ziche; Chem. Bet., 1993, 126, 2177. T. Bach and K. Joedicke; Chem. Ber., 1993, 126, 2457. S. Kim and K. M. Lim; J. Chem. Soc., Chem. Commun., 1993, 1152. F. P. Cossio, B. Lecea, X. Lopez, G. Roa, A. Arrieta and J. M. Ugalde; J. Chem. Soc., Chem. Commun., 1993, 1450. M. Driess and H. Pritzkow; J. Chem. Soc., Chem. Commun., 1993, 1585. H. Nakano and H. Hongo; Chem. Pharm. Bull,, 1993, 41, 1885. S. Guertler, M. Johner, S. Rub and H. H. Otto; Helv. Chim. Acta., 1993, 76, 2958. W.-B. Wang and E. J. Roskamp; J. Am. Chem. Soc., 1993, 115, 9417. K. Suda, K. Hotoda, F. lemuro and T. Takanami; J. Chem. Soc., Perkin Trans. 1, 1993, 1553. D. Moderhack; J. Heterocycl. Chem., 1993, 30, 579. A. D. Woolhouse, G. J. Gainsford and D. R. Crump; J. Heterocycl. Chem., 1993, 30, 873. X. Zhang, C. S. Foote and S. I. Khan; J. Org. Chem., 1993, 58, 47.

78

Four-Membered Ring Systems

93JOC5771

G. I. Georg, P. He, J. Kant and Z. J. Wu; J. Org. Chem., 1993, 58, 5771. M. Weidenbruch, E. Kroke, K. Peters and H. G. von Schnering; J. Organomet. Chem., 1993, 461, 35. H. Wild; The Organic Chemistry of fl [Beta]-Lactams, ed. G. L tTeorg, VCH, New York, 1993, 1. A. Zeroual, R. Jebli, N. Lahbabi, J. Chanet-Ray, R. Vessiere and M. Soufiaoui; J. Soc. Maroc. Chim., 1993, 2, 18. H. Wild; The Organic Chemistry of ~ [Beta]-Lactams, ed. G. I. Georg, VCH, New York, 1993, 49. J. Kant and D. G. Walker; The Organic Chemistry of [Betal-Lactams, ed. G. I. Georg, VCH, New York, 1993, 121. R. J. Ternansky and J. M. Morin Jr.; The Organic Chemistry of f~ [Beta]-Lactams, ed. G. I. Georg, VCH, New York, 1993, 257. G. I. Georg and V. T. Ravikumar; The Organic Chemistry of [Beta]-Lactams, ed. C,. L Georg, VCH, New York, 1993, 295. Y. H. Lee, C. H. Lee, J. H. Lee and W. S. Choi; Bull. Korean Chem. Soc., 1993, 14, 415. 'The Organic Chemistry of 13-Lactams', ed. G. I. Georg; VCH, New York, 1993. D. Geffken and A. Burchardt; Pharmazie, 1993, 48, 669. R. M. Schonk, C. W. Meijer, B. H. Bakker, S. Zoellner, H. Cerfontain and A. de Meijere; Recl. Trav. Chim. Pays-Bas., 1993, 112, 457. H. Ishibashi, C. Kameoka, A. Yoshikawa, R. Ueda, K. Kodama, T. Sato and M. Ikeda; Synlett, 1993, 649. A. C. Royer, R. C. Mebane and A. M. Swafford; Synlett, 1993, 899. G. Barbaro, A. Battaglia, P. Giorgianni and D. Giacomini; Tetrahedron, 1993, 49, 4293. D. P. Becker and D. L. Flynn; Tetrahedron, 1993, 49, 5047. J. Y. Becker and E. Shakkour; Tetrahedron, 1993, 49, 6285. P. Golding, R. W. Millar, N. C. Paul and D. H. Richards; Tetrahedron, 1993, 49, 7051. L. Banff, G. Guanti and E. Narisano; Tetrahedron, 1993, 49, 7385. F. Bertha, J. Fetter, M. Kajtar-Peredy, G. M. Keseru, K. Lempert, L. Parkanyi and J. Tamas; Tetrahedron, 1993, 49, 7803. M. Zoghbi and J. Warkentin; Tetrahedron, 1993, 49, 10229. A. Marinetti and L. Ricard; Tetrahedron, 1993, 49, 10291. L. Di Nunno and A. Scilimati; Tetrahedron, 1993, 49, 10965.

93JOM35 93MI1 93MI18 93MI49 93MI121 93MI257

93MI295

93MI415 93MI20000 93PHA669 93RTC457

93SL649 93SL899 93T4293 93T5047 93T6285 93T7051 93T7385 93T7803

93T10229 93T10291 93T10965

Four-Membered Ring Systems

93TA1441

93TA1925 93TL3505 93TL5247 93TL5951 93TL6325 93TL6677 93TL6921 93TL6997 93ZN(B)1193

79

H. L. van Maanen, J. T. B. H. Jastrzebski, J. Verweij, A. P. G. Kieboom, A. L. Spek and G. van Koten; Tetrahedron: Asymmetry, 1993, 4, 1441. S. Cammas, I. Renard, K. Boutault and P. Cuerin; Tetrahedron: Asymmetry, 1993, 4, 1925. M. A. Ciufolini, M. A. Rivera-Fortin and N. E. Byrne; Tetrahedron Left., 1993, 34, 3505. W. Adam, M. Ahrweiler, M. Sauter and B. Schmiedeskamp; Tetrahedron Lett., 1993, 34, 5247. H. Aoyama, H. Sagae and A. Hosomi; Tetrahedron Lett., 1993, 34, 5951. P. Claudio, J. M. Aizpurua, J. I. Miranda, A. Mielgo and J. M. Odriozolo; Tetrahedron Lett., 1993, 34, 6325. T. Axenrod, C. Watnick, H. Yazdekhashi and P. R. Dave; Tetrahedron Lett., 1993, 34, 6677. R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi and L. Raimondi; Tetrahedron Lett., 1993, 34, 6921. K. T. Mead and S. K. Pillai; Tetrahedron Lett., 1993, 34, 6997. J. Grobe and H. Ziemer; Z. Naturforsch., Teil B, 1993, 48, 1193.

93ZOB 1906 93ZOR574 94AG493 94AG(E)77 94AG(E)1247 94CC441 94CC2449 94CL827 94CPB512

94H1879 94IC628

P. P. Onys'ko, T. V. Kim, E. I. Kiseleva and A. D. Sinitsa; Zh. Obshch. Khim., 1993, 63, 1906. I. M. Bazavova, A. N. Esipenko, V. M. Neplyuev and M. O. Lozinskii; Zh. Org. Khim., 1993, 29, 574. H. Meier and A. Mayer; Angew. Chem., 1994, 106, 493. W. Ziche, C. Seidenschwarz, N. Auner, E. Herdtweck and N. Sewald; Angew. Chem., Int. Ed. Engl., 1994, 33, 77. A. Hergel, H. Pritzkow and W. Siebert; Angew. Chem., Int. Ed. Engl., 1994, 33, 1247. A. Padova, S. M. Roberts, D. Donati, A. Perboni and T. Rossi; J. Chem. Soc., Chem. Commun., 1994, 441. M. Matsumoto and H. Suganuma; J. Chem. Soc., Chem. Commun., 1994, 2449. S. Matsubara, M. Yoshiska and K. Utimoto; Chem. Lett., 1994, 827. H. Hashizume, H. Ito, K. Yamada, H. Nagashima, M. Kanao, H. Tomoda, T. Sunazuka, H. Kumagai and S. Omura; Chem. Pharm. Bull., 1994, 42, 512. J. Frohlich, F. Sauter and K. Blasl; Heterocycles, 1994, 37, 1879. A. Vij, R. L. Kirchmeier, J. M. Shreeve, T. Abe, H. Fukaya, E. Hayashi, Y. Hayakawa and T. Ono; Inorg. Chem., 1994, 33, 628.

80

94IJC(B)913 94JA2159 94JA8087 94JCS(P1)1549 94JFC101 94JHC271 94JHC565 94JMC2059 94JOC240 94JOC932 94JOC1608 94JOC2172 94JOC3040 94JOC3131 94JOC3161 94JOC3642 94JOC4090 94JOC5189 94JOC5499 94JOM25 94MI23 94MI475 94MI853 94NKK146

Four-Membered Ring @stems

Z. Kaluza, W. Abramski and M. Chmielewski; Indian J. Chem., Sect. B, 1994, 33B, 913. G. Alcaraz, A. Baceiredo, M. Nieger and G. Bertrand; J. Am. Chem. Soc., 1994, 116, 2159. K. Bieger, J. Tejeda, R. Reau, F. Dahan and G. Bertrand; J. Am. Chem. Soc., 1994, 116, 8087. Y. Tamai, M. Someya, J. Fikumoto and S. Miyano; J. Chem. Soc., Perkin Trans. 1, 1994, 1549. F. Forohar and D. D. DesMarteau; J. Fluorine Chem., 1994, 66, 101. A. R. Katritzky, D. J. Cundy and J. Chen; J. Heterocycl. Chem., 1994, 31, 271. M. S. Malamas; J. Heterocycl. Chem., 1994, 31, 565. M. S. Malamas and T. C. Hohman; J. Med. Chem., 1994, 37, 2059. C. Palomo, J. M. Aizpurua, M. Iturburu and R. Urchegui; J. Org. Chem., 1994, 59, 240. M. Jayaraman, A. R. A. S. Deshmukh and B. M. Bhawal; J. Org. Chem., 1994, 59, 932. A. P. Marchand, D. Rajagopal, S. G. Bott and T. G. Archibald; J. Org. Chem., 1994, 59, 1608. R. H. Higgins, W. J. Faircloth, R. G. Baughman and Q. L. Eaton; J. Org. Chem., 1994, 59, 2172. H. Tanaka, A. K. M. Hai, S. M. Abdul, H. Okumoto and S. Torii; J. Org. Chem., 1994, 59, 3040. M. Sakamoto, M. Takahashi, N. Hokari, T. Fujita and S. Watanabe; J. Org. Chem., 1994, 59, 3131. H. Schick, R. Ludwig, K.-H. Schwarz, K. Kleiner and A. Kunath; J. Org. Chem., 1994, 59, 3161. Y. Pu, C. Lowe, M. Sailer and J. C. Vederas; J. Org. Chem., 1994, 59, 3642. M. Zoghbi, S. E. Home and J. Warkentin; J. Org. Chem., 1994, 59, 4090. N. De Kimpe and M. Boeykens; J. Org. Chem., 1994, 59, 5189. A. P. Marchand, D. Rajagopal, S. G. Bott and T. G. Archibald; J. Org. Chem., 1994, 59, 5499. W. Madnggele, A. Heine, M. Noltemeyer and A. Meller; J. Organomet. Chem., 1994, 468, 25. C. J. Bums; Contemp. Org. Synth., 1994, 1, 23. M. North: Contemp. Org. Synth., 1994, 1,475. V. S. Masteryukov, L. V. Khristenko, L. V. Vilkov, Yu. A. Pentin and J. E. Boggs; Zh. Fiz. Khim., 1994, 68, 853. Y. Taguchi, A. Oishi, T. Tsuchiya and I. Shibuya; Nippon Kagaku Kaishi, 1994, 146.

Four-Membered Ring Systems 94S805 94SC745

94T2939 94T4185 94T5821 94TL1527 94TL2161 94TL3379 94TL3441 94TL5887 94TL6737 94ZN(B)831

81

G. Cainelli, M. Panunzio, D. Giacomini, B. Di Simone and R. Camerini; Synthesis, 1994, 805. M. Garcia-Alvarez, F. Lopez-Carrasquero, E. Tort, A. Rodriguez-Galao and S. Munoz-Guerra; Synth. Commun., 1994, 24, 745.

R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, F. Ponzini and L. Raimondi; Tetrahedron, 1994, 50, 2939. J. Fetter, L. T. Giang, T. Czuppon, K. Lempert, M. Kajtar-Peredy and G. Czira; Tetrahedron, 1994, 50, 4185. R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi and L. Raimondi; Tetrahedron, 1994, 50, 5821. W. Eisfield, M. Slany, U. Bergstrasser and M. Regitz; Tetrahedron Lett., 1994, 35, 1527. A. Mayer and H. Meier; Tetrahedron Lett., 1994, 35, 2161. W. Cabri, I. Candiani, F. Zadni and A. Bedeschi; Tetrahedron Lett., 1994, 35, 3379. P. J. Gilligan and P. J. Krenitsky; Tetrahedron Lett., 1994, 35, 3441. T. Shimamto, H. Inoue, T. Yoshida, R. Tanaka, T. Nakatsuka and M. Ishiguro; Tetrahedron Lett., 1994, 35, 5887. N. W. A. Geraghty and P. A. Murphy; Tetrahedron Lett., 1994, 35, 6737. N. Auner, C. Wagner and W. Ziche; Z. Naturforsch., Teil B, 1994. 49, 831.

Chapter 5.1 Five-Membered Ring Systems: Thiophenes & Se, Te Analogs RONALD K. RUSSELL

The R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA

and

JEFFERY B. PRESS

Emisphere Technologies Inc., Hawthome, NY, USA ,

5.1.1

i

i,ill i

i

INTRODUCTION The study of thiophenes has continued to receive significant attention during the period covered by this review (late 1993 and 1994). An increase in the number of thiophene derivatives under study in preclinical and clinical situations, further progress in superconductor research as well as continued need to understand the commercially important hydrodesulfurization (HDS) process underscore the importance of research on thiophene systems. The organization of this review follows that of the past, beginning with a discussion of electronic and physical properties of the thiophene ring and subsequent discussion of substitution and ring formation. The use of thiophene derivatives, both as intermediates as well as in various applications, is then discussed. The number of references to selenophene continues to be very modest and most of these references are incorporated into the pertinent sections in the discussion of thiophene chemistry. An interesting aspect of thiophene chemistry is the differences in reactivity between thiophene and its more aromatic isostere, benzene, and its less aromatic isosteres, furan and pyrrole. One interesting facet of this contrast is that metal cation-exchanged clay catalyzed Diels-Alder reactions work for furan and pyrrole to produce reaction with o~,~-unsaturated carbonyl compounds; the thiophene examples do not react <94JCS(Pl)761>. 5.1.2 E L E C T R O N I C S AND DESULFURIZATION Studies to further understand the electronic and spectral behavior of thiophene and its derivatives have continued. Vibrational spectroscopic studies of furan, pyrrole and thiophene have shown that earlier frequency assignments are correct and idealgas thermodynamic properties differ little from calorimetric data <94MI765>. Spin-spin couplings between 13C nuclei and 5-membered ring heteroaromatic ring systems may predict levels of aromaticity in these heterocycles. Of the 11 rings studied, only 1,2,3-thiadiazole, 1,3-thiazole and 1,2-thiazole are more aromatic than thiophene <94MI62>. The electronic structure of angular dithien,~pyridine isomers shows that they may be divided into two groups represented by I and 2. The mode of annelafion is reflected in bond lengths of both thiophene and pyridine rings <9MCS(P2)2045>. Further studies of b-side 82

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

83

contra c-side thiophene annelation to benzene or pyridine show electrophilic substitution, metallation and cycloaddition reactions occur at positions predicted by theoretical calculations <94JHC641>. Through-space interactions of phenylseleno- and phenylthio- moieties on 1,9-dibenzothiophene (3)cause significant distortion while dibenzofuran analogues are nearly planar <94JOC7117>. R1

1

2

R2

3

Studies of hydrodesulfurization (HDS) continue unabated. An excellent review of this process using transition metal complexes to remove sulfur (usually present as thiophene, benzo- and dibenzothiophene) from petroleum feed stocks discusses various mechanisms of heterogeneous HDS (for example, Scheme 1 depicts hydrogenolysis) <94MI287>. Another review models the HDS reaction of thiophene on a MoS2/AI203 catalyst at the molecular level <94JC288>. Fenske-Hall molecular orbital calculations for transition-metal complexes of thiophene show thiophene to be a poorer electron donor but better electron acceptor than cyclopentadienyl (Cp) complexes <94OM2628>. HDS of dibenzothiophene using Ni-Mo/AI203, Mo/AI203 and Ni/AI203 has been studied using a 35S label and shows that sulfur bonded to both Mo and Ni is more labile <94JC171>. Scheme 1

4-

s. I

E!I

Mo--- S - - - M o - - S -

s. ,

Mo

~

iT

s.

Mo--- S - - - M o - S -

Mo

sII

T

s

II M o - - S--- M o - S-- Mo

Chemistry studies of Ir, Co, Cr and Re complexes of thiophene have shown them as good model systems for HDS. Thermolysis of thiophene complex 4 produces thioallyl complex 5 by stereospecific endo migration. Further heating causes liberation of 2,5- and 2,3-dihydrothiophene and [(PPh3)2Ir(CO)3]PF6 <94OM721>. Reaction of TI4-benzene iridium complexes with benzo[b]thiophene produces the unprec~ented complex 6 which rearranges upon heating to a iridabenzothiabenzene complex <94JA4370>. Heating of [(C5Me5)IrH3]2 in thiophene gives a desulfurized cleavage product which liberates butadiene upon treatment with CO <94JA198>.

P 4

.,

,p

(D) H

5

S

84

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs

Reaction of Cp*Co(C2H4)2 with thiophene produces a C-S insertion product (Eq. 1) which further reacts with H2S to produce a butadienedithiolate complex <94JOM311>. Since thiophene and its derivatives are the most difficult to desulfurize during HDS, presumably due to aromaticity, Cr complexes of both thiophene and selenophene were studied; rotational barriers for 7 and its selenophene isostere are larger than for Cr(CO)3(q6-arene) complexes as a consequence of chromium-heteroatom interactions <94OM1821>. Bimetallic Re complexes of benzothiophene (8) protonate on the Re coordinated with sulfur <94OM179>. Reactions of q l(S)-coordinated thiophenes with base produce thienyl complexes which form thienylcarbene complexes upon acidification (Eq. 2) <94JA5190>. +

CP*C~ O~_

S

(

/'~

~

Eq. 1

Co--

Cp*

~O

Cp*

R--~C_r~'~ R

Re- CO

,,

CO

C III O

7

+

I

[Re]

]

,, de" CO Op ~CO

Base _

-H+

$

[Re]

o

_ ~_ .H§ .

[Re]

o] +

Re = Op(NO)(PPh3)Re

Eq. 2

5.1.3

RING SUBSTITUTION Substitution reactions may be effected on saturated analogues as well as on aromatic species. An interesting reaction of Tebbe's reagent with succinic thioanhydride derivatives 9 rapidly leads to monoolef'mation and, more slowly, to bisolefination. Acidic isomerization of the bis-adduct leads to 2,5-dimethyl thiophene derivatives (Eq. 3) <94JOC494>.

~,~R=~ O~'-~ S / ' ~ O

Cp'n(CHa)2 ....... ~

~

pTSA = ~ H3

R1

R2

Eq. 3 CH3

9

Electrophilic reactions on the electron-rich, aromatic thiophene nucleus continue to provide a powerful mute to substituted derivatives. Comparison of positional selectivity of the heteroarenium ions derived from furan, pyrrole or thiophene suggest that ease of [3-substitution correlates with the relative stabilities N + > S + > O + <94H2029>. Freidel-Crafts reaction of 2,5dichlorothiophene with aromatic compounds produces 10 which may be used as a precursor to 2,3-diaryl and 3,5-diaryl thiophene derivatives (Eq. 4) <94BCJ2187>.

Five-Membered Ring @stems: Thiophenes & Se, Te Analogs

85

Ar

AICla ~ / CI

CI

~CI" ~ S ~ 10

AICI3

Ar Ar

1. H~

SO2CI2

9

CI

Eq. 4 Ar

AICls

1

N-Halosuccinimides effectively halogenate thiophene using H + ion exchange or ultrasonic irradiation <94MI377>. Control of electrophilic phenylselenenylation of thiophene may lead to mono, di-, tri- or poly(phenylseleno)thiophenes which may be utilized synthetically <94T10549>. Reaction of perfluoroalkanesulfonyl chloride with thiophene catalyzed by RuCI2(PPh3)3 leads to 2-perfluoroalkylated derivatives with loss of SO2 <94SL69>. More detailed study of this reaction shows that it occurs with substituted benzenes and thiophenes but not with pyrroles <94JCS(P1)1339>. Electrophilic reaction of chlorosulfonylisocyanate with thiophene or indole produces N-chlorosulfonylamides which are converted to analogous nitrile derivatives by treatment with triethylamine <94T6549>. Nitrile ylide elcctrophilic reaction on thiophene leads to novel tricyclic derivatives (Eq. 5) <94JCS (Pl) 1193>.

Eq. 5 "C--N--" CPh

H

h

Methyl 4,5,6,7-tetrafluorobenzo[b]thiophene-2-carboxylate is oxidized by trifluoroperacetic acid or m-CPBA to form a 2,3-epoxysulfone; reaction with chlorine or sulfuryl chloride produces a 2,3-dichloride derivative <94JFC51>. HOF-MeCN is a novel oxidant which oxidizes a variety of thiophene derivatives to S,S-dioxides <94CC1959>. Bromination of thieno[c]fused 1,5-naphthyridines occurs with tetrabutylammonium perbromide <94H331> or with dibromoisocyanuric acid/sulfuric acid <94JHC521>. The ease of producing 2-1ithio- and 3-1ithiothiophene derivatives by halogen-metal exchange or by deprotonation leads to synthetically useful intermediates for a variety of reactions. Thus, 11, a precursor for electropolymerization reactions, forms by quenching 3-1ithiothiophene with the appropriate perfluoroalkyldimethylsilyl chloride <94AM637>. 3-Bromo-, 3,5dibromo- and 3,4,5-tribromo-2-thienyllithium derivatives form by brominelithium exchange and react with DMF to produce 2-carbaldehydes <94JCS (P1)2735>. Reaction of 2-thienyllithium with 2,3-O-isopropylidene-5O-trityl-D-ribofuranonse forms C-ribonucleoside i2 after deprotection <94CL265>. The 2-1ithio derivative of benzo[b]thiophene is exchanged for the 2magnesium bromide analogue which reacts with N-glycosyl nitrones to prepare (+)-(R)- and (-)-(S)-zileuton <94JOC6103>. 3-Lithiothiophene is stable in hexane at room temperature and reacts with diiodoethane, n-Bu3SiCl, (n-BuS-)2, allyl bromide and MeSSMe to give 3-iodo-, 3-tri-n-butylsilyl-, 3-n-butylthio-, 3-

86

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs

allyl and 3-methylthiothiophene, respectively <94TL3673>. Mercaptophosphonate 13 undergoes an S~C phosphonyl group migration after deprotonation with LDA <94TL3083>. 2,5-Dibromothiophene and dihalobenzene react with Rieke metals to form intexmediates which react further with a variety of electrophiles <94SC2379>. Directed lithiation of thiophene 2imidates occurs exclusively at the 5-position which contrasts to the 2-oxazoline directing influence at the 3-position <94T4149>. CHs I HO S,tCH2CH2(GF2)sGFs CHs q , ~ $ ~ S ~ P(O-I-Pr)=

~

11

HO OH

12

15 Metal catalyzed cross-coupling reactions are powerful tools in organic synthesis and work exceptionally well for thiophene and its derivatives. Molecular wires are prepared by itcrative divergent/convergentprocessesutilizing acctylenic derivatives such as 14 which form by CI2Pd(PPh3)2 coupling of 2iodo-3-ethyl thiophene and TMS acetylene <94PP202>. Palladium-catalyzed coupling of 2,5-dibromothiophene with ethyl acrylate produces 2,5-thiophene diacrylate <94H759>. Coupling of 2-iodothiophene derivatives with 1,2di(tributylstannylethene) catalyzed by palladium complexes produce 15, a precursor to elcctrochromic polymers <94SM223>. Similar coupling of stannyl allenes produces 2-allenylthiophene <94SC789>. 2-Stannyl thiophene derivatives also react; palladium-catalyzedcoupling with 4-iodoisoxazoles is a route to 3-thienyl-2,4-pentanediones <94SC709>. 2-Stannylthiophene also couples with pyrimidinyl triflates to produce 16 <94H501>. R

14

TMS

15

R1

R

16

S'-'u

Photochemical processes also produce coupling reactions. Bithienyl 17 forms by irradiating 3-(2-thienyl)allyl acetate with the corresponding 2substituted-5-iodothiophene; the alcohol fails to react <94JCS(PI)I245>. Photochemical coupling of indene with 5-iodo-2-nitrothiophene produces the unusual substitution of the nitro moiety to form 18 (75%) and 19 (25%) <94TL633>. Other photochemical reactions of 2-iodo-5-nitrothiophene in aromatic solvent produce the expected awl coupling at the 2-position <94G195>.

17

lS, X=I 19, X-, H Other means of forming biaryl derivatives include the use of zinc/silvergraphite reaction with aryl and heteroaryl (including thiophenyl) iodides

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

87

<94TL1047>. "Higher order" cuprates composed of one or two heteroaromatic ligands undergo oxidative coupling <94TL815>. 3-Thienyl zinc bromide couples with 4-alkylphenyl iodide to produce a compound that electmpolymerizes to form an isotropic conducting polymer <94TL8329>. Nucleophilic displacement reactions also produce substituted thiophene derivatives. Thus, potassium carbonate induced reaction of methyl 3hydroxyphenylacetate with 3-bromothiophene produces 20 <94JMC1402>. Similarly, 21 forms by alcohol displacement of the 2-chloro analogue <94M927>. When salicylates are used in this reaction, 21 is the precursor to thienoannellated [1,4]benzoxazepines <94JHC1053>. 2-Methoxy-3nitrothiophene derivatives react with amines to form 22 <94H1529>. Diether 23 forms by phenoxide displacement of the dichloro precursor and provides the basis of thiophene-based poly(arylene ether)s <94MI3782>. Conductive crown ether 24 forms by di-displacement of 3,4-dibromothiophene <94PP269>. Lastly, CsF provides the fluoride source to displace 3-chloro-2-cyanothiophene to produce the 3-fluoro derivative <94SC95>.

o

C02Me

OR

20 NO2

21

X ' ~ N(CH2). A r O ~ s ~0 23 22

OAr

24

5.1.4 T H I O P H E N E RING FORMATION Construction of the thiophcne ring may be accomplished utilizing sodium sulfide, phosphorus pentasulfide, sulfur dichloride or sulfur as the heteroatom source. Bromination of methyl neopentyl ketone produces a bromomethyl ketone which reacts with sodium sulfide; pinacol coupling then forms 2S <94TL2709>. 2,2'-Dilithio-l,l'-bicyclooctenyl reacts with sulfur dichloride to form 26 <94TL9197>. Lawesson's reagent reacts with diketones to form thiophene derivatives such as 27 <94JOC4308> or 28 <94JOC3695>. Reaction of phosphorus pentasulfide with 7-hydroxyketones affords dihydrothiophenes <94OPP349>. 3-Trifluoromethyl derivative 29 forms by reaction of P4S 10 with ~,3,-unsaturated ketones <94JFC13, 94H819>. Decomposition of a diazo compound in molten sulfur leads to a thione which reacts with additional diazo material to ultimately provide a dicyclo[b,d]thiophene derivative <94SL217>.

HOOH I

I

25

CH2.t.Bu /

~8__~ 26

Ph

P

Ph-

27

Ph9

88

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs

R1

28 Ph

F

29

Fs

C02Me

3O

Sulfur dioxide trapping of photochemically-generated quinodimethane leads to dihydrobenzo[c]thiophene derivatives (Eq. 6) <94TLA743>. Mercaptans may also provide the heteroatom source for the synthesis of thiophenes. The lithium salt of an isoquinolinethiol reacts with dimethyl acetylenedicarboxylate (DMAD) to form 30 <94JFC143>. 2-Mercaptoacetate forms a variety of thiophenes including 31 <94H1299> or thieno[2,3d]pyridazines <94S669>. Reaction with malonaldehyde derivatives gives 4-alkylor 4-aryl-2-thiophenecarboxylate products <94SC1721>. Utilizing benzenethiol, benzo[b]thiophene forms from a-bromoketones <94JCR(S)98>. Nitrothioacetamides react with a-bromoketones to form 2-amino-3-nitro-4substituted thiophenes <94H347>. 2-Ethoxycarbonylcyclopropyl(triphenyl)phosphonium fluoroborate reacts with thiolates to produce 4,5-dihydro-3thiophenecarboxylates (Eq. 7) which aromatize by the action of DDQ <94JCS(P1)2403>.

OR

0

OR

I~

H

OH

hv

OR

OH

H -

OR

Ph

/ N t o ~ E

NH2 C02Et

OR

Eq. 6

2

OR [

0

C02EI + . ~ _....~ PPhs BF4 MS R +

/,~

02Et

Eq. 7

R

-

31

Production of a thiophene ring from acetylene and its derivatives has led to a variety of interesting compounds. An excellent review of thiophene synthesis by heterocyclization gives an overview of catalytic preparations <941VII23>. An extremely interesting [3+2] dipolar cycloaddition of cc,J3-alkynyltungsten carbene complexes with 1,3-thiazolium-4-olates, the synthetic equivalent of thiocarbonyl ylide, gives thienyl tungsten carbene complexes (Eq. 8) <94CL859>. Compound 32 forms by reaction of 4-hydroxydithiocoumarin with propargyl halides <94LIC(B)216>. Arylmethylthiols react with 1,4-disubstituted 1,3-butadiynes to produce 2-aryl-3-benzyl-5-phenylthiophenes <94JOC4350>. Free radical addition of alkanethiols to alkynes give J3-thiovinyl radicals which ring-close to form thiophene derivatives <94JOC2818>. As an alternative to intermolecular condensation, detritylation of 33 by HBr provides a facile synthesis of 3bromothiophene derivatives (Eq. 9) <94TL9387>. Treatment of bis(propargylic)sulfidr with KOH causes rearrangement to a bis(allenic)sulfide

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs which ring closes <94TL1023>.

%W(CO)s MeO +

to a

3-vinylic thiophene by a diradical intermediate

.~~R2+O-

R1 Ph

S

0 R2,~N I~ R I ~ Ph

Ph

CHRR1 O

89

W(CO)5 OMe

= Ph" ~ S~ Ph Eq.8

N(CO)s Br

R/

\STr AcOH

Eq.9

33

32

Thermolysis of 2,5-dimethyl-3-hexyne-2,5-diol with elemental sulfur forms thieno[3,2-b]thiophene via the intermediacy of 2,5-dimethyl-1,5-hexadiene3-yne <94H143>. Similarly, reaction with selenium produces seleno[3,2b]selenophene. 1-Phenyl-l-benzothiophenium salts (35) form by acid-catalyzed ring closure of 1-[o-(phenylthio)phenyl]-2-(2-p-methoxyphenyl)ethyne (34) (Eq. 10) <94JCS(P1)1907>. Photocyclization of arylthiofluoro aromatic derivatives leads to the synthesis of benzo[b]thiophenes <94H1443>. Photolysis or thermolysis of 1,9-disubstituted dibenzochalcogenophenes produce dibenzo[bc, fg][1,4]dithia- and diselenapentalenes which were studied to determine their HOMO and LUMO <94H541>.

~SPh

(>

OMe

Ph I ~"

OMe Eq.10

Some examples of thiophene ring formation by ring contraction of larger rings have been reported. Treatment of 2,7-di-tert-butylthiepine with bromine gives either 36 or a thiopyran derivative depending on reaction conditions <94JCS(P1)2631>. Dithiin 37 is a kinetically stabilized disulfide and does not extrude sulfur to produce thiophene as is typical of dithiins but rather undergoes sulfur insertion to form a 1,2,3-trithiepine <94TL1973>.

3e

87

5.1.5 R I N G A N N E L A T I O N O N T H I O P H E N E Electrocyclic reactions provide a powerful tool for the creation of ring fused systems and the formation of thiophene rings is no exception. 3,4-Dimethylenetetrahydrothiophene (38) reacts with difluorocyclopropene to produce

90

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs

cyclopropa[f][2]benzothiophene 39 <94HCA1826>. The preparation of 4//- and 5H-thieno[3,4-c]pyrroles begins with the tricyclic material 40. Treatment of this material with tosic acid produces a thienopyrrole in situ which is trapped with Nphenylmaleimide to afford the adduct 41 <94JCS(P1)3065>. An efficient synthesis of benzothiophene analogues of 1-arylnaphthalene lignans relies on the in situ preparation of 2-substituted thieno[2,3-c]- and thieno[3,2-c]furan followed by Diels-Alder reaction with DMAD <94JOC7353>. 5,5-Dimethyl-5Hthieno[3,2-b]pyrans are reported to exist in equilibrium with their open form 42 <93JOC4629>. Further investigations show that these trienones undergo an Eto Z-isomerization when exposed to acid or iodine; however, when X = H, the Ztrienone forms a single dimeric product 43 (Eq. 11) <94JOC5088>.

CI

CI

38

R1

39

~

R1

'lN TsOH

Et02 O

40

42

---S

h

C02E t

jJ. =

o

NH+ R I = R 2 =

o

o

H

41

o.

0

11 43

Intramolecular electrocyclic reactions are also an excellent method to afford novel structures. Thermolysis of thiophene or benzothiophene alkynyl nitrones 44 gives either thienopyrrole 45 and/or thieno-a-pyridone 46 ~ products. The product ratio is strongly influenced by the terminal R substituent which suggests an oxo carbene as a pivotal intermediate (Eq. 12) <94CB247>. The hereto DielsAlder of thiophene or benzothiophene thioketones with a-bromoacrylic esters produces thieno- or benzothienothiopyrans 47 <94S727>. Flash vacuum pyrolysis of 5.methylthienyl benzoate affords 2,5-dimethylene-2,5dihydrothiophene. This material forms the dimeric and trimeric products 48 and 49 in degassed solutions. However, in solutions without exclusion of oxygen, the major product is the cyclic bisperoxide 50 <94TLA175>. Intramolecular cycloadditions onto the thiophene ring can be accomplished using a cobaltmediated process. Thus, the treatment of 51 with CpCo in bis(trimethylsilyl)acetylene produces either 52 or 53, depending on substiment R (Eq. 13). The conversion of 52 to 53 is postulated to occur by an enol ether "walk" mechanism <94JA11153>.

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

91

o

Eq 12

44 R2

R~

R2

R

B1

n s ~ N O

R,..=~ "S ~

.

R'

and/or

Me

45 R2

46

R2

R

H H H H H ,-Bu CH=CH-CH=CH H CH=CH-CH=CH t-Bu

E 0 I 0

0 I 0

R3

R1=R2 =H R1-R~'= CH=CH-CH=CH 47

48

SiMe3 ~ S i M e 3

49

SO ~ ~ ~ ~

SiMe3

51 53 Friedel-Crafts chemistry provides a convenient route to thienoquinolizidinones 54 or [1]benzothieno[b]quinolizidinone. These materials are converted by the Schmidt reaction or the Beckmann rearrangement of the corresponding oximes to the piperidino[1,2-a] [1,3]- or [1,4]diazepines fused to a thiophene ring <94JHC495>. 10H-Pyrrolo[ 1,2-a]thieno[3,4-e][ 1,4]diazepin5(4H)-one is prepared from carbonylazide 55 when exposed to AICI3 at 140 "C <94JHC341>. 8-H-Thieno[2,3-b]pyrrolizine derivatives 56 are prepared from the corresponding 2-thiophene-N-pyrrolidinocarboxamide <94JHC501>. Ketone 57 is prepared in 80% overall yield from 3-thienyl propionic acid. This material is used to prepared a dimer (McMurry conditions) that affords a conducting polymer with a rigidified structure <94CC2249>. An improved yield of thieno[2,3c]pyridine is realized when aceta158 was treated with concentrated hydrochloric acid in dioxane at reflux <94DDDl>.

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

92

0

H

S4

R

CON3

Ar

55

0

0

BeckmannProduct

SchmidtProduct

56

Tos

0

57

NH

OMo

58

Palladium-catalyzed coupling is also a well suited method for ring annelation of thiophene. Palladium-catalyzed coupling of 2-iodothiophene with homochiral N-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-oneunder a carbon monoxide atmosphere in the presence of TIOAc produces a mixture (1:1) of 59 and 60 <94TL3197>. The thiophene boronic acid derivatives 61 and 62 as well as the tin derivative 63 afford the thieno[c]-fused 13- and 1,8-naphthyridines when coupled with the necessary 3-amino-2-iodo- or 2-amino-3-bromopyridines <94JHC11>. Twelve thieno[b]fused naphthyridines are prepared by Pd(0)catalyzed coupling of thiophenes 64-66 with various trimethyltin pyridinecarboxaldehydes <94JHCl161>. The Pd(OAc)2 coupling of Nphenylsulfonyl compound 67 to spiroindoline 68 is accomplished in a modest 24-26% yield (Eq. 14). The addition of TIOAc (1 equivalent) to the Pd(II)coupling conditions produces 68 in 41% <94T359>. Other interesting fused thiophene derivatives are prepared by radical mediated cyclizations. Tributyltin hydride treatment of bromide 69 produces the mixture 70 in 59% yield (trans:cis = >5:1) <94TL5301>. Treatment of malonate 71 with various olefins and managanese (III) acetate produces 72. Examples of intramolecular cyclization are also reported <94SC1493>. O

..H

f/ S\ H

B(OH)~OH(;.

"no. J'Z40 59

~'~ 63

SnBu3

c"~

60

CHO

61

62

NHCO2t-Bu Br~NHCO2t-Bu ~

Br

Br 64

B(OH)2

NHCOit-Bu 65

66

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

iS02Ph~ - ~

PhO~% A

........

67

s

68

0Me

s

69

Eq. 14

~'~'~ N t S02Ph

I

0Me

_S

"~r

S02Ph

93

_

J~.. / CO2Me ' '

,~1~ "[ ~ \S~ CO,~ 71

70 ~

A

~'C02Me

C02ie

R 72

The photochemical ring closure of a l-chloronaphtho[2,l-b]thiophene derivative produces the complex heterocycle 73 (Eq. 15) <94JHC553>.

0 73 0 Other annelation reactions as well as bond reorganizations form interesting thiophene derivatives. Anion 74 was found not to cyclize to the desired dihydrothiepino[2,3-b]pyridine, but the thieno[2,3-h][1,6]naphthyridine forms instead as a result of anion rearrangement (Eq. 16). This material may be oxidized by DDQ to afford the thiophene analogue <94CC1767>.

C

,CN

a

~

H2N"

CN

CN~

S"

NH2

Eq. 16 ,>S N "~N

O2 7S

76

94

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

Carbon-carbon bond forming reactions are not the only method of forming fused thiophene derivatives. For example, 3-amino-2-carbomethoxythiophene is transformed to its 3-sulfonyl chloride derivative that is then converted to the thienoisothiazol-l,l-dioxide 7S <94PHA317>. Sequential treatment of 3,4diaminothiophene with phenyl isothiocyanate and tfimethylsilyl chloride in pyridine produces thienothiadiazole 76 <94H693>. Tetrathiafulvalene ~-electron donors 77 and 78 are both produced from the tosyl hydrazone of tetrahydrothiophen-3-one <94JOC3307>. A simple four step synthesis of [l]benzothieno[3,2-b]furan 79 starts with methyl thiosalicylate <93CCC2983>.

0~

77

78

79

5.1.6 T H I O P H E N E S AS I N T E R M E D I A T E S Extrusion of sulfur dioxide from oxidized thiophene derivatives is an exceptional method to prepare cis-~enes as components for Diels-Alder reactions. An example of this approach utilizes the Diels-Alder reactivity of the furan ring in substituted 4H,6H-thieno[3,4-c]furan.5,5-dioxides to react with a variety of dienophiles such as DMAD, dimethyl male.ate and dimethyl fumarate which then lose SO2 to form another reactive diene (Eq. 17) <94H961>. A review of the preparation and use of 4H,6H.thieno[3,4-c]furan-5,5-dioxides as well as other heteroaromatic-fused 3-sulfolenes is reported <94H1417>. The preparation of dihydrothienooxazole 80 requires the careful control of the reaction time and temperature as well as the reactants molar ratio <94JOC2241>. Specific control of the alkylation conditions for 81 (X = COCH3) allows for the preparation of either 1,4-disubstituted or 1,6-disubstituted 4H,6H-thieno[3,4-c]furan-5,5dioxides. These molecules could be used as intermediates for the preparation of novel pentacyclic compounds <94JCS(P1)1371>. R

-~ 02 81

+ S 02 80

~

,*UlX

Eq, 17

C02Me

The proper choice of substituents at the 2-position of the 2,5dihydrothiophene-1,1-dioxide ring system provides, after cheletropic expulsion of SO2, uniquely substituted bicyclic compounds. The preparation of bicyclic Tand 8-1actones 82 is accomplished in a modest yield from ester 83 <94MI448>. A similar strategy is used to prepare hexahydroindene and octahydronaphthalene ring systems 84 <94JOC2010>. The key synthetic step in an apoyohimbine synthesis was SO2 extrusion from a sulfolene starting material. The proper choice of reaction temperature and time was critical in optimizing the yield of an isoquinoline intermediate <94TL1071>. An example of a 3-substituted sulfolene-

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

95

1,1-dioxide is the pyridinium bromide 85. When this material is warmed to 140 "C, the diene 86 is formed in a quantitative yield and is stable at room temperature for over 1 month <94JOC4367>. S02Ph

0 O

n=0,1

0

02 ~..

A+

(CH2)n

82

O

m=1,2 x ,, H, TMS, PhS 84

83

H

O

H_ --

~

Ph- N

L

O

n

N- Ph O

Oz

S

R = S4Me3

85

86

87

Ph

88

The thiophene-l,l-dioxide moiety is also used as a diene in Diels-Alder reactions. These molecules react with dienophiles such as N-phenylmaleimide to produce disubstituted phthalimides or in some cases the bismaleimide adduct 87 <94T[A425>. When a bisthiophene crown ether is treated with MCPBA and Nphenylmaleimide, a bicyclic sulfoxide is isolated. When this material is treated with potassium permanganate, the SO moiety is oxidatively removed to form phthalimide crown ether 88 <94JCS(P1)2323>. The 2,5-disubstituted thiophene1,1-dioxide 89 reacts with piperidine at 100 "C to form the piperidine adduct 90 <94S40>. The addition of DMAD to thiophene 91 affords the quinoline compound 92 after bisaddition of the DMAD followed by bond reorganization and loss of MeS- <94JHC771>. Treatment of thieno[3,4-c][1]benzopyran 93 with dimethyl maleate or dimethyl fumarate produces the dimethylphthalate 94 after loss of H2S. However, when 93 is treated with DMAD a thiepine product is isolated instead <94JCS (P1)2191>. The acid-catalyzed rearrangement of dihydrothiophene carbinol 95 was found to be much slower than the corresponding dihydrofuran case and product distribution was dependent on the ring size of 9$ <94H187>. /

Me

SiMes Me3Si.,. ~ Me

4

02

Me ~

89

~

l

N" J

I

J. 90

NC

NH2

eS

CO2Me MeO2C" 91

SH

T

CO,

NH2

- N" 92

- CO2Me

96

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs c%Me ,~

NH2

-0"

" NH

95

93

5.1.7 I N T E R E S T I N G T H I O P H E N E D E R I V A T I V E S There are thiophcne derivatives with very interesting structures not easily categorized. For example, the air Sensitive naphtho[l,8.bc:4,5-b'c'idithiophene (96) was prepared by a bisintramolecular Wittig-Homer reaction. The electronic spectrum of 96 is contrasted to its isoelectronic hydrocarbon, pyrene, and isomer 97 <94CC1859>. The design and synthesis of a-oligothiophenes 98 allows for the investigation of intramolecular interactions. This cofacially oriented arrangement of thiophene rings along the pefi positions of naphthalene ring could provide insight into new molecular switches <94TL3957>. $

/F'3

S

s

98

McMurry coupling of selected dialdehydes allows for the synthesis of novel porphyfin-like and extended conjugated ring systems. Thioozaphyrin (99) is an example of a stable conjugated 22 ~-electron porphyrin-like molecule <94JOC2877>. The macrolido 100 is another example of a conjugated 22 ~ ring system. This is the first example of a neutral 22 ~ annulene that is comprised solely of thiopheno and methine units <94TL3493, 94JOC8071>. Extended electron delocalization is also present in the &cation 101; largely through the two i-PrS-C-C-C-SPr-i moieties <94JHC325>. Treatment of tri(2thicnyl)methane with 3.3 equivalents of LDA followed by Ar2C--O affords the corresponding triol. When this triol is dissolved in TFA and studied by 1H NMR, the dication is observed which shows considerable resonance contribution of the tetrapolar structure 102 <94CL1901>.

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

97

Pr

Pr

--:t['i'Pr~

SPr-i

2+

i

/-

r-i

r

(BF4-)2

100

99

101

Thiophene derivatives also form interesting metal complexes that are unrelated to the HDS process. The macrocycle trithienocyclotriyne CIVIC) was prepared by the Stephens-Castro coupling reaction of 3-ethynyl-2-iodothiophene (Eq. 18) and was compared by X-ray to tribenzocyclotriyne (TBC). TIC has a larger cavity than TBC which significantly alters the way TIC binds to transition metals such as cobalt <94OM451>. Ar S

H

__ is

+

Ar

$

102

Ar

s -2,py ,uxOIl

.....O

Ar

The preparation of thiophene-cyclopentadienone cooligomers 104 is accomplished by treating the bisalkyne 103 with 2,6-xylyl isocyanide (XyNC) in the presence of Ni(c~)2 (Eq. 19) <94CC229>. R R

R

R

R = CO2Et 103 The presence of a thiophone moiety in several biologically interesting molecules is noteworthy. The syntheses of the desmethyl (105) <94H783> and 5-hydroxy (106) <94T8699> analogues of the novel GABA reuptake inhibitor, tiagabine, are reported. The key intermediate in each report is the cyclopropyl alcohol 107. 3-Substituted thieno[2,3-b][1,4lthiazine-6-sulfonamides 108 are a novel class of topically active carbonic anhydrase inhibitors (CAIs). None of these compounds were as active as the thienothiopyran-2-sulfonamide clinical

98

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs

candidates MK-927 or MK-507 in the normotensive albino rabbit model <94JMC240>. R2

R1 $

R2

~ ~

~~~e's~'~HC

R1

~q,~~

I

N

S~ ~ "

CO,H ~

Me 105R1,R2- H

OH R " ~

"~

~~S S02NH2

R2 o~ S

Me

106 R~ = Me; R2 = OH

107

108

5.1.8 S E L E N O P H E N E S A N D T E L L U R O P H E N E S As mentioned in the introduction, very few examples to selenophene or tellurophene were reported this year. Metallacycle transfer from zirconium metallacycles such as to the corresponding selenophenes can be accomplished in "one-pot" synthesis (Eq. 20) <94JA1880>. Treatment of the dilithio intermediate 109 with either red selenium or tellurium powder affords the corresponding 1benzometalloles. The trimethylsilyl group is later removed with TBAF <94CPB 1437>.

Me

I.i 109

Me

Eq. 20

THF Me

Me

5.1.9 C O N D U C T I V I T Y A N D P O L Y M E R S The unique chemical and electronic properties of thiophene make it the subject of continued intense study for the design of low-gap polymers as organic conductors, molecular switches (electrochemical or photochemical), nonlinear optical devices as well as other electrochemical devices. Linearly-condensed polythiophenes, push-pull thiophenes connected by ethylene and acetylene bridges, 3-substituted oligothiophenes and thiophene-pyrrole mixed polymers are the subjects of most interest. Reviews that cover some of these topics are reported <94MI353, 94MI1893, 94H2069>. The brevity of this section is not an indication of low interest in the area but rather of space limitations. Polymerization and electrochemistry of thiophene and its derivatives represents the greatest single area of thiophene research as judged by the number of citations. Light-triggered electrical and optical switching devices such as push-pull thiophenes <94MCLC323>, carboxyalkyl or alkyl mercaptan containing benzothiophenes <94JA9894>, and polythiophenes <94CC2123> use the hexafluorocyclopentene backbone to place the bisthien-3-yl moiety in proximity such that a "switch" from open- to closed- form results upon irradiation. This "switching" causes extended conjugation and dramatic color changes. An extension of this theme is the preparation of dual mode switch compound 110 (Eq. 21) <94CC1011>.

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

F 2 ~

~

,~..~l F2~~.~~)..,.~ F2

UV(321nm) Ar~r~S/~

/ ' ~ S / --Ar

99

~

-(2e',2H+)

VIS(>600rim) JJ ~ ~ ~(2e',2H") F2 A r / ~ S " ~ -"S~'~"Ar

Ar -~ 1

1

0

~

O" "~

Eq.21

-:"

0

The push-pull (donor-acceptor) design is a typical approach for examining extended conjugation of organic metals. This concept is apparent in the thienothiophene I U <94CM2210>. Examples exist where the dicyano moiety is replaced with N,N-diethylthiobarbituric acid. This acceptor group enhances the second-order hyperpolarization by extended charge-separation <94MI485, 94CM1603>. The rigidity offered by the thienothiophene ring system as well as the cyclopenta[2,l.b;3,4-b']~thiophen-4-one moiety is often used to prepare polymeric derivatives <94JOC442> or novel monomers, such as 112 <94CC1765>. The 1,3-bis(2-thienylmethylene)thieno[3,4-c]thiophene ring system is prepared by Knoevenagel-type condensation of the starting 2-oxide with 2-thiophenecarbaldehyde. Reduction with 2-chloro-l,3,2-benzodioxaphosphole affords 113 which serves as a precursor for polymerization <93S634, 93SMI 193, 93CB 1487>. R O R

111

CN

R = SMe 112

S

CN

,......,.

NG

0"

NC

CN R

113

114

R = t-Buor Me 115

R

100

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

A series of benzobithiophene derivatives are electron accepters in chargetransfer complexes. Of the three isomers reported, 114 is the most stable and soluble <93SM1910, 94JOC3077>. [3]Radialene derivative 115 was also prepared as an electron accepter. Extensive delocalization of these molecules produces powerful accepters with E11/2 to be more positive by 0.2-0.25 V than the reference compound 2,5-bis(dicyanomethylene)-2,5-dihydrothiophene <94CC519>. A related t r i s [ 5 - ( 3 , 5 - d i - t - b u t y l - 4 - h y d r o x y p h e n y l ) - 2 thienyl]cycloproponylium ion is also reported <93CL911>.

5.1.10 REFERENCES 93CB 1487 93CCC2983 93CL911 93JOC4629 93S634 93SM1193 93SM1910 94AM637 94BCJ2187 94CB247 94CC229 94CC519 94CC1011 94CC1765 94CC1767 94CC1859 94CC1959 94CC2123 94CC2249 94CL265 94CL859 94CL1901

M. Hanack, U. Schmid, U. ROhrig, J.-M. Toussaint, C. Adant and J.L. Br&ias; Chem. Bet., 1993, 126, 1487. J. Svoboda, M. Nic and J. Palecek; Collect. Czech. Chem. Commun., 1993, 58, 2983. K. Komatsu, R. Tsuji, Y. Murata and K. Takeuchi; Chem. Left., 1993, 911. I.J. Turchi, J. B. Press, J. J. McNally, M. P. Bonner and K. L. Sorgi; J. Org. Chem., 1993, 58, 4629. M. Hanack, U. Schmid, S. Echinger, F. Teichert and J. Hieber; Synthesis, 1993, 634. H. Ritter, K.-M. Mangold, U. R6hrig, U. Schmid and M. Hanaek; Synth. Met., 1993, 55-$7, 1193. M. Fujii, Y. Aso, T. Otsubo and F. Ogura; Synth. Met., 1993, 5557, 1910. C. Thobie-Gautier, A. Guy, A. Gorgues, M. Jubault and J. Roncali; Adv. Mater., 1993, 5, 637. T. Sone, K. Sato, Y. Umetsu, A. Yoshino and K. Takahashi; Bull. Chem. Soc. Jap., 1994, 67, 2187. J. Bussenius, N. Laber, T. MOiler and W. Eberbach; Chem. Ber., 1994, 127, 247. K. Tamao, S. Yamaguchi and Y. Ito; J. Chem. Soc., Chem. Commun., 1994, 229. K. Takahashi and S. Tarutani; J. Chem. Soc., Chem. Commun., 1994, 519. S.H. Kawai, S. L. Gilat and J.-M. Lehn; J. Chem. Soc., Chem. Commun., 1994, 1011. H. Brisset, C. Thobie-Gautier, M. Jubault, A. Gorgues and J. Roncali; J. Chem. Soc., Chem. Commun., 1994, 1765. K. Sasaki, R. A. S. Shamsur, S. Kashino and T. Hirota; J. Chem. Soc., Chem. Commun.o 1994, 1767. K. Takimiya, T. Otsubo and F. Ogura; J. Chem. Soc., Chem. Commun., 1994, 1859. S. Rozen and Y. Bareket; J. Chem. Soc., Chem. Commun., 1994, 1959. T. Saika, M. lrie and T. Shimidzu; J. Chem. Soc., Chem. Commun., 1994, 2123. J. Roncali, C. Thobie-Gautier, E. H. Elandaloussi and P. Fr&e; J. Chem. Soc., Chem. Commun., 1994, 2249. M. Yokoyama, A. Toyoshima, T. Akiba and H. Togo; Chem. Lett., 1994, 265. I.Y. Jung, Y. J. Yoon, K. S. Rhee, G. C. Shin and S. C. Shin; Chem. Lett., 1994, 859. T. Kawase, C. Wei, N. Ueno and M. Oda; Chem. Lett., 1994, 1901.

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

94CM1603 94CM2210 94CPB1437 94DDD1 94G195 94H143 94H187 94H331 94H347 94H501 94H541 94H693 94H759 94H783 94H819 94H961 94H1299 94H1417 94H1443 94H1529 94H2029 94H2069 94HCA1826 94IJC(B)216 94JA198 94JA1880 94JA4370 94JA5190 94JA9894 94JAl1153 94JC171

101

S. Gilmour, R. A. Montgomery, S. R. Marder, L.-T. Cheng, A. K.-Y. Jen, Y. Cai, J. W. Perry and L. R. Dalton; Chem. Mater., 1994, 6, 1603. V. P. Rao, K. Y. Wong, A. K.-Y. Jen and K. J. Drost; Chem. Mater., 1994, 6, 2210. J. Kurita, M. Ishii, S. Yasuike and T. Tsuchiya; Chem. Pharm. Bull., 1994, 42, 1437. J. H. Wikel, K. G. Bends, K. Kurz, M. L. Denney, B. W. Main, R. A. Moore, T. Smith, L. Shingleton and D. R. Holland; Drug Des. Discovery, 1994, 11, 1. M. D'Auria; Gazz. Chim. Ital., 1994, 124, 195. K. S. Choi, K. Sawada, H. Dong, M. Hoshino and J. Nakayama; Heterocycles, 1994, 38, 143. L. A. Paquette, U. Dullweber and B. M. Branan; Heterocycles, 1994, 37, 187. J. Maim, A. B. HOrnfeldt and S. Gronowitz; Heterocycles, 1994, 37, 331. K. V. Reddy and S. Rajappa; Heterocycles, 1994, 37, 347. J. Sandosham and K. Undheim; Heterocycles, 1994, 37, 501. T. Kimura, Y. Ishikawa, Y. Minoshima and N. Furukawa; Heterocycles, 1994, 37, 541. S. Tanaka, M. Tomura and Y. Yamashita; Heterocycles, 1994, 37, 693. G. Karminski-Zamola, J. Dogan, M. Bajic, J. Blazevie and M. Malesevic; Heterocycles, 1994, 38, 759. M. S. Chorghade, P. Ellegaard, E. C. Lee, H. Petersen and P. O. Sorensen; Heterocycles, 1994, 37, 783. K. Burger, B. Helmreich V. Y. Popkova and L. S. German; Heterocycles, 1994, 39, 819. T. Suzuki, K. Kubomura and H. Takayama; Heterocycles, 1994, 38, 961. C. Peinador, M. C. Veiga, J. Vilar and J. M. Quintela; Heterocycles, 1994, 38, 1299. K. Ando and H. Takayama; Heterocycles, 1994, 37, 1417. Z. Jiang and J. Marquet; Heterocycles, 1994, 37, 1443. C. Arnone, G. Consiglio, V. Frenna, E. Mezzina and D. Spinelli; Heterocycles, 1994, 37, 1529. L. I. Belen'kii; Heterocycles, 1994, 37, 2029. G. A. Pagani; Heterocycles, 1994, 37, 2069. P. MOiler and Z. Miao; Heir. Chim. Acta, 1994, 77, 1826. K. C. Majumdar, S. Saha and A. T. Khan; Indian Y. Chem., Sect. B, 1994, 33B, 216. W. D. Jones and R. M. Chin; J. Am. Chem. Soc., 1994, 116, 198. P. J. Fagan, W. A. Nugent and J. C. Calabrese; Y. Am. Chem. Soc., 1994, 116, 1880. C. Bianchini, A. Meli, M. Peruzzini, F. Vizza, S. Moneti, V. Herrera and R. A. S~chez-Delgado; Y. Am. Chem. Soc., 1994, 116, 4370. M. J. Robertson, C. J. White and R. J. Angelici; J. Am. Chem. Soc., 1994, 116, 5190. M. Lie, O. Miyatake, K. Uehida and T. Eriguchi; J. Am. Chem. Soc., 1994, 116, 9894. R. Boese, D. F. Harvey, M. J. Malaska and K. P. C. Vollhardt; J. Am. Chem. Soc., 1994, 116, 11153. T. Kabe, W. Qian and A. Ishihara; Y. Cata/., 1994, 149, 171.

102

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

94JC288 94JCR(S)98 94JCS(Pl)761 94JCS(Pl)l193 94JCS(P1)1245 94JCS(P1)1339 94JCS(Pl)1371 94JCS(Pl)1907 94JCS(Pl)2191 94JCS(P1)2323 94JCS(Pl)2403 94JCS(Pl)2631 94JCS(P1)2735 94JCS(P1)3065 94JCS(P2)2045 94JFC13 94JFC51 94JFC143 94JHC11 94JHC325 94JHC341 94JHC495 94JHC501 94JHC521 94JHC553 94JHC641 94JHC771 94JHC1053 94JHCl161 94JMC240

E. Diemann, T. Weber and A. MUller; Y. Cata/., 1994, 148, 288. J. Zhu, N. Srikanth, $. C. Ng, O. L. Kon and K. Y. Sire; J. Chem. Res. (S), 1994, 98. J.M. Adams, S. Dyer, K. Martin, W. A. Matear and R. W. McCabe; J. Chem. $oc., Perk,in Trans. 1, 1994, 761. H. Finch, D. H. Reece and J. T. Sharp; J. Chem. $oc., Perkin Trans. 1, 1994, 1193. A. D'Agostini and M. D'Auria; J. Chem. $oc., Perkin Trans. 1, 1994, 1245. N. Kamigata, T. Ohtsuka, T. Fukushima, M. Yoshida and T. Shimizu; J. Chem. $oc., Perkin Trans. 1, 1994, 1339. K. Konno, Y. Kawakami, T. Hayashi and H. Takayama; J. Chem. $oc., Perkin Trans. 1, 1994, 1371. T. Kitamura, T. Takachi, M.-a. Miyaji, H. Kawasato and H. Taniguchi; J. Chem. Soc., Perk.in Trans. 1, 1994, 1907. E. Nyiondi-Bonguen, E. Sopbu6 Fondjo, Z. Tanee Fomum and D. DOpp; J. Chem. Soc., Perk.in Trans. 1, 1994, 2191. Y.Q. Li, T. Thiemann, T. Sawada and M. Tashiro; J. Chem. Soc., Perk,in Trans. 1, 1994, 2323. P. Chatterjee, P. J. Murphy, R. Pepe and M. Shaw; J. Chem. Soc., Perkin Trans. 1, 1994, 2043. S. Yamazaki, A. Isokawa, K. Yamamoto and I. Murata; J. Chem. $oc., Perkin Trans. 1, 1994, 2631. D. W. Hawkins, B. Iddon, D. S. Longthome and P. J. Rosyk; J. Chem. Soc., Perkin Trans. 1, 1994, 2735. C.-K. Sha and C.-P. Tsou; J. Chem. Soc., Perkin Trans. 1, 1994, 3065. W. A. Brett, P. Rademacher, R. Boese, S. Gronowitz and Y. Yang; J. Chem. $oc., Perkin Trans. 2, 1994, 2045. K. Burger, B. Helmreich and O. Jendrewski; J. Fluorine Chem., 1994, 66, 13. I.M. Shirley; J. Fluorine Chem., 1994, 66, 51. G.M. Brooke and C. J. Drury; J. Fluorine Chem., 1994, 67, 143. J. Maim, B. Rehn, A.-B. H6rnfeldt and S. Gronowitz; J. Heterocycl. Chem., 1994, 31, 11. A. Tsubouchi, H. Inoue and K. Yanagi; J. Heterocycl. Chem., 1994, 31, 325. A. Daich, J. Morel and B. Decroix; J. Heterocycl. Chem., 1994, 31, 341. S. Marchalin and B. Decroix; J. Heterocycl. Chem., 1994, 31, 495. J.-C. Lancelot, B. Letois, S. Rault, M. Robba and M. Rogosa; J. Heterocycl. Chem., 1994, 31, 501. J. Malta, A. B. H6rnfeldt and S. Gronowitz; J. Heterocycl. Chem., 1994, 31, 521. M.J. Musmar and R. N. Castle; J. Heterocyci. Chem., 1994, 31, 553. S. Gronowitz; J. Heterocycl. Chem., 1994, 31, 641. Y. Tominaga, J.-K. Luo and R. N. Castle; J. Heterovycl. Chem., 1994, 31, 771. I. Laimer and T. Erker; J. Heterocycl. Chem., 1994 31, 1053. P. Bj~rk, A.-B. H6rnfeldt and S. Gronowitz; J. Heterocycl. Chem., 1994, 31, 1161. C.A. Hunt, P. J. Mallorga, S. R. Michelson, H. Schwam, J. M. Sonde),, R. L. Smith, M. F. Sugrue and K. L. Shepard; J. bled. Chem.,

Five-Membered Ring @stems: Thiophenes & Se, Te Analogs

94JMC1402

94JOC442 94JOC494 94JOC2010 94JOC2241 94JOC2818 94JOC2877 94JOC3077 94JOC3307

94JOC3695 94JOC4308 94JOC4350 94JOC4367 94JOC5088 94JOC6103 94JOC7117 94JOC7353 94JOC8071 94JOM311 94M927 94MCLC323 94MI23 94MI62 94MI287 94MI353 94MI377 94MI448 94MI485 94MI765

103

1994, 37, 240. J. J. Kulagowski, R. Baker, N. R. Curtis, P. D. Lesson, I. M. Mawer, A. M. Moseley, M. P. Ridgill, M. Rowley, I. Stansfield, A. C. Foster, S. Grimwood, R. G. Hill, J. A. Kemp, G. R. Marshall, K. L. Saywell and M. D. Tricklebank; J. Med. Chem., 1994, 37, 1402. M. Kozaki, S. Tanaka and Y. Yamashita; J. Org. Chem., 1994, 59, 442. M. J. Kates and J. H. Schauble; J. Or&. Chem. Soc., 1994, 59, 494. S.-S. P. Chou, C.-S. Lee, M.-C. Cheng and H.-P. Tai; J. Org. Chem., 1994, 59, 2010. T. Chou, H.-C. Chen and C.-Y. Tsai; J. Org. Chem., 1994, 59, 2241. L. Benati, L. Capella, P. C. Montevecchi and P. Spagnolo; J. Org. Chem., 1994, 59, 2818. D. C. Miller, M. R. Johnson and J. A. Ibers; J. Org. Chem., 1994, 59, 2877. S. Yoshida, M. Fujii, Y. Aso, T. Otsubu and F. Ogura; J. Org. Chem., 1994, 59, 3077. C. Rovira, J. Veciana, N. Santal6, J. Tarr6s, J. Cirujeda, E. Molins, J. Llorca and E. Espinosa; J. Org. Chem., 1994, 59, 3307. F. Freeman, M. Y. Lee, H. Lu, X. Wang and E. Rodriguex; J. Org. Chem., 1994, $9, 3695. J. P. Parakka, E. V. Sadanandan and M. P. Cava; J. Org. Chem., 1994, $9, 4308. F. Freeman, H. Lu, Q. Zeng and E. Rodriguez; J. Org. Chem., 1994, 59, 4350. S.-J. Lee, C.-J. Chien, C.-J. Peng, I. Chao and T. Chou; J. Or&. Chem., 1994, 59, 4367. J. B. Press, K. L. Sorgi, J. J. McNally and G. C. Leo; J. Or&. Chem., 1994, 59, 5088. A. Basha, R. Henry, M. A. McLaughlin, J. D. Ratajczyk and S. J. Wittenberger; J. Org. Chem., 1994, 59, 6103. T. Kimura, Y. Ishikawa, K. Ueki, Y. Horie and N. Furukawa; J. Org. Chem., 1994, 59, 7117. T. Kuroda, M. Takahashi, T. Ogiku, H. Ohmizu, T. Nishitani, K. Kondo and T. Iwasaki; J. Org. Chem., 1994, 59, 7353. Z. Hu, J. L. Atwood and M. P. Cava; J. Org. Chem., 1994, 59, 8071. W. D. Jones and R. M. Chin; J. Organomet. Chem., 1994, 472, 311. I. Puschmann and T. Erker; Monatsh.Chem., 1994, 125, 927. S. L. Gilat, S.H. Kawai and J.-M. Leh; Mol. Cryst. Liq. Cryst. Sci. Technol., Sect. A, 1994, 246, 323. M. A. Ryashentseva; Rev. Heteroat. Chem., 1994, 10, 23. M. Witanowski and Z. Biedrzycka; Magn. Reson. Chem. 1994, 32, 62. R. A. S~chez-Delgado; J. Mol. Catal., 1994, 86, 287. P. Otto; Int. J. Q.uan:wn Chem., 1994, 52, 353. Y. Goldberg and H. Alper; ]. Mol. CoJal., 1994, 88, 377. H. W. Lee, W. B. Lee and I.-Y. C. Lee; Bull. Korean Chem. Soc., 1994, 15, 448. S. Gilmour, A. K.-Y. Jen, S. R. Marder, A. J. Neissink, J. W. Perry, J. Skindhoej and Y. M. Cai; Mater. Res. Soc. Syrup. Proc., 1994, 328, 485. T. D. Klots, R. D. Chirico and W. V. Steele; Spectrochim. Acta, Part

104

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

94MI1893 94MI3782 94OM179 94OM451 94OM721 94OM1821 94OM2628 94OPP349 94PHA317 94PP202

94PP269 94S40 94S669

94S727 94SC95 94SC709 94SC789 94SC1493 94SC1721 94SC2379 94SL69 94SL217 94SM223 94T359 94T4149 94T6549 94T8699 94TI0549 94TL633 94TL815

94TL1023 94TL1047

A, 1994, $0A, 765. T. M. Swager, M. J. Marsella, Q. Zhou and M. B. Goldf'mger; J. Macromol. Sci., Pure Appl. Chem., 1994, A31, 1893. V. V. Sheares, J. M. DeSimone, J. L. Hedrick, K. R. Carter and J. W. Labadie; Polymer, 1994, 35, 3782. M. J. Robertson, C. L. Day, R. A. Jacobson and R. J. Angelici; Organometallics, 1994, 13, 179. D. Soloold, J. D. Bradshaw, C. A. Tessier and W. J. Youngs; Or&anometallics, 1994, 13, 451. C. Bianchini, A. Meli, M. Peruzzini, F. Vizza, V. Herrera and R. A. Sfmchez-Delgado; Organometallics, 1994, 13, 721. M. J. Sanger and R. J. Angelici; Or&anometaUics, 1994, 13, 1821. S. Harris; Organometallics, 1994, 13, 2628. S. P. Rajendran and P. Shanmugam; Or&. Prep. Proced. Int., 1994, 26, 349. B. Unterhalt and S. Moghaddam; Pharmazie, 1994, 49, 317. D. L. Pearson, J. S. Schmmn, L. Jones, II and J. M. Tour; Polym. Prepr. 1994, 35, 202. L. K. Bicknell, M. J. Marsella and T. M. Swager; Polym. Prep., 1994, 35, 269. S. Gronowitz, A.-B. HOmfeldt, E. Lukevics and O. Pudova; Synthesis, 1994, 40. V. Dal Piaz, G. Ciciani and M. P. Giovannoni; Synthesis, 1994, 669. T. Saito, T. Shizuta, H. Kikuchi, J. Nakagawa, K. Hirotsu, H. Ohmura and S. Motoki; Synthesis, 1994, 727. A. El Kassmi, F. Fache and M. Lemaire; Synth. Commun., 1994, 24, 95. S. S. Labadie; Syrah. Cornmun., 1994, 24, 709. I. S. Aidhen and R. Braslau; Synth. Commun., 1994, 24, 789. C.-P. Chuang and S.-F. Wang; Synch. Commun., 1994, 24, 1493. G. Kitsch and D. Prim; Synth. Commun. 1994, 24, 1721. M. S. Sell, M. V. Hanson and R. D. Rieke; Synth. Commun. 1994, 24, 2379. N. Kamigata, T. Ohtsuka and T. Shimizu; Sulfur Lett., 1994, 17, 69. A. Senning, T. B. Christensen, V. K. Belsky and E. Zavodnik; Sulfur Lett., 1994, 17, 217. M. Catellani, S. Luzzati, A. Musco and F. Speroni; Synth. Met., 1994, 62, 223. R. Grigg, P. Fretwell, C. Meerholtz and V. Sridharan; Tetrahedron, 1994, 50, 359. R. A. Barcock, D. J. Chadwick, R. C. Storr, L. S. Fuller and J. H. Young; Tetrahedron, 1994, 50, 4149. H. Vorbr0ggen and K. Krolikiewicz; Tetrahedron, 1994, 50, 6549. K. E. Andersen, M. Begtrup, M. S. Chorghade, E. C. Lee, J. Lau, B. F. Lundt, H. Petersen, P. O. Sorensen and H. Thogersen; Tetrahedron, 1994, 50, 8699. M. Tiecco, L. Testaferri, M. Tingoli, F. Marini and S. Mariggib; Tetrahedron, 1994, 50, 10549. M. D'Auria; Tetrahedron Lett., 1994, 35, 633. B. H. Lipshutz, F. Kayser and N. Maullin; Tetrahedron Lett., 1994, 35, 815. S. M. Kerwin; Tetrahedron Lett., 1994, 35, 1023. A. Fttrstner, R. Singer and P. Knochel; Tetrahedron Lett., 1994, 35,

Five-Membered Ring @stems: Thiophenes & Se, Te Analogs

94TL1071 94TL1973 94TL2709 94TL3083 94TL3197 94TL3493 94TL3673 94TL3957 94TL4175 94TL4425 94TL4743 94TL5301 94TL8329 94TL9197 94TL9387

1047.

105

J. Leonard, D. Appleton and S. P. Fearnley; Tetrahedron Lett., 1994, 35, 1071. W. Schroth, E. Hintzsche, R. Spitzner, H. Irngartinger and V. Siemund; Tetrahedron Lett., 1994, 35, 1973. ]. Nakayama and K. Yoshimura; Tetrahedron Lett., 1994, 35, 2709. S. Masson, J.-F. Saint-Clair and M. Saquet; Tetrahedron Lett., 1994, 35, 3083. R. Grigg, H. Khalil, P. LeveR, J. Virica and V. Sridharan; Tetrahedron Lett.o 1994, 35, 3197. Z. Hu end M. P. Cava; Tetrahedron Lett., 1994, 35, 3493. X. Wu, T.-A. Chen, L. Zhu and R. D. Rieke; Tetrahedron Left., 1994, 35, 3673. M. Kumda, J. Nakayama, M. Hoshino, N. Furusho and S. Ohba; Tetrahedron Lett., 1994, 35, 3957. C.-S. Huang, C.-C. Peng and C.-H. Chou; Tetrahedron Lett., 1994, 35, 4175. A. R. M. O1)onovan and M. K. Shepherd; Tetrahedron Lett., 1994, 3S, 4425. G. Attardo, W. Wang, I.-L. Kraus and B. Belleau; Tetrahedron Lett., 1994, 35, 4743. D. C. Harrowven and R. Browne; Tetrahedron Left., 1994, 35, 5301. D. Melamed, C. Nuckols and M. A. Fox; Tetrahedron Lett., 1994, 35, 8329. A. Maercker and U. Girreser; Tetrahedron Left., 1994, 35, 9197. T. Masquelin and D. Obrecht; Tetrahedron Lett., 1994, 35, 9387.

Chapter 5.2 Five-Membered Ring Systems: Pyrroles and Benzo Derivatives RICHARD J. SUNDBERG University of Virginia, Charlottesville, VA, USA A review updating progress in the synthesis of pyrroles from ketoximes and acetylenes, the Trofimov synthesis, was published. <94H(37)1193> An extensive discussion of ~ f f - and if-sandwich complexes of pyrrole and other heterocyclic analogs of cyclopentadiene appeared. <93CCR237>. 5.2.1

Structure and Reactivity

New data was obtained on the s t a b i l i t y of the previously uncharacterized 3H-tautomer of indole. <94AGE1153> Photodecomposition of 1 in diethyl ether generated a mixture of 3H-indole and the enol of acetophenone. 3H-Indole can also be generated by photolysis of indoline in aqueous solution. The 3Htautomer is formed by disproportionation of the 2indolinyl radical which is generated by electrontransfer. By following spectroscopic changes in the resulting solution i t was possible to measure the lifetime of 2. The photolysis can be done in aqueous buffer solution and the rate of conversion to indole determined as a function of pH. The rate of tautomerization is given by the e~uation" Rate = 4.9 x I0 [2][H § At pH 9, the lifetime is about 100 sec. The equilibrium constant favoring IH-indole is I0 e"

~ H ~ ,, 1

~[.~0

..---.-~ . ~ 2

Ph

~----

3

H

Recent ab i n i t i o molecular orbital calculations have yielded relative energies for 2H- and 3H-pyrrole. Calculations at the MP3 level find the 2H-tautomer to be

106

Five-MemberedRing @stems: Pyrroles

107

1.5 kcal/mol more stable than the 3H-isomer, <940M4732> while using the MP2/6-3]G* level indicates a difference of 2.2 kcal/mol. <93JOC5414> Nakajima and coworkers used PM3 and AMI semiempirical calculations in an effort to understand reactivity patterns for pyrrole and simple methyl derivatives. <93JST199> The best agreement with experimental trends was found i f both the HOMO distribution and electrostatic potential were taken into account in predicting reactivity. 5.2.2

Synthesis

Additional examples of synthesis of pyrroles by cyclocondensation of nitroalkenes and isocyanoacetate esters were reported. It is clear that this reaction is a versatile pyrrole synthesis. A wide variety of 3- and 4-substituent groups can be introduced by appropriate choice of the nitroalkene. Several 3,4-disubstituted pyrrole-2-carboxylates were prepared by heating ~acetoxynitroalkanes and benzyl isocyanoacetate with DBU in THF. Yields were usually around 70%. <94JHC707>. ~CCH 3

CH3 ,~,._.~CH2CH2CO2CH3 "N" -C~C(CH3)3

4

5

6

H

57%

Similar conditions were used to prepare pyrroles from both t-butyl and benzyl isocyanoacetate. <94JHC255, 94S170> The reaction was also effective for preparing some rather hindered 3-aryl-4-methylpyrrole-2carboxylates. Several @-methylnitrostyrenes were prepared by condensation of an aromatic aldehyde with nitroethane. These nitrostyrenes condensed with ethyl or methyl isocyanoacetate. Even o,o'-disubstituted systems gave adequate yields. <93BSF779> OCH3

.OCH3

O2N ~ . . 1 _ CH3 i,I Lr....OCH3 O2N

>=/-x

OCH3

7

+

DBU C;-NCH2CO2CH3 ~

02 ~

OH3

# ~

8 9

OCH3

~H~

'%'N "r~CO2CH3 I H 70%

Even the nitro-substituted 9,10-double bonds of anthracene and 1,10-phenanthroline are sufficiently reactive to give the corresponding fused pyrroles. <94TL2493>

Five-Membered Ring Systems: Pyrroles

108

A number of 2-aryl and 2-heteroarylpyrroles were obtained starting with 1-propargylbenzotriazole. <94S93> The lithium anion adds to N-tosylimines to generate 3-(benzotriazolylmethyl)propargylsulfonamides. In hot ethanolic sodium ethoxide these undergo cyclocondensation to the 2-arylpyrroles. The cyclization evidently occurs via allenic isomers formed under the basic conditions. The synthesis can also be adapted to 5-alkyl-2-arylpyrroles by alkylating the 1-propargylbenzotriazole prior to cyclization. ~~~

I) n-BuLi ~ 2) ACH:NTs

R -CHC ~CH

10 R = H or al~l

~~:N 11

Ar I

RCHC 5CCHNHTs

~NaOEt N ~ EtOH R ~

Ar

H

12

A synthesis of 2,3-diarylpyrroles was based on the use of a difunctional phosphine imine which is capable of both Wittig and aza-Wittig condensation. <94JOC4551> The reagent is prepared from benzotriazole, formaldehyde, sodium azide and triphenylphosphine which gives the precursor 13. Reaction with methylidenetriphenylphosphorane and butyllithium generated14 which reacted with benzil derivatives to give the pyrroleso OO

~ N 13

1) CH2=P,h,~

i

2) BuLi

CH2N=P(Ph)3

(Ph'3P=CHCH2N=P(Ph)3

A~-~Ar , ~

Ar

Ar

14

15 H

Several 2-(2-thienyl) and 2-(3-thienyl)pyrrole-3carboxylates were made by reaction of acetylthiophene oximes with methyl propiolate or dimethyl acetylenedicarboxylate. <93JCR(S)210> This reaction is related to other sigmatropic rearrangements which have been used in pyrrole and indole synthesis.

CH3 c=NOH 16

CO2CH3

XC~CC~CH3 CH3 ~I~ DMSO El3N~ ~C=NO~ =CHc~cH3heat~ ~ I ~ ~ ~ X 17

18

Methyl propiolate converts arylhydroxylamines to indole3-carboxylates by a similar sigmatropic rearrangement and cyclization. <94JOC1577> N-Benzyl derivatives gave the indoles in 50-80% yield but unsubstituted arylhydroxylamines gave N-(carbomethoxy-vinyl)indoles. These are formed by an initial N-vinylation followed by 0-vinylation and sigmatropic rearrangement.

109

Five-MemberedRing Systems: Pyrroles CO2CH3

X0%

X ~N

HC~--CCO2CH 3 NOH

19

R

R = H orCH2Ph

20

R = CH=CHCO2CH3 or CH2Ph

A new route to pyrroles which begins by conjugate addition of ~-ketoesters to phenyl vinyl sulfoxide was developed. <94JCS(P])2355> The adducts are subjected to Pummerer rearrangement which generates 2-phenylthiodihydrofurans as intermediates. Treatment with amines and HgC12 leads to formation of the pyrroleso

O

CO202H 5 CO2C2H5 1)HgCI2 ~ N ~ R R 2) R'NH2 24 I~'

jj 1) NaOEt ~ PhSCH=CH2 + RCCH2CO2C2H5' "= 21 22 2) Ci3CCO2H~ PhS AC20 23

The facile synthesis of 2,3-difluoro-2-iodo-4oxoalkanoate esters has provided starting materials for synthesis of 4-fluoropyrrole-2-carboxylate esters. The starting materials are prepared by photo-induced radical addition of difluoroiodomethyl ketones to acrylate esters. On reaction with ammonia, pyrroles were formed. <94TL4319> Someof the esters were converted to primary amides by aminolysis under the reaction conditions. 0 I, RCCF21

CH2=CHC~R ' ~

25

0I I RCCF2CH2CHC~R, I 26

NH3 ~

F e

k

~)~'~\

R 27

C~R'

i H

An e f f i c i e n t and f l e x i b l e synthesis of analogs of the calcium channel activator FPL 64176 was developed using the route to pyrroles introduced by Attanasi and coworkers. <860PP299> The procedure involves addition of a 1,3-dione to an unsaturated azo compound. The unsaturated azo compounds can be prepared from 2-chloro3-oxoalkanoic acids by reaction with N-tbutoxycarbonylhydrazine, followed by base-catalyzed elimination of HCI. The reaction proceeds through protected N-aminopyrroles. <94S207>

O OR~~O IF,,CO2CH3 ArC Ar + N=="*"W~R2 --------~R5~ II

NCO2C(CH3)3

28

29

30

O CO20H3 HCI ArC .CO2CH3 EI---"0-~R5~ 2 R RONO R2 II

I NHCO2C(CH3)3

31

0 H

Additional examples of the cyclization of l~cyanoketones to 2-chloropyrroles were reported. <94TL5989> The reaction requires an electron-

Five-Membered Ring Systems: Pyrroles

110

withdrawing group at C3, perhaps because of the instability of chloropyrroles lacking such substituents. Good yields of 5-alkyl, 4,5-dialkyl and 5-aryl-2chloropyrroles were obtained. 4

o x

,, , R~-CCHCHC -_-N l~4

x

HCI

~ i-PrOH

R

32

33

CI

' H

X = CO2C2H5, CN R4= H, alkyl 5 R = alkyl, an/I

The interesting pyrrole 35 was prepared as a precursor of porphyrins with bulky substttuents on both faces. The Diels-Alder adduct of dicyanoacetylene and 2,3,6,7-tetramethylanthracene was reduced by DiBA1H to give the pyrrole in 33% yield. <94AGE889> H i

CH3 1 ~ 34

~

~

-CH3 +

2) 'DiBAIH

'

~

CH3" ~ 35

CH3

There was further exploration of a c a t a l y t i c method for reduction of nJtrostyrenes to jndoles. A PhC12(PPh3)2-SnC1= system catalyzes cycllzation with CO as the reductant. <94J0C3375> Several representative nJtrostyrenes, such as 2-nJtrostilbene and methyl 2 n itrocJnnamate gave the expected products. R3 ~ ~ ~ N

R3 R2

36

CO, 100 _--~ P dCI2~ P h3)3 SnCI4

R2 I~

37

R2

R3

CO2CH3 Ph H H

H H H CH3

yield (%) 62 75 50 57

While the reaction shows some "nitrenoid" characteristics, no cyclization was observed with 2ethylnitrobenzene or even with 2-nitrobiphenyl.

Additional examples of conversion of oacylanilides to indoles by low-valent titanium were reported. <94CB1125> A number of 5-methoxy and 5,6dimethoxy indoles were prepared, including compound 39 which is a precursor of the tumor inhibitor zindoxifene. O ml

38

NHC~OCH3 O " - "

CH30" ~ THF

39

CH3

~

H

Five-Membered Ring Systems: Pyrroles

111

Use of 2,5-dimethoxy-2,5-dihydrofuran in a Heck reaction with ethyl N-(2-iodophenyl)- carbamate resulted in the formation of methyl I-carboethoxyindole-3acetate. <94SL499> The reaction is formulated as occurring through a Heck vinylation to give 41 which undergoes cyclization on treatment with TFA.

~0

40

NHCO2C2H5

F:~

Pd(OAc)2, 3 mol %

IL ~ L

~ ~ PhCH2N+Et3 c r 41 iPr2NEt

O C H 3

CH2CO2CH 3

OCH3

....... C NHCO2 2H5

~'~I~*~N" 42

s H

Additional examples of closure of the indole ring by intramolecular Heck reactions have been reported. The 3,4-disubstituted indole-2-carboxylate ester 45, which is encountered as part of the antibiotic nosiheptide, was obtained starting with the condensation of aniline 43 with benzyl 2-oxobutanoate. After protection of the hydroxyl group, Heck cycl ization occurred in 46% yield. <94SL761> CH2OTHP C.H2OH

O

C H2OTHP

I 43

1)CH3CH2CCO2CH2Ph '' m H2 2) THP

~ I

~,~ I ~

44

v

P d(OAc)2

/CH 3 NaH_~CO 3 .~ Bu4N+Cr "N- "CO2CH2Ph H 45

C H3 CO2CH2Ph

,

H

46%

In a study of the structure of kinamycins, the 4oxotetrahyrocarbazole 47 was obtained from 46 by oxidative cyclization with Pd(0Ac)2. <94JA2209> O

O CH3

46

OCH3H

HOAc

CH3 CH30

47

i~I

Palladium(II)-promoted oxidative cyclization was also applied to benzo[b]carbazole-6,]]-diones. <94T]0893> A synthesis of the 1,3,4,5-tetrahydropyrrolo[3,3,2-de]quinoline ring, which appears in several natural products, was accomplished by using an indole ring closure. The cyclization would be expected to be disfavored by the strain which must be overcome in the ring closure. The successful approach was to construct the dihydroquinoline 48 which was then reduced to the amine 49. Cyclization to 50 occurred in 58% yield under acidic conditions. <94T7879>

Five-Membered Ring Systems: Pyrroles

112

H32 H2cHN32 H2/Pt

48

I CH3

~

H

TsOH

I

CH3

49

I

50

CH3

A versatile route to N-substituted oxindoles has been developed by extending the u t i l i t y of d i l i t h i a t e d o-alkylanilines. Treatment of N-alkyl-2-methylaniline with one equiv, of n-butyllithium, followed by C02 and then a second equiv, of n-butyllithium gave a dilithiated intermediate which reacted with C02 to give an oxindole. <94H(37)701> The method was applied to several ring-substituted oxindoles and to 5- and 7-azaoxindoles. ~CH3 X 51

1) ~ nBuLi X- ~ i ~ ~

NR i H

2) C~

52

2) 1) ~ nBuLi A_ X~ ~ N ,

R

Li

~

CH~

53

O

R

Preliminary results on the synthesis of oxindoles by intramolecular Heck cyclization followed by tandem arylation have been outlined. <94JHC631> CH3

CH2 54

"O I CH2Ph

Pd0

II

CH3

ArB@H)2 I

55

CH2Ph

I

56

CH2Ph

The use of rhodium catalysts to obtain 3-carboethoxyoxindoles from N-(2-diazomalonyl)anilines was explored. <94JOC2447> Rhodium(II) trifluoroacetamide and rhodium(II) perfluorobutanamides were found to be preferable to rhodium carboxylates both in terms of reaction rate and selectivity for oxindole formation. The perfluoroalkanamide catalysts favor aromatic insertion over insertion or addition involving the Nsubstituent. The starting materials can be prepared readily from ethyl 2-diazomalonyl chloride and anilines. The oxindoles were subsequently converted to 0 - t r i a l k y l s i l y l and 0-benzoyl indoles. i~ 57

2C ~ ? C2H5Rh4(NHCOCF3)4 ~ ~ N _ ~ N, R 58

C~CH3 O

A new method for synthesis of isatins which is based on directed l i t h i a t i o n of t-butoxycarbonanilides

Five-Membered Ring Systems: Pyrroles

113

was developed. The N,o-dilitihiated intermediate 60 was prepared by reaction of 2.2-2.4 equiv, of either n-, s-, or t-butyllithium, depending upon the substituents. The intermediates were treated with diethyl oxalate at -78"C to give ketoesters which were deprotected and cyclized under hydrolytic conditions. <94TL7303> 0

2 RLi

X

~

59

NH i CO2C(CH3)3

X

60

EtO2CCO2EI Li I CO2C(CH3)3

0

61

I H

A new route to 2-t-butoxycarbonylisoindole has been reported. The sequence starts with f u r f u r a ] which was converted to 62. Reaction with K0-t-Bu then generated the dihydroisoindole 65 by a reaction which presumably involves an intramolecular Diels-Alder reaction of the allene 63. The isoindole formed by dehydration is trapped by reactive dienophiles. <94JCS( CC) 1535> ~CH2~CO2C(CH3)3 62 HC -CCH2

KOIBu

/~CIH2 ~ ~NCO2C(CH3)3 CH2 =C=CH - NCET2C (CH3)3 64

--CO2C(CH3)3 66

5.2.3

XCH=CHX

HO- v 65

~-

NCO2C(CH3)3

Ring Substitution and Modification

Several improvements and extensions of methodology for introducing or modifying ring substitution have been reported. Investigations involving organometallic intermediates have been especially f r u i t f u l . A new Nprotected 3-1ithioindole synthon was developed. NSulfonylated Indoles are prone to 3-~2 migration of lithium and to ring fragmentation. <82JOC757, 83JOC48> N-t-Butyldimethylsilyl-3-1ithioindole was prepared by halogen metal exchange from the 3-bromo precursor and nbutyllithium at -78 . T h i s 3-1ithio reagent showed no tendency to undergo rearrangement or fragmentation, even at 25~ Goodyields of the expected products were obtained by reactions with alkyl iodides, allyl bromides and typical carbonyl compounds. <94JOCI0>

114

Five-Membered Ring Systems: Pyrroles

Several groups have reported procedures for palladium-mediated cross-coupling of indoles. This can involve the indole reacting as the nucleophilic (eg. stannane, zinc or boronic acid derivatives) or electrophilic (halide or t r i f l a t e ) component. The variety of such procedures that are now available indicates that Pd-catalyzed cross-coupling is the most versatile method for synthesis of many aryl and vinyl indoles. Several N-protected indol-2-yltributylstannanes were examined in Pd-catalyzed cross-coupling with aryl halides and t r i f l a t e s , acyl chlorides and benzylic and a l l y l i c bromides. <94JOC4250> The l-methyl and 1-(2trimethylsilylethoxymethyl) (SEM) derivatives reacted readily whereas the 1-t-butoxycarbonyl derivative was somewhat less reactive. The SEM group is removable with Bu,N* F, providing acces to the deprotected 2substituted indoles. 1-t-Butyldimethylsilylindol-2-ylzinc chloride proved to be an effective reagent for 3-arylation using heteroaryl bromides and chlorides. <94TL793> The reagent was prepared from 3-bromo-1-TBDMS-indole by low temperature lithiation followed by reaction with ZnCl2. The coupling catalyst was prepared in situ by reduction of PdCl2(PPh3)2 with DiBAIH and the coupling reaction occurred in refluxing THF. Both 1-phenylsulfonylindol-2-ylzinc iodide and 1-phenylsulfonylindol-3-ylzinc iodide have also been prepared directly from the corresponding iodoindoles by oxidative addition to activated zinc. The reagents prepared in this way also undergo Pd-catalyzed coupling with aryl and heteroaryl halides. <93TL5955> 1-p-Toluenesulfonyl-3-(tributylstannyl)indole undergoes cross-coupling with aryl iodides and vinyl t r i f l a t e s or iodides in good yield. <94TL2405> The efficacy of several catalyst systems was explored and the best results were obtained with (dibenzylideneacetone)dipalladium in the presence of AsPh3. With halides as reactants the inclusion of 10% Cul cocatalyst was also beneficial. Both 6- and 7-bromoindole can be coupled with a variety of arylboronic acids in the presence of

Five-Membered Ring @stems: Pyrroles

115

Pd(PPh3),. Yields were in the range of 70-90%. No protection of the indole-N was necessary. <94SL93> This procedure was applied to coupling of 6-bromoindole with 4-fluorophenylboronic acid and proceeded in 90% yield. <94JMC4423> 1-p-Toluenesulfonylindole-3-boronic acid was conveniently prepared by mercuration of l-tosylindole, followed by react ion with diborane. Excellent yields of coupling products with enol t r i f l a t e s derived from Nsubstituted 3-piperidones were obtained using Pd(PPh3), as the catalyst. <94H(37)1761> ,/'-~ B (OH)2 ~'s

~ . . / N CH3 CF3SO3

67

CH3

LiCl, Na2CO3

68

i 69

Ts

90%

The marine imidazole alkaloid nortopsentin D was prepared by two successive cross-coupling of 2,4,5tribromoimidazole with l-t-butyldimethylsi lyl indole-3boronic acid. Coupling occurs f i r s t at C2 and then at C4. The C5 bromine is removed by lithium exchange followed by protonolysis. <94JCS(CC)2085> Br Br 70

B (OH)2

i SEM

Br

Br Br

i TBDMS

71

H ' N

1) BuLl

~

SEM 72 TBDMS

2) H20 3) Bu4N+F

N

H

t TB DM S I ~ repeat

N 73

SEM

I TBDMS

Procedures for Pd-catalyzed coup] ing with carbonylation to give 2-acylindoles were also reported. Triethyl(]-methylindol-2-yl)borate, which can be prepared from ]-methylindole by ] i t h i a t i o n followed by addition to triethylborane, was coupled with ary] iodides and vinyl t r i f l a t e s to give 2-acylindoles in 2080% yield. <94JOC2634> The reactions were run with PdCI2(PPh3)2 as catalyst under 15 atm of CO at 90~

75

I H

76

CO, 15 aim, 90 ~

77

65%

Five-Membered Ring Systems: Pyrroles

116

Heck reaction conditions have been applied to introduction of the dehydroalanine side-chain on to indoles. Under catalytic conditions, 4-bromo-1tosylindole is converted to the 4-isomer of dehydrotryptophan in 90% yield. However, with a stoichiometric amount of PdCl2 in acetic acid the 3 position was substituted, albeit in only 17% yield. A much better yield of the 3-substitution product was obtained by changing from acetyl to an N-ethoxycarbonyl protecting group in the dehydroalanine. <94CPB832> Both of these reactions presumably involve indolylpalladium species. Under the Heck conditions the 4-indolylpalladium(II) species is formed by oxidative addition. With the stoichiometric amount of PdCl2, the dominant reaction is electrophilic palladation at the 3-position. NHCOCH3 B~N NHCOCH3 Br CH=CCO2CH3 PdCi2(PPh3)2 CH~C~CH3 ~ N ~ PdCl2 78 Ts ' NaOAc'Et3N~ ~ N + CH2=CC~CH3 +S 79 NHCOCH3 80 90% An intramolecular Heck reaction with the ~ - a l l y l tryptophan derivative 8] yielded a mixture of three cyclization products in overall 88% y i e l d <94JOC4418> 81

Ts 17%

CH2=CHCH2 C~CH3 C~,~...N ~= CH3 Br I ~N/~'~'-NHC~CH2Ph C H 3 [ ~ HC~CH2Ph ~H2~C~cH3 Pd(OAc)2 f~----~ NHC~CH2Ph ------~ EI3N,PPh3 ~"~N I ~N I H H 83 H 22% 81 82 44% plusex~yclic isomer (22%)

Oxidative cyclization by stoichiometric amounts of Pd(OAc)2 has been shown to be an effective means of bringing about formation of new fused aromatic rings from properly constructed indole derivatives. For example, the diindolylsuccinimide 84 was cyclized to 85, a precursor of staurosporine in 75% yield. <93TL8361> H H I I Oa:~N~:::O ~c~~ Pd(OAc)2 HOAc 84

I

H

I

H

85

HI

HI

Five-Membered Ring Systems: Pyrroles

117

Ethyl 3-bromomethyl-4-iodoindole-l-carboxylate, which can be prepared from the zirconocene intermediate 87 has been shown to be a versatile precursor for preparation of several 3,4-disubstituted indoles. <94JOC7164> The bromide can be readily displaced by such nucleophiles as cyanide, carbanions and amines. The 4-iodo group is reactive towards Pd-catalyzed coupling procedures. These two types of reactions can be used sequentially to prepare a number of novel structures. The intermediate can also be used to prepare [c,d]-fused derivatives. For example, reaction first with benzylamine, followed by Pd-catalyzed carbonylation gave 90. !CH21 Cp2~ Z r

(CH2CH=CH2)2 2 IBuLi

2) CIC~C2H5

86

t

87

C~C2H5

88

CH2CH=CH2

2) NBS

CH2Ph

NCH2Br

1) PhCH2NH2 2) PdCI2(PPh3)2 Et3N, CO

!

9O

CO2C2H5

i

CO202H5 89

The iodomethyl group of 91 can be dehydrohalogenated generating methyleneindolines. These compounds readily undergo ene react ions with electrophilic alkenes and alkynes and other electrophiles. Iminium ions give rise to tryptamine derivatives. <94JA11797> OH

CH2=N__~ R2

91

I CH2Ph

~'~N 92

V'~F~'NI CH2Ph

I CH2Ph

93

The reaction sequence has also be extended to systems having r substituents. A similar zirconocene intermediate prepared from N-ally1-2-bromoani line was used in the early stages of a synthesis of the A-ring structure of the antitumor antibiotic CC-1065. The second pyrrole ring was installed by a Hegedus-type cyclization. <94JOC192> I

~ B r

1) Cp2Zr(CH3)CI ~ JH2I CH3 N~NSO2 , t'BuLi~ =~ ii" ~ T '~ several PhCH20- " ~ "NCH2CH=CH2- 2) 12 -PhCH20"q"~'~N" slep---"~ PhSO2 SO2Ph H O 94

95

96

P

118

Five-Membered Ring Systems: Pyrroles

An investigation of the reactivity of N-magnesiopyrrole toward =-bromoesters has shown that good yields of pyrroleacetate esters can be obtained. <94JOC5230> For pyrrole, substitution occurred at C2. 2,5-Dimethylpyrrole undergoes substitution at C3. A useful regioselectivity was observed for the Friedel-Crafts acylation of 1-acylindoles by chloroacetyl chloride and other ~-haloacyl chlorides. While acetyl chloride tends to give primarily 3-acylation under these conditions, chloroacetyl chloride and longer homologs give nearly exclusively 6-acylation. <94TL2699> A new method for introduction of the tryptophan side chain was applied to 4-bromoindole using methyl 3-ethoxy-2-nitroacrylate. The vinylation occurred in 85% yield without the need for any catalyst. The ~-nitroacrylate substituent was then reduced in sequential fashion using Pt/C for reduction of the nitro group and Rh(PPh~)3Cl to reduce the double bond. <94JOC4418> ~r

97

I H

_

NO2

,, = 98

ar 2H=COO2OH3 1) H2, PIIC l 2H2~ 002cH3 NO2 ' ' = 2) HCO2H,Ac20 ~i I ~ N / O I 3) H2, Rh(PPh3)3CI = H 99 H

There has been increasing interest in radical substitution and cyclization reactions of pyrroles and indoles. Both 2- and 3- carboethoxypyrroles undergo radical cyclizations (at C5 and C2, respectively) with appropriately placed iodoalkyl substituents. <94JOC2456> Radicals are generated by the Fe(II)-H202DMS0 system which involves iodine abstraction by methyl radicals. <89JOC5224> 002C2H5

N, 100

CO202H5

Fe(ll)' ~ DMSO H202 ~

CH2CH2CH21

101

CH3 HOH2OH2OH FeO2 102

"N" "CO2C2H5 DMSO H

44-47%

103 CH3 H

56-60%

This reaction was adapted to the synthesis of the pharaoh ant pheromone monomorine. ~CC ICH2CH2CH2C.,CH3 104 H

3H7

Fe(ll), H202 ~ ~ DMSO

~C3H7

~ ~ H clio 105 78%

three steps

I ~

... C4H9

~ OH3 106 (andstereoisomers)

Five-Membered Ring Systems: Pyrroles

119

Similar reactions were observed with N(~-iodoalkyl)indoles having 3-EW substituents. The substituents are beneficial but not absolutely necessary. The unsubstituted indole gave a small amount of cyclized product but the 3-methyl derivative gives a 60% yield of the cyclization product. Oxidation of dimethyl alkylmalonates by Mn(OAc)3 generates bis-carbomethoxyalkyl radicals. Whenapplied to indoles 109, 53-85% yields of cyclization products were obtained. <94SC1493> cH2CHCH(cO2CH3)2 X Mn(OAr 109

m SO2Ph

X = H, CN,CO2CH3,SO2Ph

~ 110

O

X2 CH3 i CO2CH3 SO2Ph

Tandem addition-cyc] ization was observed when dimethy] ]-p-toluenesulfony] indol-3-ylmethylmalonate was oxidized in the Presence of alkenes. CH2CH~CH3)2 ~ N 111

+

RCH~H2

S~Ph

-CO20H3 Mn(OAc)3 ~ C ~ C H 3 112

S~Ph

Another kind of tandem cyclization was observed when 1-benzoylindoles with 3-EW substituents reacted with dimethy] malonate and Mn(OAc),. Tetracyclic products are obtained in good yield. <94TL1283> I t is presumed that the reaction involves i n i t i a l attack by the bis-carbomethoxymethy] radical on the indole ring at C2, followed by a second oxidation and cyclization. X

X

M n(OAc)3__~ O~~ 113

X

CH~CH3~ Mn(O-.~~ Ar ~[~.N~P'~--O~CH3

CH2~O2OH3~ 114

O~~

115

~

X = C~CH3, COCH3,CN

Aryl radicals generated electrochemically from halides react with pyrrole and indole. For pyrrole there was a regiochemical preference for 2-substitution ranging from 4:] to 20:], while indole gave 3substitution. <94S366> These reactions are believed to occur by an S,N! mechanism and to involve the anions of the heterocyles. The reactions were carried out in liquid ammonia and have the potential to be catalytic rather than stoichiometric in current consumption.

Five-Membered Ring Systems: Pyrroles

120 Ar-X

~_

~

+

-

.~

Ar-X

~9

Ar

~

At'

I/-~

" N ~ Ar I 1 ~

+

X

Ar-X

/Z ~ Ar -N" H

--.--i.

H

+

Ar-X'"

Perfluoroalkyl radicals can be generated from perfluorosulfonyl chloride using RuCI2(PPh3)3 as a catalyst. In the presence of ]-substituted pyrroles good yields of 2-perfluoroalkylpyrroles were obtained with N-substituents such as acetyl, benzenesulfonyl or trimethylsilyl. With tris-isopropylsilyl, however, 3substitution was preferred. <94SC2049, 94JCS(PI)1339> Synthetic routes to vinylpyrroles and vinylindoles continue to be of interest because of their potential as Diels-Alder dienes. Work by Settambolo and coworkers demonstrated that 3-acyl-1-p-toluenesulfonylpyrroles can be converted to 3-vinylpyrroles by standard methods such as Wittig olefination or organometallic addition followed by dehydration. <94G173>The tosyl group can be removed by alkaline hydrolysis.

O

~H2

II

CCH3

Ph3P=CH2 ,

' Ts

116

or

I)CH3MgBr

CCH3

.~

2)DMso.~eo~

~~N 117

§

~H2

5MNaOH ~ MeOH

~

CCH3

~

118

The reaction of N-protected 3-formyl and 3acetylindole with m-chloroperoxybenzoic acid has been investigated, l-Benzenesulfonyl-3-formyl and 1-acetyl3-formylindoles gave modest yields of 3-indolones via hydrolysis of unstable formate esters. Someof the corresponding 2-hydroxyindol-3-ones were also formed. The 3-acetoxy derivative of 1-benzenesulfonylindole is more stable and was isolated in 80% yield from the oxidation of 3-acetyl-l-benzenesulfonylindole. <94S411> There was further study of indole-2,3-epoxides and indole-2,3-dioxetanes. Dioxetanes can be isolated from ]-acylindoles by photo-oxygenation and are accompanied by more stable hydroperoxides. The oxetanes can be converted to indole-2,3-epoxides by deoxygenation with dimethyl sulfide. <94JOC2733, 94JCS(P2)1503> The epoxides can also be prepared by oxidation of 1-acylindoles by dimethyldioxirane. The indole-2,3-epoxides

Five-Membered Ring @stems: Pyrroles

121

react by rupture of either the C2-0 or the C3-0 bond. Triphenylphosphine can also be used to convert the dioxetanes to epoxides. <94TL6063> "CH2R3

C.H2R3 ~~vl O.

02

CH2R2 CR 119 O'" CH3 O ~ CH3~.-(~

------=tetraphenylporphyrin CH2R3 O

O.H2R 3

121

.CR O' O =l

3

~I~~NCCH2R 2 CH3C O CH2R3

125

2R2

'~

H2R 2

122 O"'cR

..CR O

H2R 2

/CH3)2S

CHR 2 ~ 124

.CR O"

120

"CHR3 +

123

O

..CR O

Another application of CuBr2 to bromination of pyrroles was described. 2-(o-Hydroxybenzoyl)pyrrole can be converted to either the 4-bromo or 4,5-dibromo product, depending upon reaction conditions. Use of 3 equiv, of CuBr2 gave ]27as the major product (72%) whereas 6-6.5 equiv, gave mainly ]28(95%). S t i l l higher amounts of CuBr2 result in bromination of the phenol ring. <94JHC941> Br

cu., .

OH O 126

5.2.4

H

CHCI3

Br

ou.r

_

_ _ .

OH O 127

H

CHCI3

OH O 128

H

Br

Annulation Reactions

Cycloaddition reactions continue to find application in the synthesis of natural products and related substances containing indole and carbazole rings. Moodyhas published a summary of syntheses of carbazole alkaloids in which cycloadditions of pyrano[3,4-b]indol-3-ones figure prominently. <94SL681> There have been additional studies on the synthesis of carbazoles from vinylindoles by Diels-Alder cycloaddition. 3-(1-Methoxyvinyl)indoles can be generated in situ by deprotonation of salts of 3-(1methoxyalkylidene)indolenines. These salts are prepared

Five-Membered Ring Systems: Pyrroles

122

by reaction of indoles with methyl orthoacetate Modest yields of 4-methoxycarbazoles can be obtained with reactive dienophiles such as dimethyl acetylenedicarboxylate. <94JHC981> CH30'C=CH2

129

I CH3

NaH 130

= CH3

CH30

CH302CC--CCO2CH3 . m

CO2CH3 131

= CO2CH3 45% CH.~

A similar reaction occurs with Jndole i t s e l f but the major product is also substituted at nitrogen by a ],2dJcarbomethoxyvJny] group.

Some highly substituted carbazoles were obtained by photo-induced Diels-Alder reactions of 2-(l-cyanovinyl)indoles using stabilized enamines as dienophiles. <94SL141>

Ar

~,,~N 132

§ (CH3~NCH=CHX Ar

N H

Ar

CH3

X= C~CH3, CN

133X = C~CH3 74%

H

134X = CN 13%

A new intramolecular Diels-Alder reaction involving an imJne as the dJenophile and a vJnylindole generated by an aminocyclopropane fragmentation resulted in the formation of ]37 which can be isomerized to eburnamonine. <94J0C7197> CH=CH2

~~_ .O~CH2OH2TMS~N,~ 135 O C 2 H 5 / ~

CH=CH2 1~

O

N~~C2H

C2H5

137

O

A study of the s t e r e o s e l e c t i v i t y of the radicalcation DJels-Alder reaction of indole with the diene 139 gave a mixture of both cis and trans adducts. This lack of stereospecifJcity is consistent with other evidence that the radical-cation cycloaddjtJon is non-concerted. <93TL639]> CH3

~~N + C~ 138

I H

139

CH3

Ar --~-IP ~

Ar

Ar

CH3 ~ 140

= H

CH3

An electrocycl ization was used to synthesize the

Five-MemberedRing @stems: Pyrroles

123

carbazole alkaloid hyellazole. The enol ester ]4] was constructed from isatin and an enone by condensation, reduction and acylation. Heating in decalin gave a 3ethoxycarbazole intermediate. Hydrolysis and O-methylation gave hyellazole. Several similarly substituted carbazoles were also prepared. <94JCS(PI)579Z OH3, C=CHPh

CH=d

'~COC2H5 ~~/~--O2COC2H5 141

I) heat

OCH3

2) NaOH ~ Nail, CH~

m H

CH3 H=

142

Ph

Clay treated with transition metals, Fe3§ and Cr3+ were especially effective, has been found to catalyze Diels-Alder reactions and pyrrole was among the dienes which was examined. Using the Cr3+ catalyst, pyrrole gave a 4"1 mixture of exo and endo adducts with methyl vinyl ketone. (940CS(P1)76~The relative effectiveness of the various metals examined does not appear to correlate with either Lewis acidity or redox potential. A tentative suggestion is that the metal cations may f a c i l i t a t e reaction through coordination complexes. H I N

O + CH2=CHCCH3 143 H

144

13 da~

H3

145

The pyrrole annulatJon strategy for synthesis of Jndoles has been applied to the enantJoselectJve synthesis of both c i s and t r a n s - t r i k e n t J n s and to herbindole A, B and C, all of which contain fused cyclopentano[g] rings. <94CPB846> The route relies on construction of pyrrolyl-3-carbJnols of genera] structure ]46 by organometallJc addition to ~-acyl-1benzenesulfonylpyrroles. Conditions for acid-catalyzed cyclJzatJon were improved by inclusion of benzyl mercaptan which promotes isomerJzation of dehydration products which are otherwise inert to cyclJzation. R

5 R4

_TsOH, iPrOH PhCH2SH ~-~

146 R

R R

N

SO2Ph

Ph 147

R

A useful innovation was the use of benzenesulfonylmethyl as the 4-substituent. The sulfonyl group proved to be

Five-Membered Ring Systems: Pyrroles

124

reactive toward nucleophilic displacement and this allowed elaboration of the 4-position.

CH3~

CH2SO2Ph

EI2AICICH~ 3 * CH2=CHCH2Si(CH3)3

t48

CH2CH2CH=CH2

150

When these methods were combined with enantioselective syntheses of the cyc-lopentane precursors, it was possible to obtain the natural products and assign absolute configurations. <94CPB854> A Nazarov cyclization of the enone 15] was used to synthesize analogs of yuehchukene. The cyclization reaction proceeds in 83% yield. After reduction of the corresponding carbinol, reaction with indole in the presence of BF3 introduces the indolyl substituent with trans stereoselectivity. <94SC65>

~2

-C(CH3)3

I~C~C~H3)3 AIC'3~

~~" 151

6

H

1)DB i AIH

80"-"-~olj~J~N , "O 2)indole,BF3 152

H

H

153

"N H=

78%

A method for [c,d]-fusion began with the t e r t i a r y carbinol ]54. Reaction with the silyl enol ether 155 generated ]56 which was cyclized to ]57 by BF3. <94CPB1393> The cyclization product was eventually converted to the natural substance hapalindole 0.

(CH3)30CO2 (0H3)30002 ~~CH3 ~CH3 HO-C.(CH3)2 (CH3)3CC~.cH3 1 ["CH=CH2 CH3 "'CH=CH2 ~N ~ j''CH=CH2 SnCl4 O H / 3 [ ~ ' ' BF3.~_.~C H 3 ~ ' +

I

154

Ts

155

OSi(CH3)3

~"~,'~'~N

156

~-~N

Ts

157

§

An annulation of indole-2-carboxaldehyde to 3carboethoxy-~ -carboline was accomplished by using reductive amination to install a side chain with a ~acetal functionality. Cyclization occurred on reaction with TiCl~. <94T6299> Methyl 4-methyl-~-carboline-3carboxylate was prepared by a similar protocol.

~~~~N cH=O + H2NCHCH(EX32H~2 i)NaB"3CN ~ = CO2C2H5 2) 158

H

TiCI 4

159

160

CO202H5

i

i

H

57%

Five-Membered Ring @stems: Pyrroles

125

A tandem radical cylization was used to form an indole ring with a [c,d]-fused cyclohexane ring starting with an N-allyl-2-bromo-3-vinylaniline. <94T2183>

X~

x

x

R

162

By incorporating a substituted N-allyl group at the 4position a third tandem addition was accomplished. Both exo-5 and endo-6 were observed, depending on the substitution on the a l l y l group. For example, with the lysergic acid structure 164 was generated, along with some of the exo-5 product 165. The former product could also be obtained by a prior cyclization of the 4 substituent to generate a tetrahydropyridine ring.

CH302C,~,N,CH3

CH302C~ N oCH3

~Br

Bu3SnH~

NCH2CH=CH2 163 O"CCH3 CH302C~ I

\

References

82JOC757 83JOC607 860PP299 89JOC5224 93BSF779 93CCR237

HH~ I

..CCH3

164 O "CH3~u3SnH

.H

CH302CV/''N. H

:H3~~,/_N I

.CCH3

165 O

~I~Br 166 or

NCH2CH=CH 2

M. G. Saulnier and G. W. Gribble, J. Org. Chem., 1982, 47, 757. G. W. Gribble and M. G. Saulnier, J. Org. Chem., ]983, 48, 607. O. A. Attanasi and L. Cagliotti, Org. Prep. Proced. Int., ]986, 18, 299. F. Minisci, E. Vismara and F. Fontana, J. Org. Chem., ]994, 54, 5224. J. P. Alazard, O. Boye, B. Gillet, D. Guenard, J. C. Beloeil and C. Thal, Bull. Soc. Chim. Ft., 1993, 130, 779. A. P. Sadimenko, A. D. Garnovskii and N. Retta, Coord. Chem. Rev., ]993, 126, 237.

126

93JCR(S)210 93JOC5414 93JST199 93TL5955 93TL6391 93TL8361 94AGE889

94AGE1153 94CB1125 94CPB832

94CPB846 94CPB854 94CPB1393 94G173

94H(37)701 94H(37)1193 94H(37)1761

Five-Membered Ring Systems: Pyrroles

G. A. Pinna, M. A. Pirisi and G. Paglietti, J. Chem. Res. (Synopses), ]993, 210. S. M. Bachrach, J. Org. Chem., ]993, 58, 5414. Y. Nakajima, Y. Sakagishi, M. Shiibashi, Y. Suzuki and H. Kato, J. Mol. Struct. (Theochem), 1993, 288, 199. T. Sakamoto, Y. Kondo, N. Takazawa and H. Yamanaka, Tetrahedron Lett., ]993, 34, 5955. O. Wiest and E. Steckhan, Tetrahedron Lett., ]993, 34, 6391. W. Harris, C. H. Hi]], E. Keech and P. Malsher, Tetrahedron Lett., 1993, 34, 8361. Y. Ramondenc, R. Schwenninger, T. Phan, K. Gruber, C. Kratky and B. Krautler, Angew. Chem., Int. Ed. Engl., ]994, 33, 889. I. G. Gut and J. Wirz, Angew. Chem., Int. Ed. Engl., 1994, 33, 1153. A. Furstner, D. N. Jumbam and G. Seidel, Chem. Ber., 1994, 127, 1125. Y. Yokoyama, M. Takahashi, M. Takashima, Y. Kohno, H. Kobayashi, K. Kataoka, K. Shidori and Y. Murakami, Chem. Pharm. Bull., ]994, 42, 832. H. Muratake, A. Mikawa, T. Seino and M. Natsume, Chem. Pharm. Bull., 1994, 42, 846. H. Muratake, A. Mikawa, T. Seino and M. Natsume, Chem. Pharm. Bull., ]994, 42, 854. M. Sakagami, H. Muratake and M. Natsume, Chem. Pharm. Bull., ]994, 42, 1393. R. Settambolo, M. Mazzetti, D. Pini, S. Pucci and R. Lazzaroni, Gazz. Chim. I t a l . , 1994, 124, 173. G. W. Rewcastle and W. A. Denny, Heterocycles, ]994, 37, 701. B. A. Trofimov and A. I. Mikhaleva, Heterocycles, ]994, 37, 1193. Q. Zheng, Y. Yang and A. R. Martin, Heterocycles, ]994, 37, 1761.

Five-Membered Ring Systems: Pyrroles

94JA2209 94JA11797 94JCS(CC)1535 94JCS(CC)2085 94JCS(PI)579 94JCS(Pl)761 94JCS(PI) 1339 94JCS(PI)2355 94JCS(P2)1503 94JHC255 94JHC631 94JHC707 94JHC941 94JHC981 94JMC4423

94JOCI0 94JOC192 94JOC1577

127

S. Mithani, G. Weeratunga, N. J. Taylor and G. I. Dmitrienko, J. Am. Chem. Soc., Igg4, 116, 2209. J. H. Tidwell and S. L. Buchwald, J. Am. Chem. Soc., ]gg4, 116, 11797. M. Lee, H. Moritomo and K. Kanematsu, J. Chem. Soc., Chem. Commun., Igg4, 1535. I. Kawasaki, M. Yamashita and S. Ohta, J. Chem. Soc., Chem. Commun., Ig94, 2085. E. M. Beccalli, A. Marachesini and T. P i l a t i , J. Chem. Soc., Perkin Trans. I, Igg4, 579. J. M. Adams, S. Dyer, K. Martin, W. A. Matear and R. W. McCabe, J. Chem.Soc., Perkin Trans. I, Igg4, 761. N. Kamigata, T. Ohtsuka, T. Fukushima, M. Yoshida and T. Shimizu, J. Chem. Soc., Perkin Trans. I, Igg4, 1339. W. H. Chan, A. W. M. Lee, K. M. Lee and T. Y. Lee, J. Chem. Soc., Perkin Trans. I, Igg4, 2355. W. Adam and D. Reinhardt, J. Chem. Soc., Perkin Trans. ~, Igg4, 1503. M. A. Drinan and T. D. Lash, J. Heterocycl. Chem., Igg4, 31, 255. R. Grigg, J. Heterocycl. Chem., Igg4, 31, 631. N. Ono, H. Katayama, S. Nisyiyama and T. Ogawa, J.Heterocycl.Chem., Igg4, 31,707. S. Petruso, S. Bonanno, S. Caronna, M. Ciofalo, B. Maggio and D. Schillaci, J. Heterocycl. Chem., 1994, 31, 941. U. Pindur, M. Rogge, C. Rehn, W. Massa and B. Peschel, J. Heterocycl. Chem., Igg4, 981. S. K. Davidson, J. B. Summers, D. H. Albert, J. H. Holms, H. R. Heyman, T. J. Magoc, R. G. Conway, D. A. Rhein and G. W. Carter, J.Med.Chem., Igg4, 37, 4423. M. Amat, S. Hadida, S. Sathyanarayana and J. Bosch, J.Org.Chem., Igg4, 59, 10. L. F. Tietze and T. Grote, J. Org. Chem., Igg4, 59, 192. J. R. Hwu, H. V. Patel, R. J. Lin and M. O. Gray, J. Org. Chem., Igg4, 59, 1577.

128

94JOC2447

94JOC2456 94JOC2634 94JOC2733 94JOC3375 94JOC4250 94JOC4418 94JOC4551 94JOC5230 94JOC7164 94JOC7197 940M4732

94S93 94S170 94S207 94S366 94S411 94SC65

Five-Membered Ring Systems: Pyrroles

D. S. Brown, M. C. E l l i o t t , C. J. Moody, T. J. Mowlem, J. P. Marino, Jr., and A. Padwa, J. Org. Chem., 1994, 59, 2447. D. R. Artis, I.-S. Cho, S. JaimeFigueroa and J. M. Muchowski, J. Org. Chem., ]994, 59, 2456. M. Ishikura and M. Terashima, J. Org. Chem., 1994, 59, 2634. W. Adam, M. Ahrweiler, K. Peters and B. Schmeideskamp, J. Org. Chem., 1994, 59, 2733. M. Akazome, T. Kondo and Y. Watanabe, J. Org. Chem., 1994, 59, 3375. S. S. Labadie and E. Teng, J. Org. Chem., 1994, 59, 4250. D.C. Horwell, P. D. Nichols, G. S. Ratcliffe and E. Roberts, J. Org. Chem., ]994, 59, 4418. A. R. Katritzky, J. Jiang and P. J. Steel, J. Org. Chem., ]994, 59, 4551. G. C. Schloemer, R. Greenhouse and J. M. Muchowski, J. Org. Chem., ]994, 59, 5230. J. H. Tidwell, A. J. Peat and S. L. Buchwald, J. Org. Chem., ]994, 59, 7164. M. D. Kaufman and P. A. Grieco, J. Org. Chem., ]994, 59, 7197. L. S. Sunderlin, D. Panu, D. B. Puranik, A. J. Ashe, I l l , and R. R. Squires, Organometallics, ]994, 13, 4732. A. R. Katritzky, J. Li and M. F. Gordeev, Synthesis, 1994, 93. T. D. Lash, J. R. B e l l e t t i n i , J. A. Bastian and K. B. Couch, Synthesis, ]994, 170. A. J. G. Baxter, J. Fuher and S. J. Teague, Synthesis, 1994, 207. M. Chahma, C. Combellas and A. Thiebault, Synthesis, ]994, 366. A. S. Bourlot, E. Desarbre and J. Y. Merour, Synthesis, ]994, 411. K.-F. Cheng, G. A. Cao, Y.-W. Yu and Y.C. Kong, Synth. Commun., ]994, ~4, 65.

Five-Membered Ring Systems: Pyrroles

94SC1493 94SC2049 94SL93 94SL141 94SL499 94SL681 94SL761 94T2183 94T6299 94T7879 94TI0893 94TL793 94TL1283 94TL2405 94TL2493 94TL2699 94TL4319

94TL5989 94TL6063 94TL7303

129

C.-P. Chuang and S.-F. Wang, Synth.

Commun., 1994, 24, 1493.

N. Kamigata, T. Ohtsuka, M. Yoshida and T. Shimizu, Synth. Commun., 1994, 24,2049o G. M. Carrera, Jr. and G. S. Sheppard, Synlett, 1994, 93. C. F. Gurtler, S. Blechert and E. Steckhan, Synlett, 1994, 141. K. Samizu and K. Ogasawara, Synlett, 1994, 499. C. J. Moody, Synlett, 1994, 681. F. Sbrogio, F. Fabris and O. De Lucchi, Synlett, 1994, 761. Y. Ozlu, D. E. Cladingboel and P. J. Parsons, Tetrahedron, 1994, 50, 2183. M. Dekhane and R. H. Dodd, Tetrahedron, 1994, 50, 6299. C. Estevez, L. Venemalm, M. Alvarez and J. A. Joule, Tetrahedron, 1994, 50, 7879. H.-J. Knolker and N. O'Sullivan, Tetrahedron, 1994, 50, 10893. M. Amat, S. Hadida and J. Bosch, Tetrahedron Lett., 1994, 35, 793. C.-P. Chuang and S.-F. Wang, Tetrahedron Lett., 1994, 35, 1283. P. G. C i a t t i n i , E. Morera and G. Ortar, Tetrahedron Lett., 1994, 35, 2405. T. D. Lash, B. H. Novak and Y. Lin, Tetrahedron Lett., 1994, 35, 2493. S. Nakatsuka, K. Teranishi and T. Goto, Tetrahedron Lett., 1994, 35, 2699. Z.-M. Qiu and D. J. Burton, Tetrahedron Lett., 1994, 35, 4319. L. H. Foley, Tetrahedron Lett., 1994, 35, 5989. W. Adam, M. Ahrweiler, D. Reinhardt and M. Sauter, Tetrahedron Lett., 1994, 35, 6063. P. Hewawasam and N. A. Meanwell, Tetrahedron Left., 1994, 35, 7303.

Chapter 5.3 Five-Membered Ring Systems: Furans and Benzo Derivatives WILLY FRIEDRICHSEN and KARSTEN PAGEL Institute of Organic Chemistry, University of Kiel, Germany 5.3.1 INTRODUCTION The chemistry of furans was a field of lively research in the last two years. There are several reasons for this activity. It is well known, that the furan ring- both in its native as well as in its reduced form occurs in a number of natural products. These compounds can exhibit a remarkable pharmaceutical activity. There were numerous reports of studies in this field (isolation, synthesis) <94SL40, 94SL46, 94TL1247, 94JOC4698, 94TL2517, 92MI53001, 95T21, 94TL9435, 94JCS(Pl)I975, 94CC1605 94T3363 94JOC715 94T11315 94MI53003, 94JOC3433 94CL2143, 94IJC(B)I48, 94JOC3472, 94MI53004, 94JPSl163, 94JOC1598, 94P1325, 94CPB1163, 94MI53005, 94CPB1175, 94P249, 94P213, 94P1469, 94MI53006, 94MI53007, 94MI53008, 94CPB1370, 94P1588, 94P1585, 94P1371, 94P1499, 94MI53009, 94CPB1216, 94CPB1202, 94P163, 94P1297, 94P1271, 94P1285, 94P1267, 94P39, 94MI53010, 94P1375, 94P133, 94P1527>, and there is continuing interest in regioand stereoselective synthesis of furans. Additionally, furans can act as building blocks <94S1450> as do benzo[c]furans (isobenzofurans) <94JA9921>. 5.3.2 REACTIONS Regioselective metallation of 2-substituted furans with subsequent reaction of the metallated species provides a route to 2,5-disubstituted furans <93MI53001, 93UC(B)566, 94TL5335, 94JCS(PI)2493>. 2,3,5-Trisubstituted furans can be prepared similarly. A stereospecific synthesis of 2,3-difunctionalized tetrahydrofurans via a transmetallation-alkylation process of 2-(tri-butylstannyl)tetrahydrofurans was reported <94TL4183, 94TL4187>. The addition of 2-1ithiofuran to chiral ot-alkoxynitrones provides a stereoselective approach to o~-epimeric13-alkoxy-~-aminoacids <94S 1450>.

R

N-,Bn 8~n

I 2-1ithiofuron/ EtaAICI

11

130

Five-Membered Ring Systems: Furans

131

2-Arylfurans were prepared by reaction of 2-1ithiofuran with unhindered aryl triflates in the presence of LDA <93JOC4722>. Alkylfuran-2-acetic acids are accessible by a regioselective ring opening reaction of anhydride 1 <93SL40>. R

0

R o

--'---"

-'~

R co2Et

COIH

------"

0

The reaction of phenyltriflate and 2,3-dihydrofuran in the presence of a base and a Pd((R)-BINAP) catalyst gave (R)-2-phenyl-2,3-dihydrofuran with a small amount of the (S)-isomer <93OM4188, 93MI53002>. The first example of a stereoselective homolytic substitution of furan (and other fivemembered heterocycles) with a chiral carbon radical derived from Oppolzer's camphor sultana was desribed <94SL821>.The Zn-catalyzed addition of silyl enol ethers to 2,3-dihydrofurans in the presence of PhSCI yields trans-adducts exclusively <93JOM(C3)>. The Pd-catalyzed reaction of organoboraxines 2 and o-bis(bromomethyl)arenes gives cross-coupled products and bifurans. Furan3,4.diyl trimers, tetramers, and an octamer were obtained by this method <93AG406, 93AG~)432, 94JOC33>.

o-bis(bromomethyl)orene Pd(PPh3)4

R'

§ 0

2

A base catalyzed isomerization of readily available 3-methylene tetrahydrofurans provides a convenient entry to 2,5-dihydrofurans <94CC303>. Tetrahydrofurans can be oxidized to 7-butyrolactones with molecular oxygen/Co(III) <93CL1513>. There is continuing interest in porphyrin related compounds. In extension of Vogel's investigations the synthesis of tetraoxa[22]porphyrin(2,2,2,2)-dication (3) and tetraoxo[24]porphyrinogen-(2,2,2,2) (4, mixture of conformers) was reported <94AG121 l>. H

H

H

H

3_ (c=)

H

H

H

H

4_ (c,)

An intramolecular alkylation of a furan was described <94TL4887>. Oxidation of furylcarbinols provides a convenient route to hydroxypyranones <94JCS(P 1)3231, 94JCS(P 1)2091>.

Five-Membered Ring Systems: Furans

132

OH H

[0] 0

5-Hydroxyfizran-2(5I-I)-ones were prepared from furans <94S944>. The synthesis of new fluorobutenolides as templates for synthesis was reported <94IOC1210>. (S)-(+)-3-Hydroxytetrahydrofuran was used as starting material for an asymmetric synthesis of (S)-(+)-atrolactic acid <94IJC(B)200>. Furan- and pyrrole-containin= a-oligothiovhenes were prevared <94H1393>.

5

The preparation of furo- and benzofuro-2H-thiapyrans from furans and benzofurans was achieved <94S727>. (E)-2-Formyl-3-(2-furyl)-propenenitrile reacts with primary aromatic amines to form enaminonitriles in 76-88% yield <93CCC555>. C~

R-NH2

NHR

CH-'O

~:-~-.~., H NHR Diels-Alder reactions with furans offer a versatile route to many interestin8 ring systems. Treatment of furanophanes with cyanoacetylene provides an access to oxepinof'uranes <93PAC47>. The DielsAlder adducts of' furans and dichloro(neopentyi)silaethene rearrange to monocyclic Si-O seven-membered rings <93CB575>. In the presence of' an oxazaborolidine filran and 2-bromoacrolein yield the corresponding 7-oxabicyclo[2.2. ! ]heptene with high enantioselectivity <93TL3979>. Oxanorbomenones are also available from fiJrans <94HCA869>. Diastereoselective cycloadditions using furan substituted with a nonracemic amine were reported <94JOC3246>. ]ntramolecular Diels-Alder reaction of' vinylfiJrans leads to furanodecalins <93JCS(P])2395>. Further cycloadditions with vinylsubstituted furans were reported <93H537>. Furans may act as 2~-components in ],3-dipolar cycloadditions with nitrones <94JOC6843>. o-Quinodimethane derivatives are versatile synthons in or8anic chemistry. Preparation and reaction of f'uran-based o-quinodimethanes were reported <94JOC2594, 94JOC2613, 94SL459>. Cycloaddition reactions with f'uro[2,3-c]pyrroles and benzofuro[2,3c]pyrroles were also desribed <95T193>. The synthesis of' furoscrobiculin B 6a (and its epi.derivative 6b) was accomplished by an application of'the Kanematsu procedure <94CC ! 979>. OBn| "

~

V

0

OBn

o8o

base /

0

OBn

'

~ "

R1 .-R2

0 OH

~ =

R1 = OH ; R2 = Me b: RI = Me ; R2 .. OH

o:

~

0 6.~o.b_

Five-Membered Ring Systems: Furans

133

For further intramolecular Diels-Alder reactions with furans see <94TA1411, 94H1507>. Intramolecular cycloaddition of 4H,6H-thieno[3,4-c]furan-5,5-dioxide with subsequent extrusion of sulfur dioxide was reported <93JCS(Pl)2387>. The synthesis of cyclooctanoids was achieved by an intramolecular [4+3] reaction of oxyallylic (and alkoxyallylic) cations with furans <93JOC7393, 94JOC1241>. Dioxirane oxidation of furocoumarines (e.g., 7) yields an unstable epoxide, which is in equilibrium with a quinone methide. This latter compound can be trapped in a Diels-Alder reaction with ethyl vinyl ether <94LA689>.

OMe

OMe

OMe

7

Further work in this area: <94CB941, 93CB2697, 93JA8603>. Methylbenzofurans can be converted to salicylaldehydes by ozonolysis <93CPB 1166>. Furfural in the presence of sodium alcoholate oxidizes aliphatir and alicyclic alcohols to carbonyi compounds <93KGS25>. Furanoacetylene phytoalexins (wyerone, dihydrowyerone) were synthesized in multigram quantities starting from furfural <93TL2465>. Synthesis and chemical transformations of 5-hydroxymethylfurfural were summarized <94SC939>. 5.3.3 SYNTHESIS Fused 3-methylfurans are readily obtained by reaction of an allenic sulfonium bromide and the enolate anion of a cyclic 1,3-dicarbonyl compound <93JOC3960, 94JOC5970>. R3 0-" V

~'0

~" - - - " - - - ~ S'Me2Br"

i, NaOEt, EtOH

R3

ii. TsOH

R2 R1

Highly functionalized cyclopropanes were converted to furans <93TL7583>. MeO,,~ (~

SO2Ph

i, Bu"L;, N-ocylimidozole SO2Ph

ii. TsOH

R'I

R2

RI

A simple 4-step procedure to 2-substituted 4-(ethoxycarbonyl)furans starting from aldehydes was developed <93H1333>. C,02Et

RCH--O

*

~==CH 2

C02Et

--- =

R

CH2Br

3-(2'-Cyclopentenyl)-4-hydroxT[1]benzopyran-2-one (or its acetate) reacts with pyridine hydrotribromide to give a fused furochromene <94TL5927>.

C rsr 0

Five-Membered Ring Systems: Furans

134

4-Bromo-3-hydroxyketones, which are available by condensation of methylketones with 2-bromoketones in the presence of Bu' OMgBr, on boiling in pyridine/ethanol yield 2,4-disubstituted furans <94JOU202>. Higher condensed furans were also prepared from enolized -f-hydroxyketones <94JOC6606>. Fur-3-yl thiocyanates as well as other S-containing analogues were synthesized by a Michael-type addition of thiocyanic acid, thioacetio acid, alkanethiols, and sodium thiosulfate to alkynones followed by cyclization <93HCA2528>. Addition of allylic alcohols and alkynes in the presence of ruthenium catalysts yields a 13,y-unsaturated ketone, which after dihydroxylation and acid catalyzed cyclization creates a furan. This simple 2-step methodology was used for the synthesis of rosefuran <94JOC 1078>. ~OH

. R2-C--_.H

Ru-cotolyst ~

0

~ ~ R~

R2

i, Os-cotolyst ii, H" --_-

~ 1 R2

An efficient 3-step procedure was reported for the synthesis of 2,3-disubstituted furans from (ptolylsulfonyl)alkanes and 2-benzyloxyethanal. In this sequence l-benzyloxy-3-tosylalkenes are used as ena113 anion equivalents <93TL7487>. R~Tos

R1

i, LDA ii, (EtO)2P(O)CI, 8_ iii, H~ iv, BuaLi / R2CH-O v, H"

9B u O , / ' ~ , O H

R2

2,3,5-Trisubstituted furans are available by a selenium-promoted cyclization of or-substituted 13#-unsaturated ketones <94SL373>. Compounds of this type are also obtained by acid-catalyzed decomposition of 1,2-dioxan-3-ols, which are available from a Mn(II)- or Mn(III)-mediated cyclization of alkenes with active methylene compounds <94fHC1219>. King closure of y-ketoacids with phosphorous oxychloride/DMF gives 2-chloro-4-formylfurans <93SC2593>. Depending on substituents reaction of cr with (2,2-diethoxyvinylidene)triphenylphosphorane (or (2,2-diethoxyvinyl)triphenylphosphonium tetrafluoroborate) yields 2,2-diethoxy-2,5-dihydrofurans <94ZN(B)389>.

R2~ .R,

HO" ~ 0

Ph3P'--C

----K/OCt

",,--/!F 9 R" o(tl

xOEt

L

ph3p

Et

"BF4."

~

"

,~_~,R~R'

=- .j~,~^,,,'~ Rz u OEt

A facile approach to polysubstituted chiral dihydrofurans starts from pyranose triflates and monoanions of 1,3-dicarbonyl compounds <94CC1735>. Treatment of cyclopropylsulfides of type 9 with ammonium cerium nitrate (CAN) gives furans by a tandem oxidative ring cleavage-cylization reaction <94CC 1529>. RI.~,.SAr -

'

-

-

-

9

The bis-tetrahydrofuran fragment of asteltoxin was prepared by an acid-catalyzed ring closure of a partially protected y-hydroxyacetal <94JOC 1160>. Tetrahydrofurans are available from protected 7hydroxyalkanals <93MI53000>. An acid catalyzed ring closure was also used for the preparation of the C46-C55 fragment of cignatoxin <94CL1611>. A Sn(IV)-promoted [3+2]cycloaddition reaction of allylsilanes to ot-keto esters offers an attractive route to tri- and tetrasubstituted tetrahydrofurans <94CL627, 94TL8401>.

Five-Membered Ring Systems: Furans

R,~OR2

. . . ~ ~ $ i M e 2 Ph

0

RZOzC. ~ . ,

Me

=

135

'SiMe2Ph

RI "~'~"0/"" Me

Tetrahydrofurans are available by an electrophile induced cyclization of hydroxyalkenes <94JOC 6643, 94JOC5485>. The direct transformation of C-5-allylated 1,2-O-isopropylidenefuranose into tetrahydrofurans by treatment with iodonium dicollidine perchlorate ([DCP) was reported <94JOC 7986, 95"13.,649>. Trifluormethylated ~rans are available via iodocyclization of y-unsaturated trifluoroacetates <93JCS(P1)2787>. Homoallylalcohols were oxidized with high regioselectivity to or alkoxytetrahydrofurans using molecular oxygen and a Pd catalyst <94"13.,455>. Tetrahydrofurans of type 10 are available from ethyl-6-acetyloxy-2-aikenoates with sodium ethoxide <93SC 1009>. R ,,R AcO~CO2Et

......R ~CO=Et

~

10

A synthesis of enantiomerically pure trans-2,5-oligotetrahydrofurans was described. The stereochemical outcome was achieved by chelation control <93TL2299>. R~ .

~

t~=

.

_-... .

^

.= ^ .

.o-" .

.,..:2--

"--o.

Optically active furfuryl alcohols and hydroxy butenolides of the followin 8 type were prepared ~om trmts-l-trimethylsilyl-3-alken-]-ynes by successive asymmetric dihydroxylation and hydromagnesiation reactions <93TL 4975>. Me3Si.

Me3Si.

Intramolecular acylation of y-acyloxysuifones leads to 2,3-dihydrofurans <941OC2014>. 0

i,

ii, NH,Cl ~SOzTol

O

iii, TsOH

ol

Functionalized homoallyl alcohols can be cyclized with Pd(0) catalysts to give chiral 3-methylenetetrahydrofurans <93TL4655>. The cyclization of I],y-dihydroxyketones in the presence of acids yields fiJrans. Starting with (+)-Wieland-Miescher ketone this method was used for a total synthesis of (+)-pallescensin A <93JCR(S)58>. ?-Substituted ?-butyrolactones of high enantiomeric purity can be obtained from aldehydes by the following sequence of reactions <94JOC365>. R--CH=O

i, osymmetric ollylborotion . ii, protection OPG R'~'~

OPG ~

i, deprotection C02H

ii, lactonisotion

i, hydroboration

!o .

ii, CrO.1 O ~ R

0

Five-Membered Ring Systems: Furans

136

In a Passerini type reaction treatment of arylglyoxals with cyanoacetic acid and isocyanide yields 3aryl-2-cyanoacetoxy-3-oxopropionamides. Cyclization of these compounds under basic conditions gives 2-hydroxyfurans (2-furanones), albeit in low yield <93S783>. O Ar,~I,,,.CH=O + NCCHzCOzH § R_~__C O

O

= Ar~NHR CN,,,~O

Et3N =

~~11

NHR O

O

The condensation of o~-bromoketones with aromatic aldehydes provides a convenient route to substi.. tuted tetrahydrofurans <94TL9367>. Ar O /J~ K2CO3 / MeOH pri CHzBr + 2 ArCH=O Me ,..M e~M~O Tetrahydrofurans can also be prepared by the reaction of carbonyl compounds with 13,y-unsaturated ketones under the influence of a rhodium catalyst <93TL7971>. 0

R1, ' ~ . R2 §

Oh ~ ~.,~

[Rh(CI)(C2H4)2].

SnC= l~ 9RPh'

0

Treatment of ~-lactones of type 11 with TiCI~Et3SiI-Ioffers a stereoselective route to 2,5-substituted tetrahydrofurans <93TL6997>. 0

~~--'~O

TiCl, / Et3S;H M e ~ C H 2 C 0 2 H H v H

11 A base induced rearrangement of hydroxyoxazoline was reported to give tetrahydrofurans <93JOC 6180>. Synthetic approaches to 3-hydroxy-2(SH) furanones (isotetronic acids) starting with 2-Oalkyl-3,4-O-benzyliden-D-ribono-1,5-1actone were described <93T6717>. y-Z-Alkylidenbutenolides are available from y-bromoq3,y-unsaturated acids <93TL5963>. A versatile method for the preparation of 2-substituted 4-trimethylsilylfurans starting from allyltrimethylsilansand acid chlorides was reported <94SC2915>. Ring closure of y-hydroxyketones, which were prepared by a reductive ring opening of dihydroisoxazols, yields furans <94H641>. Furans can be also obtained by a rutheniumcatalyzed cyclization of hydroxyenones <94CC493> and by base-assisted cyclization of l-[3[hydroxy(substituted methyl))]propargyl]benzotriazoles <93JOC3038>. Treating l-(l,2-epoxyalkyl)2-alkynyl esters with Sm(II)/Pd(0) gives E/Z-mixtures of 2-alken-4-yn-l-ols, where the Z-isomer can be transformed directly into substituted fiJrans <94H223>. Cyclization of 13- and u allylic alcohols with base yields furans <94JOC 1703, 94JOC6110, 93JOC3602, 93JOC3435>. Allenes and lalkynyl-2,3-epoxyalcohols may also serve as starting materials <93JOC7180, 94JOC324, 94JOC 76, 94CC1879>. A molybdenum carbonyl complex promotes the cycloisomerisation of l-alkyn-4-ols to 2,3-dihydrofurans. Chromium and tungsten carbonyls give metal carbenes <93JOC6952>. R

Me(CO)s* NMe3 /~.~,~R OH

Cr(CO)s o r W(CO)s

R

M(CO)s

Five-Membered Ring @stems: Furans

137

2,3-Disubstituted furans were also prepared from ~lkynediols <93CC764>. Treatment of 2-(3-alkenl-oxy)-2-chloro acetates with a catalytic amount of Cu(bpy)Cl gives good yields of functionalized tetrahydrofurans . Avenaciolide and isoavenaciolide were prepared by this method <94JOC1993, 94JOC6671>. R3 R4 Rs R2

Cu(bpy)Cl

R4

R~/ -.0 r -,C02Me

R1

OzMe

5-Trimethylsilyl-2,3-dihydrofurans are available from p-trimethylsilyloxyketones using lithium trimethylsilyldiazomethane <94SL46 I>. An alkynol is an intermediate in this reaction. Examples of the newly developed tetrahydrofuran synthesis via radical and anionic cyclization were reported <94TL 5837, 94TL584 I>. Examples of free radical cyclization were published <93T4559>. A short enantioselective synthesis of (+)-nonactic acid and (-)-8-epi-nonactic acid induced by a chiral sulfoxide group was described <94JOC3898>. Compound 13 can be prepared by an enzyme-triggered ring closure <94T8661>. enzyme .,,~0

CMezOH

12

13

2,4-Disubstituted tetrahydrofurans are available from the fluorinated sulfoxide 14 <93T4253>.

0 Ri .F

Rz

Tol/~-~0/~R3

= Bu3SnH

R~ CHR2R3 0 Tol/~~~O-~

14

A stereoselective synthesis of substituted tetrahydrofurans was achieved by a nickel catalyzed carbozincation of 2-halogenmethylethyl allyl ethers <94TL8349>. X RIo~L~o

"~R

Et2Zn 2

/ ~

Ni(~176

RiO

H2ZnX R2

X -Br, [

Enolethers can be transformed to dihydrofurans using a molybdenum alkylidene complex as catalyst <94JOC4029>. pr i

ph.....~J.LO,~...,~__~ " cot.= p h ~ p

h

cot.:

,CMe(CF3)= I N-- MIO--" CH(CMe2Ph) "-"~prl CMe(CF3)2

Benzofurans were also prepared by this methodology. lntramolecular carbo-hydrogen insertion of carbenes generated by catalytic diazo decomposition is a facile method for carbon-carbon bond formation. Furans and derivatives thereof can be prepared by

Five-Membered Ring Systems: Furans

138

this procedure <94JA4507, 93JOC21, 93MI53004>. The synthesis of rac.-dihydrosesandn was reported <94TL3985>. ct-Suifonyl-s-acetylenic ketones on treatment with ButOK and Pd(dppe) may give furans <94SL447>. Probably palladium carbenoids are involved in this reaction.

ii. Pd(dppe)

Divalent palladium-catalyzed cyclization of allylic alkynoates yields a-alkyliden-y-butyrolactones <94PAC 1501, 93JCR(S)366>.

o o.r

The use ofbisphosphine ligands as chiral modifiers in the Rh(1)-catalyzed Diels-Alder reaction of 15 was studied <94T6145>. R'

'~~,,,~

_____

R'

R2

R2

15

Iododiols of type 16 can be cyclized in a carbonylation reaction to give (Z)-3-alkyliden-4,5-dihydro4-hydroxy-2(3 H)- furanones <94S 567>.

~.~

..CO = cot.

I

16

Dihydrofuraldehydes were prepared by an intramolecular silyl nitronate olefin cycloaddition with subsequent acidic workup <94JOC3783>.

~ R!

R2

!

i. TMSCl / Et3N

N02

ii, H"

0

H:O

The Pd-catalyzed annulation of 2-propargyi-l,3-dicarbonyl compounds with vinylic or aryl triflates or halides in the presence of potassium carbonate yields 2,5-disubstituted 3-acylfurans <93TL2813>. o

RI Me r ~'0

H_ e

R2

X~]~R 2

Pd(PPh3)4 / K2CO,~

Me "r ~ o / ~ R 2

N,N-Bis(trimethylsilyl)ynarnines react with DMAD (molar ratio: 1/2) to afford 3-cyclopropenylfu-

Five-Membered Ring @stems: Furans

139

rans <94CB 1287>. A new route to 2(SH)-furanones via ruthenium-catalyzed oxidative cyclocarbonylation was reported <94CC755>.

Ph

P~.~

RuCl2(PPh3)z I K2C03~ CO, ollylocetate

Ph,. Ph

0

Photocycloaddition of 2-alkynyl-substituted cyclohexenones with isobutene (and tetramethylethene) leads to tricyclic furans <94]0C5393>.

"['he synthesis of tetrasubstituted furans fi'om photocycloaddition of' conjugated acetylenic ~-diketones with alkenes was reported <94CC1821>. 4-Hydroxy-2-cyclobutenone on treatment with lead tetraacetate gives 5-acetoxy-2(SH)-furanones and 5-alkyliden-2(SH)-furanones <94JOC4707>. Photolysis of a cyclobutanone in the presence of methanol was reported to give a 2-methoxytetrahydrofuran <93JOC7913>. 6,6-Disubstituted furo[3,4-c]isoxazoles were prepared by intramolecular 1,3-dipolar cycloaddition of nitrones <94FRIC797>. An efficient synthesis of furanopyrone 17 starting with D-glucose was reported <94ffC(B)562>. i, cyclohexonone/H" ii, 70~ AcOH

D-glucose

iii, NolO4 iv, Ph3P"CHCOsEt

._.~v... T O ,,,O ~ // ~'~''O

17

Propargylic carbonates react with 13-ketoesters under catalytic influence of Pd(0) to give methylenefurans <93S1109, 93MI53005>.

//~.J

"

o

Oge

OMe

2,5-Dihydro-2-fiaranylamines were synthesized from N-protected 3,6-dihydro-l,2-oxazines by treatment with base <93TL961>.

C v

O

LDA

"C02Bu t

HBoc

The reaction of arylethoxymethylene iron complex 18 with alkynoates produces furans in 19-80% yield <93]A9848>. e(CO)4 RI

OEt

R=

alkynoate

f~~COsMe R1.__17_ ii

v

~OEt

The synthesis of tetrahydrofuran esters based on a formal [3+2]cycloaddition reaction of allyl(cyclo-

140

Five-Membered Ring Systems: Furans

pentadienyl)iron(H) dicarbonyl with carbonyl compounds was reported <93OM4280>. *

re(co)~(a,,y,)

=0

i, BF.I*Et20 ii ButOK

MeO

iii, CAN/CO/MeOH

Lithiation of propargylether 18 and subsequent treatment with metal hexacarbonyls (Cr, W) leads to 2-oxacyclic carbene complexes. OMe (

i, BunLi ii, M(CO)s

Ph

00Me

(CO)sM.~.~u % ~ P h

18

M = Cr M

= W

(44~.) (SSX)

The tungsten complex undergoes a Diels-Alder reaction with cyclopentadiene <95CB 157>. The preparation of the highly reactive ketipin acid dilactone (19) was reported <94LA961>.

o@o 2-Substituted cycloaikanoylfurans are available from cycloalkanones and 2,5-dihydro-2,5-dimethoxyfuran <94H2709>. 2).

+ MeO

OMe

R = Me, Et ;

H20, THF

L(CH2) a

n ,. 2-4

Asymmetric carbene C-O insertion reaction into oxetanes using optically active bipyridine-copper as catalyst yields tetrahydrofurans <94CL1857>. Several known methodologies were applied for the preparation of novel furans, e.g., cycloaddition of carbonyl ylides with alkenes <94JCS(PI) 2353>, addition of cyclic rhodium carbenoids to alkynes <94TL6229, 94TL6231>, and furans from oxazoles <94TL3609, 94TL3613, 93MI53006>. A versatile access to 4,6,7-trimethylbenzofurans is possible through one-electron oxidation of mesityl-substituted enols <94J-PR325>.

OH 2

2 eqs. of one -electron oxidant

R2

I

R'

one-electron oxidants: Fe(phen)3(PF6).~, CAN, N " (p-CsH(Br) 3 SnCl e"

The triethylamine-promoted selfcondensation of o-hydroxy-~-chloro-~-nitrostyrenes yields 1lH-benzofuro[3,2-][l]benzopyrans <94.rHC1021>. A versatile route to methyl 3-benzofuranylacetate employs the Heck reaction between 2-iodophenol and 2,5-dihydro-2,5-dimethoxy~ran <94H1745>. The well established interconversion between benzofurans and o-hydroxyphenylacetylenes was used for the synthesis of dihydrotremetone, a toxic ketone isolated from the weeds Eupatorium uracaefolium and Aplopappus heterophyllus <94H2463>. The successful use of flash vacuum pyrolysis for

Five-Membered Ring Systems: Furans

141

the preparation of benzo[b]furans starting with stabilized phosphorans was reported <94JCS(PI) 2455>. 0

PPh3

i, FVP, 700*C ii;, FVP, 850=C___

R

"OMe

Enantiomeric tetrahydrofuro[2,3-b]benzofurans were generated by an oxaza-Cope rearrangement of suitably functionalized O-aryloximes <94JOC3775>. R2

R2 OR s

OR5

H

i, -R2 ~

RI ~

Rz

ii, H"

' " ~ v , ~ ~ 0 s" .'

The synthesis of the furo[2,3-b]benzofuran fragment present in an aflatoxin was reported <94SL 437>. The occurrence of a dihydrobenzo[b]furan during the in-situ generation of a 3-(13-hydroxyalkyl)benzyne was observed <93TL6939>. The oxymercuration-reduction procedure of an o-ailyl substituted phenol was proved to be valuable for the synthesis of (-)aplysin <94JOC74>. Benzofuranones were generated by an oxidative cyclization of 2'-hydroxychalcones with TI(HI) <94TL 6441>. 2H[ 1]Benzopyrans and benzofurans were prepared by Clalsen rearrangement of aryl propargyl ethers <94LIC(B)593> and allyl aryl ethers <93H497>. For a CsF-mediated Clalsen rearrangement of aryl propargyl ethers see <93CPB 1166>. The formation of 5-hydroxy-2,3-dihydrobenzo[b] furans by a [3+2]cycioaddition of methacrolein N,N-dimethylhydrazone with 1,4-benzoquinones was reported <93H1553>. Highly functionalized benzo[b]furans are available in a Pd(0)/Cu(I) catalyzed reaction from iodophenols and trimethylsilylacetylene <93SL269>. Cyclization of dimedone with alkynes in the presence of Hg(lI)acetate in DMSO afforded tetrahydrobenzofurans <93ZORI067>. A facile synthesis of linear and angular 2-methylfurobenzopyranones by Pd assisted oxidative cyclization of allyl substituted phenols was reported <94BCJI972>. Dihydrobenzofurans were prepared by a three component Pd catalyzed cyclization-carbonylation anion capture process <94TL4429>.

'

oc

CO, NoBPh4

Benzofurans are also accessible from a-aryloxyacetophenons <94SL225>, by an intramolecular Friedel-Crafts reaction <94SC 1859, 94H177>, by a Pd-assisted C(3)-ring closure of an o-fluoroaryl alkyl ether <93TL5205, 93TL5209>, and an o-bromoallylphenylether <94PAC2087>. The synthesis of spirobenzofurans via base-mediated spiroarmulation of aromatic aldehydes and ketones with 2-chlo. rohexanone was reported <93TL3915>. The reaction of alkynyl-(p-phenylene)-bisiodonium triflates with sodium phenoxide gives benzo[b]furans <93TL4055>. Tf

OTf

PhONe, MeOH -0

R

A useful strategy for the regiospecific synthesis of highly substituted benzofurans rests on the re-

Five-Membered Ring Systems: Furans

142

arrangement of 4-hydroxy-2-cyclobuten-l-ones <94JOC3284>. OH

OH

Toluene,110=C

Me,,),..~_J

OH

Me

4-Chloro-2,3-disubstituted 2-cyclobutenones undergo a Pd-assisted cross-coupling reaction with 2stannylated furans to give 4-hydroxybenzofurans <93JOC3550>. RI .0 ~ 2~R3 CI * Bu%Sn R

R4 Rs

Pd-cotolyst

R R

OH ~

R4 R5

The Pd-catalyzed cross-coupling reaction of o-iodomethoxybenzenes with bromo olefins gives benzofurans <931OC6426>. The total synthesis of corianddn, an antiviral agent with benzofuran structure, was reported <94JOC4735>. The well known lactonization of olefins mediated by Mn(III) was carried out under ultrasonic irradiation at low temperatures <93T10705>. New approaches to the synthesis of rotenone were reported <94MI53002>. Benzo[c]furans have remained a field of active research, especially as trapping agents for unstable alkenes (and related compounds) <93CB1827, 93CB2531, 93JA2637, 93JA7173, 93JCR(S)293, 93JCS(P 1)321, 93JOC4113, 93TL6151, 93SL415> and as synthons for the construction of complex molecules <93CB2543, 93ZN(B)213, 94JA9921, 94SL75>. The reaction of furofurans, thienofurans, furobenzofurans, benzothienofurans and furoindoles were investigated <93CB775, 93SL333>. [2,2](4,7)Isobenzofuranophane (20, R-Ph) was prepared in a conventional manner by reduction ofthe corresponding o-diacyl arene.

2_Ao The parent compound (20, RfH) could be generated by a retm Diels-Alder reaction and trapped with p-benzoquinone <94CB2263>. The preparation of an iptycene by a Diels-Alder reaction was reported <93TL5331>. The unusual stability ofN-methyl maleinimide cycloadducts was studied by computational methods (MP2/6-31G*//HF/6-31G*) <93JOC6701>. 5.3.4MISCELLANEOUS

Reviews of furans as bulding blocks in organic synthesis <93M153003>, of synthetic mutes to 2,5disubstituted tetrahydrofurans <93TA1711>, of syntheses of s <94OPPI>, of syntheses of 1,4-dicarbonyl compounds and cyclopentenonesfrom furans <94S867>, and of synthetic approaches to butenolides <94M]5300]> were published. A detailed 'H-NMR analysis of bistetrahydros was carried out <94TL3919>. A systematic investigation of the mesogenic potential of furan derivatives in terms of geometrical and polar structural characteristics was undertaken <93H1225>.

Five-Membered Ring Systems: Furans

143

5.3.5 REFERENCES 92M153001 93AG406 93AG(E)432 93CB575 93CB975 93CB1827 93CB2531 93CB2543 93CB2697 93CC764 93CCC555 93CL1513 93CPB1166 93H497 931-1537 93H1225 93H1333 93H1553 93HCA2528 931JC(B)566 93JA2637 93JA7173 93JA8603 93JA9848 93JCR(S)58 93JCR(S)293 93JCR(S)366 93JCS(Pl)321 93JCS(Pl)2387 93JCS(Pl)2395 93JCS(Pl)2787 93JOC21 93JOC3038 93JOC3435 93JOC3550 93JOC3602 93JOC3960 93JOC4113 93JOC4722 93JOC6180 93JOC6426 93JOC6701 93JOC6952 93JOC7180 93JOC7393 93JOC7913 93JOM(C3) 93KGS25 93M153000 93M153001 93M153002 93MI53003 93M153004 93M153005

N.Kongkathip, B.Kongkatldp, J.sei.Soc.Thailand 1992, 18, 225; Chem.4bstr. 1994, 121, 255443 Z.Z.Song, Z.Y.Zhou, T.C.Mak, H.N.C.Wong, Angew.Chem. 1993,105, 403 Z.Z.Song, Z.Y.Zhou, T.C.Mak, H.N.C.Wong, Angew.Chem., Int.Ed.Engl. 1993,32, 432 N.Auner, A.Wolff, Chem.Ber. 1993, 126, 575 W.El~rbar N.Laber, J.BussenJus,H.Fritz, G.Rihs, Chem.Ber. 1993, 126, 975 G.Maier, R.Wilmes, H.Fuchs, M.Leinweber, Chem.Ber. 1993, 126, 1827 B.K0nig, B.KnJeriem, K.Rauch, A.de Meijere, Chem.Ber., 1993 126, 2531 H.Schirmer, A.-D.SchlQter, V.Enkelmann, Chem.Ber. 1993, 126, 2543 W.Adam, M.Sauter, Chem.Ber. 1993,126, 2697 J.Ji, X.LII,J.Chem.,~., Chem.Commun. 1993, 764 P.Safar, F.Povaz~ec, L.Zalibera,D.Berkes, ColI.C:ech.Chem.Commun. 1993, JS, 555 E.Hala, T.Takai, T.Mukaiyama, Chem.Lett. 1993, 1513 H.hhii, S.Ohta, H.Nishioka, N.Hayashida, T.Harayama, Chem.Pharm.Bull. 1993, 41, 1166 K.M.Kim, H.R.Kim, E.K.Ryu, Heterocycles 1993, 36, 497 J.Ancerewicz, P.Vogel, Heterocycles 1993. $6, 537 G.Costa, A.Gandini, S.Morinelli, B.Valenti, Heterocycles 1993, 36, 1225 R.C.Anand, V.Singh, Heterocycles 1993, 36, 1333 J.A.Valderrama, M.F.Gonzalez,Heterocyeles 1993, 36, 1553 U.Huber, D.Bergamin, Helv.Chim.Acta 1993, 76, 2528 E.-S.A.AIy, Indlan.J.Chem., Sect. B 1993, 32, 566 A.Padwa, D.J.Austin, Y.Gareau, J.M.Kassir, $.L.Xu,J.Am.Chem.~. 1993, liJ, 2637 R.Pinkos, J.-P.Melder, K.Weber, D.Hunider, H.Prinzbach,J.Am.Chem.,~c. 1993, 115, 7173 W.Adam, L.Hadjiarapoglou,K.Peters, M.Sauter,JAm.Chem.Soc. 1993, llJ, 8603 Atiq-ur.Rehman, W.F.K.Schnatter, N.Manolache,J.,4m.Chem.Soc. 1993, II.T, 9848 K.Shishido, K.Umimoto, M.Ouchi, O.Irie, T.Omodani, T.Takata, M.Shibuya,J.Chem.Res. (S) 1993, 58 Y.S0tbeyaz, M.Ceylan, H.Sefen, J.Chem.Res.(~) 1993, 293 G.Zhu, S.Ma, X.Lu, J.Chem.Res.(S) 1993, 366 M.S.Baird, H.L.Fitton, W.Clegg, A.McCamley,J.Chem.Sor Perkin Trans. 11993, 321 T.Hayashi, Y.Kawakami, K.Konno, H.Takayama,J.Chem.~c., Perkin Trans. 11993, 2387 P.Cornwall, C.P.DelI, D.W.Knight,J.Chem.,~c., Perkin Trans. 11993, 2395 J.P.Begue, D.Bonnet-Delpon,R.Dogbeavou,M . ~ t c h , J.Chem.Soc., Perldn Trans 11993, 2787 A.Padwa, F.R.Kinder,J.Org.Chem. 1993, 58, 21 A.P,.Katritzky, J.Li, M.F.Gordeev,J.Org.Chem. 1993, J8, 3038 J.A.Marshall, W.J.DuBay,J.Org.Chem. 1993, $8, 3435 L.S.Liebeskind, J.Y.Wang, J.Org.Chem. 1993, ,TS,3550 J.A.Marshall, W.J.DuBay,J.Org.Chem. 1993, J8, 3602 M.Aso, A.Ojida, G.Yang, O.J.Cha, E.Osawa, K.Kanematsu,J.Org.Chem. 1993, 58, 3960 J.Podlech, K.Polborn, G.Szeimies,J.Org.Chem. 1993, J8, 4113 K.H.Reuter, W.J.Scott,J.Org.Chem. 1993, 58, 4722 K.J.Wilson, G.J.McGarvey,J.Org.Chem. 1993, J8, 6180 G.Dyker,J.Org.Chem. 1993, JS, 6426 D.Tobia, R.Harrison, B.Phillips, T.L.White, M.DiMare, B.Rickborn,J.Org.Chem. 1993, .T8, 6701 F.E.McDonald, C.B.Connolly,M.M.Gleason, T.B.Towne, K.D.Treiber,J.Org.Chem. 1993, 58, 6952 J.A.Marshall, K.G.Pinney,J.Org.Chem. 1993, 58, 7180 M.Harmata, B.F.Herron,J.Org.Chem. 1993, 58, 7393 A.Mittra, $.Biswas, R.V.Venkates~varan,J.Org.Chem. 1993, 58, 7913 J.R.Studley, M.Will$,J.OrganometChem. 1993, 455, C3 Y.M.Shapim, Khim.GeterotsikI.Soedin. 1993, 25; Chem.Abstr. 1993, 119, 270933 B.Xu, Y.Ke, X.Xu, Youfl Huarue 1993, 13, 61; Chem.Abstr. 1993, 118, 233796 E.-S.A.AIy, Proc.Pak.Acad.Sci. 1993, 30, 163; Chem,4bstr. 1994, 121, 255539 F.Ozawa, A.Kubo, T.Hayashi,AC$ Symp.Ser. 1993, JlT, 75; Chem.Abstr. 1993,118, 254652 M.E.Maier, Nachr.Chem.Techn.Lab. 1993, 41, 696 S.Kim, J.R.Cho, Bull.Korean Chem.Soc. 1993,14, 664; Chem.Abstr. 1994, 121, 9054 L.Geng, X.Lu, Chln.J.Chem. 1993, il, 91; Chem,4bstr. 1994, 120, 323122

144

93MI53006 93OM4188 93OM4280 93PAC47 93S783 93S1109 93SC1009 938C2593 93SLA0 93SL269 93SL333 93SL415 93T4253 93"1"4559 93T6717 93T10705 93TA1711 93TL961 93TL2299 93TL2465 93"1"I,2813 93TL3915 93TL3979 93TL4055 93TL4655 93TL4975 93TL5205 93TL5209 93TL5331 93TL5963 93TL6151 93TL6939 93TL6997 93TL7487 93TL7583 93TL7971 93ZN(B)213 93ZORI067 94AG1211 94BCJI972 94CB941 94CB1287 94CB2263 94CC303 94CC493 94CC755 94CC1529 94CC1605 94CC1735 94CC1821 94CC1879 94CC1979 94CL627 94CL1611

Five-Membered Ring Systems: Furans W.Pei, J.Pei, J.Chen, Y.Li, X.Ye, Befln8 Daxue Xuebao Ziran Kerueban 1993, 29, 129, Chem~4bstr. 1994, 121, 9053 F.Ozawa, A.Kubo, Y.Matsumoto, T.Hayashi, E.Nishioka, K.Yanagi, K.Moriguchi, Organometailics 1993, 12, 4188 S.Jian& E.Turos, Organometallics 1993, 12, 4280 H.Hopf, B.Witulski, Pure AppI.Chem. 1993, 65, 47 R.Bossio, S.Marcaccini, P,.Pepino,T.Torrcba, Synthesis 1993, 783 N.Greeves, J.S.Torode, Synthesis 1993, 1109 R.A.Bunce, M.J.Bennett, $),nth.Commun. 1993, 23, 1009 M.Venugapal, B.Balasundamm, P.T.Perumal, Synth.Commun. 1993, 25, 2593 R.W.Carlin8, P.D.Leeson, S),nlett 1993, 40 l.Candiani, S.DeBemardinis, W.Cabri, M.Marchi, A.Bedeschi, Synlett 1993, 269 Y.Miki, H.Hachiken, ~ l e t t 1993, 333 H.M.R.Hoffmann, A.Wulferding, Synlett 1993, 415 A.Arnone, P.Bravo, F.Viani, G.Cavicchio, M.Crucianelli, V.Malchetfi, 7"etrahedron 1993, 49, 4253 C.Hackmann, H.J.Schafer, Tetrahedron 1993, 49, 4559 J.Bigorra, J.Font, C.Ochoa de Echaguen, R.M.Ortuno, Tetrahedron 1993, 49, 6717 M.Allegretti, A.D'Annibale, C.Trogolo, Tetrahedron 1993, 49, 10705 J.C.Harmange, B.FHgadere, Tetrahedron Asymmetry 1993, 4, 1711 M.C.Desai, J.L.Doty, L.M.Stephens, K.E.Brishty, Tetrahedron Lett. 1993, 34, 961 U.Koert, M.Stein, K.Harms, Tetrahedron Lett. 1993, 34, 2299 l.Delamarche, P.Mosset, Tetrahedron Left. 1993, 34, 2465 A.Arcadi, S.Cacchi, R.C.Larock, Telrahedron Left. 1993, 34, 2813 T.Sumathi, K.K.Balasubramanian, 2"etrahedron Lett. 1993, 34, 3915 E.J.Co~'y, T.P.Loh, Tetrahedron Left. 1993, 34, 3979 T.Kitamura, L.Zhen8, H.Taniguchi, M.Sakurai, R.Tanaka, Teirohedron Left. 1993, .~4,4055 T.A.J.van der Heide, J.L.van der Baan, E.A.Bijpost, F.J.J.de Kanter, F.Bickelhaupt, G.Klumpp, Tetrahedron Lett. 1993, 34, 4655 K.Tani, Y.Sato, S.Okamoto, F.Sato, Tetrahedron Lett. 1993, 34, 4975 Z.Jin, P.L.Fuchs, Tetrahedron Left. 1993, 34, 5205 S.W.Lee, P.L.Fuchs, Tev'ahedron Left. 1993, 34, 5209 F.M.Raymo, M.F.Parisi, F.H.Kohnke, 7"etrahedronLett. 1993, 34, 5331 X.Lu, X.Huang, S.Ma, Tetrahedron Left. 1993, 34, 5963 B.Halton, A.J.Kay, A.T.McNichols, P.J.Stang, Y.Apeloi& 7"etrahedron Left. 1993, J4, 6151 M.A.Birkett, D.W.Knight, M.B.Mitcheil, Tetrahedron Left. 1993, 34, 6939 K.T.Mead, S.K.Pillai, Tetrahedron Left. 1993, 34, 6997 D.Craig, C.J.Etheridge, Tetrahedron Lett. 1993, 34, 7487 P.H.Lee, J.S.Kim, Y.C.Kim, S.Kim, 7"etrahedron Left. 1993, 34, 7583 V.V.Ipalkin, l.P.Kovalev, A.V.Ignatenko, G.I.Nikishin, Tetrahedron Lett. 1993, 34, 7971 J.Nagel, W.Friedrichsen, T.Debaerdemaeker, Z.Naturforsch., 11, 1993. 48, 213 Z.A.Chobanyan, T.L.Badanyan, M.R.Tirakyan, S.O.Badanyan, Zh.Org.Khtm. 1993, 29, 1067; Chem~4bstr. 1994, 120, 269980 G.Markl, H.Sauer, P.Kreitmeier, T.Burgemeister, F.Kastner, G.Adolin, H.N0th, K.Polborn, Angew.Chem. 1994, 106, 1211 Y.J.Rao, G.L.D.Kntpadanam, Bali.Chem.Soc.Jpn. 1994, 67, 1972 W.Adam, M.Ahrweiler, M.Sauter, Chem.Ber. 1994, 127, 941 N.Schulte, M.H.Moeiler, U.Rodewald, E.-U.W0rthwein, Chem.Ber. 1994, 127, 1287 B.KC)nig, S.Ramm, P.Bubenitscheck, P.G.Jones, H.Hopf, B.Knieriem, A.de Meijere, Chem.Ber. 1994, 127, 2263 J.-P.Dulcere, N.Baret, J.Rodrisuez, J.Chem.~c., Chem.Commun. 1994, 303 B.Seiller, C.Bruneau, P.H.Dixneuf,J. Chem.Soc., Chem.Commun. 1994, 493 T.Kondo, K.Kodoi, T.Mitsudo, Y.Watanabe,J.Chem.Soc., Chem.Commun. 1994, 755 Y.Takemoto, T.Ohra, S.Furuse, H.Koike, C.lwata, 3.Chem.Soc., Chem.Commun. 1994, 1529 G.R.Pettit,Z.A.Cichacz, C.L.Herald, F.Gao, M.R.Boyd, J.M.Schmidt, E.Hamel, R.Bai, J.Chem.Soc., Chem.Commun. 1994, 1605 T.H.AI-Tel, Y.AI-Abed, W.Voelter,J.Chem.Soc., Chem.Commun. 1994, 1735 A.K.Mukherjee, W. C.Agosta, J. Chem.Soc., Chem.Commun. 1994, 1821 C.M.Maron, S.Harper, R.Wrigglesworth,J.Chem.Soc., Chem.Commun. 1994, 1879 T.Ogino, C.Kurihara, Y.Baba, K.Kanematsu, J.Chem.Soc., Chem.Commun. 1994, 1979 T.Akiyama, K.Ishikawa, S.Ozaki, Chem.Lett. 1994, 627 T.Oka, A.Murai, Chem.Lett. 1994, 1611

Five-Membered Ring @stems: Furans 94CL1857 94CL2143 94CPB1163 94CPB1175 94CPB1202 94CPB1216 94CPB1370 94H177 941-1223 94H641 94H1393 94H1507 94H1745 94H2463 941-12709 94HCA869 94UC(B)I48 941JCtB)200 94UC(B)562 94UC(B)593 94JA4507 94JA9921 94JCS(Pl)I975 94JCS(Pl)2091 94JCS(Pl)2353 94JCS(Pl)2455 94JCS(Pl)2943 94JCS(Pl)3231 94JHC797 94JHC1021 94JHC1219 94JOC33 94JOC67 94JOC74 94JOC324 94JOC365 94JOC~15 94JOCI078 94JOC1160 94JOC1210 94JOC1241 94JOC1598 94JOC1703 94JOC1993 94JOC2014 94JOC2594 94JOC2613 94JOC3246 94JOC3284 94JOC3433 94JOC3472 94JOC3775 94JOC3783 94JOC3898 94JOC4029

145

K.Ito, T.Katsuki, Chem.Lett. 1994, 1857 N.Hayashi, T.Mine, K.Fujiwara, Chem.Lett. 1994, 2143 M.Sahai et al., Chem.Pharm.BulL 1994, 42, 1163 Y.Fujimoto, C.Murasaki, H.Shimada, S.Nishioka, K.Kakinuma, S.Singh, M.Singh, Y.K.Gupya, M.Sahai, Chem.Pharm.BuU. 1994, 42, 1175 H.Hcymm~ Y.Tczuka, T.Kikuchi, S.Supriyatn& Chem.Pharm.Bull. 1994, 42, 1202 T.Matsuda, M.Kumyanagi, S.Sugiymna,K.Umehara, A.Ucno, ICNishi, Chem.Pharm.Bull. 1994, 42, 1216 F.Nagashima, S.Takaoka, Y.Asakaw& S.Huncck, Chem.Pharm.BulL 1994, 42, 1370 L.Novak, P.Kovacs, P.Kolonits, C.Szantay,Eeterocycle$1994, 38, 177 J.M.Aurrr M.Solay-lspizua,Heteroc'ycles 1994, .:17,223 K.Shishido, K.Umimoto, M.Shibuy~ Eeterocycles 1994, 38, 641 L.-H.Chen, C.-Y.Wang, T.-M.H.Luo,Heterocycle$1994, 38, 1393 H.-J.Wu, S.-H.Lin, C.-C.Lin, Heterocycles 1994, 38, 1507 K.Samizu, K.Ogasawara, Heterocycles 1994, 38, 1745 K.Hiroya, K.Hashimura, K.Oguawam, Heterocycles 1994, 38, 2463 O.Duval, A.Rguigue, L.M.C~m~, Heterocyclcs 1994, 38, 2709 L.Meerpoel, M . : M . V ~ B.Deguin, P.Vogel, Helv.Chim~tcta 1994, 77, 869 A.S.R.Anjaneyulu, M.J.R.V.Venugopal, C.V.S.Pmkash,Indian J.Chem., ~r B 1994,33, 148 V.K.Tandon, V.Agarwal, A.M.van Lou~n, Indian J.Chem., ~ct.B 1994, 35, 200 S.Baskaran, G.ICTrivedi,Indian J.Chem., Sr 1994, 33, 562 C.P.Rao, A.Prashant, G.L.D.Krupadanam,Indian J.Chem., Sect.B 1994, 33, 593 M.P.Doyle, A.B.Dyatkin, G.H.P.Roo$,F.Canas, D.A.Pierson, A.van Basten, P.lViueller, P.Polleux, J~tm.Chem.Soc. 1994,116, 4507 J.A.Wendt, P.J.Gauvreau, R.D.Bach,J,4m.Chem.Soc. 1994, 116, 9921 H.Makabe, A.Tanaka, T.Oritani, J.Chem.~o.o Perktn Trans. 11994, 1975 T.Honda, M.Hoshi, K.Kanai, M.Tsubuki,J.Chem.,~o., Perkln Trans. 11994, 2091 M.Kotera, K.Ishii, O.Tamura, M.gakamoto,or.Chem.Soc.,Pcrkin Trans. I 1994, 2353 R.A.Aitken, G.Burt~ J.Chem.Soc., Perkin Trans. 11994, 2455 J.-Y.Lenoir, P.Ribc~reau,G.Qu~guincr,J.Chcm.Soc., Perkin Trans. 11994, 2943 Z.-C.Yang, W.Zhou,J.Chcm.Soc., Perkln Trans. 11994, 3231 R.Sr P.C~rardin, B.Loubinoux,J.Heterocycl.Chem. 1994, 31, 797 D.Dauzonnc, C.Grandjean, J.Heteror 1994, M, 1021 C.-Y.Qian, J.Hiro~, H.Nishino, K.Kurozawa,J.HeterocycI.Chem. 1994, 31, 1219 Z.Z.Song, H.N.C.Wong,J.Org.Cbem. 1994, 59, 33 S.Hormuth, H.U.Reissig,J.Org.Chem. 1994, 59, 67 H.Nemoto, M.Nagamochi, H.lshibashi, K.Fulmmoto,J.Org.Chem. 1994, .59, 74 J.A.Marshall, B.Yu, J.Org.Chem. 1994, .59, 324 H.C.Brown, S.V.Kulkami, U.S.Racherla,J.Org.Chem. 1994, 59, 365 M.Sasaki, M.Inoue, K.Tachibana, J.Org.Chem. 1994, .59, 715 B.M.Trosk J.A.Flyga~, J.Org.Chem. 1994, .59, 1078 J.Mulzer, J.-T.Mohr,J.Org.Chem. 1994, .59, 1160 T.B.Patrick, M . V . ~ C.Yang, J.K.Walker, C.L.Hutchinson, B.E.Neal, J.Org.Chem. 1994, .59, 1210 M.Harmata, g.Elahmad, C.L.Barnes,J.Org.Chem. 1994, .59, 1241 J.-G.Yu, X.E.Hu, D.K.Ho, M.F.Bean, R.E.$tephens, J.M.Cassady,L.g.Brinen, J.Clardy, J.Org.Chem. 1994, .59, 1598 J.A.Marshall, W.I.DuBay,J.Org.Chem. 1994, .59, 1703 J.H.Udding, Kees (C.) J.M.Tuijp, M.N.A.van Zanden, H.Hiemstra, W.N.Speckamp,J.Org.Chem. 1994, .59, 1993 H.K.Jac,obs, A.S.Gopalan,J.Org.Chem. 1994, .59, 2014 W.g.Trahanovsky, Y.J.Huang, M.Leung,J.Org.Chem. 1994, .59, 2594 W.S.Trahanovsky, C.-H.Chou, T.J.Cassady, J.Org.Chem. 1994, .59, 2613 R.H.$chlessinger, T.R.R.Pettus, J.P.Springer, K.Hoogsteen,J.Org.Chem. 1994, .59, 3246 H.Liu, L.M.Gayo,R.W.Sullivan, A.Y.H.Choi, H.W.Moore,J.Org.Chem. 1994, .59, 3284 R.D.Walkup, S.W.Kim,J.Org.Chem. 1994, .59, 3433 Z.Gu, X.Fang, L.Zeng, R.Song, J.H.Ng, K.V.Wood, D.L.gmith, J.L.McLaughlin,J.Org.Chem. 1994, 59, 3472 E.R.Civitello, H.Rapoport,J.Org.Chem. 1994, .59. 3775 J.L.Duffy, M.J.Kurth, J.Org.Chem. 1994, 59, 3783 G.Soiladi6, C.Dominguez,J.Org.Chem. 1994, .59, 3898 O.Fujimara, G.C.Fu, R.H.Gmbbs,J.Org.Chem. 1994, .59, 4029

146

94JOC4698 94JOC4707 94JOC4735 94JOC5393 94JOC5485 94JOC5970 94JOC6110 94JOC6606 94JOC6643 94JOC6671 94JOC6843 94JOC7986 94JOU202 94JPR325 94JPS1163 94LA689 94LA961 94MI53001 94M153002 94MI53003 94M153004 94MI53005 94M153006 94M153007 94M153008 94MI53009 94M153010 94OPPI 94P39 94P133 94P163 94P213 94P249 94P1267 94P1271 94P!285 94P1297 94P1325 94P1371 94P1375 94P1469 94P1499 94P1527 94P1588 94P1588 94PAC1501 94PAC2087 94S567 94S639 94S727 94S867 94S944 94S1450

Five-Membered Ring Systems: Furans J.Kobayashi, N.Yamaguchi, M.Ishibashi,J.Org.Chem. 1994, $9, 4698 Y.Yamamoto, M.Ohno, S.Eguchi,J.Org.Chem. 1994, Jg, 4707 G.A.Knms, J.Ridgcway,J.Org.Chem. 1994, 59, 4735 P.Mar~ $.l~ichow, W.C.Agosta,J.Org.Chem. 1994, $9, 5393 N.Dc Kimpe, M.Boclens, J.Baclc,J.Org.Chem. 1994, .59, 5485 A.Ojida, F.Tanoue, K.Kanematsu,J.Org.Chem. 1994, .59, 5970 J.A.Marshall, C.E.l~nnr J.Org.Chem. 1994, .59, 6110 N.Harada, T.Sugioka, H.Uda, T.Kuriki, M.Kobayashl, l.Kitagawa,J.Org.Chem. 1994, .59, 6606 P.Galatsis, $.D.M/llan, P.Nechala, G.Fcrguson,J.Ors.Chem. 1994, 59, 6643 J.H.Uddin& J.P.M.Gi~selink, H.Hiemst~ W.N.$pcckamp,J.Org.Chem. 1994, .59, 6671 C.Camiletti, L.Poletti, C.Trombini,J.Org.Chem. 1994, .59,6843 W.Shan, P.Wilson, W.Lang, D.P.Mootov,J.Org.Chem. 1994, .59, 7986 A.V.Kerin, O.G.Kulinkovich, J. Org.Chem.U ~ (En$1.Transl.) 1994, 30, 202 M.Roeck, M.Schmittel,J.Prakt.Chem. 1994, $36, 325 M.Sahai et al., J.Pharm.ScL 1994, 42, 1163 W.Adam, M.Sauter, LiebigsAnn.Chem. 1994, 689 H.D.Stachel, M.Junskenn, C.Koser-Gnoss,H.Poschentieder, J.Redlin, Llebi&sAnn. Chem. 1994, 961 D.W.Knight, Contemp. Org.~/nth. 1994, !, 287 S.A.Ahmad-Junan, P.C.Amos, G.S.Cockeriil,P.C.l.~-vett,D.A.Whitin$, Biochem.~r Trans. 1994, 22, 237; Chem~4bstr. 1994, 121, 205017 T.Umezawa, M.Shimada, Moku:ai Gakkaishi 1994, 40, 231; Chem.Abstr. 1994, 121, 157395 G.M.K~nig, A.D.Wrisht, J.Nat.Prod. 1994, .57, 477 T.C01man-Saiza~itoria, J.Zambrano, N.R.Ferrigni, Z.-M.Gu, J.H.N8, D.L.Smith, LL.McLaushlin,J.Nat.Prod. 1994, .57, 486 R.C,Lih, A.L.Skaitsounif,,E.Seguin, F.Tillequin, M.Koch, Planta medica 1994, 60, 168 J.Wandji, Z.T.Fomum, F.Tiilequin, A.L.Skaitsouni&M.Koch, Planta medlca 1994, 60, 178 A.Fontana, E.Tdvellone, E.Mollo,J.Nat.Prod. 1994, .57, 510 G.Trimurtulu, D.J.Faulkner,J.Nat.Prod. 1994, .57, 501 H.Itokawa, O.Shirota, H.Morita, K.Takeya,Y.litaka, J.Nat.Prod. 1994, .57, 460 A.J.Allen, V.Vaillancour~K.F.Abizati, Org.Prep.Proc.lnt. 1994, 26, 1 M.Nakatani, P,.C.Huang, H.Okamura, H.Naoki, T.lwasawa, Phytochemistry 1994, 36, 39 $.P,astogi, ~Pal, D.K.Kuis~tha, Phytochemistry 1994, J6, 133 R.D.lknnett, $.Hasegawa, R.Y.Won& PhytochemIstr,/1994, 36, 163 W.-S.Sheen, l.-L.Tsai, C.-M.Ten& l.-S.Ch 9 Phytochemistry 1994, 3.5, 213 R.Torres, L.Villaroel, A.Urzua, F.D.Monache, G.D.Monache, E.Gacs-Baitz, Phytochemistry 1994, 36, 249 J.Hohmann, Z.Dini, l.Pelczer, G.Jerkovieh,Phytochemistry 1994, $5, 1267 A.F.Barrero, J.F.Sanehez, E.J.Alvarez-Manzaneda,M.M.Dorado, A.Haidour, Phytochemistry 1994, 3,5, 1271 P.l.Bozov, G.Y.Papanov, P.Y.Malakov,Phytochemistry 1994, 3.5, 1285 H.R.EI-Seedi, A.C.Hazell, K.B.G.Torssell,Phytochemlstry 1994, 3.5, 1297 A.Hisham, G.Sunith& U.Sreekala, L.Pieters, T.De Bruyne, H.Van den Heuvel, M.Claey$, Phytochemlstry 1994, 3.5, 1325 M.Bruno, C.Fazio, S.Passananti, M.P.Paternostro, J.G.Diaz, W.Herz, Phytochemistry 1994, 35, 1371 ~N.Yadav, V.Thakur, Phytochemistry 1994, 3.5, 1375 N.P.Lopes, S.D.C.Franca, A.M.S.Pereira, J.G.S.Maia, M.J.Kato, A.J.Cavalheiro, O.R.Gottlieb, M.Yoshida, Phytochemtstry 1994, 3.5, 1469 F.No~lia, P.Mendes, E.R.Silveira, Phytochemlstry 1994, 3.5, 1499 H.Achenbaeh, H.HQbner, W.Brandt, M.Reiter, Ph.vtochemistry1994, JS, 1527 M.L.Ybarra, C.A.N.Catalan, J.G.Diaz, W.Herz, Phytochemistry 1994, 3.5, 1585 E.C.De Riscala, M.A.Fortun& C.A.N.C.atalln, J.G.Diaz, W.Herz, Phytochemistry 1994, 3.5, 1588 X.Lu, $.Ma, J.Ji, G.Zhu, H.Jiang, Pure AppI.Chem. 1994, 66, 1501 A.P.Kozikowski, D.Ma, L.Du, N.E.Lewin,Pure AppI.Chem. 1994, 66, 2087 W.Adam, P.KIu8, Synthesis 1994, 567 S.V.Levy,J.Norman, W.P.Grifl]th, $.P.Marsden, b)rnthesis 1994, 639 T.Saito, T.Shizuta, H.Kiguehi, J.Nakagawa, K.Hirotsu, H.Ohmura, S.Motoki, Synthesis 1994, 727 G.Piancatelli, M.D'Auria, F.D'Onofrio,Synthesis 1994, 867 M.Rosario Iesce, F.Cermola, M.L.Graziano, R.Scarpati, ~thesls 1994, 944 A.Dondoni, F.lunquera, F.L.Merchan, P.Merino, T.Tejero, Synthesis 1994, 1450

Five-Membered Ring Systems: Furans

94SC939 94SC1859 94SC2915 94SL40 94SL75 94SL225 94SL373 94SIA37 94SIA47 94SIA59 94SL461 94SL821 941"3363 94T6145 94T8661 941'11315 94TA1411 94TIA55 94TL1247 94TL2517 94TL3609 94TL3613 94TL3919 94TL3985 94TIAI83 94TL4187 94TIA429 94TIA887 94TL5335 94TL5837 94TL5841 94"11.,5927 94TL6229 94TL6231 94TL6441 94TL8349 94TL8401 94TL9367 94TL9435 94ZN(B)389 95CB157 95T21 95T193 95TL649

147

L.Cottier,O.Descotes,J.Lewkowsld, ~,ntb.Commun. 1994, 24, 939 K.M.Kim, H.R.Kim, K.H.Chung, J.H.Song, E.K.Ryu, S vnth.Commun. 1994, 24, 1859 K.-T.Kan8, J.S.U, S.S.Hwang, K.K.Jyun& Synth.Commun. 1994, 24, 2915 K.Horita, M.Nagasawa, S.Hachiya, O.Yonemitsat,~ynlett 1994, 40 M.LOlller, A.-D.Schl0ter, ~lett 1994, 75 O.Prakash, N.Saini, P.K.Sharnut, Synlett 1994, 225 M.Tiecr L.Testaferri, M.Tingoli, F.Marini, ~,nlett 1994, 373 J.Bujons, L.Roura, A.Meueguer, bynlett 1994, 437 N.Monteiro, J.Gor~ B.Van Hemelryck, G.Balme, Synlett 1994, 447 M.AI Hariri, F.Pautet, H.Fillion, ~,nlett 1994, 459 K.Miwa, T.Aoymna,T.Shioiri, Synlett 1994, 461 E.Bacioc~hi, E.Muraglia, C.Villani, b3/nlett 1994, 821 J.-Y.Saneeau, R.Dahl, E.Brown, Tetrahedron 1994, ,50, 3363 L.McKinstff, T.Livinghouse, Tetrahedron 1994, 50, 6145 M.Mischitz, A.Hackinger, l.Francesconi, K.Faber, Tetrahedron 1994, -$0,8661 P.Somfai, Tetrahedron 1994, 50, 11315 S.Wo, B.A.Keay, TetrahedronAsymmetry 1994, .~, 1411 T.M.Meulemal~, N.FLKiers,B.L.Fering& P.W.N.M.van Leeuwen, Tetrahedron Lett. 1994, 3-$, 455 I-I.Kigoshi,M.Ojika, K.Suenasa, T.Mutou, J.Hirano, A.Sakakura, T.Ogawa, M.Nisiwaki, K.Y~nad& Tetrahedron Left. 1994, 35, 1247 U.Koert, Tetrahedron Lett. 1994, 3-$,2517 J.S.Yadav, M.Vailuri, A.V.Rama Rao, Tetrahedron Lett. 1994, 3-$,3609 A.V.Rama Rao, J.S.Yadav, M.Valluri, Tetrahedron Left. 1994, 3-$,3613 L.Autissier, P.Bertrand, J.-P.Gesson,B.Renoux, Tewahedron Lett. 1994, 35, 3919 G.Maid, S.Adhikari, S.C.Roy, Tetrahedron Lett. 1994, 35, 3985 Y.Zhao, R.L.Beddoes, p.Quayle, Tetrahedron Left. 1994, 35, 4'183 Y.Zhao, R.L.Beddocs, p.Quayle, Tetrahedron Lett. 1994, 35, 4187 R.Grigg, J.Redpath, V.Sridharan, D.Wilson, Tetrahedron Lett. 1994, 3.$, 4429 G.Majetich, Y.Zhang, S.Liu, Tetrahedron Lett. 1994, 3-$,4887 J.A.Niemann, B.A.Keay, Tetrahedron Left. 1994, 35, 5335 S.D.Burke, K.W.Jung,, Tetrahedron Left. 1994, 35, 5837 $.D.Burke, K.W.Jtmg, R.E.Perri, Tetrahedron Lett. 1994, 35, 5841 K.C.Majumdar, P.K.Choudhmy, M.Nethaji, Tetrahedron Leo. 1994, 3-$, 5927 M.C.Pirnmg, J.Zang, A.T.Morehead, Tetrahedron Left. 1994, 3.$, 6229 M.C.Pirrung, Y.R.Lu, Tetrahedron Left. 1994, 3-$,6231 K.Thakkar, M.Cushman, Telrahcdron Lett. 1994, 35, 6441 A.Vaupel, P.Knochel, Tetrahedron Left. 1994, JS, 8349 T.Akiymna, T.Yasusa, K.Ishikawa, S.Ozaki, Tetrahedron Left. 1994, 3.$, 8401 Y.Dong, T.P.Clearly, L.J.Todaro, Tetrahedron Lett. 1994, 35, 9367 M.Litaudon, J.B.Hart, J.W.Blunt, R.J.Lake, M.H.G.Munro, Tetrahedron Lett. 1994, 3.$, 9435 R.W.Saalfrank, W.Hafner, J.Markmann, A.Welch, K.Peters, H.G.v.Schnering, Z.,Vmurforsch, B 1994, 49, 389 J.Christoffers, K.H.D0tz, Chem.Ber. 1995, 128, 157 I.-S.Lee et.al., Tetrahedron 199S, 51, 21 C.-K.Sha, R.-S.I,ee, Y.Wan& Tetrahedron 1995, -$1, 193 H.Zhang, P.Wiison, W.Shan, Z.Ruan, D.R.Mootoo, Tetrahedron Lett. 1995, 36, 649

Chapter 5.4 Five-Membered Ring Systems: With More than One N Atom S. A. L A N G , JR American Cyanamid Company, Pearl River, NY, USA and

V.J. LEE Microcide Pharmaceuticals Inc., Mountain View, CA, USA 5.4.1

INTRODUCTION

The azoles continue to be targbasedets of considerable research activity, g V a r i o uan s iotensin II receptor antagonists, on azoles, were reported'[94JMC(37)2371, 94MI(103)1, 94USP5281604]. Other therapeutic areas also includegrowth hormone secretagogue compounds [94JMC(37)897], adenosine antagonists [94MI(4)2539], 5-HT1 receptor agents [94EUP581538], antiviral nucleosides [93JHC(30)1289], topoisomerase I inhibitors [94MI(4)2871], HIV protease inhibitors [94MI(4)903, 94MI(4)2441], azolopyrimidiniumthiomethyl cephalosporins [94JMC(37)3828], and leukotriene B4 receptor antagonists [94JMC(37)2411]. Several new azole-based natural products, e.g. mauritamide A (1) [94TL(35)1375], were reported. Other natural products, e.g. hymenin (2) [94TL(35)351] and (:l:)-tetrahydromyricoidine (3) [93T(49)6797] were targets for synthesis from azole precursors. The chromophore, coelenterazine ( 4 , . p plo. Ohorus luciferin), was studied extensively as a model of aequorin, a calcium-binding protein from Aequorea vicutoria (jellyfish) which mediates a luminescence process [94TL(35)2565, 94TL(35)8181]. While this is not a comprehensive review, the citations highlight interesting aspects of the azole literature since tl~e last review. .,--

o,

P.

%

c.. O,,R=.,. o,c., .....,,=,.

.~-,,

A

~

~

--

(3)

_

~

B,-- ~.,," ~

.

(2)

~,

,,,

-"",.r'~

I

II

6

M,.N, J~-.S ~

~ Me

.o.

La/

_.1,

L~tt$ ~ ~

I...~$

M,,,Nr )k,. s. ~"

Me

.~,.

t /

Fundamental studies on the aromatic properties of the azoles was reported durinf" this period. In a study of the role of zwitterions in the tautomerism of hydroxy ant mercaptoheterocycles, the introduced aromaticity index [IA] for the 1,2,3-triazok thiolates (5, 5') was 99.8 and 99, respectively. These values are higher than the predicte, value of 90 which indicates considerably more aromaticity than expected for this syster [94H(37)249]. The substituent effects of the trifluoromethyl group on the structure anG basicity of the 1,2,4-triazole nucleus was determined from studies with the mono- an, 148

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

149

bis(trifluoromethyl)-l,3,4-triazoles (6). Further, the substituent effects on other azoles were also inferred [94JOC(59)1039]. Extensive protonation studies, based on 13C and 15N NMR spectroscopy analysis, on N-methylazoles were reported [93M(31)791]. 5.4.2

PYRAZOLES AND FUSED-RING DERIVATIVES

New methods or variations of existing methods for pyrazole synthesis continued to be reported. Notable are several hydrazine-based annelations which afford highly substituted pyrazoles; for example, the perfluorinated silyl alcohol (7) with hydrazines affords the fluorinated pyrazoles (8) [94TL(35)409]. In contrast, the ketene dithioacetal (9) shows different chemoselectivity depending on the hydrazine used [94MI(86)129]. Addition of 1,3-diketones to 1-amino-2(1H)-pyridin-2-imines (12) affords an efficient synthesis of pyrazolo[1,5-a]pyridines (13) [94JHC(31)1157]. Aryldiazonium couplings to a-(phenylsulfonyl)-13,[~-dichloroacetone provides (x-ketohydrazones (14) which cyclize to the fully substituted pyrazolols (15) [94JHC(31)205]. The synthesis of 4H-pyrazolo[1,5-a]indoles (17) by a novel cyclization of (x-formylhydrazones (16) in the presence of mild Lewis acids. This appears to be applicable to the synthesis of some monocyclic pyrazoles (e.g., 18) and other fused pyrazoles (e.g., 19)[93JCS(P1)2087]. A chiral pyrazole ligand (20) from (+)-3-carene wasreported [94MI(5)479]. C4F~CFaCF2-C(OH)R-TMS C4Ft~~~8~R M;TN'HsNy'tl)'

N~t-Bu t-BMe~~(9) C~ PhNHNH,Me~CO-t-BU.~N MeS"~,~(10) NH,NH, sM, n"~ (11) H'

RS~COR

Me

H '

Ph RsC~.~

R'

CH3o. CH3 H

L .3) (12)

H

H

Me

H

R I = H, C ~ H s, 4-MeOC~H4; R 2 = Me, Et, C.H s, 2- furyl, 2-thienyl,4-MeC~H4; R 3 = H, Me; R4 = H, Me, 4-NO2C~H4; R"~ = Me, C~H s, EtO; Y = C-CN, N

I} C,H~SNa CICHzCOCHCIz 2)~./.H,O. PhSO,

PhSO2 1) CI 2) Na~)CCH, ~ ~/

~

R R = 4-XC~H4 (X = Me, MeO, CI, CN, NO2); RI = H. Me

120)~ H R

R = 4-XC~H 4, 2-XC~H 4 (X = H, Br, C], F, Me, MeO)

(16)

OH

R

8)

Ph

N-'N~

/ ~ N

(19)

Direct functi~ of the pyrazole nucleus continues to be an expedient strategy for preparing highly substituted pyrazoles. Several notable examples use the readily avail-able pyrazolones. The 3-chloro-5-(trifluoromethyl)pyrazole (22), obtained from the pyrazolone (21), undergoes either metallation or electrophilic addition at C-4. The anion, on quenching with either trimethyl borate or iodine, affords intermediates (2324) for subsequent StilI-e arylations (cf., 28). Pyrazoleboronic acid (23) is also further converted to the pyrazolols (26-27). Alternatively, electrophilic functionalization at C-3 of 29 is a facile process [94JHC(31)1377]. Nitrosation of pyrazolones affords 4-nitrosopyrazolones (30) which occur in a solvent-polarity dependent equilibrium with the isomeric 5-hydroxy-4-nitrosopyrazoles [94JHC(31)561]. 2H-Pyrazolo[3,4-b]pyridin-3-ols (31) have been obtained in two-steps from pyrazolones [94JHC(31)925]. The synthesis of a diazafulvalene-type system was accomplished by reacting cyclopentadienide anion with the pyrazolium salt (32) [94AP(327)385]. Depending on the leaving groups on the

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

150

pyrazolium salt, either mono- (33) or disubstitution (34) occurs. A s a sideline, the anomalous reaction of DBU and DBN with 1-nitro-3,5-dimethyl-4-halopyrazoles (35) involves a diazafulvene intermediate [94T(50)865]. Severalpreparatively useful syntheses of indazoles have been refined. Treatment of arylazosulfides (37) with a non-nucleophilic base generates a transient methylidenediazocyclohexadiene which undergoes electrocyclization to the 1H-indazoles (38)

o ;,

cF,

.o o "1' ~

/ f , ~

O

!

T (25)

(22) "

C.H._

~

CI

CF3

E=

29)

Br, CI, N O 2

COR 200-~ss% c /J so

Me

(HO)a~O H , l ~ . N.,,,.'~ N/

Me

Me

(26) Y CI ~ e =

Me

1~10,

H ~

XMe

( 3 0 ) ~ R

X = SO 2

R = Et, n-C6H B, n-C~H17

f", ,T

'~ " I ]

| Me

-N

N-PPh~

Y= CN, CChEt : ) / CO2EI f "

_ _ (33) Me

At' Ph (47)

RNCO

N,...N

X , Ar

RO2C RO:

~N--~ Ph A)

she

/ x

~

'Hr (41a) ~ X

~

/

J~l~

x

~

CN

COIEt

• = CN, CONHvCO,Et;

~/ "

N/] ~

Pr

S

.CO2Et

(39) R= 4-XC,H, (X= F, Me, MeO); X= NOv COzEt; Y= H, CO2Et x

'

p--A, ,~--F--~+

R (38) H

iC.H,},P

(46)

X = O

Ro,c---~ ~

R = H, Me, OMe, CI, Br, NO2; R t = H, Me, Et, viny !

/~

(32)

_-

R (37)

Ha

4-CIC~H 4, EtO; X = CN, COzE t

(36)

O

R

R = Me, i-Pr, CsHsCHv

(27) Y = H

"[ (35) NO2

(3"4~1~)R

PIr"~ T ~

0II EMMN ~ ] / ~ I ~ I H

R = Me, Ph, 4-MeC,H4, 4-CIC,H4

p~'/-"" 1~.

Ar CO, R Ar

(48)

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

151

[94T(50)3529]. An analogous procedure based on a tandem Staudinger reaction - ring closure sequence provides indazole N-iminophosphoranes (39) which react with isocyanates to afford pyrazolo[1,2-b]indoles (40) [93T(49)7599]. Examples of ambident reactivity profile of aminopyrazoles in fused-ring pyrazole syntheses was further documented [94JHC(31)239]. The 3-aminopyrazole (41-a)reacts with ethyl ethoxymethylenecyanoacetate (EMCA) and ethoxymethylenemalonitrile (EMMN) to afford pyrazolo[1,5-a]pyrimidines (42), however, the EMCA adducts (43) cyclize to the pyrazolo[1,5-a]pyrimidin-7(4H)-ones with p_otassium carbonate. In contrast, the 1-alkyl (aryl) pyrazoles (41b, X = CONH2) and EMMN give pyrazolo[3,4d]pyrimidin-4(5H)-ones (45). The imidazo[1,2-b]pyrazole (46)was obtained from 416 (X -- CO2Et) by alkylation with 1-bromo-2-pentanone and cyclization [94MI(4)35]. Few synthetic methods exist for imidazo[4,5-c]pyrazoles, but the photolysis of the pyrrolo[2,3-d][1,2,3]triazoles (47) to the 1,3a,6,6a-tetrahydroimidazo[4,5-c]pyrazole (48) is notable. A putative 1,2,3,5-tetrazocine intermediate is believed to be formed by a disrotatory cleavage of the central C-C bond of 47 [93PCS(P1)2757]. 5.4.3 IMIDAZOLES AND FUSED-RING DERIVATIVES Syntheses of highly substituted imidazoles continue to be reported. In a variant of the [N-C-C-N + C] format, the pyridylimidazolone (49) is converted expeditiously to pyridoimidazole (50) with anhydrides and magnesium chloride catalyst [94TL(35)5775]. Cyclization by the [C-C + N + C + N] and [C-N-C + N-C] formats was shown in the 9 syntheses of 51 and 52, respectively [94TL(35)1635, 94TL(35)273]. The N-hydroxyimidazole (54) was obtained in a [C-C-N+ C + N] cyclization from the ~-oximinoketone (53) [94CPB(42)560]. /R MsCI~. R~

RCOtH, (RCO)~O

O

Rt

NH,OAr AtOH

.

=

R

R

>

OEt

Rt

O~Et

O (49)

H

(50)

H

R = n-Pr, Calls; RI = H, n-Pr, Call s

H

R = alkyl (C I - C4); R t = H. Me; R2 = H, Me, Et; R3 = H, Me fr~ "

2) I-BuOK, 25~

.3) RCN . .

N

v. (52)

oH

(53)

N "~,

N-.-~

I~ ,/'~1"~

3) n-BuLl, DMF

/

~"

I

'~',~

R "-~

Li

-

,If ~ " r ~ ~ ' ~ , ~

II

o

~

'

Pd[(C H ).P}.,

(61)

SEM (56)

Br-

~ l

ex. C H.SnM%,

CH~C~Hs Br~

'

CH,

_! (C, Hs)~C'

CH~C~Hs

c H B(OH).,

~

C(C6Hs)s

co f t"Bu ~"~

(69)

R = H, Me, C~Hs; R1 = H, Me, C~H s

C6Hs

C.,

s,...

~-

' ~(NaOEt) ,.o.

CH2CH,CN

CH302C (67)

SCH ~ CH2C6Hs

~

(70)

R R = Me, i-Pr, n-Bu,

UOH

(C.H O) POH,

(66) ~ CH2C.Hs

Br

..x

(69) ~',

c.,o.c

~

~r~ x : /'~--r

C(C6Hs),

.g, c o Brx

3-pyr

" ~ "" (54) OH

,~,

R,

(c . i~.: b ~

~

(58)

clc. co-t...

I

\\

NH.OAc.AcOH Rt -~ R' = aryl

allyl benzyl

N., (68)

SCH 3 8 CH2C.Hs

~.R

152

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

Nuclear modification of imidazoles continue to be popular research topics. Sequential metallation of the phenylimidazole (55) afforded tile trisubstituted imidazole (56) [94TL(35)3817]. Subtle reactivity differences were observed when 2-1ithioimidazole (57a, W = trityl, R = R 1 = H) was quenched with t-butyl haloacetates. Iodination and chloroacetylation occurred with t-butyl iodoacetate and t-butyl chloroacetate, respectively [94JHC(31)857]. In contrast, t-butyl bromoacetate gave the succinate (60). Under identical conditions, the lithioimidazole (57b, W = SO2NMe2, R = R1 = H) undergoes chloroacetylation exclusively. Palladium-mediated cross-coupling reactions were employed for the synthesis of bis(imidazole) (61) [94S681], the phenylimidazoles (63, 65) [94JHC(31)1637] and the phosphonoimidazoles (67-68) [94JHC(31)1701]. Different reaction conditions were required for the coupling of 62 and 64. Empirically, the 2-bromoimidazoles are amenable to coupling with stannane-based reagents vs. the 4-bromoimidazoles which work best with boronic acids. Azolium rearrangement, while of scientific curiosity, have found practical use in synthesis. For example, the direct N-alkylation of NH-imidazoles and benzimidazoles is typically complicated by competing bis-alkylation, short of using a multistep process requiring robust protecting groups. 1-(Cyanoethyl)imidazoles (69) and benzimidazoles undergo quaternization to the 3-substituted-l-(cyanoethyl)azolium salts, which undergo alkaline-promoted Hofmann elimination to the N-substituted azoles (70) [94S102]. Tile rearrangement of the ortho-imidazolylamine (75) to the fused imidazole (77) with acetic anhydride is sterically controlled by the R substituent which hinders N-acetylation and forms a N-acetylimidazolium intermediate (76) [94JHC(31)287]. A non-classical aldolbased imidazole syntheses was employed in the synthesis of the isomeric imidazonaphthyridines (71-74) ]~romcreatinine [94JCR(S)268].

"N "f

"'N'~,--N

~

=

=

(71,

NH a

"~",.,.~'N~.C'C"~N (72)

CH~

~NH,:)

CH~C02.

.I

~'Nr

,.I

//'--NH,

(73) X = N ; Y = C H (74) X = C H ; Y = N

(76)

1771

"

"

i W = C H , N; R = C H a, C 2 H s ;

5.4.4

R! = H, imidazolyl

1,2,3-TRIAZOLES A N D FUSED-RING DERIVATIVES

Cycloadditions of i) azides with acetylene equivalents {N=N=N + C=C] or ii) diazoalkanes and amide equivalents [C=N=N + C=N] continue to be used for the synthesis of monocyclic 1,2,3-triazoles. Notably, diazoalkanes add to 3,5-dichloro-2H-1,4-oxazin-2ones (78) and 3-chlorobenzoxazin-2-ones (81) to afford [1,2,3]triazolo[5,1-c]-[1,4]oxazin-4ones (79) and [1,2,3]triazolo[5,1-c][1,4]benzoxazin-4-ones (82), respectively. These adducts are further modified to the triazoles (80, 82-83). The regioselectivity of this method is opposite to that for the azide addition to nonsymmetric acetylenic acceptors which give predominantly 4-substituted isomers. Addition of azide, in lieu of diazoalkanes, affords the corresponding 1,5-disubstituted tetrazoles [94TL(35)9767]. Regiospecific synthesis of 2-substituted-l,2,3-triazoles are rare. 5-Carbomethoxy-2carbomethoxymethyl-4-trinitromethyl-l,2,3-triazole (84a)was prepared by 1,3-dipolar cycloaddition/alkylation of NCC(NO2) 3 with MeO2CCHN 2. X-ray crystallographic data shows the trinitromethyl substituent of 83a is a strained Sp 3 center which infers chemical reactivity comparable to that observed for polynitromethanes; thus, 84a with ethanolic KOH afforded potassium 4-dinitromethyl-l,2,3-triazole salt (84b)[93ZOR(29)1231]. Copper-catalyzed oxidative cvclizations of arylhydrazones, while sensitive to substituent effects, provides 2-aryl-l,2,3-t'riazoles (85) [94H(38)739].

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

153

!

81-91"/.

s0- 9s'/.

I~b~

COW

"

X = H, CI

41 -

7s~, "~

9

COW

9

9

S9 7s'/. = "

(8

e H ~ Ph--'l~ ~ - - " R

Jr

(83) l . ~

X R = Me, Ph, 2,6-C!2CaH3; R ! = H, Me, Et;

(84a) X = NO 2

U , ~

RI

~

,

C.H.N,

Cu(OAe),

I/

~

R Ph R = CH, COCH 3 R! = piperldinyl, 3-HOCaH40

~X

W = OMe, EttN, n-PrNH, OH

Spirocyclic triazolines are rare entities, however reduction of (x-azidocycloalkylnitriles (or amides) affords spirocyclic triazolines in variable amounts. Azide (85a) afforded cyanoamine (86a) and spiro-l,2,3-triazole (87) in 56% and 16% yield, respectively. Similarly, azide (85b) afforded the spiro-l,2,3-triazolone (88) in 25%yield along with some starting material, some reducedlinear triazine and the amine (86b). When 88 was thermolyzed in acetic acid, the a-acetoxyamide (89)was obtained [94JOC(59)6853]. PhO2S..

~ PhOaS..

~

N3 (85a)

A/CONH2 P h O a S " ~ ' ~ ' ' N, .

(85b)

PhO2S,.

PhO2S" , "NH2 (86a) X = CN (86b) X = CONH 2

N (87)

~ PhOaS" V

"N~ NI~IH = (88)

(87')

CONH2 -

PhO2S"

:

(sS3

i~ N

A ~ PhOaS

74%

"'

y

"O2CCH3

(89)

The syznthetic versatility of the benzotriazole-based synthons continue to be reported. However, for some transformations, efficient N(1)-alkylation (or arylation) is . * The regioselectivitlty of N-alkef~ectslationon benzotriazole and 1,2 94-triazole was re q fired studied by several groups. Marginal on ratios of N(1), N(2) or dialkylation were observed for benzotriazole, irrespective of conditions employed (basic media, solvent free phase transfer conditions, or microwave irradiation). More.~pronounced effects were observed for 1,2,4-triazoles [94H(38)793]. In a non-basic me~a, excess benzotriazole reacts with activated halides in non-polar solvents to afford higher regioselectivity. The higher N(1):N(2)-alkylation ratio is attributed to a highly-ordered dimer (e.g., 90) of 1Hbenzotriazole in which N(2) is protected by hydrogen-bonding [94S597]. The electron-withdrawingeffect of the benzotriazole nucleus has profound effect on the diverse reactions that benzotriazole-based synthons undergo. For example, carbanions of 1-methyl- and 2-methylbenzotriazole reacted with 2-(methylthio)benzothiazole to afford the 1-substituted-benzotriazole (91) and the corresponding 2substituted benzotriazole [94H(38)1041]. Immonium cations derived from 1-hydroxymethylbenzotriazole (92) are also effective acceptors for ketones, 1,3-dicarbonyl and select enamine synthons under Lewis acid reaction conditions [94JHC(31)917].

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

154

The a-BtH activated amines and amides have also been stannylated (2 eq. Bu3SnLi) to give 0~-stannylamines (amides) [94S904]. The stannylamines can be further transmetallated to affordthe versatile aminomethyllithiums [94S907]. The related N-(benzotriazolylmethyl)aminosilanes (93), prepared from benzotriazole, formaldehyde and alkylamino(methyltrimethylsilane), react as azomethine ylide equivalents with ~x,l]unsatt~ated esters and (x,l$-alkynoates to afford pyrrolidines (94) and 2,5-dihydropyrroles (95) in 90% yield [94T(50)1257]]. 9Benzotriazole. is a key comp0nen t in the conversion of aldehydes to sec-alkyl primary amines. Benzotnazole is reacted with pivalaldehyde in the presence of SOCI2 and NaN 3 to generate the r (96) in 42% yield. Sequential treatment of intermediate (96) with i) (C6Hs)3P and C6HsMgBr in ether and ii) hydrolysis of the phosphonium intermediate yields the primary amine (97) [94SC(24)2955]. Other substituted benzotriazoles can be obtained from simpler N-alkylated benzotriazoles. For example, benzotriazole-l-acetic acid is converted to the 2-(1-benzotriazolyl)vinamidinium salts (98) which react with bifunctional nucleophiles to give 1-(4pyrazolyl)benzotriazoles or 5-(pyrimidinyl)benzotriazoles (99-100) [93T(49)10205]. N(3)-Hydroxytriazolo[4,5-b]pyridine [101, HOAt], as its uronium or phosphonium salts, demonstrated superior performance in solid state peptide synthesis as compared to N-hydroxybenzotriazo-le [102, HOBt]. This feature enhances the automated synthesis of peptides containing hindered amino acids or hindered amines [94CC201].

B%SnCi

BICH(R3)NRtR 2

(92)

~CH20H

R = ME, Et,C6Hs O/~ --one~

~

"

~ (CC~IItlI~,;B r I

I "~"

-

!~

R=allyl, s.Bu, n.hexyl, c.C~,Hn;

~r"c~

195)

R

R' - C,Hs, COOEr

n--n~

CIO 4"(Ply) (98)

5.4.5

194)

R

TMSCHI--I~

c","

oo,,

R

193)

= B%SnCH(R3)NRIR a

NRIR 2 - NMe v NEt2, N(i-Pr)2, N-morpholinyl, N(CI'~Ph) v N-pyrrolidinyl, N-piperidyl, NMe(c-C~Hsl), N-indolyl, MeCONH, i-PrCONH, PhCONH, 4-MeOCaH4CONH; R 3 = H, Pr, i-Pr, n-CsHll

x

R R = H, BrCaH 4, CICaH 4,

CH,,C.,O

X = H, CH 3, Ph, OCH 3, SCI'I3, N(CH3)2

1,2,4-TRIAZOLES A N D FUSED-RING DERIVATIVES N

Ar OH 001) x --N 1102) X - CH

~Me R 003)

)

~

O

~

P U

.,1~ H

Oq

"~Ar (105)

(109)

MeS

~

N

MeS (106)

....

MeS

H 1107)

H

!~ H 1108)

-~ (CHal3NH2

Ar

CN "

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

155

Annelations wit h acylhydrazines or their equivalent derivatives are the cornerstone for many 1,2,4-triazoles syntheses. For example, thiosemicarbazides react with aroyl chlorides or aryl carbohydrazones react with isothiocyanates to produce 1-aroylthiosemicarbazides which cyclized upon treatment with bicarbonate to generate the 1,2,4triazole-3-thiones which were methylated-oxidized to the alkylsulfiny[-4H-1,2,4-triazoles (103) [94JMC(37)125]. Methacryloyl isocyanate reacts with aryl hydrazines to generate semicarbazides which when treated with 10% aq. KOH afforded the expected triazoles (104), while ring closure in xylene without base [12h, reflux] produced the isomeric triazole (105). These semicarbazide intermediates were also usedto generate additional heterocyclic compounds [94H(38)235]. In a variant of the ring chain transfer approach, the reaction of isothiosemicarbazide hydrohalides with cyclic lactam equivalents generate the lactam semithiocarbazide (106) which exist in equilibrium with the spiro isomer (107). This isomer converts to the 2-(aminopropyl)-l,2,4-triazoles (108) under alkaline conditions [93JHC(30)1061]. A synthesis of 3-d[cyanomethylene-l,2,4-triazoles (110) from the extended thioimidates (109) occurs in moderate yields [94H(38)113]. Several notable syntheses of 1,2,4-triazolium salts wererep0rted during this period. The [3+2] cycloaddition of 1-aza-2-azoniaallene cations (111) to isocyanates affords triazolinonium intermediates (112) which undergo [1,2]-alkyl shift to produce the salts (113). Similarly, with dialkylcarbodiimides, the analogous [1,2]-alkyl shift products (114) were obtained. Even nitriles participate in the cycloaddition reactions as shown for the synthesis of 1,3,5-trisubstituted-l,2,4-triazoles (115-116). Similarly, cycloaddition to alkenes affords pyrazolium salts (117) [93T(49)9973, 94CB(127)947, 94CB(127)2519]. .

1) t.hOCl

n3

2) SbCI s ( A I C I ~ ) ' ~ _

R~

NHR ~

.

.

(E). EtCH=CH-Et

~c

R~

R~

R3

R.2-

N~

R3

R'~N~C~o

M.e Me-~

*

X"

R'N=C=NRj Et ' " ~ y ~ R 3 Et R ' ' y ' R ' -

R4~N'~~R3 " (112)

R..,,,N,C~ l~~s

lSk,.RS

[I,3l-shift

0

ll,21-.hift

X "~ SbCl.', AICI 4

(114)

[1,21-.hlft

Me'~H

~' (113)

~.R~

~k,.R~

O

R I = alkyl (CI-C3), c-C3Hs; R2 .= alkyl (CfC3), c-C3Hs; R3 = 2,4,6..CI3Ct,H2; R4 alkyl (Cf.C3); c-C6Hiv C6H s, 4..CIC6H4, 3,4-C!2C~H3, 2-MeC,~H4; R5 = i-Pr, c..C6Hw C6H 5

1~ =

~

allyl

~ =

x coopt

'

~

x cooFt (llS)

t-Bu

"'-,.~n'" (116)

In a variation of an earlier procedure, cyclc dehydrogenation of arylhydrazones of pyrimidinyl ketones with 2,4,4,6-tetrabromoc,.rclohexa-2,5-dien-l-one (TBB) affords v-triazolopyrimidinium salts (117-118) [94JHC(31 )1041].

N RI

76 - 90%

=1

W,,,JI~~/

II,N

~II~~,~~N

"

(:18) ~ ,.+

/~'

BF4"

RI

35 . ~%

I RI

BF: RI R = H, CH 3, CH~O; RI = CH 3, C6Hs, 4-CIC6H 4

156

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

~ ~

N,~. H (

(122) X = O(CH2)~;Me,S(CH2)~Me

Direct functionalization of 1,2,4-triazoles continue to provide numerous new molecules. Triazole (119) was prepared by the coupling of 3-mercapto-l,2,4-triazole with benzenediazonium salts [94JAP(K)06:80,651]. The 1,2,4-dithiazole (120) is a useful nthon for the synthesis of substituted triazoles and other heterocycles [94AP(327)389]. e synthesis of prostaglandin mimics, with a triazole moiety substituting for the normally found cyclopentane units, was initiated from 3-nitro-l,2,4-triazole by reaction withI P ro PYlene oxide to g enerate 121 9sul~rSe aration of the al~l~rop riate isomer and disp]( acement of the nitro by an oxygen or moiety -- providea Key _ intermediate (122) wh ch was further elaborated into the final targets. An alternate synthesis starting from 1,2,4-triazole to the same intermediate was also discussed [94H(38)481]. Majority of references for 1,2,4-triazoles deal with syntheses of fused-ring systems starting with 1,2,4-triazole based starting materials and only some of the more interesting fused systems are highlighted. The novel ring (124) was prepared by reacting triazole (123) with methylene dibromide [94JHC(31)997]. The phosphorus containing fused system (126) was obtained from aminotriazole (125) and phosphorochloridoisocyanate [94SC(24)59]. 3-Aryl-l,2,4-triazole-5-thiones react with chloroacetic acid followed by cyclization with phosphoryl chloride to generate 2-arylthiazolo[3,2-b][1,2,4]triazol-5(6H)ones (129) [941JC(B)(33B)634]. [1,2,4]-Triazolo[3,4-d][1,3,5]dithiazines (128)were repared by the acid-catalyzed cyclization (Pummerer reaction) of 3-(sulfinylmethylthio)2,4-triazoles (127) [93JCR(S)508]. A comparative analysis of the product distribution of 3-amino-l,2,4-triazoles and various unsymmetrical 1,3-dicarbonyl synthons was reported. The 7-substituted triazolo[1,5-a]pyrimidines (130) are the major isomers obtained, however the chloropropeninium sal-ts gave exclusively the 7-isomers. The ratio of isomers favor the 5-isomers (131), if 13-chloroenals are used For the 3-carbon synthons [94T(50)12113]. c~,/OEt .~--~

/~S

~.~

~z (123)

_.,~/ __N--N'/JI'I / L _ OCNP(OEt)CI" RS"~ N~_~ . j p .~ H

' '

1~ (124) N=N

Ar

~N~N

=

Ar

S

,,s-

(125) N'--N 7 Ar SCH2SOMe_ ~ (127)

H

(129)

HX" " S Ar = Ph, 4-CIC~H4;X = PhN, 2-MeC6H4N,c-C~.H.,S --

~t,,N ~ N H H [

2

._./

(131)

major isomer

minor isomcr

(132)

o/~"-~/-'~ a

o.y

x

ye

(130)

-o

(128)

.

and

-

O

(126) H

CI

x

H

C!

Me~ N~,.%,~ NMe=

X

CIaHC

N.._~ S'_~

O

.Fn,

o

t

urea, 1600c

N~'" -N

orCS~,n-BuOH,,~

C~

"CH2CI

" N" --N=P(C.Hs)'

(139) T /

"~

v ,,,

(!40) Y / ~1 Z = OH, SH ~ 1 ~ ~ X

"

N" ", H N.~

,

pIr~x ~ ' ~ .'N~NHR

I ,, = Nx\p(c6as)3 RNCO-E~,N X " ~ " ' N ~ I ~ " (137)

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

157

Additional novel annelation procedures were reported. N-t-Butyl-N-(2,2-dichlorovinyl)carbamoyl chloride (132) is a novel synthon for the synthesis of various azoles; for example, the bis-substituted hydrazine (133) is cyclized to 134 with KOH in DMSO [94S782]. Fused mesoionic 1,2,4-triazolium-3-thiolates (135) were synthesized from isothiocyanates and 1-amino-l,4-dihydro-2,3-quinoxalinedione [94MI(15)517]. Bis(iminophosphorane) mediated cyclizations (e.g., 136) have been used to generate imidazolo[1,2b][1,2,4]triazoles ( 1 3 7 ) a n d 1,2,4-triazolo[1,5-a]benzimidazoles in 40-70% yields [94H(37)997]. Treating phenylenediamines with 2-chloromethyloxadiazole yielded the tricyclic triazoles (139) [94JAP(K)06:121261]. The intermediate triazolopyrimidines [140, X = NH 2, C], for angiotensin II receptor antagonists, were obtained from the hydrazinopyrimidines (139)via a Dimroth-type transformation [94JMC(37)2371]. Triazolo a n d tetrazolo fused derivatives cyclized to cyano-hydrazinopyrazines yielded a variety of interesting bicyclic structures [94SC(24)1895]. In contrast, the polyphosphoric acid fusion of 4-amino-6-(aroylhydrazino)-5-nitropyrimidines generates a transient triazolopyrimidine which undergoes fragmentation to 2-(3-aryl-l,2,4-triazol-5-yl)-2-nitro1,1,-ethenediamines [94JHC(31)I171] (cfi, Section 5.4.6 for analogous transformation of 1 7 2 -->174). The triazolopyridazine (141) was prepared in a two-step process from 3-chloro-6ha/~odrazinopyridazine, ando.a protected, as'Ptec~nmart laldeh,y,,de. Other fused heterocycles, were prepared in 75-86 '/o yields using this que w4JHC(31)1259]. Nucleosmde analog [144, Y = NMe2] was prepared via intermediate triazole [143, Y = 1-[1,2,4-triazole] by treatment with NHMe 2 (97% yield) [94JA(116)9331]. The electron-withdrawing effects of the triazole unit makes it a potent leaving group for Sn2Ar reactions on 6n azaheterocycles in lieu of the traditional halogens. Intermediate (143) is obtained from 142 by reaction with bis(dimethylaminometlaylene)hydrazine.

N O (141) ~

,q

~-

OOMe

'

N (142)

~,

"-

=-

l

R

(144)

NHCOCF 3

l

(143)

R

S

H" ! ~ "

l

R

(145)

N

X = N M e 2, O M e , S M e

R - Me, tri-O-acetylribosyl

NyN~Me'~ /

MeS

Fused 1,2,4-triazoles have been conveniently prepared by reacting chlorothiadiazole with 00-aminotriazoles and aminoazoles. However, when this reagent was reacted with 1-methyl-3-amino-5-thiomethyl-lH-1,2,4-triazole, only the linear compound (145)was obtained [94T(50)7019]. C,Hs ~ ~ . . ~ 0

~CHft-Bu

OMe

.

O/ " 0

t-BuCH,"~~~/

t.BuCHa/-

[

I O

(151) ~ , , " l ~ C ,

O O KOH-EIOH ~

(152)

Me O (154)

H"

TMSO""J

I,,,.OTMS

Hs

O

, (156)

, O

O I~ Me

N-Phenyltriazolinedione [PTD] continues to be a popular probe for the study of reactions of alkenes and dienes. Synthetically, PTC can serve as either a N=N synthon or a 1,3-diene protecting group. The reaction of thiophene dioxide (150) with PTD (2 eq.) generated his adduct (151) with the loss of SO2. Intermediate (151) decomposed with KOH-MeOH toyield the pyrazine (152) in 84% [94TL(35)2709]. Urazole (153), several steps removed from a PTD cycloaddition, when treated with KOH-EtOH yielded the novel oxazolidinone (154) [94JCS(P1)2335]. The PTD cycloadduct was used as a

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

158

protecting group for a diene in the synthesis of 1r D 3 analogs [94JCS(P1)1809, 94MI(4)1523]. The mechanism of the PTD ene-reaction with olefins was found to be influenced by solvents similar to that seen with Diels-Alder reactions [94T(50)1821].The first example of a diene-transmissive hetero Diels-Alder reaction with a cross conjugated triene is reported. N-Methyltriazolinedione reacts with the cross conjugated triene (155) to generate the cross-type product (156) in essentially quantitative yield [94CL1833]. 5.4.6

TETRAZOLES AND FUSED-RING DERIVATIVES

Tetrazoles are typically_ prepared from either nitriles or amide derivatives by the use of NAN3, mineral acid--s and heat or n-Bu3SnN3. While these methods are highly reliable [94AP(327)181, 94JAP(K)06-41,140, 94MI(WO)94:12,492], for preparative purposes they suffer from either the formation of excess hydrazoic acid, toxici~, stench and isolation difficulties. The combination of trimethylaluminum-trimethylsilyl azide at 80 ~ C (toluene) effectively converts all nitriles [aryl and alkyl] to tetrazoles in 40-98% yields. It is speculated that the Me3Al does not act solely as a Lewis acid catalysist. When 5 equivalents of Me3AI was used with nitrile (157) concomitant methylation was observed to give 158 [93TL(50)8011]. With activated nitriles, trimethylsilylazide can substitute for hydrazoic acid as illustrated for 2-(1H-tetrazol-5-yl)-2-cyano betaines (160) [93S873]. The Schmidt transformation of ketones to 1H-tetrazoles (predominantly isomer A) with sodium azide-titanium tetrachloride was reported by Suzuki et al [93S1218]. Mechanistically, a geminal diazide undergoes loss of-nitrogen to form an a-azidonitrene which undergoes a [1,2]-substituent shift to lead to preferential formation of isomer A. However, in a few cases [R 1 = Call 5 and E2 = 4-MeOC6H4; R1 = C6H 5 and R2--- CH3] isomer B was also formed. A similar intermediate is invoked in the photolysis of the the diazido sugar (161) andpyranosyldiazides (166) and to the tetrazoles (162,163) and (167, 168), respectively [94TL(35)89, 94CL(L)1107]. However, when diazide (161) was thermolyzed a chain-shortening rearrangement occurs. N ~ C O 2 E t

k..,,..,,..a...,./!~COOMe I (157)

(158)

R1

R~N3

N3 O

o

~Oen

1159)

~'--OBn= "v

FOBn ~"OBn CH2OBn

BnO~[ and r o B n

Ii~ maj!or isomer

(162)

FOBn r--oBn CH2OBn

FOBn CH2OBn (163)

'~

1

$

R minor isomer

_ NvNH BnO--'~

BnO--1 OBn "" OBn C164) CH~OBn

F

F

(165)

OBn '-~ OBn CH2OBn

(161)

.o

.o RO-

N3 R ~- Ac, Bn (166)

FOBn

~n

~=~

..~ IN

Nj~

BnO"--I

and R,

1

N--

N~N" NH BnO'-1

S'

o..

~......N,,,NI,, N and RO / "~'N" RO RO (167) major isomer (168) minor isomer(

~ ,'~Nw CN CO2Me (160)

N-Alkylations (arylations) of tetrazoles are continuously reported, however regioselectivity is problematic with substrates containing other reactive azole centers. The combination of alcohols or epoxides, activated with either zinc triflate or dibenzyl N,N-diethylphosphoramidate, in acetonitrile, nitromethane or dichloromethane alkylates

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

159

tetrazole, with exclusion of imidazoles or triazoles [94TL(35)9681]. The chemoselectivity is a consequence of the pK a of the different azoles. For example, 4,5-dicyanoimidazole is N-alkylated under the Mitsunobu reaction conditions [94TA(5)181] but not imidazole. In contrast to the above azoles, annelation reactions with aminotetrazoles are often complicated by competing reactions where the newly formed tetrazole system is in equilibrium with the tautomeric azide. The equilibrium is sensitive to the electron density of the adjacent ring system, as exemplified with tetrazolo[1,5-a]pyrimidines. Aminotetrazole reacts initially with phenylmalonate to afford the triethylamine salt which on protonation with strong acids affords the tetrazolo[1,5-a]pyrimidines (169). The pKa values for 169 are estimated to be 3.5 [tetrazole proton] and6.3 [pyrimidine OH]. While azide absorption in the IR is only weak, these compounds can exist as an equilibrium between fused tetrazole and azide. This ambiguous chemical nature is pointed out in the varied reactivity of 169. When treated with SO2CI2 or Br2, the tetrazole ring remains intact and 5-(acylamido)tetrazoles (171) are produced. When treated with PPh3 or H2/Pd, the pyrimidine ring survives and 170 is produced [93JHC(30)1267]. Similarly, the addition of azide to 4-chloro-5-nitropyrimidines affords a transient tetrazolopyrimidine (172) which adds water at the electron deficient C=N bond and fragments to the 5-(13.13-diamino-0~-nitrovinyl)tetrazoles (174) [94TL(35)103]. Et N 2) Strc~"$acid

N--

X H I ~ N/N

"\

(171)

Ph-

......

~

"

k~

"1i"

R = C,H,C,a HO'TK''N~/~I~ er,, H,O (or SO,ClrH,O)

.

Ph

(169)

p

.

,. (170)

.....

NR' R! __.P(C~Hs)3' H2

X = PhCBrtCO, PhCHCICO

Other rearrangements of 5-aminotetrazole intermediates have also been reported. The reaction of aminotetrazole with diethyl bromomalonate and chloroacetyl chloride followed by dehydrochlorination yielde d the 4,5,6,7-tetrahydrotriazolo[1,5-a]pyrimidine (176! instead of the tetrazolyl-13-1actam (175) [93MI(130)683]. Treatment of azotetrazole (177) with dilute H2SO4 generated the mesoionic 2-(tetrazol-5-yl)-6-imino-l,2,3,4,5pentazine (178) [93KGS468]. N,,~ ~ " ' N H R

L~'~

NH R

~

N~N]~NH R ....

R = ribosyl, 2-clfloropyridin-5-yl OaEt

(172)

HO

~,,_.

NHR

H (173)

R

NO 2 (174)

~

(175) 5.4.7

(176) CO2Et

077)

(178)

AZOLE-METAL COMPLEXES

Numerous azole-metal complexes were reported in 1994, however, the notable examples are presented. The macrocycle (179) prepared from 3,5-diacetyl-l,2,4-triazole with thiocarbohydrazide or carbohydrazide in the presence of Pb or Cu salts which formed the basis for their characterization. The /nixed macrocycle (180) was also prepared under similar conditions [94ZN(B)(49)665]. Novel tribenzhexaazaporphyrins (181) incorporating one 1,2,4-triazole ring were prepared as phthalocyanine analogs. A bis-complex of both was obtained as a minor side product. The major components-were prepared by reacting 1,3-diiminoisoindoline and 3,5-diamino-l,2,4-triazole in 3:1 ratios in the presence of NiBF4 in 65% yield. Efforts to prepare a non-metal containing form were unsuccessful [94CC1525]. N-Methyltriazoline dione reacts with CH2(GeCIMe2) 2 to generate the fused triazologermanium (182). When Me2GeCl 2 was employed, the tricyclic

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

160

structure (183)was isolated. When i n t e r m e d i a t e s w e r e n o t e d [94MI(18)953].

M

.

(179) W = X = -NHCONH-,-NHCSNH(180) X = -NHCONH,-(CH2)3-; W = -NHCONH-,-NHCSNH-

divalent

81)

~ Me'N

.Ge.,. Me

>r>+.,,,.+o,,+,

O

REFERENCES

93JCR(S)508 93JCS(PI)2087 93JCS(Pl)2757 93JHC(30)1061 93JHC(30)1267 93JHC(30) 1289 93KGS468 93M!(31)791 93M!(130)683 93S873 93SI218 93"1"(49)6797 93T(49)7599 93T(49)9973 93T(49)10205 93TL(34)8011 93ZOR(29)I231 94AP(327)181 94AP(327)385 94AP(327)389 94CB(127)947 94CB(127)2519

94CL I 107 94CL1833

transient

~e (182)

Me ~'-'N

94CC 1525

only

NN.

M

94CC201

used,

Me /N

5.4.8

GeCI 2 was

L. D. S. Yadav and A. Vaish, J. Chem. Res. (S), 508 (1993); CA 120:323514 J.-K. Shen, H. Katayama, N. Takatsu and !. Shiro, J. Chem. Soe., Perkin Trans. 1, 2087 (1993). R. N. Butler, D. M. Colleran, D. O'Shea, D. Cunningham, P. McArdle and A. M. Giilan J. Chem. Sot., Perkin Trans. i, 2757 (1993). U. Radios and J. Liebscher, J. Heteroeycl. Chem., 30, 1061 (1993). T. Kappe, P. Roschger and G. Faerber, J. Heterocycl. Chem., 30, 1267 (1993). Y. H. R. Jois, C. D. Kwong, J. M. Riordan, J. A. Montgomery and J. A. Secrist, iil, J. Heterocycl. Chem., 30, 1289 (1993). A. G. Mayants, V. N. Vladimirov, V. A. Shlyapochnikov, L. M. Tischenko, S. S. Gordeiehuk and S. V. Mikhailova, Khim. Geterotsikl. Soedin., 468-75 (1993); CA 120:164064. R. A. Claramunt, D., Sanz, G. Boyer, J. Catal~in, J. L. G. de Paz and J. Elguero, Magn. Reson. Chem., 31,791 (1993). J. Fetter, M. Kajtar-Peredy, E. Keskeny and K. Lempert, Acta Chim. Hung., 130, 683 (1993); CA 120:323468. D. Kikeij and R. Neidlein, Synthesis, 873 (1993). H. Suzuki, Y. S. Hwang, C. Nakaya and Y. Matano, Synthesis, 1218 (1993). J. Song and M. Hesse, Tetrahedron, 49, 6797 (1993). P. Molina, C. Conesa, A. Alias, A. Arques, M. D. Velasco, A. L. Llamas-Saiz and C. Foces-Foces, Tetrahedron, 49, 7599 (1993). Q. Wang, A. Amer, S. Mohr, E. Ertel and J. C. Jochims, Tetrahedron, 49, 9973 (1993) J..T. Gupton, F. A. Hicks, S. Q. Smith, A. D. Main, S. A. Petrich, D. R. Wilkinson, J. A. Sikorski and A. R. Katritzky, Tetrahedron, 49, 10205 (1993). B. E. Huff and M. A. Staszak, Tetrahedron Lett., 34, 8011 (1993). T. D. Ladyzhnikova, K. V. Altukhov and D. V. Manuel, Zh. Org. Khim., 29, 1231 (1993). T. Patonay and A. Levai, Arch. Pharm. (Weinheim), 327, 181 (1994). K. Hartke and X.-P. Popp, Arch. Pharm. (Weinheim), 327, 385 (1994). D. Briel and S. Leistner, Arch. Pharm. (Weinheim), 327, 389 (1994). Q. Wang, S. Mohr and J. C. Jochims, Chem. Ber., 127, 947 (1994). Q. Wang, A. Amer, C. Troll, H. Fischer and J. C. Jochims, Chem. Ber., 127, 2519 (1994). L. Carpino, A. EI-Faham, C. A. Minor and F. Albericio, J. Chem. Sot., Chem. Commun., 201 (1994). F. Fernandez-Lazaro, A. Sastre and T. Torres, J. Chem. Soc., Chem. Commun., 1525 (1994). M. Yokoyama, S. Hirano, T. Hachiya and H. "logo., Chem. Lett., 1107 (1994). O. Tsuge, T. Hatta, K. Yakata and H. Maeda, Chem Lett, 1833 (1994).

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

94CPB(42)560 94EUP581,538 94EUP589,335 94EUP608,753 94EUP613,890 94H(37)249 94H(37)997 94H(38)113 94H(38)235 94H(38)481 94H(38)739 94H(38)793 94H(38)!041 941JC(B)(33B)634 94JA(116)9331 94JAP(K)0612826 I 94JAP(K)0641140 94JAP(K)0680651 94JCR(S)268 94JCS(P I ) 1809 94JCS(PI)2335 94JHC(3 I)205 94JHC(3 !)239 94JHC(31)287 94JHC(3 I)561 94JHC(31)857 94JHC(31)917 94JHC(31)925 94JHC(31)997 94JHC(31) 1041 94JHC(3 I)! 157 94JHC(31)1171 94J HC(31 ) 1259 94JHC(3 I)1377 94JHC(3 I) 1637 94JHC(3 I)1701 94JMC(37)125

94JMC(37)158

161

A. Tanaka, K. Ito, S. Nishino, Y. Motoyama and H. Takasugi, Chem. Pharm. Bull, 42, 560 (1994). R. Baker, V. Matassa, A. Reeve, F. Sternfield and L. Street, Eur. Pat. Appl. EP581,538: CA 120:298632. G. Jaehne, M. Helsberg, !. Winkler, G. Gross and T. Scholl, Eur. Pat. Appl. EP589,335; CA 121:!34145. A. Marhold, B. Baasner and G. Haenssler, EP 608,753 (1994); CA 121:179597s. H. Kodama, N. Yamamoto, Y. Niwano and M. Yoshida, Eur. Pat. Appl EP613,890; CA 121:300899. C. W. Bird, Heterocycles, 37, 249 (1994). P. Molina, E. Ailer and A. Lorenzo, Heterocycles, 37, 997 (1994). A. Lorente, P. G,4mez and M. del Mar Contreras, Heterocycles, 38, 113 (1994). O. Tsuge, T. Hatta and R. Mizuguchi, Heterocycles, 38, 235-41 (1994). S. Sano, M. Tanba and Y. Nagao, Heterocycles, 38, 481 (1994). M. H. Elnagdi, A. H. H. Elghandour, A. F. A. Harb, A. H. M. Hussien and S. A. M. Metwally, Heterocycles, 38, 739 (1994). D. Abenhaim, E. Diez-Barra, A. Hoz, A. Loupy and A. Sanchez-Migallon, Heterocycles, 38, 793 (1994). A. Katritzky, I. Ghiviriga and D. Cundy, Heterocycles, 38, 1041 (1994). R. Pal, R. Sharma, S. Kumar, R. Dahiya and H. Pujari, Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 33B, 634 (1994). V. Samano, R. W. Miles and M. J. Robins, J. Amer. Chem. Sot., 116, 9331 (1994). T. Makino and T. Kato, Jpn. Kokai Tokkyo Koho JP 06128261; CA 121:179599. J. Go, Gyokuka Ro, Y. S. Hotoku and Y. Gyoten, Jpn. Kokai Tokkyo Koho JP 06041140; CA 121:35332. M. Takeuchi and M. Okada, Jpn. Kokai Tokkyo Koho JP 06080651; CA 121:205358. S. Grivas and E. Ronne, J. Chem. Res. (S), 268 (1994). N. Kobayashi, J. Kitahori, H. Mano, S. Hidetoshi and K. Shimada, J. Chem. Soc., Perkin Trans. I, 1809 (1994). S. Tanaka, K. Seguchi, K. Itoh and A. Sera, J. Chem. Sot., Perkin Trans. I, 2335 (1994). M. Takahashi, M. Zheng, T. Oshida and K. Narahara, J. Heterocycl. Chem., 31, 205 (1994). K. Nagahara, H. Kawano, S. Sasaoka, C. Ukawa, T. Hirama, A. Takada, H. B. Cottam and R. K. Robins, J. Heterocycl. Chem., 31,239 (1994). J. W. Lampe, S. V. Di Meo and J. A. Traina, J. Heterocycl. Chem., 31,287 (1994). J. Bartulfn, J. Belmar, H. Gallardo and G. Le6n, J. Heterocycl. Chem., 31,561 (1994). 1. G. C. Coults, S. Jieng, G. D. Khandelwahl and M. L. Wood, J. Heterocycl. Chem., 31,857 (1994). A. R. Katritzky, B. Galuszka, S. Rachwal and M. Black, J. Heterocycl. Chem., 31, 917 (1994). M. T. Cocco, C. Congiu and V. Onnis, J. Heterocycl. Chem., 31,925 (1994). L. Pongo, P. Sohar, J. Reiter, P. Dvortsak and G. Bujtas, J. Heterocyci. Chem., 31, 997 (1994). S. Bfitori and A. Messmer, J. Heterocycl. Chem., 31, 1041 (1994). P. KOckritz, B. Riemer, A. Michler, A. Hassoun and J. Liebscher, J. Heterocycl. Chem., 31, 1157 (1994). F. Gatta, M. R. Del Giudice, A. Borioni, C. Mustazza and C. Fazio, J. Heterocycl. Chem., 31, 1171 (1994). J. Svete, B. Stanovnik and M. Tisler, J. Heterocycl. Chem., 31, 1259 (1994). J. P. Chupp, J. Heteroeycl. Chem., 31, 1377 (1994). D. Wang and J. Haseitine, J. Heterocycl. Chem., 31, 1637 (1994). J. Lin and C. M. Thompson, J. Heterocycl. Chem., 31, 1701 (1994). J. M. Kane, M. A. Staeger, C. R. Dalton, F. P. Miller, M. W. Dudley, A. M. L. Ogden, J. H. Kehne, H. J. Ketteler, T. C. McCIoskey et al.,J. Med. Chem., 37, 125 (1994). J. Bird, R. C. DeMello, G. P. Harper, D. J. Hunter, E. H. Karran, R. E. Markwell, A. J. Miles-Williams, S. S. Rahman and R. W. Ward, J. Med. Chem., 37, 158 (1994)

162

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

94JMC(37)897 94JMC(37)2371 94JMC(37)2411 94JMC(37)3828 94JOC(59)1039 94JOC(59)6853 94M!104 94Mi(4)35 94M1(4)903

94M!(4)2441

94M!(4)2539 94M!(4)2871

94M1(15)517 94M!(18)953 94Mi(86)129 94M1(103)1 94Ml(WO)94:00450 94MI(WO)94: ! 2492 94S 102 94S597 94S782 94S904 94S907 94SC(24)59 94SC(24)1895 94SC(24)2955 94T(50)865 94T(50)1821 94T(50)3529 94T(50)7019 94T(50)!2113 94T(50)1257 I 94TA(5)181 94TA(5)479

W. R. Schoen, J. M. Pisano, K. Prendergast, M. J. Wyvratt Jr., M. H. Fisher, K. Cheng, W.-S. W Chan, B. Butler, R. G. Smith and R. G. Ball, J. Med. Chem., 37, 897 (1994). E. Nicolai, G. Cure, J. Goyard, M. Kirchner, J.-M. Teulon, A. Versigny, M. Cazes, F. Caussade, A. Virone-Oddos and A. CIoarcc, J. Med. Chem., 37, 2371 (1994). R. W. Harper, W. T. Jackson, L. L. Froclich, R. J. Boyd, T. E. Aldridge and D. K. Herron, J. Med. Chem., 37, 2411 (1994). Y. Kim, J. Lim, J. Yeo, C. Bang, W. Kim, S. Kim, Y. Woo, D. Yang; H. Oh and K. Nahm, J. Med. Chem., 37, 3828 (1994). A. E. Tipping, P. Jimenez, E. Ballesteros, J. M. Abboud, M. Yanez, M. Esseffar and J. EIguero, J. Org. Chem., 59, 1039 (1994). Y. Gaoni, J. Org. Chem., 59, 6853 (1994). Y. Azev, 1. Loginova, O. Guseinikova, S. Shorshnev, V. Rusinov and O. Chupakhin, Mendeleev Commun., 104 ( 1994): CA 121:108718. N. Cho, K. Kubo, S. Furuya, Y. Sugiura, T. Yasuma, Y. Kohara, M. Ojima, Y. inada, K. Nishikawa and T. Naka, Bioorg. Med. Chem. Lctt., 4, 35 (1994). M. P. Trova, A. Wissner, W. T. Casscles, Jr. and G. C. Hsu, Biorg. Med. Chem. Lett., 4, 903 (1994). S. K. Thompson, A. M. Eppley, J. S. Frazee, M. G. Darcy, R. T. Lum, T. A. Tomaszek, Jr., L. A. lvanoff, J. F. Morris, E. J. Sternberg, D. M. Lambert, A. V. Fernandez, S. R. Petteway, Jr., T. D. Meek, B. W. Metcalf and J. G. Gleason, Biorg. Med. Chem. Lctt., 4, 2441 (1994). P. G. Baraldi, S. Manfrcdini, D. Simioni, L. Zappaterra, C. Zocchi, S. Dionisotti and E. Ongini, Biorg. Med. Chem. Lctt., 4, 2539 (1994). Q. Sun, B. Gatto, G. Yu, A. Liu, L. F. Liu and E. J. LaVoie, Biorg. Med. Chem. Lctt., 4, 2871 (1994). S. C. Shin, D. Ju Jeon, K. Ae Jang and Y. Lee, Bull. Korean Chem. Soc., 15, 517 (1994) J. Barrau, G. Rima, V. Cassano and J. Stage, New J. Chem., 18, 953 (1994); CA 121: 280770. W. DOlling, Phosphorus, Sulfur, and Silicon, 86, 129 (1994). Y. Yoshimura, N. Tada, J. Kubo, M. Miyamoto, Y. lnada, K. Nishikawa and T. Naka, Int. J. Pharm., 103, i (1994). A. Thomas, A., PCT Int. Appl. WO 94:00450; CA 120:217679. G. Johnson, N. Smith, R. G. Geen, I. S. Mann and V. Novack, PCT Int. Appl. WO 94:12492; CA 121:157653 A. Horv~lth, Synthesis, 102 (1994). A. R. Katritzky and J. Wu, Synthesis, 597 (1994). M. S. Novikov, A. F. Khlebnikov, A. A. Stepanov and R. R. Kostikov, Synthesis, 782 (1994). W. H. Pearson and E. P. Stevens, Synthesis, 904 (1994). A. R. Katritzky, H.-X. Chang and J. Wu, Synthesis, 907 (1994). H. Yang and R. Lu, Synth. Commun., 24, 59 (1994). A. K. EI-Shafei, A. M. EI-Sayed, H. AbdeI-Ghany and A. M. M. EI-Saghier, Synth. Commun., 24, 1895 (I 994). A. R. Katritzky, R. Mazurkeiwicz, C. V. Stevens, M. F. Gordeev and P. J. Steel, Syn. Commun., 24, 2955 (1994). H, Lammers, P. Cohen-Fernandes and C. L. Habraken, Tetrahedron, 50, 865 (1994). G. Desimoni, G. Faita, P. P. Righetti, A. Sfulcini and D. Tsyganov, Tetrahedron, 50, 1821 (1994). C. Dcll'Erba, M. Novi, G. Petriilo and C. Tavani, Tetrahedron, 50, 3529 (1994). G. L'abbe, J. Buelens, W. Dehaen, S. Toppct, J. Feneau-Dupont and J.-P. Declercq, Tetrahedron, 50, 7019 (1994). S. A. Petrich, Z. Qian, L. M. Santiago, J. T. Gupton and J. A. Sikorski, Tetrahedron, 50, 12113 (1994). A. R. Katrizky, J. Koditz and H. Y. Lang, Tetrahedron, 50, 12571 (1994). M. Botta, V. Summa, G. Trapassi, E. Monteagudo and F. Corelli, Tetrahedron:Asymmetry, 5, 181 (1994). S. A. Popov, A. Yu. Dcnisov, Y. V. Gatilov, !. Yu. Bagryanskaya and A. V. Tkachev, Tetrahedron: Asymmetry, 5, 479 (1994).

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

94TL(35)89 94TL(35)103

94TL(35)273 94TL(35)351 94TL(35)409 94TL(35)1375 94TL(35) 1635 94TL(35)2565 94TL(35)2709 94TL(35)3817 94TL(35)5775 94TL(35)8181 94TL(35)9681 94TL(35)9767 94USP 5281604 94ZN(B)(49)665

163

J.-P. Praly, C. Di St6fano, G. Descotes and R. Faure, Tetrahedron Latt., 35, 89 (1994). D. Babin, 1. Terrie, M. Girardin, A. Ugolini and J.-P. Demoute, Tetrahedron Lett., 35, 103-(1994). J. F. Hayes, M. B. Mitchell and G. Procter, Tetrahedron Latt., 35, 273 (1994). Y. Xu, G. Phan, K. Yakushijin and D. A. Home, Tetrahedron Latt., 35, 351 (1994). B. Dondy, P. Doussot and C. Portella, Tetrahedron Lett., 35, 409 (1994). C. Jim6nez and P. Crews, Tetrahedron Latt., 35, 1375 (1994). M. F. Brackean, J. A. Stafford, P. L. Feldman and D. S. Karanewsky, Tetrahedron Latt., 35, 1635 (1994). K. Teranishi, M. lsobr and T. Yamada, Tetrahedron Latt., 35, 2565 (1994). J. Nakayama and K. Yoshimura, Tetrahedron l.,r 35, 2709 (1994). P. Molina, E. Aller, A. L6pez-Lfizaro, M. Alajarin and A. Lorenzo, Tetrahedron l..r 35, 3817 (1994). C. H. Senanayake, L. E. Fredenburgh, R. A. Reamer, J. Liu, R. D. Larsen, T. Verhoeven and P. J. Reider, Tetrahedron Lett., 35, 5775 (1994). K. Teranishi, K. Ueda, H. Nakao, M. Hisamatsu and T. Yamada, Tetrahedron Lett., 35, 8181 (1994). R. Fortin and C. Brochu, Tetrahedron Lett., 35, 9681 (1994). B. Medaer, K. Van Aken and G. Hoornaert, Tetrahedron l.,r 35, 9767 (1994). J. L. Levin and A. M. Venkatesan, US Patent 5281604 (1994); CA 121:230802 P. Souza, A. l. Matesanz, A. Arquero and V. Fernandez, Z. Naturforsch., B: Chem. Sci., 49, 665 (1994).

Chapter 5.5 Five-Membered Ring Systems: With N & S (Se) Atoms This chapter was not available for inclusion this year. Two years literature will be covered next year.

164

Chapter 5.6 Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms R. ALAN AITKEN and LAWRENCE HILL University of St Andrews, UK

5.6.1

1,3-Dioxoles

and

Dioxolanes

An efficient preparation of high purity 1,3-dioxolane has been described [93JAP05271217]. The bimetallic catalyst Sn(Co[CO]4)4 is effective in acetalisation of aldehydes with ethylene carbonate [93JMOC(85)279]. Metal phthalocyanine catalysed carboxylation of epoxides to 1,3-dioxolan-2-ones has been reported [94USP5283356] and kinetic resolution in the same reaction using a chiral catalyst derived from Zr(OBut)4 and binaphthol gives the products in up to 39% e.e. [94SL69]. Palladium catalysed carbonylation of isopropenyl acetate in MeOH gives 1,3-dioxolan-4-one (1) [93CL1615]. Electrochemical reduction of substituted benzils in the presence of ArN=CCI2 gives 2-arylimino-4,5-diaryl1,3-dioxoles [94TL2365]. Oxidation of 2-methyl-3-phenylbenzofuran with a variety of oxidants gives 2-acetyl-2-phenyl-l,3-benzodioxole in addition to

Me

CO2Me

~

O,~q'je

O

0~/~

OH _

e H2N (1)

O N2

C02Me

C02Me

(2)

(3)

MeO CI

i~_~0~~ ~ OH O"- ~-" D D

(3 Cl

Cl (4)

D ~,,,D

O

121

(6)

165

166

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

other products [94T8393]. Treatment of diazotised aniline (2) with Ni(CN)2 gives (3) by an unusual intramolecular nucleophilic aromatic addition [93JOC6146]. The spiro-benzodioxole (4) is formed by periodate oxidation of 4,5,6-trichloroguaiacol [93ACS999]. Photodimerisation of o-vinylbenzaldehyde gives bridged dioxolane (5) [93CC1828]. The preparation of CH2-14C labelled 3,4-methylenedioxyphenol [93MI777] and deuterium labelled domiodol (6) [94MI303] have been reported. X-Ray structures of some dioxolan-2-ylium salts have been described [93CJC836]. A kinetic and product study on solution oxidation of simple 1,3dioxolanes with 02 has appeared [94JPR155] and oxidation of some OHcontaining dioxolanes using Pb(OAc)4 has been studied [93JSC269]. Oxidation of the side chain of (7) to the corresponding acid can be achieved without racemisation using 02 and a metal catalyst [94EP611762] while aromatic ring nitration of 2-aryl-1,3-dioxolanes with little cleavage of the dioxolane is possible using the system NO2/O3/MgO [94JCS(PI)1367]. Reaction of 1,3-dioxolane2-thiones and benzodioxole-2-thiones with Bun4NF.2HF and N-iodosuccinimide gives the corresponding 2,2-difluorodioxol(an)es [94SL251]. Thermal decomposition of (8) has been examined [93MI563]. Dioxolanone radicals (9)

,ox

Me

o3~,.~

0~.

O (7)

F 3 C / X O, . . ~ F F (8)

O (9)

0

o~

R

Me 0

~ -CO 2

HO~ 0

o

(12) X = OSiMe2But, SPh, 4-morpholinyl

\ (13)

Me

(14)

Me

CHO R

~

(HI)

have been obtained by various methods and their selectivity for C-Br, C-C and C-H bond formation trans to the But examined [93T7871]. Photochemical decarboxylation of laevoglucosenone (10) to give (11) is likely to involve homolysis of the bond shown followed by H abstraction from the resulting 2dioxolanyl radical by the acyl radical to give the dioxolan-2-ylidene which spontaneously loses CO2 to give the product [94CC2155]. Preparation and Diels-Alder reaction of vinylketene acetals (12) have been described [93TLA587]. Treatment of (13) with BF3.Et20 results in cyclisation to (14) [93ZOR1082]. Palladium catalysed hydrodecarboxylation of 4-alkynyl-1,3-dioxolan-2-ones gives homopropargylic alcohols in the presence of Bun3P but the isomeric ot-allenyl alcohols with Ph2P(CH2)2PPh2 [94SL457]. The effect of reaction conditions on the enantioselective protonation of enolates derived from dioxolanones and oxathiolanones (15) has been studied

167

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

[94CB 1981] and the same reaction of the related silyl enol ether (16) using polymer supported mandelic acid leads to (S)-mandelic acid in up to 94% e.e. [94TL2891]. Low temperature protonation of the anion derived from (17) produces mainly the cis product by kinetic control [94CB1495] and hydroboration of (18)gives the cis hydroxymethyl compound with high Me .O...,,~O

MexO 1 ~ OSiMe3

,,o><xL

Me

(15) X= O,S PPh2

O

Ph

H~O'~

~

Me" O""~ph

Rl 0 "~/,. R2

(17)

(18)

(16)

o

R O.Htco2R2

O~t'" Ph

R~ O " "

CO2tt

(20)

(19)

R~O.~

(21)

diastereoselectivity [94TL2537]. A range of dioxolane-containing ligands have proved effective in the Pd catalysed asymmetric substitution of allylic acetates with malonate anion as exemplified by (19) which gives up to 88% e.e. [94SL551]. Conditions have been developed for effective separation of the enantiomers of dioxolane esters (20) using a cyclodextrin coated chiral GC column [93MI703]. Further applications of benzodioxole acid (21) as a chiral derivatising agent for TLC separation of (R) and (S) amino acids have been reported [93TA1431]. n-Cl0H21 ~ O ~ h §

ncSHl7 Me

"\ I . . H

Br- Me3N(CH2)70.~'~'/ (CH2)sN+Me3Br(22) E F 0

OH

O~O

~ ~ 0

(23)

H

CO2Na

N

O

(24)

CI

~

O

~

CO2Na

25)

New applications of dioxole containing compounds include the use of (22) as a second generation double-chain cleavable surfactant [93TL6985], the dioxolanyl coumarin (23) as an antioxidant [93SUP1806141], difluorobenzodioxole (24) as a herbicide [93MIP24483] and [33-selective adrenergic agonists such as (25) as antiobesity agents [94EP608568].

168

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

5.6.2

1,3-Dithioles

and

Dithiolanes

A range of 4-alkylthio-1,3-dithiole-2-thiones (26) have been prepared by treatment of xanthates EtOC(=S)SCH2 R1 with CS2 and R2X under basic conditions [94PS(88)155] and subsequent reaction with Hg(OAc)2 gives the corresponding dithiol-2-ones (27) [93PS(83)223]. The preparation, X-ray structure and non-linear optical properties of 4,5-bis(2,4-dinitrophenylthio)-1,3dithiole-2-thione have been described [94MI138] as have the preparation and Xray structure of 4-ferrocenyl-l,3-dithiol-2-one [94CC53] and a series of ctdithiolylidene ketones (28) [93TL4519]. The bis(sulfenyl chloride) F3CC(SCI)=C(SCI)CF 3 provides access to a variety of new dithioles including (29) and (30) [94CB533]. Direct conversion of strained double bonds to 2alkylidene-l,3-dithiolanes (31) is possible by cycloaddition of Bun3P+-CS2 followed by Wittig reaction with an aldehyde. In the absence of an aldehyde the intermediate ylide (32) derived from norbomene reacts with a second equivalent of Bun3P.CS2 to give the stable zwitterionic compound (33) [94CC2603]. S

Rl

O

S SR2 (26) X = S (27) X = O

O

9

I

"NS CHO

s

cF3

S

CF3

F3C

(28) (29)

0

3c s• (30)

s

-$2C ~' Bun3p§~ S ~ . ~

(33)

S---../...-'"~13' (31)

(34)

The series of six compounds (34), X = O, S and Y = O, S, Se have been prepared [94JPR177]. A variety of simple cyclopentene- and cyclopentadienefused 1,3-dithiol-2-ones and -2-thiones have been reported [94LA183] [94PHA117]. The synthetically useful phosphonates (35) can be obtained directly from the corresponding 1,3-dithiole-2-thiones and P(OR)3 in an improved procedure [94S195] and the strongly electrophilic dithiolium salt (36) has been obtained and reacted with various nucleophiles [93CB2111 ]. A similar 2-methylthiodithiolium salt has been used to gain access to (37) which was subsequently used for Wittig reaction to generate a variety of new donor-acceptor systems [94JOC5324]. Mesoionic compounds (38) have been used to obtain various tetrathiafulvalene (qq'F) and dihydro-TI~ derivatives [93TL5289]. The 4,5-bis(methylene)dithiolones (39) have been prepared and their Diels-Alder

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

169

reactions and reductive dimerisation via the 2-position examined [94TL269]. Conditions for the selective reduction of 4-methoxycarbonyl-1,3-dithiol-2-one and -2-thione to either the aldehyde or the alcohol have been reported

Rl

PO(OR)2 F3C f

-~S

(35)

OTf- PhCOS , ' ' ' ' ~

(36)

B~4 PI2-3+ R

(37)

(38)

R1

,, oS

Rl (39)Rl, R 2 = N

(42)

H,

Br

R

S

NC

CN

R

S"'"

R~

S

(40)

IS,, N S ~ ~ S

S

(41) " S , ~

S ~ . . ~ CO2Me

(44)

NC (43) CN

s

(45)

[93SM(56)1768]. A range of donor-acceptor compounds such as (40) are reported to be efficient and thermally stable 2nd order non-linear optical materials [94CC2057]. The X-ray structures of the powerful donors (41) [94CC1431] and (42) [94CC899] have been determined. In the former case the compounds are non-planar with S-S interactions as shown but the corresponding radical cations are planar. The X-ray structure of (43) shows it to have a significant contribution from the dithiolium cyclopentadienide structure and it undergoes oxidative dimerisation via the 2-position of the cyclopentadiene ring in air [93JCS(P2)373]. The new sulfur-rich heterocycles (44) and (45) have been prepared [93IC5467]. Reviews have appeared on TTFs as building blocks in supramolecular chemistry [94CSR41 ] and oligomeric TI'Fs as extended donors for increasing the dimensionality of electrical conduction [94AM439]. New salts of BEDT-TTF (46) prepared or characterised include (46) +" PF 6- [94CC2071], ((46)+')2 Cu(CF3)42- which is a K:-phase superconductor with To= 4K [94CC1599] and (46)8 COW12040 [94AG(E)223]. The salt dibenzo-TTF +" -C(CN)3 has also been reported [93KGS269]. The correlation between one electron oxidation and E-Z isomerisation has been examined for a series of TI'F-cyclophanes [94AG(E) 1379]. Reliable syntheses of T1T-CH2OH , TTF-CO2H [94S489], TTF-SLi and TTF-SeLi [93JCS(P1)1403] and their use to elaborate further substituted TrFs have been described. Preparation and X-ray structures of TI'F-thioesters, thioamides and amides have been reported [94CM1419] and p-hydroxyphenyl-TTFs have been prepared [93BSB615]. Direct mono- and di-iodination of TTF has been achieved using LDA/C6F131

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

170

[94CC983]. Reaction of 1,4-dithiino[2,3-b]-1,4-dithiin with LDA and MeSSMe in THF gives tetrakis(methylthio)-TTF via a novel rearrangement [94CC841 ]. TTF derivatives suitable for Langmuir-Blodgett film formation have been developed [93MI39] and "bis-arborol-TI'Fs" such as (47).have been prepared with a view to manufacturing a self-assembling molecular wire [94JOC5877]. Further examples of the use of'ITF-S(CH2)2CN as a protected form of TI'F-Sin the synthesis of oligomeric and macrocyclic TTF derivatives have appeared [94S809] [94CC2715] [94S1445]. Reaction of MeS-C-C-SMe with Br2 followed by Zn directly affords extended ITF analogue (48) [94JPR355].

(46)

(47) (E)

MeS/-~ S

S

SMe

S

S (49) X = O, S, NMe MeS

$\ /

MeS Rl

S

SMe " (50)

SMe

Rl

/ Rl

S

(51)

S

R!

Extended analogues of TTF [93BCJ2330] and (46) incorporating a heterocycle, such as (49) [93SM(56)1751] have been prepared and the rigid bithiophene analogue (50) undergoes multistep oxidation and reduction with a band gap of <1.5 eV [94CC1765]. Further more complex extended donors have been obtained [93TL7475] including (51)[93TL4005]. The synthesis, X-ray structure and electrochemistry of octafluorodibenzo-TrF have been described [94S460]. A large number of new annulated TIT derivatives have again been described including phenanthrene and dihydrophenanthrene fused compounds [93JPR599], 1,2,5-thiadiazole compound (52) [93SM(56)1914], bis(dicyanopyrazino)-TI'F [94JAP0665248] [94JAP0665249], bis(ethylenedioxy) -TI~ [93SM(60)295] and the hybrids (53) [94CC817] and (54) [94JOC2626] between it and (46). A chiral dimethyl derivative of (46) has been reported [93BCJ1949]. The new donor (55) and several related compounds have been described [94JOC3307]. A variety of unsymmetrical bis-annulated TrFs have been reported [93ACS910] [93T6849] [93SM(56)2113] including (56) [93BCJ2770]. Cycloaddition of 1,3-dithiolanetrithione with TTF gives (57)

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

171

[93SM(56)1931]. Mono- and bis-alkylidenedithio-TrF derivatives have again been of interest [93CL1341] [93SM(56)1938]. A variety of compounds containing two TTF units either directly fused as in (58) [93CL1337] [94CC459], or joined by CO [93AM741] or more complex groups [93SM(56)2007] [93MI141] have been reported. The preparation, X-ray

Sf

O (52)

-'S

(53)

S

(54)

S

S

(55)

S (57)

Rl

S..,~ --,.S

S ~ .,, RRI

S

(58)

X

S

S

R2

(59)

structures and properties of (59) have been described for X = S [94CC2775] and X - Te [94CC2115]. Compounds containing from three up to five separate TrF units linked in various ways have also been reported [93SM(56)2108] [94S613] [94S926]. The regioselectivity of dithiolane formation from unsymmetrical 1,4diketones has been examined [93SUL157]. Electrocyclic reaction of allyl dithiobenzoate with TCNE gives bicyclic dithiolane (60) [94SULl19]. Substituent effects on the cycloaddition of dithioesters with alkynes to gives 1,3dithioles have been investigated [93ZOR1089]. Reaction of aliphatic dithioacid dianions with CS2 followed by electrophiles leads to a variety of 1,3-dithiole C~ ~ , , ~ N

O

N Me "'/--Me

phR'~

//" s Me / (60)

V"S

(6I)~S

(62)SN~ OMe oMeO,~,./~

R R3 S

~

N

S

S R (65)

S

HO.

Ne,,~NHL (67)

s-"'x~ (63)

(64) ., CO2Me S ' ~ A rPhT . Sx S..~ Ph/-~S (66) CN

172

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

structures [93LA1081]. Acid catalysed cyclisation leading to 1,3-dithiolo[4,5c]quinolines has been described [92PJC1597]. Reaction of 2-thiazoline-5-thiones with CH2N2 gives a mixture of products including (61) [93HCA1715]. Transketalisation of dioxolane containing polymers to give dithiolane or oxathiolane units has been achieved [94CC2063]. Selective mono-deprotection of the bis-ethylenedithioketal of dimedone is possible using ceric ammonium nitrate [94IJC(B)516]. An improved method for preparation of 2-methylene- 1,3dithiolane has been reported [93OS175] and it adds to tropone to give (62) [93OS 181]. Spirobi(dithiole) (63) is oxidised by mCPBA to the monosulfoxide but by N-halosuccinimides to the monosulfone [93SUL109]. The tautomeric compound (64) has applications in optoelectronics [93USP5237067], (65) are radioprotective agents [94EJM121], (66) has been used for treatment of liver disease [93JAP05310730] and dithiolane-containing N-hydroxyureas (67) have been evaluated as PAF receptor antagonists and 5-1ipoxygenase inhibitors [94MIP06790]. 5.6.3

1,3-Oxathioles and Oxathiolanes

Resolution has been used to obtain chiral 1,3-oxathiolanes such as (68) [93MI97] and (69) [94MI156] for use in synthesis of nucleoside analogues and racemic (70) has been used similarly [94MIP14802]. Reaction of 1,2dinitroalkenes with 2-mercaptoethanol gives 2-(2-nitroalkyl)-l,3-oxathiolanes among other products [94JOC1053]. Cycloaddition of thioketene S-ylide (71) to carbonyl compounds gives oxathiolanes (72) [94TL3555]. Reaction of ketene dithioacetals ArCOCH=C(SMe)2 with Na in dioxane gives (73) in good yield [93MI242]. Treatment of ArNHC(=S)NMe2 with ArlC(=O)CH2Br affords PhCO0~ ~ , S ~OEt

(68)

-

O.

(69)

EtOzC

0

/ ~

OEt

(70)

o

/

. ~ S+i CH2(71) O

o .-ro Ar

/

O T R2

O"- ~Ar l (74) PhCH21

(73) ::~~~X PhCH2NHCON (76)

(75) M e O ~ o R

l~~tS/~(77) O ..

(72) O ~ Me ~ CO2Me

e

MeM ~ O OMe (78)

e O-

O

2-imino-l,3-oxathioles (74) [92MI56]. Various enolates RCH=C(O-)X react with (75) to give the 2-imino-l,3-oxathioles (76) [94JCS(P1)1263]. Selective deprotection of 1,3-oxathiolanes to the corresponding carbonyl compounds is

Five-Membered Ring @stems: With 0 & S (Se, Te) Atoms

173

possible using transketalisation with p-nitrobenzaldehyde catalysed by Me3SiOTf [94CC1937]. Substitution of 1,3-oxathiolan-5-ones at the 4position can be achieved by Pummerer reaction of the corresponding S-oxides [93JHC663]. A series of 5-aryl-4-benzoyl-l,3-oxathiolan-2-ones has been prepared and their reactivity with amines examined [93JHC501 ]. The preparation of benzoxathiole S-oxide (77) in enantiomerically pure form and its Diels-Alder reaction with cyclopentadiene have been reported [93TL8201 ]. 5.6.4

1,2-Dioxolanes

The complex mixture of products from ozonolysis of hexamethyl Dewar benzene includes the tricyclic 1,2-dioxolane (78) [94T7625]. 5.6.5

1,2-Dithioles

and

Dithiolanes

The dithiolodithiole (79) is obtained directly by heating diphenyldiacetylene with sulfur [93PS(79)87]. Cycloaddition of thiosulfines Ar2C=S=S to dipolarophiles such as maleic anhydride gives 1,2-dithiolanes (80) [93CL1599]. A variety of methods for formation of 1,2-dithiole-3-thiones have been reported including treatment of [3-ketodithioacids with P2S5 [93PS(84) 191 ], Br2 in liquid H2S [93TL3703] and N-chlorosuccinimide/(Me3Si)2S/catalytic imidazole [93TL7231]. The thienothiophene based example (81), a new C8S8 isomer, has been reported [93ZN(B)1621], as has the C6S8 isomer (82) [93IC5467]. A radical cation salt of 2-t-butyltetrathiotetracene with C(CN)3has been described [93KGS269]. Nucleophilic ring opening of 4,4-disubstituted1,2-dithiolanes by thienyllithiums has been examined [94PS(88)189] and this type of compound has also been examined as a model for the biological action of S--S

Ar.

S~S

S~ S

S~ S

S

Ph S--S (79)

0 ~

(81)

(80)

S (82)

O

S---S Ph (83)

S'--S

S~S

S--"S (88) X = O, S, NAr

HO Me

O X

(85)

(84)

O

(89)

(90) G

0

~

Rl (86) X = H2 (87) X = O

174

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

lipoic acid [94CC291]. Base catalysed reaction of naphthodithiole (83) with PhC---CH gives (84) [93SUL215]. The reactivity of pyridodithiolone (85) towards primary amines has been investigated [93JHC1079]. Good diastereoselectivity has been observed for the 1-oxidation of substituted 1,2dithiolan-3-ones with dimethyldioxirane [94TL3887]. An unusual sequence involving treatment with NaNO2, Na2S and then CH20/H + results in overall conversion of (86) to (87) [94CC131]. Cycloaddition of dithiolodithiole derivatives (88) with DMAD provides access to a wide variety of new heterocyclic adducts [94S 1067]. Some 5-styryl-1,2-dithiol-3-ones are useful in the treatment of heart disease [93JAP05301868] and compounds such as (89) show antimicrobial and anticancer activity [94JAP0616658]. 5.6.6

1,2-Oxathioles

and Oxathiolanes

The diastereoselectivity of intramolecular conjugate addition in ~,sulphonoxy-oc,13-unsaturated esters leading to sultones has been examined using LDAJCuCN or AgCN as base [94SL185]. Treatment of 4-alkenyl-l,3,2dioxathiane S-oxides with BF3.Et20 leads to ring contraction to the cyclic sultones, 3-alkenyl-l,2-oxathiolane S,S-dioxides [93TL3667]. The sulfur centred spiro compound (90) has been prepared in racemic form and the enantiomers separated using chiral stationary-phase chromatography [93TA2329]. An unusual rearrangement of the related spiro sulfurane (91) leads to the anhydride/sulfoxide (92) [94JST(317)279]. o

o

(91) 5.6.7

~Oj~ ~

Me.-~~~M e S Me (93) Me Se"Se'Se (94)

(92)

(95) P r i _ ~

Pri

Three Heteroatoms

The thermally stable bis-ozonide (1,2,4-trioxolane) of hexamethyl Dewar benzene has been isolated and its X-ray structure determined [94T7625]. Bicyclic oxadithiolane (93) has now been prepared by intramolecular reaction between dithiirane and ketone functions [94AG(E)777]. An efficient synthesis of benzotrithiole oxide (94) has been reported [93SUL5] and the stable benzotriselenole (95) has been prepared [94CC 1593]. 5.6.8

92M156

References

Ya. Gutsu, L. V. Boy, S. B. Maiga, P. Inthapanyaand N. A. Barba, Bul. Acad. Stiinte Repub. Mold., Stiinte Biol. Chim., 1992,56 [Chem. Abstr., 1994, 121, 35386].

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

175

A. Maslankiewicz and L. Skrzypek, Pol. J. Chem., 1992, 66, 1597 [Chem. Abstr., 1994, 121, 280573]. 93ACS910 F.C. Krebs, J. Larsen, K. Boubekeur and M. Fourmigu6, Acta Chem. Scand., 1993, 47, 910. 93ACS999 K.C. Arnoldsson, L. Eriksson and C. A. Wachtmeister, Acta Chem. Scand., 1993, 47, 999. 93AM741 T. Sugimoto, S. Yamaga, M. Nakai, H. Nakatsuji, J. Yamauchi, H. Fujita, H. Fukutome, A. Ikawa, H. Mizouchi, Y. Kai and N. Kanehisa, Adv. Mater. (Weinheim, Ger.), 1993, 5, 741. 93BCJI949 S. Matsumiya, A. Izuoka, T. Sugawara, T. Taruishi, Y. Kawada and M. Tokumoto, Bull. Chem. Soc. Jpn., 1993, 66, 1949. 93BCJ2330 K. Takahashi, T. Nihira, M. Yoshifuji and K. Tomitani, Bull. Chem. Soc. Jpn., 1993, 66, 2330. 93BCJ2770 S. Ikegawa, K. Miyawaki, T. Nogami and Y. Shirota, Bull. Chem. Soc. Jpn., 1993, 66, 2770. 93BSB615 J.M. Fabre, D. Serhani, K. Saoud and A. K. Gousmia, Bull. Soc. Chim. Belg., 1993, 102, 615. 93CB2111 S. Mono, H. Pdtzkow and W. Sundermeyer, Chem. Ber., 1993, 126, 2111. 93CC1828 S.V. Kessar and A. K. S. Mankotia, J. Chem. Soc., Chem. Commun., 1993, 1828. 93CJC836 R.F. Childs, R. M. Orgias, C. J. L. Lock and M. Mahendran, Can. J. Chem., 1993, 71, 836. 93CL1337 Y. Misaki, T. Matsui, K. Kawakami, H. Nishikawa, T. Yamabe and M. Shiro, Chem. Lett., 1993, 1337. 93CL1341 Y. Misaki, H. Nishikawa, T. Yamabe, T. Mori, H. Inokuchi, H. Mori and S. Tanaka, Chem. Lett., 1993, 1341. 93CL1599 K. Okuma, M. Shimasaki, K. Kojima, H. Ohta and R. Okazaki, Chem. Lett., 1993, 1599. 93CL1615 K. Kudo, K. Mitsuhashi, S. Mori, K. Komatsu and N. Sugita, Chem. Lett., 1993, 1615. 93HCAI715 M. K~igi, A. Linden, H. Heimgartner and G. Mloston, Heir. Chim. Acta, 1993, 76, 1715. 93IC5467 D.D. Doxsee, C. P. Galloway, T. B. Rauchfuss, S. R. Wilson and X. Yang, Inorg. Chem., 1993, 32, 5467. 93JAP05271217 H. Minora, H. Okamoto and H. Morishita, Jpn. Pat. 05 271 217 (1993) [Chem. Abstr., 1994, 120, 106983]. 93JAP05301868 K. Sasaki, S. Mita, N. Oodo, K. Kawai, M. Mori and K. Watanabe, Jpn. Pat. 05 301 868 (1993) [Chem. Abstr., 1994, 120, 217648]. 93JAP05310730 I. Shibuya, K. Yonemoto, M. Yasumoto, Y. Taguchi, T. Tsucha and M. Mizuno, Jpn. Pat. 05 310 730(1993) [Chem. Abstr., 1994, 120, 323557]. 93JCS(PI)I403 A.J. Moore, M. R. Bryce, G. Cooke, G. J. Marshallsay, P. J. Skabara, A. S. Batsanov, J. A. K. Howard and S. T. A. K. Daley, J. Chem. Soc., Perkin Trans. 1, 1993, 1403. 93JCS(P2)373 D. Nalewajek, M. H. Luly, M. L. Kaplan, M. R. Churchill, J. Ziller and P. M. Schaber, J. Chem. Soc., Perkin Trans. 2, 1993, 373. 93JHC501 H.X. Chang and G. Kollenz, J. Heterocycl. Chem., 1993, 30, 501. 93JHC663 J.V. Frechina, P. Palanca, T. Pichet, V. Sanz and J. A. Ramirez, J. Heterocycl. Chem., 1993, 30, 663. 93JHC 1079 P. Borgna and M. Pregnolato, J. Heterocycl. Chem., 1993, 30, 1079. 93JMOC(85)279 A. Cabrera, L. Velasco, M. L. Christ, M. Salmon and J. L. Arias, J. Mol. Catal., 1993, 85, 279. 93JOC6146 C.A. Panetta, Z. Fang and N. E. Heimer, J. Org. Chem., 1993, 58, 6146. 93JPR599 E. Fangh[inel, L. van Hinh and G. Schukat, J. Prakt. Chem. / Chem.-Ztg., 1993, 335, 599. 93JSC269 Z. Petrovic, A. V. Teodorovic, S. Konstantinovic and M. L.Mihailovic, J. Serb. Chem. Soc., 1993, 58, 269 [Chem. Abstr., 1994, 120, 298509]. 93KGS269 V. Kokars, V. E. Kampar and O. Ya. Neiland, Khim. Geterosiki. Soedin., 1993, 269 [Chem. Abstr., 1994, 120, 30701]. 93LA1081 K. Hartke, N. Rettberg, D. Dutta and H.-D. Gerber, Liebigs Ann. Chem., 1993, 1081. 93MI39 Y. Zhu, Yanbian Daxue Xuebao, Ziran Kexueban, 1993, 19, 39 [Chem. Abstr., 1994, 121, 280572]. 93M197 J.L. Kraus and G. Attardo, Chirality, 1993, 5, 97 [Chem. Abstr., 1994, 120, 270183]. 93MI141 X. Yang, P. Wu and D. Zhu, Hecheng Huaxue, 1993, 1, 141 [Chem. Abstr., 1994, 121, 108745]. 93MI242 M. Ruan, P. Lu and J. He, Hangzhou Daxue Xuebao, Ziran Kexueban, 1993, 20, 242 [Chem. Abstr., 1994, 121, 108580]. 92PJC1597

176

93M1563 93M1703 93M1777 93MIP24483 93OS175 93OS181 93PS(79)87 93PS(83)223 93PS(84)191 93SM(56)1751 93SM(56)1768 93SM(56)1914 93SM(56)1931 93SM(56)1938 93SM(56)2007 93SM(56)2108 93SM(56)2113 93SM(60)295 93SUL5 93SUL109 93SUL157 93SUL215 93SUP1806141 93T6849 93T7871 93TA1431 93TA2329 93TL3667 93TL3703 93TL4005 93TL4519 93TL4587 93TL5289 93TL6985 93TL7231 93TL7475 93TL8201 93USP5237067 93ZN(B)I621 93ZORI082 93ZORI089 94AG(E)223 94AG(E)777

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

M. H. Hung and W. B. Farnham, J. Chin. Chem. Soc. (Taipei), 1993, 40, 563 [Chem. Abstr., 1994,120, 244774]. K. Jaques, W. M. Buda, M. Pattie, J. Van der Eycken, M. Vandewalle, A. Venema and P. Sandra, J. High Resolut. Chromatogr., 1993, 16, 703 [Chem. Abstr., 1994,121, 35382]. K. W. M. Lawrie and D. C. Rustidge, J. Labelled Compd. Radiopharm., 1993, 33, 777 [Chem. Abstr., 1994, 120, 164027]. H. Rempfler, PCT Int. Appl. WO 93 24483 [Chem. Abstr., 1994, 120, 245064]. K. R. Dahnke and L. A. Paquette, Org. Synth., 1993, 71, 175. K. R. Dahnke and L. A. Paquette, Org. Synth., 1993, 71, 181. J. Blum, Y. Badrieh, O. Shaaya, L. Meltser and H. Schumann, Phosphorus, Sulfur and Silicon, 1993, 79, 87. W. DOlling, V. Birkner, A. Perj6ssy and Z. Sustekov& Phosphorus, Sulfur and Silicon, 1993, 83, 223. S. E. Zayed and I. A. Hussin, Phosphorus, Sulfur and Silicon, 1993, 84, 191. A. S. Benahmed-Gasmi, P. Frere, M. Jubault, A. Gorgues, J. Cousseau and B. Garrigues, Synth. Met., 1993, 56, 1751. T. Nozdryn, D. Clemenceau, J. Cousseau, V. Morisson, A. Gorgues, J. Orduna, S. Uriel and J. Garin, Synth. Met., 1993, 56, 1768. A. E. Underhill, I. Hawkins, S. Edge, S. B. Wilkes, K. S. Varrna, A. Kobayashi and H. Kobayashi, Synth. Met., 1993, 56, 1914. V. V. Khodorkovsky, J. Y. Becker and J. Bernstein, Synth. Met., 1993, 56, 1931. H. Nishikawa, K. Kawakami, H. Fujiwata, T. Uehara, Y. Misaki, T. Yamabe, T. Mori and M. Shiro, Synth. Met., 1993, S6, 1938. K. lkeda, K. Kawabata, K. Tanaka and M. Mizutani, Synth. Met., 1993, 56, 2007. M. Adam, U. Scherer, Y. J. Shen and K. MUllen, Synth. Met., 1993, 56, 2108. P. Blanchard, G. Duguay, J. Cousseau, M. Salle, M. Jubault, A. Gorgues, K. Boubekeur and P. Batail, Synth. Met., 1993, 56, 2113. J. M. Fabre, D. Serhani, K. Saoud, S. Chakroune and M. Hoch, Synth. Met., 1993, 60, 295. S. Chida, T. Yoshida, T. Shimizu and R. Sato, Sulfur Lett., 1993, 16, 5. R. Sato, M. Yamashita, M. Fujiwara, S. Chida and S. Ogawa, Sulfur Lett., 1993, 16, 109. L. Ho, M. H. Pera, G. Taillandier and G. Leclerc, Sulfur Lett., 1993, 16, 157. M. Tazaki, S. Nagaham and M. Takagi, Sulfur Lett., 1993, 16, 215. D. I. Gezalyan, S. R. Babayan, O. M. Martirosyan, M. I. Agadzhanov and A. A. Avetisyan, USSR Pat. 1 806 141 (1993) [Chem. Abstr., 1994, 120, 270367]. G. J. Marshallsay, M. R. Bryce, G. Cooke, T. Jergensen, J. Becher, C. D. Reynolds and S. Wood, Tetrahedron, 1993, 49, 6849. A. L. J. Beck'with and C. L. L. Chai, Tetrahedron, 1993, 49, 7871. Y. Nishida, M. Abe, H. Ohrui and H. Meguro, Tetrahedron: Asymmetry, 1993, 4, 1431. S. Allenmark and S. Claeson, Tetrahedron: Asymmetry, 1993, 4, 2329. D. E. Duffy, F. H. Condit, C. A. Teleha, C.-L. J. Wang and J. C. Calabreses, Tetrahedron Len., 1993, 34, 3667. T. J. Curphey and H. H. Joyner, Tetrahedron Lett., 1993, 34,3703. A. Belyasmine, P. Fr/~re, A. Gorgues, M. Jubault, G. Duguay and P. Hudhomme, Tetrahedron Lett., 1993, 34,4005. P. Fr~re, A. Belyasmine, A. Gorgues, G. Duguay, K. Boubekeur and P. Batail, Tetrahedron Lett., 1993, 34,4519. J. P. Konopclski and R. A. Kasat, Tetrahedron Lett., 1993, 34,4587. D. Lorcy, M.-P. Le Paiilard and A. Robert, Tetrahedron Lett., 1993, 34,5289. D. A. Jaeger and S. G. G. Russell, Tetrahedron Lett., 1993, 34,6985. T. J. Curphey and H. H. Joyner, Tetrahedron Lett., 1993, 34,7231.. M. Sail6, A. J. Moore, M. R. Bryce and M. Jubault, Tetrahedron Lett., 1993, 34,7475. J. Martynow, M. Dimitroff and A. G. Fallis, Tetrahedron Lett., 1993, 34,8201. R. Schumaker, US Pat. 5 237 067 (1993) [Chem. Abstr., 1994, 120, 107073]. R. Gompper, R. Knieler and K. Polbom, Z. Naturforsch., B, 1993, 48, 1621. A. A. Kron, G. V. Cherkaev and Z. M. Fedotova, Zh. Org. Khim., 1993, 29, 1082 [Chem. Abstr., 1994, 120, 217370]. V. N. Drozd, Zh. Org. Khim., 1993, 29, 1089 [Chem. Abstr., 1994, 120, 270188]. C. J. G6mez-Garcfa, L. Ouahab, C. Gimenez-Saiz, S. Triki, E. Coronado and P. Delha~s, Angew. Chem., Int. Ed. Engl., 1994, 33, 223. A. Ishii, T. Akazawa, T. Maruta, J. Nakayama, M. Hoshino and M. Shiro, Angew. Chem., Int. Ed. Engl., 1994, 33, 777.

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms 94AG(E)I379 94AM439 94CB533

94CB 1495 94CB1981 94CC53 94CC131 94CC291 94CC459 94CC817 94CC841 94CC899 94CC983 94CC1431 94CC1593 94CC1599 94CC1765 94CC1937 94CC2057 94CC2063 94CC2071 94CC2115 94CC2155 94CC2603 94CC2715 94CCn.775 94CM1419

94CSR41 94EJMI21 94EP608568 94EP611762 941JC(B)516 94JAP0616658 94JAP0665248 94JAP0665249 94JCS(PI)I263

177

K. Boubekeur, C. Lenoir, P. Batail, R. Carlier, A. Taller M.-P. Le Paillard, D. Lorcy and A. Robert, Angew. Chem., Int. Ed. Engl., 1994, 33, 1379. M. Adam and K. M011en,Adv. Mater. (Weinheim, Ger.), 1994, 6, 439. S. Reimann-Andersen, H. Pritzkow and W. Sandermeyer, Chem. Ber., 1994, 127, 533. S. HUnig, Y. Keita, K. Peters and H. G. van Schnefing, Chem. Ber., 1994, 127, 1495. U. Gerlach, T. Haubenreich and S. HUnig, Chem. Ben, 1994, 127, 1981. S. B. Wilkes, I. R. Butler, A. E. Underhill, A. Kobayashi and H. Kobayashi, J. Chem. Sac., Chem. Commun., 1994, 53. M. Abazid, H. O. Bertrand, M. O. Christen and J. L. Burgot, J. Chem. $oc., Chem. Commun., 1994, 131. M. Tazaki, H. Tanabe, S. Nagahama and M. Takagi, J. Chem. Sac., Chem. Commun., 1994, 291. Y. Misaki, K. Kawakami, T. Matsui, T. Yamabe and M. Shiro, J. Chem. $oc., Chem. Commun., 1994, 459. J. Hellberg, M. Moge, D. Bauer and J.-U. van Schlitz, J. Chem. $oc., Chem. Commun., 1994, 817. S. Nakatsuji, Y. Amano, H. Kawamura and H. Anzai, J. Chem. Sac., Chem. Commun., 1994, 841. K. Ono, S. Tanaka, K. lmaeda and Y. Yamashita, J. Chem. Sac., Chem. Commun., 1994, 899. C. Wang, A. Ellern, V. Khodorkovsky, J. Bernstein and J. Y. Becker, Y. Chem. Sac., Chem. Commun., 1994, 983. T. Suzuki, T. Sakimura, S. Tanaka, Y. Yamashita, H. Shiohara and T. Miyashi, J. Chem. $oc., Chem. Commun., 1994, 1431. S. Ogawa, T. Kikuchi, S. Niizuma and R. Sara, J. Chem. Sac., Chem. Commun., 1994, 1593. J. A. Schlueter, U. Geiser, J. M. Williams, H. H. Wang,'W.-K. Kwok, J. A. Fendrich, K. D. Carlson, C. A. Achenbach, J. O. Dudek, D. Naumann, T. Roy, J. E. Schirber and W. R. Bayless, J. Chem. $oc., Chem. Commun., 1994, 1599. H. Brisset, C. Thobie-Gautier, M. Jubault, A. Gorgues and J. Roncali, J. Chem. Sac.. Chem. Commun., 1994, 1765. T. Ravindranathan, S. P. Chavan, J. P. Varghese, S. W. Dantale and R. B. Tejwani, J. Chem. Sac., Chem. Commun., 1994, 1937. A. K.-Y. Jen, V. P. Rao, K. J. Drost, K. Y. Wang and M. P. Cava, J. Chem. Sac., Chem. Commun., 1994, 2057. M. J. Green, A. R. Lucy, S.-Y. Lu and R. M. Paton, J. Chem. $oc., Chem. Commun., 1994, 2063. P. Fr~re, R. Carlier, K. Boubekeur, A. Gorgues, J. Roncali, A. Tallec, M. Jubault and P. Batail, J. Chem. Sac., Chem. Commun., 1994, 2071. C. Wang, A. Ellem, V. Khodorkovsky, J. Y. Becker and J. Bernstein, J. Chem. Sac., Chem. Commun., 1994, 2115. S. Yamada, H. lshikawa and M. Matsumoto, J. Chem. Sac., Chem. Commun., 1994, 2155. R. A. Aitken, T. Massil and S. V. Raut, J. Chem. Sac., Chem. Commun., 1994, 2603. J. Becher, J. Lau, P. Leriche, P. MCrk and N. Svenstrup, Y. Chem. Sac., Chem. Commun., 1994, 2715. E. Aqud, J. Y. Becker, J. Bernstein, A. Ellern, V. Khodorkovsky and L. Shapiro, J. Chem. SOC.o Chem. Commun., 1994, 2775. A. S. Balsanov, M. R. Bryce, G. Cooke, A. S. Dhindsa, J. N. Heaton, J. A. K. Howard, A. J. Moore and M. C. Petty, Chem. Mater., 1994, 6, 1419. T. Jt~rgensen, T. K. Hansen and J. Becher, Chem. Sac. Rev., 1994, 23, 41. H. Law, M. H. Pera, G. Taillandier, M. Fatome, J. D. Laval and G. Leclerc, Eur. J. Med. Chem., 1994, 29, 121. J. W. Epstein, G. H. Bimberg, G. E. Walker, M. D. Dutia and J. D. Bloom, Fur. Pat. 608 568 (1994) [Chem. Abstr., 1994, 121, 179619]. J. Manero and E. Leupold, Eur. Pat. 611 762 (1994) [Chem. Abstr., 1994, 121, 280627]. A. Nangia and P. S. Chandrakala, Indian J. Chem., Sect. B, 1994, 516. Y. Kanda, T. Fukuyama, H. Saito, K. Gomi and Y. Nomura, Jpn. Pat. 06 16658 (1994) [Chem. Abstr., 1994, 121, 35591]. M. Matsuoka and N. Matsui, Jpn. Pat. 06 65248 (1994) [Chem. Abstr., 1994, 121, 57531 ]. M. Matsuoka, Jpn. Pat. 06 65249 (1994) [Chem. Abstr., 1994, 121, 83371]. G. L'abb6, J. Buelens, W. Dehaen, S. Tappet and L. Van Meervelt, J. Chem. Sac., Perkin Trans. 1, 1994, 1263

178

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

94JCS(PI)I367 94JOC1053 94JOC2626 94JOC3307 94JOC5324 94JOC5877 94JPRI55 94JPRI77 94JPR355 94JST(317)279 94LA183 94MI138 94MI156 94MI303 94MIP06790 94MIPI4802 94PHA 117 94PS(88)155 94PS(88)189 94S195 94S460 94,5489 94S613 94S809 94S926 94S1067 94S1445 94SL69 94SL185 94SL251 94SL457 94SL551 94SULl19 94T7625 94T8393 94TL269 94TL2365 94TL2537 94TL2891 94TL3555 94TL3887 94USP5283356

H. Suzuki, S. Yonezawa, T. Mori and K. Maeda, J. Chem. Soc., Perkin Trans. 1, 1994, 1367. K. P. Park, I. Yi and C. O, J. Org. Chem., 1994, 59, 1053. A. I. Kotov, C. Faulmann, P. Cassoux and E. B. Yagubskii, J. Org. Chem., 1994, 59, 2626. C. Rovira, J. Veciana, N. Sanlal6, J. Tarr(~s, J. Cirujeda, E. Molins, J. Llorca and E. Espinosa, J. Org. Chem., 1994, 59, 3307. T. K. Hansen, M. R. Bryce, J. A. K. Howard and D. S. Yufit, J. Org. Chem., 1994, 59, 5324. M. Jergensen, K. Bechgaard, T. Bj~)rnholm, P. $ommer-Larsen, L. G. Hansen and K. Schaumburg, J. Org. Chem., 1994, 59, 5877. D. Schnurpfeil and M. Teubner, J. Prakt. Chem./Chem. Ztg., 1994, 336, 155. M. Wagner, R.-M. Olk and E. Hoyer, J. PraY. Chem. / Chem. Ztg., 1994, 336, 177. A. M. Richter, J. Bauroth, E. Fanghanel, L. Kutschabsky and R. Radeglia, J. Prakt. Chem. / Chem. Ztg., 1994, 336, 355. A. Kalman, L. Parkanyi and D. Szabo, J. Mol. Struct., 1994, 317, 279. K. Hartke and C. Timpe, Liebigs Ann. Chem., 1994, 183. Q. Fang, Z. Qu, Y. Yang, H. Wang, H. Sun and X. You, Huaxue Xuebao, 1994, $2, 138 [Chem. Abstr., 1994, 121, 35384]. M. A. Siddiqui, H. Jin, C. A. Evans, M. P. Dimarco, H. L. A. Tse and T. S. Mansour, Chirality, 1994, 6, 156 [Chem. Abstr., 1994, 121, 83116]. P. Ferraboschi, P. Grisenti and E. Santaniello, J. Labelled Compd. Radiopharm., 1994, 34, 303 [Chem. Abstr., 1994, 121, 179515]. T. Y. Shen and D. M. Goldstein, PCT Int. Appl. WO 94 06790 [Chem. Abstr., 1994, 121, 57515]. T. Mansour, A. Tse, C. A. Evans, H. Jin, B. Zacharie, N. Nguyen-Ba and B. Belleau, PCT Int. Appl. WO 94 14802 [Chem. Abstr., 1994, 121, 179593]. K. Hartke and C. Timpe, Pharmazie, 1994, 49, 117. V. J. Ram, N. Haque, S. K. Singh, M. Nath and A. Shoeb, Phosphorus, Sulfur and Silicon, 1994, 88, 155. M. Tazaki. H. Tanabe, T. Hieda, S. Nagahama, K. Inoue and M. Takagi, Phosphorus, Sulfur and Silicon, 1994, 88, 189. R. P. Parg, J. D. Kilburn and T. G. Ryan, Synthesis, 1994, 195. B. W. Knight, S. T. Purrington, R. D. Bereman and P. Singh, Synthesis, 1994, 460. J. Garfn, J. Orduna, S. Uriel, A. J. Moore, M. R. Bryce, S. Wegener, D. S. Yufit and J. A. K. Howard, Synthesis, 1994, 489. R. P. Parg, J. D. Kilburn, M. C. Petty, C. Pearson and T. G. Ryan, Synthesis, 1994, 613. N. Svenstrup, K. M. Rasmussen, T. K. Hansen and J. Becher, Synthesis, 1994, 809. G. J. Marshallsay, T. K. Hansen, A. J. Moore, M. R. Bryce and J. Becher, Synthesis, 1994, 926. E. Fanghiinel, T. Palmer, J. Kersten, R. Ludwigs, K. Peters and H. G. yon Schnering, Synthesis, 1994, 1067. S. Zeltner, R.-M. Olk, M. Wagner and B. Olk, Synthesis, 1994, 1445. M. Brunner, L. Mussmann and D. Vogt, Synlett., 1994, 69. N. Asao, M. Meguro and Y. Yamamoto, Synlett., 1994, 185. M. Kuroboshi and T. Hiyama, Synlett., 1994, 251. C. Darcel, S. Bartsch, C. Bruneau and P. H. Dixneuf, Synlett., 1994, 457. C. G. Frost and J. M. J. Williams, Synlett., 1994, 551. I. V. Magedov, V. N. Drozd, S. Yu. Shapakin, D. S. Yufit and Yu. T. Struchkov, Sulfur Lett., 1994, 17, 119. K. J. McCuilough, S. Tanaka, K. Teshima and M. Nojima, Tetrahedron, 1994, $0, 7625. W. Adam and M. Sauter, Tetrahedron, 1994, $0, 8393. R. M. Renner and G. R. Burns, Tetrahedron Left., 1994, 35, 269. A. Guirado, A. Zapata and J. G~llvez,Tetrahedron Left., 1994, 35, 2365. E. Untersteller, Y. C. Xin and P. Sinai, Tetrahedron Lett., 1994, 35, 2537. F. Cavelier, S. Gomez, R. Jacquier and J. Verducci, Tetrahedron Lett., 1994, 35, 2891. Y. Tominaga, S. Takada and S. Kohra, Tetrahedron Lett., 1994, 35, 3555. R. S. Glass and Y. Liu, Tetrahedron Lett., 1994, 35, 3887. E. T. Marquis and J. R. Sanderson, US Pat. 5 283 356 (1994) [Chem. Abstr., 1994, 120, 217649].

Chapter 5.7 Five-Membered Ring Systems: With 0 & N Atoms G. V. BOYD

The Hebrew University, Jerusalem, Israel 5.7 .1 I SOXAZOLES A review of metalation of isoxazoles has appeared (93OPP515). The reaction of arylcyclopropanes I (R = H, Me or Ph) with sodium nitrite in trifluoroacetic acid affords isoxazoles 2 q u a n t i t a t i v e l y (94MI186); in contrast, l , l - d l c h l o r o - 2 - p h e n y l c y c l o p r o p a n e yields only 13% of 3 - c h l o r o - 5 - p h e n y l i s o x a z o l e 3 in this reaction (94M1357). 5-Acetyl-3p h e n y l i s o x a z o l e is formed from b e n z o n i t r i l e oxide and the captodative olefin 4; no intermediates could be isolated (93H591). Acylation of oxime dianions with N-methoxy-Nmethylalkylamides, followed by acidic hydrolysis and cyclodehydration, gives 3-substituted 5-alkylisoxazoles (94JOC5828). The action of molybdenum hexacarbon71 on the isoxazole ketones 5 (R = Me, Ph or n-hexyl) leads to the pyridones 6 with cleavage of the nitrogen-oxygen bond (94H853). The n i t r e n i u m ion 8 is produced by photolysis of l-t-bury13,5-dimethyl-2, l-benzisoxazolium tetrafluoroborate 7 (94TL4943). 179

180

Five-Membered Ring Systems: With 0 & N Atoms

R~

R

CI

Ar

CI

Ar

(1)

Ph

0

(2)

Ph I

(3)

L

o

"m'+ + I

O"

Ph

Ao

L 0

Ac

06H4N02- p

(4) 0 Me_

0

I

H (6)

(5) Me

Me~I~~.~~ 9O .

Me

._ Me

0 N+

(7) '~u, .F,Ph

(8) ~u, Ar

9H

m~0.~..,,,, Et OH

(9)

0

III m+ I 0"

(10) |

O

~,. H

NPh2

(11)

Ar, ;,..O

Ar N~

Nxo Ph

(13)

N I

Ph

(12)

Ph

Five-Membered Ring Systems: With 0 & N Atoms

181

5 .7 .2 I S O X A Z O L INES In the p r e s e n c e of m a g n e s i u m ions, s y n - i s o x a zolines, e.g. 9, are formed s e l e c t i v e l y from n i t r i l e o x i d e s and c h i r a l t e r m i n a l a l l 7 1 i c a l c o h o l s s u c h as C H = = C H C H E t O H ( 9 4 J A 2 3 2 4 ) . The c y c l o a d d u c t 12 of d i c h l o r o m e s i t o n i t r i l e o x i d e i0 (Ar = 3 , 5 - C I = - 2 , 4 , 6 - M e ~ C ~ } to the a l l e n e ii u n d e r g o e s a L e w i s - a c i d c a t a l y z e d C l a i s e n r e a r r a n g e m e n t to the i s o x a z o l e 13 ( 9 3 J C R 2 0 2 ) . The p r o d u c t s of the 1 , 3 - d i p o l a r c y c l o a d d i t i o n of n i t r i l e o x i d e to C~o f u l l e r e n e have b e e n c h a r a c t e r i z e d by X 3 N M R s p e c t r o s c o p y and highr e s o l u t i o n FAB m a s s s p e c t r o m e t r y {94CB581]. C~o F u l l e r e n e r e a c t s w i t h a c e t o n i t r i l e o x i d e to yield a m i x t u r e of t h r e e i s o m e r i c m o n o adducts (94JA7044). 3-Phenylisoxazolin-5-one condenses with a r o m a t i c a l d e h y d e s in the a b s e n c e of a solvent in the p r e s e n c e of p o t a s s i u m f l u o r i d e on a l u m i n a u n d e r m i c r o w a v e i r r a d i a t i o n to yield 4 - ( a r y l m e t h y l e n e ) d e r i v a t i v e s 14 (93SC16). 5 .7 . 3 I S O X A Z O L I D I NES The a s y m m e t r i c 1 , 3 - d i p o l a r c y c l o a d d i t i o n of n i t r o n e s to k e t e n e a c e t a l s is c a t a l y z e d by c h i r a l o x a z a b o r o l i d i n e s d e r i v e d from N - t o s y l L - u - a m i n o acids. The r e s u l t i n g 5 , 5 - d i a l k o x y i s o x a z o l i d i n e s , e.g. 15 from d i p h e n y l n i t r o n e and l , l - d i e t h o x y e t h y l e n e , are o b t a i n e d w i t h an e n a n t i o s e l e c t i v i t y of up to 62% {94TL4419]. The exo a d d u c t 16 is formed in 95% ee from d i p h e n y l n i t r o n e and 3 - c r o t o n y l o x o z o l i d i n - 2 - o n e in the p r e s e n c e of t i t a n i u m c a t a l y s t s g e n e r a t e d in situ from d i i s o p r o p y l t i t a n i u m d i c h l o r i d e and c h i r a l diols ( 9 4 J O C 5 6 8 7 ) . I n t r a m o l e c u l a r c y c l o a d d i t i o n of the n i t r o n e 17 y i e l d s the b i c y c l i c i s o x a z o l i dine 18 s t e r e o s e l e c t i v e l 7 (94JCS1661). The o x a d i a z a b i c y c l o [ 3 . 3 . 0 ] o c t a n e 21 is formed when the o x i m e 19 is heated. The r e a c t i o n p r o c e e d s by an i n t r a m o l e c u l a r 1 , 3 - d i p o l a r

182

Five-Membered Ring Systems: With 0 & N Atoms

Ph '~/

~CHAr 0

0

Ph,,,,.

Ph

(

pht N+,,,,0

+ EtOLOEt ~Ph/ N//-~.~ O/ XoEtOEt

(14)

(

(15)

0

Ph

o

Ph~ ~ N

Mo o-~o-)

Ph/N ~0" +

(16)

Me

0 phil2C~

Mo

o

Phi2C

-

(18)

(17)

II

.11

II

r"

S \

I

Y

N

N

H

\

OH

O" (21)

(20)

(19)

Ph

0

Pht,,,.~.~

0

HN,,o,~

(22)

(23)

Five-Membered Ring Systems: With 0 & N Atoms

183

cycloaddition of the tautomeric nitrone 20 (93JOC4539). The a-fallyloxy)aldoxime 22 similarly yields 23 with the stereospecific introduction of three chiral centres

(94SC1669).

Ph

,CH(OMe)2

(24)

/

1R

J

(25) N2

R2

0-"

R2

"OEt

1R

(26)

(27) ~CH2Ph

PhH2CNN._.~CH2Ph PhAo

C02H

Ph

(28)

OMe

0

cga

(29) ,

R

OEt

R

H

+ PhCHO N__~ C02Me OM

(30)

RCO2H

(31)

o-) (32)

(33)

184

Five-Membered Ring Systems: With 0 & N Atoms

5.7.40XAZOLES There are reviews of recent a d v a n c e s in the c h e m i s t r y of o x a z o l e s (93H1441) and of m e t a l a t i o n and h a l o g e n - m e t a l e x c h a n g e reactions of o x a z o l e s (94H1321). T r e a t m e n t of the a z i r i d i n e 24 with s o d i u m iodide in acetone, followed by d e h y d r o g e n a t i o n of the product w i t h nickel oxide, gives the o x a z o l e 25 (94TL2039). O x a z o l e - 4 - n i t r i l e s , 4 - p h o s p h o hates or 4 - s u l f o n e s 27 (R 9 = Et, Ar or 2thienyl; R = = CN, PO(OEt)2 or SO=Ph) are obtained by the r h o d i u m a c e t a t e - c a t a l y z e d reaction of nitriles w i t h the diazo e s t e r s 26 (94T3761). The action of t r i f l u o r o a c e t i c a n h y d r i d e on the amino acid d e r i v a t i v e 28 leads to the o x a z o l e 29 (93H2441). H e a t i n g o - n i t r o p h e n o l with N , N - d i e t h y l a n i l i n e y i e l d s 2 - m e t h y l b e n z o x a z o l e ; 2 - p r o p y l b e n z o x a z o l e is s i m i l a r l y p r o d u c e d from o - n i t r o p h e n o l and N , N - d i b u t y l a n i l i n e (93M1769). V i l s m e i e r f o r m y l a t i o n of 4 - m e t h y l o x a z o l e gives a I:i m i x t u r e of 2- and 5-formyl d e r i v a t i v e s (94H1791). A formal [2+3] c y c l o addition of b e n z a l d e h y d e to the 5 - m e t h o x y oxazole 30 (R = p-MeOC6H4), c a t a l y z e d by methylaluminium di(8-naphthoxide), affords the o x a z o l i n e 31 w i t h 98% c i s - s e l e c t i v i t y , w h i l e the t r a n s - i s o m e r is produced in the presence of titanium(IV) chloride or tin(IV) chloride (933OC7397). 5.7.5 O X A Z O L I N E S AND O X A Z O L I N O N E S The c h e m i s t r y of 2 - o x a z o l i n e s has been reviewed (94T2297). C a r b o x y l i c acids react at room t e m p e r a t u r e or b e l o w with B-amino alcohols in the p r e s e n c e of t r i e t h y l a m i n e and Ph~PCI=, g e n e r a t e d in situ from t r i p h e n y l phosphine and carbon tetrachloride, to give 2 - s u b s t i t u t e d 2 - o x a z o l i n e s , e.g. 32, in up to 80% yield; o - a m i n o p h e n o l s are s i m i l a r l y converted into b e n z o x a z o l e s 33 (93T9353). The fused o x a z o l i n e 35 is formed when the 4 - p y r o n e 34 is irradiated in a c e t o n i t r i l e (93CC1661).

Five-Membered Ring @stems: With 0 & N Atoms

185

0'''''''0

0

.-

0

Me u,

(35)

(34)

Me

----

I o

(36) (37)

[•

~

0 ,.

Me l/Me S'"~ : N - " ~

N MeMe

~f~L-~o ~ ~ (38)

Me

"O~N+

_Me r

PhH2CO2C /

..<~

...~1-'o

~ 9 Me PhH2CO2C

Scheme 1

Me

Ph

186

Five-Membered Ring Systems: With 0 & N Atoms

2,5-Diaryl-2-oxazolines 36 are dehydrogenated to the corresponding oxazoles b7 lithium bromide/calcium carbonate/bromine (94CCC1631}. Alkylation of 2-meth71-2-oxazoline at the methyl carbon atom is accomplished by treating its lithium derivative with alk71 or benz71 halides; thus a , a ' - d i c h l o r o - 2 , 2 ' - d i m e t h y l b i phenyl gave compound 37 (94TL5779). The optically active sulfoxide 38 reacted with 1-naphth71magnesium bromide to give the optically active oxazoline derivative 39 in 60% ee with transfer of chiralit7 from sulfur (93CC1489). Regio- and stereoselective 1,3-dipolar cycloadditions of oxazoline N-oxides derived from (+)-norephedrine have been described, e.g. Scheme 1 ((93TL5079).

HO 0 ~iN~ - G02 0 " = O=N--C=C=O .,~ ,~Me -MezCO H 0 0 Me (40)

~

~'0~N~O~ 0

(41)

(42)

Thermolysis of the hydroxyimino derivative 40 of Meldrum's acid generates nitrosoketene 41, which adds to ketones to give cyclic nitrones,

e . g . 42 from c y c l o h e x a n o . n e ( 9 4 C C 2 8 1 ) . (Z) - 3 - d i m e t h y l a m i n o - 2 - i s o c y a n o a c r y l a t e

Methyl reacts

with acyl chlorides to give 2-acyl-4-(dimethylaminomethylene)oxazolin-5-ones 43 (93JHC575). A mixture of the pyrroles 45 and 46, the pyridine 47 and the dihydro-2-pyridone 48 is obtained when the oxazolinone 44 is heated wi th 4-phenyl-l-tos71-1-azabuta-1,3-diene (943CS2499). The anion of the oxazolinone 49 functions as a masked Synthon of the form71 anion. Thus treatment of 49 with triethylamine and an electrophile E- derived from acetaldehyde, benzaldehyde, acrolein, methyl acrylato etc yields 50, which is cleaved to a mixture of the keto acid 51 and an aldehyde 52 b7 mild acidic hydrolysis (Scheme 2) (93TL3907).

Five-Membered Ring Systems: With 0 & N Atoms +

"C~N

NMe2

Me02 C

H

187

Me2N ~1 /~

RCOCI

+

RCO

(43)

Ph

Ph

N

+

XO__s 0

Ph

Ph

Tos

Ph

(44)

p~CH2NHT~s Ph" "N"

"Ph

Ph

Ph

(46)

~N, 0 ~

(47)

pr i

~ E

O

Pri N~------~" ~

(49)

(50)

H (45) Ph H

Ph

, ~

.CH=NTos

+

Ph

+

Ph HCOPh

I

(48) Tos pr I

O'~c/ + C02H (51)

ECHO (52)

Scheme 2 5.7.6 O X A Z O L I D I N E S

AND O X A Z O L I D I N O N E S

The reaction of (chloromethyl)oxirane with phenyl isocyanate to give the oaazolidinone 53 is catalyzed by late rare earth chlorides such as erbium, ytterbium and yttrium chlorides (94MI129).

Ph \

N II C II

0

+

/CH2CI

\o/

Ph\N_._~'CH2CI

o. o3 (53)

188

Five-Membered Ring Systems: With 0 & N Atoms

1Ar\

0 '~

N

II

C II

OH A ~ =.~Ar2

1

Ar2

HOf ~CHCIAr3

0

0

(54)

H3CA

0

CHCIAr3

(55)

~__(.

O C02H

OHGHG

. ".Ao-~ 0

(56)

Ph\

N II C II 0

O~~,CH3.._.... phx N / ~ __....~

+ o-

Ph

o2o (57)

(58) Me

o

\

/

~

\

Ph

/

....,,

: o.~o

o o

(59)

(60)

Me

Me

I ,,,, M e - N + ---(

LO....~ + Pri "" '%Ph (61)

Me

,,,Me

Me2N --'-x"

NaCN ~

NC../'""'Ph.. ~'0 Pri / - ' (62)

Five-Membered Ring Systems: With 0 & N Atoms

189

4 - H y d r o x y o x a z o l i d i n - 2 - o n e s 55 result from the action of ar71 isocyanates on the hydroxy ketones 54 (94JPR509). N-acety]-a]anine, valine or leucine and dimethylformamide/ phosphorus oxychloride yield the (formylm e t h y l e n e ) o x a z o l i d i n o n e s 56 (R = Me, i-Pr or i-Bu, respectively) (93TL4249). Treatment of diacet71 with phenyl isocyanate in the presence of triethylamine leads to the unstable d i m e t h y l e n e o x a z o l i d i n o n e 57, which undergoes a variety of reactions, such as dimerization and cyclization to 58 (93H1951). A review of d i a s t e r e o s e l e c t i v e additions of organometallics to chiral oxazolidines has appeared (94M199). The Diels-Alder reaction of (R)-2-phenyl-4-methyleneoxazolidin-5-one 59 with 2 , 3 - d i m e t h y l b u t a d i e n e proceeds with exod i a s t e r e o s e l e c t i v i t 7 to yield the adduct 60 (94T941). The action of sodium cyanide on the chiral o x a z o l i d i n i u m salt 61 leads to the cyano ether 62 s t e r e o s e l e c t i v e l 7 (93TL8325). 5.7.7 OXAD IAZOLES 4 - F o r m y l - 3 - p h e n y l s y d n o n e 63 is decarbonylated by bases; however, treatment with methyl ketones in the presence of sodium hydroxide gives condensation products, e.g. 64 with acetophenone (93MI385). The reaction of tropone 65 with the m e s o i o n i c oxazolium 4-olate 66 affords the [6~ + 4~] cycloadduct 67; in contrast, tropone undergoes a [2~ + 4~] cycloaddition with 3-phenylsydnone 68; the product 69 is converted into the fused pyrazole 70 by d e c a r b o x y l a t i o n and dehydrogenation (933CS1617). The oxime R C ( = N O H } N H C H = P h {R = p-O=NC6H4) undergoes oxidative cyclization to 3-p-nitrophenyl-5-phenyl-l,2,4-oxadiazole 71 under the influence of potassium permanganate (93ZOB2635}. 3-Trimethylsilylox7-1,2,5-oxadiazoles 72 react with triethyl orthoformate to afford comparable amounts of 3-ethoxyoxadiazoles 73 and the novel 1,2,5-oxadiazo-

190

Five-Membered Ring Systems: With 0 & N Atoms

Ph,, +

CHO + N,, 0 , , ~ 0 -

Ph~N§_~CH=CHCOPh

CH3COPh

"0

(63)

(64)

Ph

Ph

o~.1~ ~

o

Ph~ N\ Ph

h

(65)

(66)

(67)

_o~

o

Ph

Ph

%

dlN*- ~

(65)

O

R

Ph (71)

/CH=NOH

(75)

(70)

/R

// \\

N,,o,N+~.0.

""'r-~2

(69)

Me3SiO~

// \\

Ph

~

(68)

Ph\

O

N,,o/N

# \\

~\\

NxoIN

Et/Nxo/N

(72)

(73)

Ph\

02N

//

/C=NOH

(74)

o/N~ PhPh'~N~o

\\

N"O"N+~0" (76)

Nxo,N+,,,O. (77)

191

Five-Membered Ring Systems: With 0 & N Atoms

02N~

/NO2

II \\

N§

N'~O" ~0" (78)

N--N

H (79)

/

H

---

N--N

,/

(80)

---

N--N

21

R2 1R~

XO/

\k

~

(81)

lin-3-ones 74 (93T5905). The unstable oxadiazole N-oxide 76, produced by the action of dlnitrogen tetroxide on the oxime 75, decomposes to the tricyclic oxadiazole derivative 77 in hot benzene (93LA441). The synthesis of the "pernitro compound" 3, 4-dinitrofuroxan 78, has been described i93MI209). The action of chloramine T on the acylhydrazones 79 (R ~, R = = aryl or 2-furyl) generates nitrile imines 80, which undergo a 1,5-dipolar electrocyclization to the 1,3,4-oxadiazoles 81 [94SC1879). 5 . 7 .8

REFERENCES

93CC1489

R . W . B a k e r , G . R . P o c o c k a n d M.V. Sargent, J . Chem. S o t . , Chem. Commun., 1993, 1 4 8 9 . 93CC1681 F.G.West and D.J.Koch, J. Chem. S o c . , Chem. C o m m u n . , 1 9 9 3 , 1 6 8 1 . 93CCC1631 R . F . X . K l e i n , V.Horak and G.A.S. Baker, Collect. C z e c h . Chem. Commun., 1 9 9 3 , 5_88, 1 6 3 1 . 93H591 R.Jimenez, L.Perez, J.Tamariz a n d H. Salgado, Heterocycles, 1993, 35, 591. 93H1441 A.Hassner and B.Fischer, Heterocycles, 1 9 9 3 , 3_~5, 1 4 4 1 . 93H1951 R.Hernandez, J.M.Sanchez, A.Gomez, G.Tru~i]lo, R.Aboytes, G.Zepeda, R.W. Bates and J.Tamariz, Heterocycles, 1993, 36, 1951. 93H2441 M.Kawase, Heterocycles, 1993, 36, 2441. 93JCR202 G.Broggini, G.Mo]teni and G.Zecchi, J. Chem. Res., Synop., 1993, 202. 93JCSI6] 7 H.Kato, T.Kobayashi, K.Tokue and S. Shirasawe, J. Chem. Soc., Perkin Trans. I, 1993, 1617.

192

93JHC575

Five-Membered Ring @stems: With 0 & N Atoms

R.Bossio, S.Marcaccini, R.Pepino, P. Paoli and C.Polo, J. Heterocycl. Chem., 1993, 30, 575. 93JOC4539 A.Hassner, R.Maurya, O.Friedman, H. E.Gott].ieb, A.Padwo and D.AustJn, J. Org. Chem., 1993, 58, 4539. 93JOC7397 H.Suga, X.Shi and T.Ibata, J. Org. Chem., 1993, 58, 7397. 93LA441 A.M.Gasco, A.DiStilo, R.Fruttero, G.Sorba, A.Gasco and P.Sabatino, Liebigs Ann. Chem., 1993, 441. 93MI209 T.J.Godovikova, O.A.Rakitin, S.P. Golova, S.A.Vozchikova and L.I. Khmelnitskii, Mendeleev Commun., 1993, 209. 93M 1385 W.J.Hung, H.J.TEen, T.M.Choiu, L.L. Tien and C.K.Wu, J. Chin. Chem. Soc. (Taipei), 1993, 40, 385; Chem. Abstr., 1994, 120, 77232. 93MI769 T.Harayama, K.Nakatsuka, K.Murakami, H.Nishioka, Y.Ohmori and Y.Takeuchi, Chem. Express, 1993, 8, 769. 930PP515 N.R.Natale and Y.R.Mirzaei, Org. Prep. Proced. Int., 1993, 25, 515. D.Villemin, B.Martin and B.Garrigues, 93SC16 Synth. Commun., 1993, 23, 16. A.B.Sheremetev, Y.A.Strelenko, T.S. 93T5905 Novikova and L. I .Khmelnitskii, Tetrahedron, 1993, 4__99, 5905. H.Vorbrueggen and K.Krolikiewicz, 93T9353 Tetrahedron, 1993, 49, 9353.. A.Barco, S.Benetti, C.DeRisi, G.P. 93TL3907 Pollini, G.Spalluto and V.Zanirato, Tetrahedron Lett., 1993, 34, 3907. B.Balasundaram, M.Venugopal and P.T. 93TL4249 Perumal, Tetrahedron Lett., 1993, 34, 4249. T.Berranger, C.Andre-Barres, M. 93TL5079 Kobayakawa and Y. Langlois, Tetrahedron I,ett., 1993, 34, 5079. C.Andres, M.Delgado, R.Pedrosa and 93TL8325 R.Rodriguez, Tetrahedron Lett., 1993, 34, 8325. 93ZOB2635 B.I.Buzykin and O.A.Khuritonova, Zh. Obshch. Khim., 1993, 63, 2635, Chem. Abstr.,1994, 121, 300822.

Five-Membered Ring Systems: With 0 & N Awms

94CB581 94CC281

94H853 94H1321 94H1791 94JA2324 94JA7044 94JCS1661 94JCS2499 94JOC5687 94JOC5828 94JPR509

94MI99 94MI129 94MI186

94MI357

193

H.Irngartinger, C.M.Koehler, U.HuberPatz and W.Kraetschmer, Chem. Ber., 1994, 127, 581. N.Katagiri, A.Kurimoto, A.Yamada, H. Sato, T.Katsuhara, K.Takagi and C. Kaneko, J. Chem. Soc., Chem. Commun., 1994, 281. M.Nitta and T.Higuchi, Heterocycles, 1994, 3__88,853. B.Iddon, Heterocycles, 1994, ~7, 1321. M.Kulvk-Sindler, D.Vojnovic, N. Defterdarovic, Z.Marinic and D.Srzic, Heterocycles, 1994, 3__88, 1791. S.Kanemasa, M.Nishiuchi, A.Kamimura and K.Hor[, J. Am. Chem. Soc., 1994, 116, 2324. M.S.Meier, M.Poplawska, A.L.Compton, J.P.Shaw, J.P.Selegue and T.F.Guarr, J. Am. Chem. Soc., 1994, 116, 7044. M.B.Gravestock, D.W.Knight, J.S. Lovell and S.R.Thornton, J. Chem. Soc., Perkin Trans. I, 1994, 1661. P.D.Croce, R.Ferraccioli and C.La Rosa, J. Chem. Soc., Perkin Trans. i, 1994, 2499. K.V.Gothelf and J.A.Joergensen, J. Org. Chem., 1994, 59, 5687. T.J.Nitz, D.J.Volkots, D.J.Alsous and R.C. Oglesby, J. Org. Chem., 1994, 59, 5828. M.Schumann, F.G.Weber, R.Friede, R. Radeglia, H.Koeppel and M.Michalik, J. Prakt. Chem./Chem.-Ztg., 1994, 336, 509. L.N.Pridgen, Organomet. Reagents. Org. Synth., ]994, 99. C.Qian and D.Zhu, Synlett., 1994, 129. L.G.Saginova, M.Alhamdan and V.S. Petrosyan, Vestn. Mosk. Univ., Ser. 2: Khim., 1994, 35, ]86; Chem. Abstr., 1994, 121, 205245. M.Alhamdan, L.G.Saginova and V.S. Petrosyan, Vestn. Mosk. Univ., Set. 2: Khim., 1994, 35, :357; Chem. Abstr., 1994, 12___!1,255702. _

194

Five-Membered Ring Systems: With 0 & N Atoms

94SC1669

A.Hassner, K.M.Rai and W.Dehaen, Synth. Commun., 1994, 24, 1669. A.Jedlovska and J.Lesko, STnth. Commun., 1994, 24, 1879. S.G.PTne, J.Safaei-G, D.C.R.Hockless, B. W. S ke 1ton, A. N. Sobo lev and A. H. White, Tetrahedron, 1994, 50, 941. T.G.Gant and A.I.MeTers, Tetrahedron, 1994, 50, 2297. K.J.Do71e and C.J.Moody, Tetrahedron, 1994, 50, 3761. F.W.Eastwood and P.Perlmutter, Tetrahedron Left., 1994, 35, 2039. J.P.G.Seerden, A.W.A.Scholte opp Reimer and H.W. Scheeren, Te trahedron Lett., 1994, 35, 4419. R. J. Robbins and D.E. Falvey, Tetrahedron Let., 1994, 3__~, 4943. R.G.Puts and D.Y.Sogah, Tetrahedron 994, 3S, 5779.

94SC1879 94T941 94T2297 94T3761 94TL2039 94TL4419 94TL4943 94TL5779

Chapter 6.1 Six-Membered Ring Systems:

Pyridine and Benzo Derivatives

J. E. TOOMEY and R. MURUGAN Reilly Industries Inc., Indianapolis, IN, USA 6.1.1 SYNTHESIS 6.1.1.1 Reviews Recyclizations and retrosynthesis of six membered heterocycles using computer software, GREN and Heterocycland programs, were reviewed by Lushnikov and Babaev (93CHC(E)(29)1111). Synthesis of polyfimctional heterocycles was also reviewed (94SL27). Hetero Diels-Alder reactions have been reviewed (93AHC(57) 1) (94SYN(6)535). The second review covered asymmetric syntheses. As part of a larger review on synthesis of saturated nitrogen heterocycles, Steele reviewed piperidines, piperidinones, tetrahydroisoquinolines, indolizidines, quinolizidines, and hetero Diels-Alder reactions (94COS95). 6.1.1.2 Pyridines 4H-Pyranone (1) was used to make 4-amino-2,6-diethylpyridine (2) (Scheme 1) (94SC(24)1709), but unlike the dimethyl analogue, diethyl compound (1) required a more elaborate strategy and used tosylisocyanate. The order in which the two oxygen atoms were replaced with nitrogen atoms was important to the practicality of synthesis. 195

Six-Membered Ring Systems: Pyridines

196

~,

TsNCO ~ 1

.HO 61.

NH3

o)

(2) Scheme I

In a similar kind of overall transformation but using different reagents, Ram and eoworkers replaced both oxygen atoms in substituted 2H-pyranone (3) to make substituted 2-aminopyridine (4) (Scheme 2) (94JCR(S)86). SMe R2~CN

SMe NH4OAe, ~ 120 R 2 ~

RII ~'O I ~'~O

4Pyr., hr.

H2,NI(R) ~ R2 "

RI~ '~NI ~NH2

R1

Rl= 4-chlorophenyl R2=H

NH2 90%

(3)

(4) Scheme 2

Efficiency of pyridine synthesis from alkynes and nitriles is improved with light (Scheme 3) (93AOC(7)641).

~

C

N

+ HC~CH

CpCo(COD) hu,2hr.,25*C 74%

Scheme 3

Synthesis of pyridincs from acetaldehyde, formaldehyde and ammonia in the gas phase was studied with regard to metal catalyst and Si/AI ratio of the support (94CL59). Best conditions were Si/AI = 30 to 120 and use of Tl+, Pb+2, Co+2, or Zn+2catalyst. The total yield of pyridines based on aldehydes was 61%. In a variant, Vijn and eoworkers synthesized 3,5-1utidinr (5) from propionaldehyde (6) and formimine (7) in moderate yield (47%) (Scheme 4) (94SYN(6)573).

Six-Membered Ring Systems: Pyridines

tBuN=CH2 + 2 ~ C H O

piperidine, HOAe,MePh, 200*C,2-4 hr.

197

CH3~CH3

47% (7)

(6)

(5) Scheme 4

Tin dichloride was used to catalyze cyclization of 8-ketonitriles, such as (8), to yield 2-pyridones, such as (9), in high yield (Scheme 5) (93YH(13)623).

CH3 CH3

CN

SnCI2, 180-190 ~ 2 hr.

i 93% (9)

(s) Scheme 5

Two general methods for synthesizing pyridinecarbonitriles were reported by Ibrahim and eoworkers (Scheme 6) (94RTC(113)35). In the first, malononitrile (10) was condensed under basic conditions with unsaturated ketone (11) to give, initially, cyclohexane (12), which could be further transformed into pyridine (13) under basic conditions. Control of the type of base and conditions determined product distribution. In the second, one-pot reaction of acetophenone (14) and arylidenemalononitrile (15) gave nitrile (13).

Six-Membered Ring Systems: Pyridines

198

piperidine, R O "~ 25 ~ R' 35% N C ~ ~~~...R:R R" ~'~ "OH

R

NC

(lO)

(11)

(12)

OH,EtOH

l tr. KOH 79% R

NC__I R

N/

O EtOH= NCFAo~~N KOH, ~ + Ar. ~ CH3 54% Ar

(15)

,,

(14)

(13)

Scheme 6

Pyrolysis of oxime O-allyl ether (16) resulted in pyridine ring formation, (17), in reasonable yield, along with minor isomer (18) (Scheme 7) (93CPB(41)1297).

BF3 N-, 0

~"~CH3

180-190 ~ 24-48hr.

~

+

55%

CH3 25' 1

06)

07)

O8)

Scheme 7

Enamine (19) was azaa ulated using acryloyl chloride (20) to give dihydro-2-pyridone (21) in good yield (Scheme 8) (94JOC(59)1613).

199

Six-Membered Ring Systems: Pyridines

O

O

0

BuNH2, TsOH BuNH 0 .

O

84%= ~ C H 3 CH3~"~I~CH3 + ~~]J'~CI overall O' "Nr "CH3

CH3"~"~CH3

I Bu

09)

(20)

(2t)

Scheme 8

Isomeric dihydro-2-pyridone (22) can be made from condensation of aryl aldehydes with 3-alkenamide (23) (Scheme 9) (94JOC(59)291). However, many examples showed lower yields (50-70%) than the one in Scheme 9. PPE, 60 ~

O l~~Ph

+

PhCHO

95%

H

Ph kp h

(23)

(22) Scheme 9

Isothiosemicarbazone (24) having a bulky group on the terminal nitrogen reacts with ethoxymethylenemalononitrile (25) to form the triazolo[ 1,5a]pyridine ring system, (26), in modest yield (Scheme 10) (94JCS(P 1)825). As sterie bulk around the terminal nitrogen decreased, yield of (26) also decreased. CH3,

NH(tBu)

cH~N--N=~SM e

(24)

EtO CN X__/ \CN

(25)

140 ~ 50% (26)

NH(tBu)

Scheme 10

Pyrrolo[2,3-b]pyridines (27) can be conveniently made in a one-pot procedure from potassium salt of 2-formylsuceinonitrile (28) in good yield (Scheme 11) (94SC(24)2697).

200

Six-Membered Ring Systems: Pyridines

e ~ O K

1) RNH3CI MoO_ CN CN 2) KOH MoO~'~_OO~,~a ~

CN

CN

C

N

/

(80%)

R (2s)

(27) Scheme 11

5-Butyl-2-methylpyridine (29) was made in modest yield by hetero Diels-Alder reaction of enamine (30) with 1,2,3-triazine (31) (Scheme 12) (94H(38)1595). 3 ~.NsN

ZnBr2,

9ooc_ 2 hr.

CH3

52% Oo)

O1)

(29)

Scheme 12

A very selective hetero Diels-Alder reaction of azadiene (32) with maleic anhydride gave tetrahydropyridine (33) in greater than 98% d.e. under mild conditions (Scheme 13) (94T(A)557). o CH3 CH3y "N

O I

&

~H3 + ~---CH3 OH

O

O

MeCN 20 ~

~ 20 hr.

( N~ ~ / , C H 3 HO CH3

02)

03) Scheme 13

Two unusual Hantzsch ester syntheses have been reported. One involved elimination of a 4-antipyryl group during spontaneous aromatization of the 1,4-dihydropyridine intermediate (94H(37)815). Other reported formation of an oxygen-bridged tetrahydropyridine (34) (Scheme 14) (94JCR(S)106).

201

Six-Membered Ring Systems: Pyridines

~

C02Me

C02Me

70%

Me-- [-NHMe Me

04) Scheme 14

Continued study of thermolysis of dihalocyclopropyl imines, such as (35), into pyridines, such as (36) and (37), indicated yield of principal pyridine could be increased two-fold by addition of W03 (Scheme 15) (94JCS(P1)739). l

cVI

WO3L

/X/Ph

~CH--NBz

~ P h Bz

+

Ph B

78% 06)

05)

6% (37)

Scheme 15

Low yields (20-30%) of 3-arylpyridines result from rearrangement of 6aryl-5-nitrobicyclo[2.2.1 ]hept-2-enes when treated with tin (II) chloride (94TL(35)2211). Bicycloheptenes can be made from Diels-Alder syntheses. Good yields of pyddine (38) can be made from tris(isopropylthio)cyclopropenylium salt (39) when treated with lithiated isocyanides (Scheme 16) (93JHC(30)1691). s(a,0

;0Pr)

~ S(~r)J

+ PhCH2NC S(~r)

25 ~ 15hr.

60% (39)

08) Scheme 16

202

Six-Membered Ring Systems: Pyridines

6.1.1.3 Quinolines

Ring expansion of indole (40) to give quinoline (41) was accomplished in good yield (Scheme 17) (93JICS(70)567).

Ph IH

KOH CHCI3 =.. 25 ~ 6 hr.

~ N ~ C I Ph 80%

(40)

(41) Scheme 17

Imine (42) was cyclized by irradiation in MeOH to give quinoline (43) (Scheme 18) (94SYN1155). Irradiation promoted electrocyclie ring closure,

followed by [1,5] H shift to re-aromatize the benzene ring, and finally loss of hydrogen to aromatize the pyridine ring. NHPh

NHPh

CI

Ph

1) HBF4

Me

2) hu, 40 hr. Cl

Ph 81%

(42)

(43) Scheme 18

In an extension of quinoline ring formation by reaction of enolate anions with o-trifluoromethylaniline, the enolate anion was replaced with anion of nitrile (44) to give quinoline (45) (Scheme 19) (94TL(35)7597).

Six-MemberedRing Systems: Pyridines

203 F

~ "~"

CF3 + -NH2

O Et/~CN

53%

E~tN H2

(44)

(45) Scheme 19

Aryl substituted imine (46) gives quinoline (47) on oxidation with DDQ in the presence of alkyne (48) (Scheme 20) (93T(49)10157).

+ -N,~"~ph

PhCECH 55%

(46)

"~

(48)

"N" "Ph (47)

Scheme 20

6.1.1.4 Piperidines Palladium catalyzed cyclization of optically active amine (49) gave chiral piperidine (50) in excellent yield (Scheme 21) (94CL21). H

PdCI2 89% I

Cbz

Cbz (+(49)

(+)-(so) Scheme 21

Titanium tetrachloride was used to cyclize cyanoamine (51) and, like the PdCl2 case, in a stereospecific manner (Seheme 22) <94TL(35)3581). Sequence of addition was critical to cyclization.

Six-Membered Ring @stems: Pyridines

204

1

~ Pr

~

TiCI4 R=H"

N I

Bz (s~)

Me

Pr

I

Me

Bz 60%(>90%cis)

R=SiMr iCl4

Pr'......~ M e I Bz 80% (100% Vans)

S c h e m e 22

Zirconium catalyzed cyclization of doubly unsaturated amine (52) gave a mixture of cis- and trans-piperidines (Scheme 23) (94SLA51). Me ~.,.,.-.,N..,-,x,,,, ~

2) . 2 0

I

91%

Bz

--

+

I Bz

(s2)

Me

4. l

... I Bz

S c h e m e 23

Electrophilic cyclization of unsaturated imines was accomplished with bromine under mild conditions to give piperidines or pyrrolidines, depending on substitution pattern (94TL(35)1925).

6.1.2 REACTIONS 6.1.2.1

Reviews

Reviews on reactions of 1,4-dihydropyridines (93CHC(E)(29)489) and pyridylphosphines (93CR(93)2067) have been reported. Methods of generation, structure and physical chemical characteristics of pyridinium ylides in organic

205

Six-Membered Ring Systems: Pyridines

synthesis have been reviewed (93RJOC(29)1722). Reactivity of N-substituted azaaromaties (94KGS 147) and of acridinium salts and related compounds (94H(38)897) have been reviewed. A wealth ofheteroeyclic chemistry including pyridine reactivity is present in the summary of Katritzl~'s research group scientific results (1954-1993) (94H(37)3). 6.1.2.2 Pyridines

A regiospeeific synthesis of diphenyl-4-pyridylcarbinol (53) based on reaction of benzophenone with 4-eyanopyridine (54) in presence of sodium and other meta"ls is reported (Scheme 24) (94H(37)1489). High yield and regiospecificity in the reaction compared with Emmert reaction was attributed to the effect of the cyano substituent in stabilizing the intermediate radical and acting as a good leaving group. CN

CN

(54)

-

~Na O e ONa

- NaCN

OH P

ph1~'~ph

P h

0 J~ Ph~Ph i

qt.---.-

t

+

Na~

Na

H20

(53) Scheme 24

Palladium catalyzed cross coupling between 4-iodo substituted pyridines, (55) and (56), and aryl boronie acids, (57) and (58), has been used in syntheses of 1,7-naphthyridine (94JHC(31) 11 ) and 13-earboline (Scheme 25) (94TL(35)2003).

206

Six-Membered Ring Systems: Pyridines I ,

~_~ OHC

NH2

Pd(PPh3)4 Na2CO3 DME .._

B(OI-I~

+

S

=--

72% (ss)

(57)

MeO

NHCO(tBu) B(OI~

I

Pd(PPh3)4 K2CO3

PhCHs/EtOH48hr. ~ OMe (s6)

T

"NHCO(tBu)

~ F

73%

(ss) Scheme 25

Photochemical approach to azacarbolines are also reported. However, a mixture of earbolines (59) and (60) was obtained (Scheme 26) (94H(38)1241). o

o +

N (s9)

(60)

Scheme 26

Electrosynthesis of unsymmetrical polyaryls by SaN1-type reaction was reported (Scheme 27) (94JOC(59)4482).

Six-Membered Ring Systems: Pyridines

207 OH

CI

OH

tBu.~

(/)

KOtBu/NH&

KBr, e" 40 ~

tBu

( ) r

-

11"

56%

S c h e m e 27

An unusual vicarious nueleophilie substitution of alkyl substituted 3nitropyridines was observed (Scheme 28) (93KGS136).

M~NO2 Me"

"N"

+

CHCI3

"Me

NaOtBu THF/DMF

-70~

M~N~

H CC13

70%

Me" "N" "Me H

NO2

S c h e m e 28

Nitration of pyridine has been achieved using dinitrogen pemoxide sulfur dioxide system to give 3-nitropyridine (61) (Scheme 29) (94ACS(48)181).

- 78 to -11 ~

+

N205/SO2 60% (61) S c h e m e 29

Directed ortho-lithiation of iodopyridine (62) with halogen dance has been observed (Scheme 30) (93JOC(58)7832).

208

Six-Membered Ring Systems: Pyridines

1) LDA/THF - 75 ~ l hr. 2) E+, THF - 75 ~ 2 hr.

I

h .

E+=H20,E=H, 98% E+=MeI,E-Me, 93% E+=PhCHO,E=PhCH(OH),619,

(62)

Scheme 30

Diisopropyl(1,2-dihydro-2-thioxo-3-pyridyl)phosphonate (63) was synthesized from a lithiated derivative of readily-prepared O, O-diisopropyl-S-(2pyridyl)thiophosphate (64) through a S-to-C phosphonyl group migration (Scheme 31) (94TL(35)3083).

o S--tl(OiPr)2

LDA/THF -78 to 0..~~ I .~I l ,l -"

Lio

]

~N'~S__~(OiPr)2 ]

(64)

NH4CI

0 ~~(OiP02

HCi,0"-'"~~

SH (63)

Scheme 31

Selective bromination of 2-methoxy-6-methylpyridine afforded 5bromo-2-methoxy-6-methylpyridine (94SC(24) 1367). Subsequent deprotonation of the pyridine derivative in the benzilie position, or lithiumbromine exchange, allowed regiosclcctivr introduction of various r Concise regiospecifie conversion of pieolinie and isonieotinie acids into 2-benzoyl and 4-benzoyl nicotinic acids has been achieved using organolithium and related reagents (94SC(24)1789). Sulfur nucleophiles, vinylsulfide (93ZOK(29) 1501) and methanethiol (93PJC(67) 1609), have been used to displace halogens in 3-halogenated pyridincs, 3,5-dibromopyridinr and 3-ehloro-2,6-dimethylpyridine-N-oxide respectively. Palladium-catalyzed cross coupling between 3-iodopyridine and an alkynr (94S583) or between 1,2,5,6-tetrahydropyfidine-3-triflate and 3indoleboronie acids (94H(37)1761), are reported. Elcctroreductive coupling of tx-ehlorokctonc and 3-bromopyridinc has been demonstrated (94SC(24)145). Radical alkylation and carbamoylation of 4-cyanopyridine (54) have been reported. (54) has been alkylated with earboxylie acids, using trivalcnt iodine compounds as oxidant, to give (65) (Scheme 32) (93JCS(P 1)2417). (54)

209

Six-Membered Ring Systems: Pyridines

was earbamoylated with corresponding silver earboxylate using persulfate as the oxidant (Scheme 32) (93H(36)2687).

CN

AdCO2H, PhI(O2CCF3)2 8-10hr.

CN

Ad=adamanlyI (54)

Ad 88% (6s)

I (C6H!I)2NHCO(CO2H) Na2S208,AgNO3,H2SO4 H20/CHCI3,1hr.

95% Scheme 32

2-Amino-3-eyano-4-tdfluoromethyl-6-arylpyridine (66) was obtained from 3-eyano-4-tdfluoromethyl-6-aryl-2-(1H)pyridone (67) via an interesting rearrangement of 2-O-acetamido-3-eyano-4-trifluoromethyl-6-arylpyridine intermediate (Scheme 33) (94JFC(67)87).

KzCO3

CF3 Ar~'O

K co, MF

N+

Scheme 33

Mechanism of Hammiek reaction was studied using intramolecular eyclization reactions with 3-O-acylated-3-hydroxypieolinie acids (94H(37)1731).

210

Six-Membered Ring Systems: Pyridines

2-Chloropyridine (68) was converted into lithiopyridine via reductive lithiation using lithium naphthalide as an electron transfer agent (Scheme 34) (94H(37)1467). Li-naphthalide ~CI

THF'"70~

I ~~'~Lil E=I, 54%

(6s)

E=COPh,50% E-Ph, 63%

Scheme 34

The chloro substituent in 2-chloropyridines has been displaced using sulfur nucleophiles, 4-methoxybenzylthiol (94SST21), 4-chlorobenzylamine ~94JHC(31)73), and 2,2,2 trifluoroethanol (Scheme 35) ~94JFC(67)57). NaH/DMF 25~~22 hr. C I ~ C ( O C H 2 C F 3 ) 3 + CF3CH2OH 57%

"N"

"OCH2CF 3

Scheme 35

6.1.2.3 N-Oxides Sequential pedcyclic reactions between pyridine N-oxides and allenes have been evaluated in terms of PM3 calculations (94H(37)257). A new way to introduce dimethylamino groups into e2aaromatic compounds has been devised by reaction of pyridine N-oxide (69) or picoline N-oxide with hexamethylphosphoramide (Scheme 36) (94PJC(68)1343). HMPA,PPA 25-230~ 87%

NMe2 7.7" 10.0

(69) Scheme 36

Six-Membered Ring Systems: Pyridines

211

Reaction between 2,3,5,6-tetrachloropyridine N-oxide (70) and sodium dimethyldithiocarbamate in acetone forms 1-[6-(3',5',6'-trichloropyrid-2'ylthio)-3,5-dichloropyrid-2-ylthio]propan-2-one (71) as main product, which is an unusual nucleophilic substitution reaction (Scheme 37) (94TL(35)3147).

2

CI~CI

+

0 1 "N~ "CI

S A Acetone NaS NMe2.2H20

CI~ "N" "~S-~c I

(70)

Scheme 37 6.1.2.4 Applications and Uses

1-Hydroxy-7-azabenzotriazole and its corresponding immonium salts are shown to be more effective in avoiding racemization in a model solid-phase peptide segment coupling process than their benzotriazole analogues (94TL(35)2279). The good leaving group nature of the 2-thiopyridyl group has been used to advantage in simple, facile methods for 13-1actone(72) and 13lactam (73) syntheses (Seheme 38) (94H(38)281) (94H(38)277).

NO2 Me OS~Vle)2(tBu)

~~,I ZnCl2 , ~__ M,~ 0 ~ . ,

A2r HO

MeOS~1e)2(tBu)

sAir

172)

Ph ZnCI2 Me,,,,,~Ph N"ph

O// '~'Ph (73)

Scheme 38

~

NO2

Six-Membered Ring @stems: Pyridines

212

6.1.2.5 Natural Products

Four-step synthesis of (+)-tortuosamine (74) was reported in which key ring closure was an intermoleeular SRN1reaction between two parts of (75), a ketone enolate and a 2-halopyridine component (Scheme 39) (94TL(35)8145).

/N(Me)Bz

~

OMe

[~L'N""Br

OMe

1) LDA,hu 2) PhN(Tf~ 3) H2,Pt/C

NHMe

r

(75)

(74) Scheme 39

Thermal treatment of 2-pyridone derivatives, such as (76), with dimethyldiehlorosilane, triethylamine and ehloranil in benzene gives 8hydroxyquinoline (77) in high yield by oxidative intramoleeular [4+2] cycloaddition (Seheme 40) (94CC701). These isoquinolines are used in the synthesis of fully functionalized DEF rings of frederimycin A.

O

CO2Me

Me

18

-"~COaMe [ ~ CO2Me

Me2SiCI2 ~I" Imidazole Chloranil ~N.~~o..OH R 42 180hr.~ Me

'a

(76)

(77) Scheme 40

Two-step synthesis to pyridoxatin analogues was reported, starting from 4-hydroxy-2-pyridone (78) and citronellal (79) (Scheme 41) (94TL(35)531).

Six-Membered Ring Systems: Pyridines

"2--

xN OH ~

213

Me

Me

(7s)

(79)

__M~

//

Me

O

Me

0

Scheme 41 6.1.2.6 Isoquinolines

N-acyliminium ion has been generated from N-1-(tributylstannyl)alkyl carboxamide (80), or corresponding carbamate, and reacted with carbon nueleophiles (Scheme 42) (93BCSJ(66)3456).

+

Fe(Cp)2PF6 H2C=C(Ph)OSi(Me)2(tBu)

"co(tau)

'~cO(~u)

Sn(Bu)3

Ph

(so) Scheme 42

Acyliminium ions are also derived from rearrangement of BischlerNapieralski cyclization products, which are obtained from amide product of reaction of arylethylamines and 2-methoxycarbonyl benzoyl chloride. These can be captured, for example, with methoxide anion (Scheme 43) (94TL(35)2751).

214

Six-Membered Ring Systems: Pyridines MeO

MeO-/MeOH DMAP

Me<)'

~ N

[ ~C02Me

"-

MeO N

Me<)

0

Scheme 43

1,3-Dipolar eycloaddition between Nomethyl-4-hydroxyisoquinolinium iodide (81) and dipolarophile DMAD (82) has been reported (Scheme 44). Their stereochemical and regiochemieal behavior was investigated using 2DNMR experiments (94JHC(31) 187). OH

Et3N/THF iO

16 hr.

MeO2C,

N~'Me

MeO2C

+ "Me

92% O2Me

(81)

(82) Scheme 44

6.1.2.7 Quinolines

Regioselective reduction of 1-methylquinolinium ion (83) by tributyltin hydride or tris(trimethylsilyl)silanevia photoinduced electron transfer has been done (Scheme 45) (94CC287). H

+

Bu3Snl-I

H

100%

03) Scheme 45

Electron deficient 3-quinolineearboxylie acid (84) underwent ready deearboxylation in the presence of cyanide ion (Scheme 46) (94TL(35)8303).

215

Six-Membered Ring Systems: Pyridines

The addition of CN to the 2-position of the quinoline nucleus provides a i3-keto acid intermediate that readily decarboxylates. O

O

~R~~

CO2HCN" F

(84) Scheme 46

An easy access to 2-aryl-4-quinolone (85) has been achieved from 2aryl-1,2,3,4-tetrahydro-4-quinolone (86) using hypervalent iodine as the oxidizing agent (Scheme 47) (94SC(24)2167). 0

KOH/MeOH 60 ~ 12-18 hr. + Ph

0

Phi(OAth 85%

(86)

Ph

(85) Scheme 47

A four-step synthesis of 8-amino-7-quinoline earbaldehyde (87) from 8hydroxyquinoline (88) has been disclosed (Scheme 48) (94T(50)10685). Major steps involved a Bueherer reaction followed by Claisen type rearrangement, isomerization and ozonolysis. Amino aldehyde (87) underwent Friedlander condensation with 2-acetylpyridine to form 2-pyridyl-1,10-phenanthroline (89).

Six-Membered Ring Systems: Pyridines

216

Na2S205 170 oC 24 hr. +

H2N/',,~ "

(88)

I

ZnCI2 25-180 ~ 22 hr.

KOH/EtOH

NH2

NH2 1) tBuCOCl

I 2) 03 3) Na2SO3 4) HCI KOH/EtOH 12 hr.

NH2

O

(87)

(89)

Scheme 48 6.1.2.8 Bipyridines

Self assembly of catenanes and rotoxanes, based on 4,4'-bipyridine moiety, have been investigated (94AG(E)(33)433) <94CC177) (94CC181). 2,2'Bipyridine based organoplatinum dendrimers were reported (94AG(E)(33)847). Pyridine-2,6-dioxazoline (94JACS(116)2223) along with Ru metal catalyst has been used for cyclopropanation of olefins with diazoaeetates. Stable free radicals are generated from 6,6'-bis-N,N'-dihydroxyimidazolidione-2,2'bipyridine and studied (94TL(35) 1211 ) (94TL(35) 1215) (94CC741 ). Highly selective Li§ transport through liquid membranes has been observed with oligomethylene bridged bis-phenanthroline derivatives (94CL397). Very strong and selective complexation of small ions has been seen with highly preorganized open chain bipyridine-based ligands (94CC1363). Macroeyelie helicates based on pyridine-2,6-carbaldimines has been observed with metal coordination studied by X-ray analysis <94CC1391).

Six-Membered Ring Systems: Pyridines

217

6.1.2.9 Pyridiniums

Preparation of N-methylated pyridinium salts via decarboxylation of Ncarbomethoxypyridinium cations was reported (94SC(24)1923). Reduction of pyridinium salts without electron withdrawing groups to give 1,4dihydropyridines was achieved using sodium dithionate (94TL(35)707). N-Aminopyridinium salt (90) has been used in photolytic generation of N-aeylnitronium ions for synthesis of polycyelic laetams (Scheme 49) (94H(37)1463). hD (CF3)2CHOH 72 hr. 65%

C) C)

(90) Scheme 49

In a study of micelles on cyclization reactions, N-hexadecyl-2chloropyridinium iodide was used as an amphiphilie carboxy activating agent for laetonization and laetamization procedures (94JOC(59)415). Ferricyanide oxidation (Decker oxidation) of 1-substituted polyarylpyridinium salts (2,4,6triaryl, 2,3,4,6-tetram3,1, and pentaaryl) have been found to provide a general approach to synthesis of substituted pyrroles (94H(37)1347). Reaction of 1-alkoxymethyl- and 1-alkylthiomethyl-4dimethylaminopyridinium chlorides with sodium hydroxide produces the corresponding 4-pyridones (Scheme 50) (94H(37)311). NMe2

O

X=O, S CI 0

R=Mo

Scheme 50

Indolizines have been made via carbene addition to 2-vinylpyridine or dipolar addition of pyridinium ylides. 3-substituted indolizines have been obtained in a one step proeedure from reaction of ehloroearbenes with 2vinylpyridine (94CC509). Microwave irradiation has been used in 1,3-dipolar eyeloaddition of pyridinium dieyanomethylide with alkynes (94H(38)785).

218

Six-Membered Ring Systems: Pyridines

An oxidative one step synthesis of aromatic indolizine (91) by 1,3dipolar cycloaddition of pyridinium ylides with alkenes was reported (Scheme 51) (93JCS(P1)2487). Co(Py)4(HCrO4)2 pyridine/DMF 90 ~ 2 hr. + BrG

~CN

93%

CN

=~

~H2CH2Ph

\CH2Ph (91) Scheme 51

Reaction of N-alkoxycarbonylpyridinium salts with Grignard reagents has been used in synthesis of natural products Lupinine (92) (93JOC(58)7732), Solenopsin A (93) (94TL(35)829), and 2,3-dihydro-4-pyridones (94TL(35)3927). CH2OH Me.......~,.~(CH2)IoCH31H Lupinine

SolenopsinA

(92)

(93)

Regio- and stereoselective addition of nucleophiles to 1phenoxyearbonyl-2,3-dihydropyridinium salts has been investigated (94H(37)1121). 6.1.2.10 Piperidines

Oxidation of secondary amines, such as piperidine (94), with dimethyldioxirane (95) led to synthesis of cyclic hydroxamic acids (Scheme 52) (93ACS(47)1141). Acetone 0~

Me Me + (94)

_ OXO

20-25min. 71%

(95) Scheme 52

--~

~~*~O

219

Six-Membered Ring Systems: Pyridines

1,3-Dipolar cycloaddition has been used between nitrone derivative of piperidine and an alkyne to make enantiomeric 13-aminoketones (94CJC(72) 1347). Pipecolic acid has been used in stereoselective synthesis of (+)- and (-)-Lentignosine (94TL(35)8871), and hydroxylated indolizidine alkaloids (94TL(35)8843). ot-Azidonation of piperidine amides has been achieved with iodosylbenzene - trimethylsilyl azide reagent combination (94JACS(116)4501). Synthesis of substituted N-arylpiperidones has been done via organobismuth derivatives (Scheme 53) (94S775). o Cu(OAo)2 CH2C12 25 ~ 44 hr.

o

--Bi

67% F3Cr

~

Scheme 53 Electrochemistry has been used for both o~- and [3-functionalization of piperidines; for example, oxo groups have been introduced into 13-position of Nmethoxycarbonylpiperidine using electrochemical oxidation (94BCSJ(67)304). ~-Cyanation of N-benzylpiperidine was achieved using electrochemical oxidative cyanation approach (94H(38) 1711).

6.1.3 THEORETICAL ASPECTS OF SYNTHETIC IMPORTANCE Gas phase affinity of pyridines for CI+ was studied by multiple-stage mass spectroscopy (94JACS(116)2457). These values correlate well with known proton affinities, and decrease in CI+ affinity for t~-substituted pyridines was shown to be a stefic effect, not an electronic one. A review of dielectric, spectroscopic, thermodynamic, colligative and conductivity properties of complexes of carboxylic acids with pyridines and pyridine N-oxides in non-aqueous solution was reported (94H(37)627). Application of semiempifical and ab initio calculations of molecular orbitals to study of oxidation of dihydropyridines was reviewed with respect to mechanisms of NAD(P)H transformations (94H(37) 1373).

220

Six-Membered Ring @stems: Pyridines

REFERENCES 93ACS(47)1141 93AHC(57)1 93AOC(7)641 93BCSJ(66)3456 93CHC(E)(29)489 93CHC(E)(29)l 111 93CPB(41)1297 93CR(93)2067 93H(36)2687 93JCS(P1)2417 93JCS(P1)2487 93JHC(30)1691 93JICS(70)567 93JOC(58)7732 93JOC(58)7832

93KGS136

93PJC(67)1609 93RJOC(29)1722 93T(49)10157 93YH(13)623 93ZOK(29)1501 94ACS(48)181

S.M. Neset, T. Benneche and K. Undheim, Acta Chem. Scand. 1993, 47, 1141. J. Barluenga and M. Tomas, Adv. Heterocycl. Chem. 1994, 57, 1. B. Heller, J. Reihsig, W. Sehulz and G. Oehme, Appl. Organomet. Chem. 1993, 7(8), 641. K. Narasaka and Y. Kohno, Bull. Chem. Soc. Jpn. 1993, 66, 3456. A. Sausinsh and G. Duber, Chem. Heterocycl. Comp. (Engl. Transl.) 1993, 29, 489. D.E. Lushnikov and E.V. Babaev, Chem. Heterocycl. Comp. (Engl. Transl.) 1993, 29 (10), 1111. J. Koyama, T. Ogura, K. Tagahara, M. Miyashita and H. Irie, Chem. Pharm. Bull 1993, 41, 1297. G.R. Newkome, Chem. Rev. 1993, 93, 2067. F. Coppa, F. Fontana, E. Lazzarini and F. Minisci, Heterocycles 1993, 36, 2687. H. Togo, M. Aoki, T. Kuramochi and M. Yokoyama, J. Chem. Soc., Perkin 1 1993, 2417. X. Wei, Y. Hu, T. Li and H. Hu, J. Chem. Soc., Perkin I 1993, 2487. H. Kojima, K. Yamaoto, Y. Kinoshita and H. Inoue, J. Heterocycl. Chem. 1993, 30, 1691. K.C. Joshi, R. Jain and S. Arora, J. Indian Chem. Soc. 1993, 70, 567. R.S. Alaivar, S.P. Joseph and D.L. Comins, J. Org. Chem. 1993, 58, 7732. P. Roeca, C. Cochennel, F. Marsais, L. Thomas-ditDumont, M. Mallet, A. Godard and G. Queguiner, J. Org. Chem. 1993, 58, 7832. M.A. Yuvovskaya, A.Z. Afanasyev, S.V. Bolshakova and I.G. Khamlora, Khim. Geterotsikl. Soedin 1993, 136. H. Ban-Oganowska, Pol. J. Chem. 1993, 67, 1609. V.P. Litvinov, Russ. J. Org. Chem. 1993, 29, 1722. B. Bortolotti, R. Leardini, D. Nanni and G. Zanardi, Tetrahedron 1993, 49, 10157. Z.-Q. Zhang, S.-O. Gao, Q. Sun, Y.-H. Sun and L.-J. Mao, Youji Huaxue 1993, 13, 623. S.V. Amojova, V.I. Goesterskaya, G.M. Gravrilova and A.V. Afonin, Zh. Org. Khim. 1993, 29, 1501. J.M. Bakke and I. Hegbom, Acta Chem. Scand. 1994, 48, 181.

Six-Membered Ring Systems: Pyridines 94AG(E)(33)433

94AG(E)(33)847 94BCSJ(67)304 94CC177

94CC181

94CC287 94CC509

94CC701

94CC741

94CC1363 94CC1391

94CJC(72)1347 94CL21 94CL59 94CL397 94COS95 94H(37)3 94H(37)257 94H(37)311 94H(37)627

221

D.B. Amabilino, P.R. Ashton, A.S. Reder, N. Spencer and J.F. Stoddart, Angew. Chem., Int. Ed. Engl. 1994, 33, 433. S. Achar and P.J. Puddephatt, Angew. Chem., Int. Ed. Engl. 1994, 33, 847. Y. Matsumura, Y. Takeshima and N. Okita, Bull. Chem. Soc. Jpn. 1994, 67, 304. P.R. Ashton, R. Ballardini, V. Balzani, M.T. Gandolfi, D.J.F. Marquis, L.P. Garcia, L. Prodi, J.F. Stoddart and M. Venturi, J. Chem. Soc., Chem. Commun. 1994, 177. P.R. Ashton, D. Philp, N. Spencer, J.F. Stoddart and D.J. Williams, J. Chem. Soc., Chem. Commun. 1994, 181. S. Fukuzumi and S. Noura, J. Chem. Soc., Chem. Commun. 1994, 287. R. Bonneau, Y.N. Romashin, M.T.H. Liu and S.E. McPherson, J. Chem. Soc., Chem. Commun. 1994, 509. Y. Kita, H. Weno, S. Kitagaki, K. Kobayashi, K. Lio and S.Akai, J. Chem. Soc., Chem. Commun. 1994, 701. D. Luneau, J. Laugier, P. Rey, G. Ulrich, R. Ziessel, P. Legoll and M. Drillon, J. Chem. Soc., Chem. Commun. 1994, 741. G.D. Hosken and R.D. Hancock, d. Chem. Soc., Chem. Commun. 1994, 1363. D.E. Fenton, R.W. Mathews, N. McPartlin, B.P. Murphy, I.J. Scowen and P.A. Tasker, J. Chem. Soc., Chem. Commun. 1994, 1391. C. Conis, S. Mill, V. Manluso and C. Hootele, Can. J. Chem. 1994, 72, 1347. Y. Hirai and M. Nagatsu, Chem. Lett. 1994, 21. H. Sato, S. Shimizu, N. Abe and K. Hirose, Chem. Lett. 1994, 59. H. Sugihara, J.P. Collin and K. Hiratani, Chem. Lett. 1994, 397. J. Steele, Contemporary Org. Synth. 1994, 95. A.R. Katritzky, Heterocycles 1994, 37, 3. T. Matsuoka, H. Harano and T. Hisano, Heterocycles 1994, 37, 257. P. Juliuoz and M. Lucyna, Heterocycles 1994, 37, 311. Z. Dega-Szafran and M. Szafran, Heterocycles 1994, 37, 627.

222 94H(37)815 94H(37)1121 94H(37)1347 94H(37)1373 94H(37)1463 94H(37)1467 94H(37)1489

94H(37)1731 94H(37)1761 94H(38)277 94H(38)281 94H(38)785

94H(38)897 94H(38)1241

94H(38)1595 94H(38)1711 94JACS(116)2223 94JACS(116)2457 94JACS(116)4501 94JCR(S)86 94JCR(S)106 94JCS(P1)739

Six-Membered Ring Systems: Pyridines J.-J. Vanden Eynde, A. Mayence, A. Maquestiau and E. Anders, Heterocycles 1994, 37, 815. D.L. Comins, G. Chung and M.A. Foley, Heterocycles 1994, 3 7, 1121. J. Kuthan, Heterocycles 1994, 37, 1347. M.E. Brewster, E. Pop, M.-J. Huang and N. Bodor, Heterocycles 1994, 37, 1373. R.A. Abramovitch and Q. Shi, Heterocycles 1994, 37, 1463. Y. Kondo, N. Murata and T. Sakamoto, Heterocycles 1994, 37, 1467. G.L. Goe, G.F. Hillstrom, R. Murugan, E.F.V. Scriven and A.R. Sherman, Heterocycles 1994, 37, 1489. B. Bohn, N. Heinrich and H. Vorbrtiggen, Heterocycles 1994, 37, 1731. Q. Zhing, Y. Yang and A.R. Martin, Heterocycles 1994, 37, 1761. K. Hirai, Y. Iwano, I. Mikoshiba, H. Koyama and T. Nishi, Heterocycles 1994, 38, 277. K. Hirai, H. Homma and I. Mikoshiba, Heterocycles 1994, 38, 281. A. Diaz-Oritz, E. Diez-Basra, A. de la Hoz, A. Loupy, A. Petit and L. Sanchez, Heterocycles 1994, 38, 785. W. Sliwa, Heterocycles 1994, 38, 897. Y. Blachi, O. Chavignon, M.E. Sinibaldi-Troin, A. Gueiffer, J.C. Tenlade, Y. Troin and J.C. Gramain, Heterocycles 1994, 38, 1241. J. Koyama, T. Ogura and K. Tagahara, Heterocycles 1994, 38, 1595. T.K. Yang, S.T. Yeh and Y.Y. Lay, Heterocycles 1994, 38, 1711. H. Nishiyama, Y. Itoh, H. Matsumoto, S.B. Park and K. Itoh, J. Am. Chem. Soc. 1994, 116, 2223. M.N. Ebedin, T. Kotiaho, B.J. Shay, S.S. Yang and R.G. Cooks, J. Am. Chem. Soc. 1994, 116, 2457. P. Magnus, C. Hulme and W. Weber, J. Am. Chem. Soc. 1994, 116, 4501. F.A. Hussaini, V.J. Ram, S.K. Singh, M. Nath, A. Schoeb and A.P. Bhaduri, J. Chem. Res. (S) 1994, 86. A.C. Shah, R. Rehani and V.P. Arya, J. Chem. Res. (s) 1994, 106. S. Kagabu, C. Ando and J. Ando, J. Chem. Soc., Perkin Trans 1 1994, 739.

Six-Membered Ring Systems: Pyridines 94JCS(P1)825 94JFC(67)57 94JFC(67)87 94JHC(31)11 94JHC(31)73 94JHC(31)187

94JOC(59)291 94JOC(59)415 94JOC(59)1613 94JOC(59)4482 94KGS147 94PJC(68)1343 94RTC(113)35 94S583 94S775 94SC(24)145 94SC(24)1367 94SC(24)1709 94SC(24)1789 94SC(24)1923 94SC(24)2167 94SC(24)2697 94SL27

223

C. Yamazaki, Y. Miyamoto and H. Sakima, J.. Chem. Soc., Perkin Trans I 1994, 825. X.H. Qian, R. Zhang, J. Tang and W.D. Chen, J.. Fluorine Chem. 1994, 67, 57. B. Narasaiah, A. Siraprasad and R.V. Venkartaratnane, J. Fluorine Chem. 1994, 67, 87. J. Maim, B. Rehn, A.B. Hornfeldt and S. Gronowitz, J. Heterocycl. Chem. 1994, 31, 11. E. Nicolai, S. Claude and J.M. Tenlon, J. Heterocycl. Chem. 1994, 31, 73. J.C. Diasare, J.P. Burgess, S.W. Mascarella, F.I. Carroll and R.B. Rothman, J. Heterocycl. Chem. 1994, 31, 187. C.M. Marson, U. Grabowska and A. Fallah, J.. Org. Chem. 1994, 59, 291. I. Rico, K. Halverson, C. Dubrule and A. Latter, J. Org. Chem. 1994, 59, 415. K. Paulvannan and J.R. Stille, or. Org. Chem. 1994, 59, 1613. P. Boy, C. Combellas, C. Sulia and A. Thiebault, J.. Org. Chem. 1994, 59, 4482. W. Sliwa, Khim. Geterotsikl. Soedin 1994, 147. W. Czuba and J. Wodzinska, Pol. J. Chem. 1994, 68, 1343. N. Mishriky, F.M. Asaad, Y.A. Ibrahim and A.S. Girgis, Rec. Tray. Chim., Pays-Bas 1994, 113, 35. G. McGaffin and A. de Meijere, Synthesis 1994, 583. A. Banff, M. Bartoletti, E. Bellora, M. Bignotti and M. Turioni, Synthesis 1994, 775. M. Durandetti, S. Sibille, J.Y. Nedelec and J. Perichon, Synth. Commun. 1994, 24, 145. M.A. Gray, L. Konopski and Y. Langlois, Synth. Commun. 1994, 24, 1367. W.J. Watkins, G.E. Robinson, P.J. Hogan and D. Smith, Synth. Commun. 1994, 24, 1709. J. Epsztajn, A. Jozwiak and A.K. Szczesniak, Synth. Commun. 1994, 24, 1789. J.A. King, Jr. and G.L. Bryant, Jr., Synth. Commun. 1994, 24, 1923. O. Prakash, D. Kumar, R.K. Saini and S.P. Singh, Synth. Commun. 994, 24, 2167. V. Levacher, C. Leroy, G. Dupas, J. Bourguignon and G. Qu6guiner, Synth. Commun. 1994, 24, 2697. M.H. Elnagdi, A.M. Negm and K.U. Sadek, Synlett 1994, 27.

224 94SL451 94SST21 94SYN(6)535 94SYN(6)573 94SYNl155 94T(50)10685 94T(A)557 94TL(35)531 94TL(35)707 94TL(35)829 94TL(35)1211 94TL(35)1215 94TL(35)1925 94TL(35)2003 94TL(35)2211 94TL(35)2279 94TL(35)2751 94TL(35)3083 94TL(35)3147 94TL(35)3581 94TL(35)3927 94TL(35)7597 94TL(35)8145

Six-Membered Ring Systems: Pyridines

M.I. Kemp, R.J. Whitby and S.J. Coote, Synlett 1994, 451. M. Veki, M. Honda, Y. Kazama and T. Katoh, Synthesis - Stuttgart 1994, 21. H. Waldmann, Synthesis 1994, (6), 535. R.J. Vijn, H.J. Arts, R. Green and A.M. Castelijns, Synthesis 1994, (6), 573. P.J. Campos, C.-Q. Tan, J.M. Gonz~lez and M.A. Rodriguez, Synthesis 1994, 1155. C.Y. Hung, T.L. Wang, Z.Q. Shi and R.P. Thummel, Tetrahedron 1994, 50, 10685. R. Beaudegnies and L. Ghosez, Tetrahedron Asymmetry 1994, 5, 557. B.B. Snider and Q. Lu, Tetrahedron Lett. 1994, 35, 531. Y.S. Wong, C. Marazano, D. Gneico and B.C. Das, Tetrahedron Lett. 1994, 35, 707. D.L. Comins and N.R. Benjelloun, Tetrahedron Lett. 1994, 35, 829. G. Ulrich, R. Ziessel, D. Luneau and P. Rey, Tetrahedron Lett. 1994, 35, 1211. G. Ulrich and R. Ziessel, Tetrahedron Lett. 1994, 35, 1215. N. de Kimpe, M. Boelens, J. Piquer and J. Baele, Tetrahedron Lett. 1994, 35, 1925. P. Rocca, F. Marsais, A. Crodara and G. Quenguiner, Tetrahedron Lett. 1994, 35, 2003. T.-L. Ho and P.-Y. Liao, Tetrahedron Lett. 1994, 35, 2211. L.A. Carpino, A. EI-Faham and F. Alluricio, Tetrahedron Lett. 1994, 35, 2279. H. Heaney and K.F. Shuhaibar, Tetrahedron Lett. 1994, 35, 2751. S. Majjon, J.F. Saint-Clair and M. Saquet, Tetrahedron Lett. 1994, 35, 3083. A.M. Sipyagin, V.V. Kolehanov and N.N. Sveshnikov, Tetrahedron Lett. 1994, 35, 3147. T.K. Yang, T.F. Teng, J.-H. Lin and Y.-Y. Lay, Tetrahedron Lett. 1994, 35, 3581. J. Streith, A. Boiron, T. Sifferlen, C. Strehler and T. Tschamber, Tetrahedron Lett. 1994, 35, 3927. A.S. Kiselyov and L. Strekowski, Tetrahedron Lett. 1994, 35, 7597. R.R. Goehring, Tetrahedron Lett. 1994, 35, 8145.

Six-Membered Ring Systems: Pyridines 94TL(35)8303 94TL(35)8843 94TL(35)8871

225

M. Reuman, M.A. Eissenstat and J.D. Weaver III, Tetrahedron Lett. 1994, 35, 8303. M.J. Martin-Lopez and F. Bermejo-Gonzalez, Tetrahedron Lett. 1994, 35, 8843. M.K. Gurjar, L. Ghosh, M. Syamaler and V. Tayasree, Tetrahedron Lett. 1994, 35, 8871.

Chapter 6.2 Six-Membered Ring Systems: Diazines and Benzo Derivatives G. HEINISCH and B. MATUSZCZAK

Institute of Pharmaceutical Chemistry, University of Innsbruck, Austria 6.2.1 INTRODUCTION Pyridazines, pyrimidines, pyrazines and their benzo derivatives continue to be a focal point of many reports. In this contribution, the literature on their chemistry and bio-activity as covered by chemical abstracts vol. 120 and vol. 121 (1994) is reviewed. Owing to space limitations, however, many publications of merit could not be included.

6.2.2

PYRIDAZINES AND BENZODERIVATIVES

6.2.2.1 Syntheses

An efficient asymmetric synthesis of (3S)-2,3,4,5-tetrahydro-3-pyridazinecarboxylic acid (4) has been developed [93CC1179]. O

'eu~

COOCH2Ph

O

COOCHzPh

+

,

tBuO. ,ff,,N

~ 76%

O

OR

(1)

(2)

~'

5 OR

O

(3)

COOH

~ HN, 78%

N ~.,,)

(4)

3-Trifluoromethylpyridazines of type 5 could be prepared starting from 2amino- 1,1, l-trifluoro-3-phenylsulfonyl-2-propanol [93H(35)909]. Compounds of type 6 are conveniently accessible by cyclisation of 1,1,1,2,2-pentafluoro-3,4alkanedione 4-dialkylhydrazones [93TL(34)5135]. 3-(Trifluoromethyl)-4-pyridazinecarboxylates of type 7 have been obtained upon reaction of 2(alkylamino)-3-(trifluoroacetyl)butenedioates with substituted hydrazines 193JHC(30)15011. 226

Six-Membered Ring Systems: Diazines CF3 R

O

N

227

COOCH3

N'N~O

N'N')

!

R=OH,SO~Ph

Rl= Ph, 2-pyridyl

(6)

R~

R=aryLB, ~ l ,

R

Me2CH R1= Me, M%C

(6)

R=H, ~, 4-MeOCg4,

(7)

2.pyddyl,CH2Ph,CMe3 R 1=CHMe2,CH=Ph

Starting from (S,S)-3,5-dimethylmorpholine (8) as a C2-symmetric auxiliary, 4-oxohexahydropyridazines 10 could be prepared in high enantiomeric purity via 9 [94S661. ~[~0~ 1"13C

N

4 steps ~ C_H,~

" CH3

t-Bu

O N"~ N-Ph

O,~CH

(8)

3

>

2) HOAc,30 min.

[,~N~N"~

H

t-Bu O

1) {-BuOK,212hTHF 5.C,

O

~N,~ O

Iq'H

72% yield

N

,,Ph

ee=91%

(9)

(R)-(10)

Intramolecular [4+2]cycloaddition reactions of pyridazino[4,5-d]pyridazines with acetylenic side-chain dienophiles were found to provide convenient access to f-annelated phthalazine derivatives [94JHC(31)3571. Base-catalysed cyclisation of pyrazoles (11) followed by oxidation was shown to yield cinnoline-4carboxylic acid l-N-oxides (13) [93CC 1756].

HO~.N

NN

R~"L~NO?H'

NaOH, reflux NaOCl,NaOH, r~t.

O~ ,_ ,_N

~

N

R

R= H. Me, OMe, CI

(11)

H20 ~ -N,

be

(12)

C~H R

&|

(13)

4-Halocinnolines (15) could be prepared by diazotation of o-aminophenylacetylenes (14) 194SC(24) 1733 !. _~C-CR v -NH z

HX, H20, NaNO2 -15~ to +280C

114)

11-93%yield

.

,

~..

X [~~N.N 115)

R X= CI,Br

6.2.2.2 Reactions The behavior of 2-methylpyridazin-3(2H)-ones in Diels-Alder reactions has been investigated [93H(36)1975] [94T(50)5169]. %C.,~N-N.H Homolytic substitution of protonated 3-chloro.6.L.~. methylpyridazine has been shown to afford 4- or 4,5R" " r "o R= H. COOEt COR1 R ~= Me, Ph, OEI functionalised pyridazinones 16 [93TL(34)3903l. Tile (16)

228

Six-Membered Ring Systems: Diazines

reaction of 3,6-dimethoxypyridazine with hydrazine has been investigated; it was found that 4-aminopyridazine derivatives but not the 5-amino isomers are formed [93H(35) 1313]. 5-Acetyl-2-methyl-4-nitro-6-phenyl-3(2H)-pyridazinone has been shown to be a versatile precursor for pyrrolo-, thieno-, isoxazolo-, pyrido-, and pyrimido-fused pyridazines [94S669]. A surprising transformation of the pyridazinone 17 into 3-(l-naphthyl)propionic acid esters 18 has been reported [93TL(34)3777]. R2 R R

~

i O

(17)

F R

~

R~,,~OEt O R2=

i:trimethylsilyltriflate, CICHa-CH=CI,EtOH

H, Me

(18)

4-Substituted 4,5-dihydropyridazin-3,6-dione 3-hydrazones were reacted with trifluoroacetic acid to yield 3-trifluoromethyl-s-triazolo[4,3-b]pyridazinones (19) [94MI(49)21]. Reaction of catechol derivatives with 3,4,5-tfichloropyfidazine have been shown to afford 4-chloro[l,4]benzodioxino[2,3-c]pyridazines 20 and 21 [93jHC(30)789]. An efficient procedure for preparing phenyl 3-pyridazinyl ketones 22 has been published 193JHC(30)1685] [94SC(24)7731. R CI Cl 0

N

~ ~CF3 (19)

R

0 (20)

"~

~-"'~ 0"~N (21)

,"

Ph (22) O R=H,OR,NR= COPh,CHCNPh

2-Fluorophenyl 3-pyridazinyl ketone has been used as starting material for the synthesis of 3-pyridazinyl substituted 1,4-benzodiazepines, quinolines, 2,1benzisoxazolines and for the preparation of diazaacridones of type 23 and 24 [94H(38)125]. Pd(0) cross-coupling reactions of pyridazine triflates permits to prepare 3-alkynylpyridazines of type 25 [94H(38) 1273]. | | O (23)

~

N O (24)

1 c~'CR2 i,~ =',~ =" R=H,Me

R,.I~N.~I

R'= Me, Ph

R2=CH2OH,SiEI~,CH(OEI)2,etc.

(26)

Ethynylation of pyridazine and phthalazine could be achieved using bis(tributylstannyl)acetylene via N-alkoxycarbonyl quarternary salts of the substrates, followed by treatment with trifluoroacetic acid [94MI557]. Reaction of pyridazines 26 with allyltributyltin have been found to afford 4-allyl

Six-Membered Ring Systems: Diazines

229

substituted dihydropyridazines 28. This reaction type also has been applied to the allylation of pyrimidine, pyrazine and benzofused diazines [94H(37)709]. i

ii

(261

(27)

'

I COOR' (28)

i: ClCOOR', CHzCl2, 0*C ii: Bu=SnCH2CH=CH2

Cycloaddition reactions of 4,5.-dicyanopyridazine with 2,3-dimethylbuta-1,3diene have been studied [94T(50)91891. Employment of ortho-directed metalation and cross-coupling reactions H N ~ N v j has been shown to provide a new route to the antidepressant minaprine 29 193BSF(130)488].

MeaN

~

6.2.2.3 Applications

~

(29)

Ph

Structure-activity relationships of potential positive inotropic benzimidazolyl pyridazinones have been studied in detail [93MI(28)I29]193MI(28)I41]. There is also a report on the cardiotonic activity of 2,9-dihydro-6-(5-methyl-3-oxo-2,3, 4,5-tetrahydropyridazin-6-yl)pyrazolo[4,3-b I[ 1,4]benzoxazine [93MI(3) 16631. The o~-blocking activity of a series of newly synthesised 5-(4-piperazinyl)3(2H)-pyridazinones has been investigated [93MI(28)647]. 4,5-Disubstituted 6phenyl-3(2H)-pyridazinones (30) have been prepared as potential hypotensive agents 194MI(29)2491. Anticonvulsatory properties have been reported for the 3-ureidopyridazine 31 [94JMC(37)2153 ]. O

PhOny NH2

R

II

i

H3c~O|"

r

phJ~'N-N',R s

R= NHz. morpholino, NO=, CI. Br, SCH=, SOCH3 R' = H. ell=

H3C,,,-',~N,. N

0

(31)

(30)

The stereochemistry of biologically active thiosemicarbazones derived from pyridazine, pyrimidine, and pyrazine has been elucidated by means of nmr spectroscopy 193MI(61)31. 4-(3-Pyridyl)-l(2H)-phthalazinones 32 have been shown to represent a novel class of antiasthmatic agents 193JMC(36)4061]. GABA A receptor anagonistic properties of l-aminophthalazinium salts 33 have been investigated I93MI(10)231 194MI(29)951. O

,N"R

.N.H2

~N (

N N R (33)

,, (CH2)n-COOR' Br |

Six-Membered Ring Systems: Diazines

230

6.2.3

PYRIMIDINES AND BENZODERIVATIVES

6.2.3.1 Syntheses

A new alternative procedure for the preparation of the antibacterial agent trimethoprim (36) starting from 34 has been described 194H(38)1119].

M e O ~

CHO i ~, MeO~"~~~SMejL.,.. 7 CN

MeO" ~ OMe (34)

MeO"y OMe (35)

ii

I

~ MeO~

L"~NI ~ N H z OMe (36)

i: 4 steps ii: guanidine HCI 9 EtONa, reflux 61.9% overall yield

There is also a report on a novel approach to the anxiolytic agents buspirone and gepirone [93H(36)14631. 2,4-Diaminopyrimidines of type 39 have been prepared starting from alkyl and benzyl ketones (37) [94H(38)3751. i

R,'~CH3 O (37)

.._ R , " ~ N . , . ~ / N R z " ~ -I CH 3 Cl

NRz R".,~

:- ,~,.,,NI~ H3C

(38)

NR 2

(39)

i: 1. POC,3, 2. N-C-NR, ii: 1. TiCI4, 2. N--'C-NR2 R= H, Me R'= H, alkyl, (subst.)phenyl

2,4-Bis(methylthio)pyrimidines 40 have been obtained upon SMe reaction of ketones with triflic anhydride [94MI5591. Cyclo- , . ~ . , addition reactions of 1,3-diaza-l,3-butadienes with haloketenes R' N have been employed for the synthesis of pyrimidones R"'L~N"~SMe [94T(50)75791. Reaction of 2-trimethylsilyloxy- and 2-trimethyl(40) silylthio-l,3-diazabutadienes (41) with enamines derived from aliphatic aldehydes (42) leads regio- and stereoselectively to tetrahydropyrimidin-2(IH)--ones and thiones (43). This reaction type was also used for preparing quinazolines |94H(37) 11091. R1 NJ Me3SiX

.k.

(41)

R1

R3U,,. § "rl

N

NR4R s

r~z

(42)

i

1.CHzCIz 25"c, 4h 2. H20 yield: 80-93%

"

HR , N ~3, ~ /N/~ X NR4R~i I R2

(43)

X=O, S R t, R 2= an/I R 3= alkyl R4-R s_-.(CH2)n. n= 4 or 5

Pyridyl-substituted pyrimidines 44 could be obtained by reacting pyridylacetic acid derivatives with 1,3,5-triazine [94AP(327)5331. 4-Functionalised imidazoline derivatives of type 45 which are conveniently available from N-acyl~-amino ketones have been found to undergo rearrangement to arylwrimidine derivatives 46 [93JOC(58)63541.

231

Six-Membered Ring Systems: Diazines R 2

RI H )~'CI N

I

N..,. NH R= NH2: for 3- and 4-pyridyl OH for 2-, 3- and 4-pyridyl

Nail, DMF, air yield: 71-85% "

Rt

Rz N.-.

N

(4S)

(4s)

R 1, R3= (subst.) phenyl R 2= H, phenyl

Compounds of type 47 have been found to undergo cyclisation to give 4amino-2,6-dimethyl-5-phenylpyrimidines (48); the mechanism of this process has been discussed [93MI(67) 10991.

R

~

H~, :~~'-CH=C-N=C-N=C-CI | I CI'I3 CH3 NHz

50- 76%yield

-~ R ~ ~ ~ ) - - C H 3 H3C

(47)

(4el

Nl-substituted orotic acids have been obtained by ring expansion of 3amino-l-carbethoxymaleimides [93MI(48)8611. 5-Arylidene-5,6-dihydrouracil derivatives have been synthesised from methyl 3-aryl-2-isopropylaminomethyl2-propenoates with phenyliso(thio)cyanate [93SC(23)20651. Preparation of pyrimidines of type 50 and 51 has been achieved using reactions of enamines 49 with benzamidine or S-benzylthiourea [93JHC(30)1513 I.

~~~ COR

~H3 R= Me, OEt

I~NH

(51)

R= Ph, 4-morpholino

R= Ph, SCHz Ph

Treatment of alkenones 52 with urea has been found to afford 4-trihalomethyl-2-pyrimidinones (53) in satisfactory yields [9 IMI(2)118]. R 2i ~ O , ,

R~Of ~R 1 (52)

i

R 2CX~I~~. ~ I N

R1

i: urea, HCI, MeOH, reflux, 20h O

(53)

X:F,CI

N,N-Diethylaminomethylene- 1,1,1,5,5,5-hexafluoroacetylacetone was shown to react with urea derivatives to afford pyrimidines of type 54, 55, and 56 (93TL(34)7737].

Six-Membered Ring Systems: Diazines

232

/

NMe2

R1

NMe2

N~I~N "R1=NMea, NEt=,OMe ~L~RzLCF3 R2=COCF=,COOH,COOMe

(,s4) (ss)

(5s)

New synthetic routes to 4-phenylquinazolines starting from hydroxyglycines have been reported [93T(49)68991. Quinazolin-4(3H)-ones have been obtained in a one-pot reaction consisting of sodium perborate oxidation of o-amidobenzonitriles and subsequent cyclisation [93SC(23)28331. Treatment of o-aminobenzylamine with N-(l-chloroalkyl)pyridinium chlorides prepared in situ from aldehydes, pyridine and thionyl chloride has been shown to represent a simple high yield procedure for the synthesis of 2-substituted quinazolines [93S867]. Condensation of o-aminobenzylamine with glyoxal yields 2,2'-bi-(l,2,3,4tetrahydroquinazoline) [94MI4211. A series of 4-amino-8-cyanoquinazolines 57 have been prepared by reaction of 2-aminobenzene-l,3-dicarbonitriles with formamide or guanidine [93H(36)2273]. Formation of a pyrimidine system 59 has been reported to occur by a ring transformation of 58 [93MI(130)737]. R ~ N R 2 ~ N R

-

I~R

NHz

R= H, NH2 R1"3= H, Ph, Me

(67)

O

CN N3

N... NH

0"~0~

0 NO2

(58)

O ~ (59)

NO2

p-Benzoquinone derivatives 60 could be cyclised to give spiro compounds of type 61 [94TL(35)52351. O

O DMSO 120"C. 2h

F3C

(6o)

R,,N F3C

R= H; R'= lone pair electron R'= H; R= lone pair electron R'

(61)

The ring closure of anthranilic amides (62) with oxo compounds to give 1,2dihydro-4-quinazolinones 63 has been studied [94AP(327)571 I.

Six-Membered Ring Systems: Diazines

~NHR

O

1

233

R 1

R~~.~NHz

R~~'N'-H

0

0

(s3)

(s2)

6.2.3.2 Reactions

Reactions of 2-aminopyrimidine with a variety of heteroaromatic carbaldehydes have been studied [94H(37)1033]. 5-Bromopyrimidine (64) has been shown to provide access to 5-pyrimidinecarboxaldehyde (66) and ethyl 5pyrimidine~rboxylate (67) via a metal halogen exchange reaction [94SC(24)253]. N-. ~/~ ~--~Li --

"N__Y

(64)

(65)

~ ..

"~...~

<%~-/~ ~

CliO (66) COOEt

i: n-BuLi,-100~ ii: 1) HCOOR,2) H+ iii: 1) NCCOOEt,2) H+

(s7)

This reaction type also has been used to prepare C-methyl 5-pyrimidinecarboxTlic acids [94H(38)1375]. Pyrimidinylzinc halides obtained upon oxidative addition of active zinc to 2- or 4-iodopyrimidines have been shown to bc transformed into arylated pyrimidines by palladium-catalysed reaction [93T(49)9713]. Covalent hydration at the 2- and 4-position of monomethyl- and dimcthyl-5-pyrimidinecarboxylic acids has been investigated [94H(38) 1375]. Methylation reactions (N versus S) of 2-thiophenobarbital under various conditions have been performed [94MI(68)117]. There is also a report on the ratio of N- and O-alkylation of 4(3H)-quinazolinones depending on the nature of a substituent in position 2 [93CPB(41) 1114l..Quinazoline-2,4(IH,3H)-diones have bccn alkylated with 1,4-dibromo-2-methylbut-2-cne under phase-transfer conditions to give dialkylated as well as monoalkylateA products 193JHC(30)1117l. Electrophilic amination of the sulfur atom to give zwittcrionic N-ylidcs (68) or l-aminopyrimidin-2-ones has been carried out employing l-aminopyrimidinc-2-thiones and 3,3-pentamethylencoxaziddine or hydroxylamine-O-sulfonic acid [93T(49)3767]. 4,6-Dichloro-5-pyrimidinecarboxaldehydes have been employed to construct thieno[2,3-d]pyrimidincs (69) [93JHC(30)1065].

234

Six-Membered Ring @stems: Diazines |

NH2

R1

(so)

Rz

(ss)

4,6-Dihydroxypyrimidine (70) has been used as the starting material for a convenient pathway to 5-benzylthio-4,6-dichloropyrimidine (72) consisting of reaction with benzyl sulfenyl chloride and subsequent treatment with phosphorus oxychloride [93SC(23)2363 ].

//NN~~OH

i 96%

NN[ ~~,,

OH (701

ii

OH s'CH2Ph

N~~

CI

75%

OH (71)

S "CHzPh

CI (72)

i: SO=CI=,(PhCH=S)=.DMF,CCI4 ii: POCI=

An improved method for transforming 2..chloro-5-fluoro-4(3H)-pyrimidone into 2-alkoxy derivatives has been reported [93MI(4)591]. Reactions of l-amino-2-methylthiopyrimidinium salts (73) with hydraR! zines or alkylamines resulting in substitution of the ,~'2_N"N-R , 9 t.~j•174 methylthio group and Dimroth rearrangement have been .,,~;I~SQ% studied [93JHC(30)1607]. Mechanistic aspects of the m reduction of 5-arylidenebarbiturate derivatives by thiols

(73)

R=U. Me

have been presented [94TL(35)2757]. A carbon-carbon bond cleavage reaction of pyrimidinediones of type 74 has been described [93CPB(41)2073 ].

O H3C,,N~,,,~Br I

R (74)

CH~ONa X=Br. ONO=

O H3C,,N,~Br I

R

(75)

Selective bromination at C-5 of N-substituted uracils has been achieved by using CHBr3-O2 [93ACS(47)1117]. A novel three-component reaction of (uracil-6-ylimino)phosphorane, isocyanate, and pyridines has been used to prepare pyrido[l',2':3,4]pyrimido[4,5-d]pyrimidines (76). In a similar way, pyrimido[4',5':4,5]pyrimido[6,l-a]isoquinoline and -phthalazine (77) have been constructed [93 JOC(58)6976].

Six-Membered Ring Systems: Diazines

M

Me~'N

l~le

O

235

I

O~'NI

NHR

Me

(76)

(77)

X=CH,N

Pyrimidinediones 78 were found to undergo intramolecular ene reaction to afford pyrimido[4,5-b lazepine derivatives 80 194JCS(P1)5651.

H3C.NLCHO

i

O~"NI~N"",~'" R

L,p,

(78)

H3C.N

I cH=N'CH2COOEt

O

N'"x"~I'R

L CH,L,p,

]

O NHCHzCOOEt

I~1 R C~'1801 t3 l,~ph

= 1"I3C"No~.N =

(79)

i: H=NCH=COOEt,toluene,reflux

Thermal extrusion of sulfur dioxide from 81 has been reported to give 2methyl-5,6-dimethylenepyrimidone (82) which could be trapped with dienophiles and nucleophiles 193MI347]. Sensitised photooxygenation of 83 affords the corresponding 5-hydroperoxy derivatives [94BCJ(67)I2041. O O Ph R

Me"'~N ''''JSOz

=Me

1811

Ph 1821

Ph 183)

A method for the enantioselective allylation of 1,5-dimethylbarbituric acid has been proposed [94MI(220)631. Reactions of perhydro-2,2'-bipyrimidines with 1,2-dioxo compounds (glyoxal, glyoxylic acid, and ethyl glyoxylate) affording tri- or tetracyclic systems have been reported 193JOC(58)57531. Transformation of 3-methyl-5-nitropyrimidin-4(3H)-one (84) into 4,5-disubstituted pyrimidines 85 upon action of ketones in the presence of ammonia has been reported [94H(38)2491.

N~y.'NO2 =

Me

184)

N.. 3h

R~~NJJJ R'

L ~NO~ HN" "-O

1881

=

Me

(86)

substrate:cyclohexanone,1-morpholinocyclohexene, cyclopentanone,acetophenone,or styrene,p-nitroacetophenone

236

Six-Membered Ring Systems: Diazines

l-Bcnzyloxy-2(IH)-pyrimidinoncs have been found to undergo ring transformation into 5-N-(bcnzyloxy)urca-attachcd 2-isoxazolincs and isoxazolcs [94H(37)11411. 6.2.3.3 Applications Antibacterial properties were observed with Schiff bases of type 87 and metal chelates thereof [93CPB(41)951]. Pyrimidinyl substituted thiosemicarbazones 88 have been prepared as antibacterial agents [94MI(3)201 ]. R

N=CH 1871

x x= o. s

NH-C-NH-N=C' Ii

H

c,

(881

..,'

1891

Dihydroquinazolinones 89 have been shown to represent a novel type of non-nucleoside HIV-I reverse transcriptase inhibitors [94JMC(37)2437]. Hexahydropyrimidines of type 90 were prepared as nonpeptidic HIV-I protease inhibitors [94MI(4)12471. Antiviral activity has been observed also with pyrimidinones of type 91 194CCC(5916831. Acyloxypyrimidines 92 have been found to inhibit human and herpetic DNA glycosylascs [94T150)3603l. O OH

R.-NyN-R O R= H, alkyl (90|

R'

R (91 }

O"g"R '

R= allyl, PhCH 2 R'= OMe, NR"=

(92)

R= Me, CH~::~h R'= an/I, hetaryl

Analgesic activity has been observed in the series of thioxopyrimidinediones {93MI(28)6431. N-3 substituted quinazolin-4(3h3-ones have been shown to represent AT i -selective angiotensin-II receptor antagonists [93MI(3)1293] [93JMC(36)32071. 4-1[3,4-(MethylenedioxT)benzyllaminolquinazolines have been prepared as potent cGMP phosphodiesterase inhibitors [93JMC(36)3765] [94JMC(37)21061. In the series of substituted quinazolinones of type 93 moderate anticonvulsive activity has been observed [93MI(48)8941. Out of a series of newly prepared isocytosines, compound 94 has been selected for clinical investigations as a histamine H2-receptor antagonist [93MI(28)601 ].

Six-Membered Ring Systems: Diazines

R

237

OO~L jR .,

t~~N.N

S R''

O M%N.

~

N.'Jl'*'~'~v"~ ~O

(93)

(94)

Quinazolinones beating an acetic acid ester moiety at N-3 or a mercaptoacetic acid ester substructure in position 2 have been evaluated as H l-antihistaminics [93AF(43)663]. C~otoxic activities against CCRF-CEM human lymphoblastoid cells, HT-29 colon carcinoma cells and L I210/0 mouse leukemia cells have been reported for (E)-5-(2-acylvinyl)uracils [93MI(28)4731. 5-Halo-N(l)-substituted pyrimidin-2(IH)-ones were prepared as reversible metaphase arresting agents [93MI(28)463]. Newly prepared prodrugs of 2-nitrobenzoyl-[4-(2-pyrimidinyloxy)phenyllureas showed antitumor activities against P388 leukemia cells in mice [94CPB(42)571. The barbituric acid derivative 95 was prepared as a new uridine phosphorylase inhibitor [93JHC(30)1399]. Potent cytotoxicity against the growth of human promyelocytic leukemia (I-~-60) cells was found in a series of newly prepared 3-phenylquinazolin-4-ones and related oxazolo- and thiazolo-fused quinazolinones [93H(35)775]. 5-Fluorouracil derivatives containing an inhibitor of 5-fluorouracil degradation were prepared; out of this series, compound 96 is currently undergoing phase-ll clinical trials as antineoplastic agent 193CPB(41) 14981.

r OEt o

Z~N~OGH,Ph ~C ~NO r~ NO~o~F "N~I HO~o~J O~O . (96) (95)

Ph

3-Fluoroalkyl-substituted phenylpyrimidines have been prepared as chiral dopants for ferroelectric liquid crystals [93CL1243].

6.2.4 PYRAZINES AND BENZODERIVATIVES 6.2.4.1

Syntheses

2,3-Dihydropyrazine-l,4-dioxides (97) have been prepared by reaction of 1,2-bishydroxylamines with 1,2-dicarbonyl compounds [93KGS5141. An efficient approach to 5-methyl-2-hydrox3,pyrazine derivatives (99) from dipeptidyl chloromethyl ketones (98) has been reported 194TL(35)12311.

Six-Membered Ring @stems: Diazines

238 O R2"~N~ "R Rs

.~Oy~l~l~~~...Ci -O R1

0 (97)

O

6N HC,, reflux 65-90% yield

R~N

(98)

i~OH (99)

Catalytic asymmetric synthesis of piperazines (102) can be achieved by palladium-catalysed tandem allylic substitution reactions [93JOC(58)68261. MeOCO

.i.

,NHTs NHTs

MeOC (100)

Ts N

i ... 74%

N i Ts

(101)

i: Pd(0) I (R)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl THF, 40~ 24 h

(102)

~~ .,,OC2Hs

Reactions of N,N'-bis(chloroacetyl)-o-phenylenediamine with amines have been reinvestigated, it was found that quinoxalinones of type 103 are formed [93MI(48)523].

6.2.4.2 Reactions

Methyl 3-amino-2-pyrazinecarboxylate has been used to prepare pyrazino[3,1]oxazin-4-ones (104) [94S4051. N-Phenacyl quartemary salts 105 have been transformed into pyrrolo-fused pyrazines 106 using DIVI~DMA [93JHC(30)15771. O r i'~O L~NI~N/~L,,R (104)

R= (subst.) phenyl

N ~~ I~|.CH 30

r'%.-NLph (105)

XO

R DMFDMA ~

N R = COPh or Ph (106)

R' = Me

R" = Me

Lithiation reactions of 2-chloro, 2-methoxy and 2-pivaloylaminoquinoxaline using LTMP or LDA have been studied in detail [93JHC(30)1491 ]. Reactions of pyrazine N-oxides with trimethylsilyl azide in the presence of diethylcarbamoyl chloride have been reported to afford azidopyrazines of type 107 [94JCS(PI)8851. A method permitting the selective hydrogenation of 6-chloro2(IH)-hydroxyquinoxaline-4-oxide to 6-chloro-2(IH)-quinoxalinone (108) has been developed 193MI(78) 123 !.

239

Six-Membered Ring Systems: Diazines

R

R' =H,Me,Ph.CI,NH2,OMe,

R~/'~NAN3

R~=H.Ph,OMe

v

COOMe

R3= H, Me. Ph, NHi, Olde

(107)

-i~i

O

(108)

N-Monoacylated and a series of symmetrically or unsymmetrically N,N'diacylated 5,10-dihydrophenazines have been prepared from the parent system [94CB(127)17231.

6.2.4.3 Applications Aminovinyl-substituted pyrazine derivatives 109 were prepared as potential pesticides [93JI-IC(30)1571]. The total synthesis of the potent inhibitor of superoxide anion generation OPC-15161 (110) has been reported [94JCS(PI)8751. NC.,..,,~N

R

R=

o'~ L,,,,,,,..IN ~

~r~

(109)

L,,~~,.~

'

OMe , I~~L..~IAI,O

etc.

11101

Novel AT2-selective angiotensin II receptor antagonists (111) have been prepared and structure-activity relationships in this series have been established [93MI(3)2023 i. 6-( IH-Imidazol- 1-yl)-7-nitro-2,3( IH,4H)-quinoxalinedione hydrochloride (YM90K) and related compounds 112 have been synthesised as novel antiepileptic agents [94JMC137)467]. RRINCON

NCONRZR3

11111

R

~.

O

11121

REFERENCES 91MI(2)118 93ACS(47)1 ! 17 93AF143)663 93BSF(130)488

I.L. Pacholski, I. Blanco, N. Zanatta, and M.A.P. Martins, J. Brae. Chem. Soc., 1991, 2, 118. C. Moltke-Leth and K.A. Jorgensen, Acta Chem. Scand., 1993, 47, 1117. A.R.R. Rao and V. M. Reddy; Arzneim.-Forsch., 1993, 43, 663. A. Turck, N. PI6, N. Mojovie, and G. Qu~.guiner, Bull. Soc. (~aim. Ft., 1993, 130, 488.

240

93CC 1179 93CC1756 93CL1243

93CPB(41)951 93CPB(4 I)1114 93CPB(41)1498 93CPB(41 )2073 93H(35)775 93H(35)909 93H(35)1313 93H(36)1463 93H(36)1975 93H(36)2273 93JHC(30)789 93JHC(30)1065 93JHC(30)1117 93JHC(30)1399 93JHC(30)1491 93JHC(30)1501 93JHC(30)1513 93JHC(30)1571 93JHC(30)1577 93JHC(30)1607 93JHC(30)1685 93JMC(36)3207

93JMC(36)3765 93JMC(36)4061 93JOC(58)5753

Six-Membered Ring Systems: Diazines

I.H. Aspinall, P.M. Cowley, G. Mitchell, and R.J. Stoodley, J. Chem. Soc., Chem. Commun., 1993, 1179. M. Scobie and G. Tennant; J. Chem. Soc., Chem. Commun., 1993, 1756. T. Kusmnoto, K. Ogino, K.-i Sato, T. Hiyama, S. Takehara, and K. Nakamura, Chem. Lett., 1993, 1243. Z.H. Chohan and S. Kausar, Chem. Pharm. Bull., 1993, 41,951. M. Hori and H. Ohtaka, Chem. Pharm. Bull., 1993, 41, 1114. M. Hirohaslfi, M. Kido, Y. Ymnamoto, Y. Kojima, K. Jitsukawa, and S. Fujii, Chem. Pharm. Bull., 1993, 41, 1498. T. Kinoshita, H. Ohishi, and Y. Tanimoto; Chem. Pharm. Bull., 1993, 41, 2073. C.-C. Cheng, D.-F. Liu, and T.-C. Chou; Heterocycles, 1993, 35, 775. M. Takahashi, H. Kotashima, and T. Saitoh, Heterocycles, 1993, 35, 909. W.J. Coates and A. McKillop, Heterocych,s, 1993, 35, 1313. D.L. Kuo, Heterocycles, 1993, 36, 1463. P. M/ltyus, K. Fuji, and K. Tanaka; Heterocycles, 1993, 36, 1975. P. Victory, J.I. Borrell, A. Vidal-Ferran, E. Montenegro, and M.L. Jimeno, Heterocycles, 1993, 36, 2273. J.P. Chupp, C.R. Jones, and M.L. Dahl, J. Heterocycl. Chem., 1993, 30, 789. J. Clark, M.S. Shahhet, D. Korakas, and G. Varvounis, J. Heterocycl. Chem., 1993, 30, 1065. J. Reisch, M. Iding, and C.O. Usifoh; J. Hetero~cl. Chem., 1993, 30, 1117. D.L. Levesque, E.-C. Wang, D.-C. Wei, C.-C Tzeng, R.P. Panzica, F.N.M. Naguib, and M.H. el Kouni, J. Heterocycl. Chem., 1993, 30, 1399. A. Turk, N. PI6, V. Tallon, and G. Qu6guiner, J. Heterocycl. CJzem., 1993, 30, 1491. S.G. Hegde and C.R. Jones,,/. Heterocycl. Chem., 1993, 30, 1501. E.S. Ratemi, N. Namdev, and M.S. Gibson, J. Heterocycl. Chem., 1993, 30, 1513. D. Hou, A. Oshida, and M. Matsuoka; J. Heterocycl. Chem., 1993, 30, 1571. A. ~opar, B. Stanovnik, and M. Ti~ler, J. Heterocycl. Chem., 1993, 30, 1577. B. Riemer, A. Hassoun, J. Liebscher, P.G. Jones, and A. Clu'apkowski; J. Heterocycl. Chem., 1993, 30, 1607. G. Heinisch and T. Langer, J. Heterocycl. Chem., 1993, 30, 1685. S.E. de Laszlo, C.S. Quagliato, W.J. Greenlee, A.A. Patchett, R.S.L. Chang, V.J. Lotti, T.-B. Chen, S.A. Scheck, K.A. Faust, S.S. Kivliglm, T.S. Schom, G.J. Zingaro, and P.K.S. Siegl, ; J. IVied. Chem., 1993, 36, 3207. Y. Takase, T. Saeki, M. Fujimoto, and I. Saito; J. A4ed. Chem., 1993, 36, 3765. M. Yamaguchi, K. Kamei, T. Koga, M. Akima, A. Manlyama, T. Kuroki, and N. Ohi; J. Ailed. Chem., 1993, 36,406 I. D.C. Craig, A. Doughty, M. Kassiou, M.G. Machltosh, and R.W. Read, J. Org. Chem., 1993, 58, 5753.

Six-Membered Ring Systems: Diazines

93JOC(58)6354 93JOC(58)6826 93JOC(58)6976 93KGS514 93MI347 93MI(3)1293 93MI(3)1663 93MI(3)2023 93MI(4)591 93MI(10)23 93MI(28)129 93MI(28)141 93MI(28)463 93MI(28)473 93MI(28)601 93MI(28)643 93MI(28)647 93MI(48)523 93MI(48)861 93MI(48)894 93MI(61)3 93MI(67)1099 93MI(78)123 93MI(I 30)737 93S867 93SC(23)2065 93SC(23)2363

241

M. Seki, H. Kubota, K. Matsumoto, A. Kinumaki, T. Da-te, and K. Okamura; d. Org. Chem., 1993, 58, 6354 Y. Uoztuni, A. Tanahashi, and T. Hayashi; d. Org. Chem., 1993, 58, 6826. H. Wamhoff and A. Sclunidt; d. Org. Chem., 1993, 58, 6976. D.G. Mazhukin, A.Ya. Tildlonov, L.B. Volodarskii, and E.P. Konovalova; Khim. Geterotsikl. Soedin., 1993, 514; engl. translation: 1993,437. A.C. Tom6, P.M. O'Neill, R.C. Storr, and J.A.S. Cavaleiro; S vnlett, 1993,347. E.E. Allen, S.E. de Laszlo, S.X. Humig, C.S. Quagliato, W.J. Greenlee, R.S.L. Chang, T.-B. Chen, K.A. Faust, and V.J. Lotti; Bioorg. Ailed. Chem. Lett., 1993, 3, 1293. D.W. Combs; Bioorg. Med. Chem. Lett., 1993, 3, 1663. M.T. Wu, T.J. lkeler, W.T. Ashton, R.S.L. Chang, V.J. Lotti, and W.J. Greenlee; Bioorg. Med. Chem. Lett., 1993, 3, 2023. C.J. Sun, Z.C. Chen, Y. Meng, Y.G. Wang, P. Xue, J.G. Zhang, and G.X. Cui; Chha. Cheat. Lett., 1993, 4, 591. D. Catarzi, L. Cecchi, G. Filacehioni, A. Bartolini, R. Carpenedo, A. GaUi, and F. Mori; Drug Des. Discovery, 1993, 10, 23. R. Jonas, M. Klockow, I. Lues, H. Pr~lcher, H.J. Schliep, and H. Wurziger, Fur. d. Med. Chem., 1993, 28, 129. R. Jonas, H. Pr~|cher, and H. Wurziger; Eur. d. Med. Chem. 1993, 28, 141. T. Betmeche, P. Strande, R. Oflebro, and K. Undheim; Eur. d. Med. Chem. i 993, 28,463. N.G. Kundu, S.K. Dasgupta, L.N. Chaudhuri, J.S. Mahanty, C.P. Spears, and A.H. Shahinian; Eur. d. Med. Chem. 1993, 28, 473. T.H. Brown, R.C. Blakemore, G.J. Durant, C.R. Ganellin, M.E. Parsons, A.C. Rasmussen, and D.A. Rawlings; Eur. ,I. A/led. Chem. 1993, 28, 601. M. Bhalla, P.K. Naithani, V.K. Srivastava, T.N. Bhalla, and K. Shanker, Eur. d. Med. Chem. 1993, 28, 643. S. Corsano, R. Scapicchi, G. Strappaghetti, G. Marucci, and F. Paparelli; Eur. d. Med. Chem. 1993, 28, 647. E. Mikieiuk-Olasik, T. Kajkowski, and T.J. Bartczak; Pharmazie, 1993, 48, 523. M. Shopova, S. Tabakova, S. Taxirov, and E. Golovinsky; Pharmazie, 1993, 48, 861. S.A.H. EI-Feky; Pharmazie, 1993, 48, 894. J. Easmon, G. Heiniseh, and W. Holzer; Sci Pharm., 1993, 61, 3. W. Zielifmki and M. Mazik; Pol. J. Chem., 1993, 67, 1099. R.E. Malz Jr., M.P. Reynolds, and C.J. Fagouri; Stud. Surf. Sci. Catal., 1993, 78, 123. J. Fetter, M. Kajt,~r-Peredy, E. Keskeny, and K. Lempert; Acta Chim. Hung., 1993, 130, 737. J.J. Vanden Eynde, J. Godin, A. Mayence, A. Maquestiau, and E. /Xalders; Synthesis, 1993, 867. F. El Guetmnout and A. Foucaud; Synth. Commun., 1993, 23, 2065. S.H. Thang, K.G. Watson, W.M. Best, M.-A.M. Fam, and P.L.C. Keep; Synth. Commun., 1993, 23, 2363.

242

93SC(23)2833 93"I"(49)3767 93T(49)6899 93T(49)9713 93TL(34)3777 93TL(34)3903 93TL(34)5135 93TL(34)7737 94AP(327)533 94AP(327)57 l 94BCJ(67)I204 94CB(127)1723 94CCC(59)683 94CPB(42)57 94H(37)709 94H(37)1033 94H(37)1109 94H(37)1141 94H(38)125 94H(38)249 94H(38)375 94H(38)1 ! 19 94H(38)1273 94H(38)1375 94JCS(P 1)565 94JCS(PI)875 94JCS(PI)885 94JHC(31)357 94JMC(37)467

Six-Membered Ring @stems: Diazines

B. Baudoin, Y. Ribeill, and N. Vicker, Synth. Commun., 1993, 23, 2833. B. Riemer, M. Patzel, A. Hassoun, J. Liebseher, W. Friedrichsen, and P.G. Jones; Tetrahedron, 1993, 49, 3767. A.J. Hoefnagel, H. v. Koningsveid, F. v. Meurs, J.A. Peters, A. Sitmema, and H. v. Bekkmn; Tetrahedron, 1993, 49, 6899. T. Sakamoto, Y. Kondo, N. Murata, and H. Yamanaka; Tetrahedron, 1993, 49, 9713. P.G. Baraldi, S. Manfredini, D. Simoni, and G. Spalluto; Tetrahedron Lett., 1993, 34, 3777. V. Dal Piaz, M.P. Giovannoni, and G. Cieiani; Tetrahedron Lett., 1993, 34, 3903. Y. Kamitori, M. Hojo, R. Masuda, T. Ikemura, and Y. Mori; Tetrahedron Lett., 1993, 34, 5135. M. Soufyane, C. Mirand, and J. L6vy; Tetrahedron Lett., 1993, 34, 7737. H. M6hrle and M. Pycior; Arch. Pharm. (Weinheim, Ger.), 1994, 327, 533. J. Lessel; Arch. Pharm. (Weinheim, Ger.), 1994, 327, 571. Y. Mori and K. Maeda; Bull. Chem. Soc. dpn., 1994, 67, 1204. M. Mikulla and R. MOIhaupt; Chem. Bet., 1994, 127, 1723. S. Bhat; Collect. Czech. Chem. Commun.; 1994, 59,683. H. Okada, T. Koyanagi, and N. Yamada; Chem. Pharm. Bull,, 1994, 42, 57. T. ltoh, H. Hasegawa, K. Nagata, Y. Matsuya, and A. Ohsawa; Heterocycles, 1994, 37, 709. G. Musumarra and C. Sergi; Heterocycles, 1994, 37, 1033. J. Barluenga, M. Tomfis, A. Ballesteros, and L.A. L6pez; Heteroeycles, 1994, 37, 1109. A. Katoh, J. Ohkanda, A. Tamura, Y. Yoshiike, and K. Mitsuhashi; Heteroeycles, 1994, 37, 1141. N. Haider, G. Heiniseh, and J. Moshuber; Heterocycles, 1994, 38, 125. N. Nishiwaki, T. Matsunaga, Y. Tohda, and M. Ariga; Heterocycles, 1994, 38, 249. W. Zielifiski and M. Mazik; Heterocycles, 1994, 38, 375. K. Harada, T. Choshi, E. Sugino, K. Sato, and S. Hibino; Heterocycles, 1994, 38, 1119. D. Toussaint, J. Suffert, and C.G.Wennuth; Heterocycles, 1994, 38, 1273. T.J. Kress; Heterocycles, 1994, 38, 1375. T. Inazatmi, E. Harada, T. Mizukoshi, Y. Kuroki, A. Kakehi, and M. Noguehi; J. Chem. Soc., Perkin Trans. 1, 1994, 565. Y. Kita, S. Akai, H. Fujioka, Y. Tamura, H. Tone, and Y. Taniguehi; d. Chem. Soc., Perkin Trans.l, 1994, 875. N. Sato, N. Miwa, and N. Hirokawa; d. Chem. Soc., Perkin Trans. 1, 1994,885. N. Haider and C. Loll; d. Heterocycl. Chem., 1994, 31,357. J. Olunori, S. Sakamoto, H. Kubota, M. Shimizu-Sasamata, M. Okada, S. Kawasaki, K. Hidaka, J. Togami, T. Funtya, and K. Murase; d. Med. Olem., ! 994, 37, 467.

Six-Membered Ring Systems: Diazines 94JMC(37)2106 94JMC(37)2153 94JMC(37)2437

94MI421 94MI557 94MI559 94MI(3)201 94MI(4)1247 94MI(29)249 94MI(29)95 94MI(49)21 94MI(68)117 94MI(220)63 94S66 94S405 94S669 94SC(24)253 94SC(24)773 94SC(24)1733 94T(50)3603 94T(50)5169 94T(50)7579 94T(50)9189 94TL(35)1231 94TL(35)2757 94TL(35)5235

243

Y. Takase, T. Saeki, N. Watanabe, H. Adachi, S. Souda, and I. Saito; 3. Med. Chem., 1994, 37, 2106. S. Moreau, P. Coudert, C. Rubat, D. Gardette, D. Vallee-Goyet, J. Couquelet, P. Bastide, and P. Tronche; 3. Med. Chem., 1994, 37, 2153. T.J. Tucker, T.A. Lyle, C.M. Wiscount, S,F. Britcher, S.D. Young, W.M. Sanders, W.C. Lumma, M.E. Goldman, J.A. O'Brien, R.G. Ball, C.F. Hotmlick, W.A. Schleif, E.A. Emini, J.R. Huff, and P.S. Anderson; 3. Med. Chem., 1994, 37, 2437. A. Batsanov, J.C. Cole, M.R. Crampton, J. Hamid, J.A.K. Howard, and R. Millar, 3. Chem. Soc., Perkin Trans.2, 1994, 42 I. T. Itoh, H. Hasegawa, K. Nagata, and A. Ohsawa; Synlett, 1994, 557. A. Garcia Martinez, A. Hen'era Femfindez, F. Moreno-Jim6nez, M.J. Luengo Fraile, and L.R. Subramanian; S)mlett, 1994, 559. A.M. Abdel-Halim, F.S. Sayed, R.M. AbdeI-Aziz, and H.S. ElDein; Indian 3. Heterocycl. Chem., 1994, 3, 20 I. R.S. Randad, W. Pan, S.V. Gulnik, S. Burt, and J.W. Erickson; Bioorg. Med. Chem. Lett., 1994, 4, 1247. V. Dal Piaz, M.P. Giovannoni, R. Laguna, and E. Cano; Eur. 3. Med. Chem. 1994, 29, 249. V. Colotta, L. Cecchi, D. Catarzi, G. Filacchioni, A. Galli, and F. Moil; Eur. 3. Med. Chem. 1994, 29, 95. J. Lange, J. Karolak-Wojciechowska, M. Gniewosz, and J. Plenkiewicz; Pharmazie, 1994, 49, 2 I. M. Kubaszek, M. Paluchowska, E. Chmiel, and J. Bojarski; Pol. J. Chem., 1994, 68, I 17. H. Bruuner and J. Ftarst; lnorg. Chim. Acta, 1994, 220, 63. D. Enders, O. Meyer, G. Raabe, and J. Runsink; Synthesis, 1994, 66. H. Wamhoff and E. Kroth, S wathesis, 1994,405. V. Dal Piaz, G. Ciciani, and M.P. Giovannoni; Synthesis, 1994, 669. T. Rho and Y.F. Abuh; Synth. Commun., 1994, 24, 253. G. Heinisch and T. Langer, Synth. Commun., 1994, 2,~, 773. S.F. Vasilevsky, E.V. Tretyakov, and H.D. Verkruijsse; Synth. Commun., 1994, 24, !733. M. Botta, R. Saladino, G. Gentile, V. Summa, R. Nicoletti, A. Verri, F. Focher, and S. Spadari; Tetrahedron, 1994, 50, 3603. F. Farifia, M.V. Martin, and M. Romafiach; Tetrahedron, 1994, 50, 5169. S.N. Mazumdar, S. Mukherjee, A.K. Shanna, D. Sengupta, and M.P. Mahajan; Tetrahedron, 1994, 50, 7579. R. Nesi, D. Giomi, S. Turchi, and P. Paoli; Tetrahedron, 1994, 50, 9189. Y. Okada, H. Taguchi, Y. Nishiyama, and T. Yokoi; Tetrahedron Lett., 1994, 35, 1231. J.W.G. Meissner, A.C.v.d. Laan, and U.K. Pandit; Tetrahedron Lett., 1994, 35, 2757. M. Kobayashi, K. Uneyama, N. Hamada, and S. Kashino; Tetrahedron Lett., 1994, 35, 5235.

Chapter 6.3 Six-Membered Ring Systems: Triazines, Tetrazines, and Fused Ring Polyaza Systems DEREK T. HURST

Kingston University, Kingston upon Thames, UK 6.3. I INTRODUCTION

The volume of chemical literature which is published seems to increase each year, and the subjects covered in this chapter share in this increase. A large number of references have been collected through Chemical Abstracts volumes 120 and 121 and a selection of these is presented here. The death of Professor R. K. Robins, a prolific contributor to the field of N-heterocyclic chemistry, occured in 1992 and several of the papers referred to in this chapter were dedicated to his memory. Also, during the period covered in the chapter, a number of papers were dedicated to mark the 70th birthday of Professor E. C. Taylor, another tireless worker whoso contributions to N-heterocyclic chemistry are frequently mentioned in this chapter and elsewhere. 6.3.2 SYNTHESIS 6.3.2.1 Triazines

4,6-Diamino-2H-l,3,5-thiadiazine-2-thione (1) reacts with amines in DMF at ambient temperature to give adducts (2) which, on treatment with alkali, yield l-substituted-4,6diamino-l,3,5-triazine-2(1H)-thiones (3) and 4-amino-6-substitutedamino-l,3,5-triazine2(IH)-thiones (4) [93MI1].

NHz

Nil

R

H

NH2

NI-12

R= Me, Bu, and others

(l)

(2)

(3)

(4)

3-Amino-2H-azirines (5) react with salicylohydrazide to give a mixture of triazines (6) and oxadiazoles. The compound (5; R= Rl= Ph, R 2= H) gives the aromatic product (7) [93HCA1980]. 244

Six-Membered Ring Systems: Triazines

R1 R2 I~NMeR o-HOC6H~ N"N

245

Ph ~NMePh o.HOC~I~'~N "N

H

R= Me, R~- Me, Ph; R2= Me, Me2CH,H

(5)

(6)

(7)

The use of 1-methylthio-l-phenyl-2-azabutadiene-4,4-dicarbonitriles (8) with amidines yields triazines via a 6-exo-trig process (Scheme 1) [94H(38)113].

N~ CN MeSSU,~phCN +

RI~NH

R=Ph ~

NI-12

Ph N~N Ph/~N~RI

ph~,,~SMe Scheme 1.

A new method for the synthesis of triazine-N-oxides (10) involves reacting amidoximes (9) with ethyl orthoacetate in the presence of an acid catalyst. The mechanism proposed for the reaction is a Beckmann rearrangement to a carbodiimide, followed by reaction with another molecule of amidoxime and the orthoester (Scheme 2)[93JHC497].

/ NI'I2 ArC~NOH

H+ "----~"

[ArN:C:NH|

~

9H A r ~ N ~ NAt NH2 NH"

(9)

1

O"

MeC(OEt)3 Me

NH2 NH __~

(10) Scheme 2.

Six-Membered Ring Systems: Triazines

246

A synthesis of the novel 2-substituted pyrido[1,2-a]-l,3,5-triazin-4-ones (12) has been achieved by reacting N-fluoropyridinium salts (11) with cyanate ion and carbonitriles. The evidence indicates that the reaction proceeds via a carbene intermediate [94TL207].

0+

KOCN/RCN~

X"=BF4,CF3SO3

R=n-Pr, t-Bu, Ph

(11)

(12)

The parent compound (14) of a novel series of heterocyclic mesomeric betaines has been obtained by the route shown in Scheme 3 involving flash vacuum pyrolysis of the N-pyrazolyl derivative (13). An alternative product of the reaction is the pyrazolopyridazinone (15) and the proportions of the two products are temperature dependent. The optimum conditions for the formation of (14) are pyrolysis at 500 ~ (Sx10"5 Ton). The structure of the product was confirmed by X-ray crystallography. At 700 ~ (13) is converted, quantitatively, to (15) [93JCS(CC)840]. The betaine (14) undergoes deuterium exchange with deuterotrifluoroacetic acid to give the 3-deutero product and with NBS to yield the 3-bromo derivative. The action of deuteromethoxide ion in deuteromethanol leads to deuterium exchange at the 6- and 8positions [93JCS(CC)840].

-

Q

-

-

Q O

(13)

H Scheme 3.

6.3.2.2 Tetrazines and Pentazines

Few syntheses of tetrazines have been reported in the last year. However the first relne~ntative of 1,2,3,4-tetrazine-N-oxides has been synthesised. 5,7-Dibromo-l,2,3,4benzotetrazine-l-oxide (16; R= Br) has been obtained by intramolecular reaction of the dibromo-o-(tertbutylazoxy)phenyldiazonium tetrafluoroborate. The product was

(14)

Six-Membered Ring @stems: Triazines

247

characterised by NMR spectroscopy, X-ray crystallography and by its transformation into a b e n z o f u ~ (17) (Scheme 4). The parent compound (16; R - H) could not be isolated and the only product to be isolated was the benzofurazan (17; R= H) [94MC122]. O" I

O"

~N2+BF~" R

~ N R

~N R (1'7)

(16)

Reagents and conditions: i: silica gel, CHCI3,40 oc: ii: MeCN. 50 oc. lh.

Scheme 4. 2-Chloroformylhydrazones (18) react with hydrazines to yield tetrahydro- 1,2,4,5-tetrazin3(2H)-ones (19). Oxidation of the products ( R - H) with lead dioxide gives stable tetrazinyl radicals as purple, high melting (> 140 0(2) crystalline solids [94JHC319]. RI

.-

~COO

R

O~N"NH R N. N ~ R 2

H

R= Ph. 4-NO~C6H4" RI= Ph. 4-McC~4,4-MeOC6H4, and others: R2= H. Me. Ph: R3= Ph. 4-MeC~H4, and others

(18)

(19)

The sodium salt of the previously unknown pentazine mesoion (21) has been obtained, as well as some ~SNanalogues, from treatment of the azotetrazole salt (20) with acid. The compound is unstable and readily loses nitrogen in solution or decomposes, explosively, on heating [93CHE395]. M-I II

N,h-

(2o)

II

"

(21)

Six-Membered Ring @stems: Triazines

248

6.3.2.3 Purines and Purine analogues

Intramolecular cyclisation of nitrile imine ylides occurs when 2-pyridyl- (22; X= CH) or 3-pyridazinylhydrazones (22; X= N) are treated with chloramine-T to yield 1,2,4triazolo[4,3-a] pyridines (23; X= CH) and 1,2,4-triazolo[4,3-b]pyridazines (23; X= N) in a simple one-pot synthesis [93SC3195]. Me NHN-~,, At

~

N

~ x "N

N

X = N, C H

Ar (22)

(23)

Derivatives of guanine have become of great interest since the discovery of the value of acyclovir and related guanine analogues as antiviral agents. However the synthesis of these compounds is often problematic. 9-Deazaguanine (25) has been synthesised in five steps from 2-amino-6-methyl-5-nitro-4(3H)-pyrimidinone by a modification of the BatchoLeimgruber indole synthesis which proves to be a useful route due to the failure of more direct routes. A key intermediate is (24) which cyclises to give the fully protected 9deazaguanine [93TIA595].

o

Me~-I:N~N "~ ~

a

0

"NMe~

(24)

(25)

4-Ethoxymethylene-2-phenyl-5(4H)-oxazolone (26) has been shown to be a useful synthon for the synthesis of a range of fused-ring heterocycles by its reactions with suitable aminoheterocycles. Examples include the pyrazolopyrimidines (27) and (28) and others (Scheme 5) [93H(35)9551.

Six-Membered Ring Systems: Triazines

.3

,h

249

0

H

R

(27)

H

(25)

Scheme 5. 6.3.2.4 Ptcridinea and related compounds Some new pyrimido[4,5-d]pyrimidine analogues (29) of folic acid have been prepared using Mannich reactions and the preformed glutamylphenylmethylamino unit which proved to be the best approach to these compounds. Howver, the products showed disappointing results in tests on the growth of CCRF-CEM leulmemic cells [93H(35)1397]. X

2

H

X-- NH2, OH. R- H. COzEt

(29) A number of pyrido[2,3-d]pyrimidines have been synthesised by reacting arylmethyleneaeetoacetates with aminopyrimidines. The scope and limitations of the method were reviewed and it has been deduced that the success of the reaction depends on the presence of the pyrimidine having a 6-amino group and a 2-oxo, thio, or amino group. The compounds were tested but were shown to have no calcium ion ~atagonist action or vasorelaxant potency [94T8085]. A new facile reaction for the synthesis of 5,6,7,8-5-deaza-5-thiapterins (30) is afforded by the reaction of 5-bromo-6-chloro-isocytosine with cysteamines via the aliphatic $-N Smiles rearrangement in ethanolic pH7 buffer solution [94CPB806]. O

H2

R H

(30)

R, R 1= H, CH2OH

Six-Membered Ring Systems: Triazines

250

6.3.2.5 Miscellaneous Ring systzms The Aza-Wittig reactions of iminophosphoranes have proved to be extremely useful for the synthesis of a variety of N-heterocycles. The topic has been reviewed [92AHC(55)129]. The first successful attempts to prepare pyrimido[4,5-d]pyrimidines (31), 6:6:7-fused azepines (32) and isofervenulinines (33) using this methodology have now been reported. The reactions are shown in Scheme 6 [93H(35)1055].

0

Me

M,

NI~n3

N:C:N Me

(}4}

l i; PhNCO ii; DEAD

{32)

1 PhCH:NPh

Me

Me (31)

(}}} Sch 9

6.

The novel three-component reaction of (uracil-6-ylimino)phosphorane (34), isocyanate and substituted pyridines, yields the new pyrido[l',2':3,4]pyrimido[4,5-d]pyridines (35). The use of isoquinoline or phthalazine yields (36; X - CH, or N). The products are formed as dihydro compounds or as zwitterions depending upon the reaction conditions. Oxidative cleavage of the compounds (36; X = N) in nitrobenzene results in the formation of the cyanophenylpyrimido[4,5-d]pyrimidine [93JOC6976].

Mc

X

Me

Mc

Me

(35)

(36)

X=N, CH

Six-Membered Ring @stems: Triazines

251

The new zwitterionic pyrazolo[3',4":4,5]pyrimido[6,l-a]isoquinolines (37, 38), pyrazolo[3',4':4,5]pyrinddo[6,1-a]phthalazJne (39) and pyrazolo[3',4':4,5]pyrimido[6, l-a]pyrimidines (40) have also been obtained by a three-component reaction involving a heterocyclic iminophosphorane, an isocyanate and a heteroarene (Scheme 7). Another ring system to be pretmed during this work was the pyrazolo[3,4-e][1,2,4]triazolo[ 1,2-a][ 1,2,4]triazinedione (41). The structures of these compounds were established by X-ray crystallography [94JOC3985].

~Et

~NAr

O:~N~)=::O

N:pph3

At

0

Et

N~l~/'~NHPh (41)

I ArNCO

~,X Et

N,

J

~

Et (37) X= CH (39) X= N

o

P~--~N'PPh3 Me R

~

Ph Me

R= H, Me

0

phN,

Me

+

Ar~ Ph, 4-CICsH4 and others

(40)

Scheme 7.

Six-Membered Ring Systems: Triazines

252

Another group of workers have used this methodology to obtain pyrido[3',4':4,5]thieno [3,2-d]pyrimidines (42) (Scheme 8)[94T6705].

N~:PPh3

NC~

:

,~N~I~X

(42) X= O. S, NR; R= Et, Ar

Reagents: RNCO. toluene, reflux; CO2, toluene 120 oc: or CS2, toluene 120 oc

Scheme 8. 1-Chloro-l,3-bis(dimethylamino)-3-phenyl-2-azaprop-2-en-l-yl perchlorate (43) reacts with N-heterocycles having an adjacent amino group to yield bicyclic compounds containing the triazinium moiety. Examples of such products are shown in Scheme 9. Some other compounds were also made, and the reaction seems to be a general one [94JHC535]. Me

Me

+

Me2N

CI 004"

(4:$)

et--~,SN-~~2 HN-N

S..,,~N. Ph N"+N~ N

.l~e2

HN"+N~N + 004"

(3o4" NMe2

Conditions: MeCN, reflux lh.

Scheme 9. Temozolomide (44) is a promising antitumour drug whose synthesis is problematic, and which requires the use of methyl isocyanate. A new route starting from 4-aminoimidazole4-carboxamide, shown in Scheme 10, has been developed. All conventional methods to decarboxylate the acid (45; R= COzEt) failed, and the rather lengthy alternative was devised. However, it is a high yielding process and may be a satisfactory alternative synthesis of temozolomide [94JCS(CC)1687].

253

Six-Membered Ring Systems: Triazines H

H2NOC

H2~N

H2NO C" ~ N

l

o

fi ~CH2OO2Et

I

viii

(44)

H2NOC iv

~..~

H 2 ~ N

~-CH~R

(45) Reagents and conditions: i, iv: NaNO2,2M HCI, 0 oc. ii. iii; EtO2CCH2NCO, DMSO, CsHsN, 20 oc. v: 5M HCI. 45 oc. vi; Me2CHCH2OCOCl, N-methylmorpholine, -15 oc. vii: 2-mercaptopyridine N-oxide, Et3N, -15 oc. viii: Bu3SnH. AIBN, DMF, u.v. 25 oc.

Scheme 10.

2-Methylthio-2-imidazoline and 2-methylthio-l,4,5,6-tetrahydropyrimidines react with 2chloro-3-pyrazinecarbonyl chlorides to yield (46) which react with arylamines to give tricyclic linearly fused N-arylpyrimidinones (47) [93CCC1133].

e,~X~N~

t~X, ~ N -"(CHin

X= N, CH; n = 1, 2

(46)

(47)

The novel 2-amino-l-methyl derivatives of imidazo[4,5-b][1,x]naphthyridine, e.g. (48) and (49), are prepared via the Friedlander reaction from the corresponding aminopyridine carboxaldehydes and creatinine [94JCR(S)268].

Me

(48)

Me

(49)

254

Six-Membered Ring @stems: Triazines

Activated 2-benzimidazoles (2- CN, C O 2 R ) react with a variety of N-acylimidates under microwave irradiation in open vessels to provide a new synthesis of pyrimido[l,6-a] benzimidazoles (50) [94TLA5631. R2

(50) Hydrazinolysis of pyrido- and pyrimidothiazine derivatives (51) and pyridyloxamates (52) gives corresponding oxamic hydrazides (53) which cyclise in refluxing ethanolic hydrochloric acid to yield pyrido[3',2':5,6][ 1,4]thiazino[3,4-c]- and pyrimido[5',4':5,6] [ 1,4]thiazino[3,4-c][ 1,2,4]-triazines (54) [93CHE480].

0 X

R2

R

/

(Sl)

"

[

,.l,~lCOO32Et (53)

~54)

R r ' ~ N / ~ . SCH2COR2 (521 X= N. CH: R= CI. H: R 1= H. MeO: R 2= Me. Et. Pr

The new polyaza heterocycle tris(imidazo)[ 1,2-a: 1,2-c: 1,2-e]-1,3,5-triazine-2,3,5,6,8,9hexacarbonitrile (HTr) (56) which contains no hydrogen has been prepared by the thermolysis of the imidazoles (55). The compound is probably formed via a benzyne-type intermediate but no evidence for dimeric, or other oligomers, was observed. The structure of the product was confirmed ~troscopically (13C NMR and mass spectrometry). The compound is thermally stable to over 400 ~ but further studies of its properties are awaited [94JA391].

Six-Membered Ring @stems: Triazines

255

NC N

CN

!

NC

X'- CI.Br. !

(55)

CN

(56)

A number of 2- and 4-fluorobenzyl derivatives of imidazo[l,2-c]pyrazolo[4,3-e]pyrimidine (57), pyrazolo[4,3-e]-l,2,4-triazolo[l,5-c]pyrimidine (58) and 1,2,4triazolo[5, l-i]purine (59) have been synthesised and their interaction with adenosine A2 and AI receptors evaluated. The highest degree of activity was shown by compounds having furo substituents [93EJM569].

Y= fluorobenz~'l

'<--N

N Y

y

(57) 6.3.3

(58)

)4~'NH,

(59)

REACTIONS

6.3.3.1 Triazines A detailed study of the scope of the amidine Diels-Alder reaction of 1,3,5-triazines has been carried out. The thermal reaction of amidines with symmetrical 1,3,5-triazines proceeds with in situ amidine to l,l-diaminoethene tautomerism, [4 +2] cycloaddition, loss of ammonia with imine generation, imine to enamine tautomerism, then retro-DielsAlder loss of ethyl cyanoformate to yield substituted 4-aminopyrimidines. The reaction procee~ best with the amidine hydrochloride salts at temperatures around 90-100 ~ in polar aprotic solvents. The reaction seems to be essentially unaffected by the diene-dienophile ratio, but is subject to triazine substituent effects. The general reaction is shown in Scheme 11 [94JOC4950].

Six-Membered Ring Systems: Triazines

256

NRHCI

J

N

~ ~

zx

R-~H k-N

~~-x~ r'~- N

X=CO2Et;R=H,Me,Ph and othem

X Scheme 11.

The alkylation reactions of some 1,2,4-triazines have been shown to give different products depending on the substitution in the triazine, the alkylating reagent and the time of reaction. For example, the treatment of 3,5-dimethoxy-l,2,4-triazine (60) with iodomethane gives, depending on the reaction time, the triazinium iodide (61), the triazinimnolates (62) and (63), and the methoxytriazinones (64) and (65). The alkylation of several other triazines was also studied and the structures of the products confirmed spectroscopically [93JHC1317]. Me F

($N"N

Mel

/'bl+'N

(60) Me ~1~ N

(63)

Me

~bI+"N

(61)

(62)

(~N'NMe

~N"NMe

(64)

(65)

Nitroso-l,3,5-triazines (66; X= NO) are readily obtained from the hydroxyamino compounds (66; X = NHOH) by oxidation using manganese dioxide in chloroform. The stability of the products depends on the electron donating properties of the subsfituents [93CHE593].

Six-Membered Ring Systems: Triazines

257

R R- RI= piperidino. MeO. MeaN R- MeO; R 1-- M%N

(66) 4,6-Dimethoxy-l,3,5-triazine-2(1H)-thione is oxidised using 2-benzenesulfonyl-3(p-nitrophenyl)oxaziridine to yield the sulfenic acid (67) as a stable, crystalline solid with a pK, of 5.86 at 20 *(2. The ring is almost planar, shows alternating C-N bond lengths, and exists as a strongly intermolecularly H-bonded dimer in the solid state [93ZN(B)1212].

1,3,5-Triazine reacts with 2-pyridylacetonitrile in ethanol to give iminobis(pyridylpropenenitrile) (68), but a similar reaction with 3-pyridylacetonitrile yields the pyridylpyrimidine (69) [94AP533].

(68)

(69)

The reaction of 2,4-diazido- 1,3,5-triazines with an equimolar amount, or a two-fold molar excess, of ethyl cyanoacetate, in the presence of triethylamine in DMF, gives the corresponding mono or diamino derivatives of 1,3,5-triazine. On heating the 2,4-diazido1,3,5-triazines with a two-fold excess of acetylacetone, or ethyl acetoacetate, in the presence of triethylamine in ethanol, corresponding 1,2,3-triazolo- 1,3,5-triazines (70) are formed [94MC104]. R,~N,~NH~

N-N,,~r.M 9

Oo)

258

Six-Membered Ring Systems: Triazines

3-Methylthio-l,2,4-triazin-5(2H)-one (71) reacts with benzenesulfonyl chloride in anhydrous pyridine to give the triazinylpyridinium betaine (72). However, when sodium hydroxide in aqueous acetone (or methanol) is used as reactant and solvent, sulfonyltriazines (73) or (74) are obtained [93M12].

Moo

Oil

MeS*'J~~O -

(71)

MeS

(72)

tos

O

(73)

~

MeSsj~

OH

H

O ~

(74)

Vicarious nucleophilic substitution of 1,2,3-triazinium 2-dicyanomethylides (75) with 1-chloromethyl phenyl sulfone proceeds to give the 5-substituted derivatives (76). The dicyanomethylene group is readily eliminated by a radical reaction to give 5-phenylsulfonylmethyl-l,2,3-triazines (77). Direct reaction of the triazine with l-chloromethyl phenyl sulfone results in attack at the 4-position with subsequent decomposition [93H(35)58~1. so2pu ~2sozph R R RI~~R PhSO2CH2CI.~ (NII4)2S2Os R I ~ ~ R Nl~~l..,y ,,, ~ I~,~+N iPtO[-Lreflux~ N~,,~.,,N "cN NC'~'C~ .--

It, RI= Me,Et, Ph (Ts)

(76)

(77)

The Diels-Alder reaction of 1,2,4-triazines with cyclic vinyl ethers leads to a range of substituted pyridines with hydroxyalkyl and oxoalkyl side chains. With dihydrofuran the aromatisation of the 1:1 adduct is prevented and this allows 2:1 adducts to be isolated. These reactions are shown in Scheme 12 [93T5277].

R R

R

R,R1,R2=combinationofH,Me,Ph, NHA~,CO2Et Scheme 12.

R~ N

~X= OMe.OEt n=2~ R L ~ R~~CH

O

259

Six-Membered Ring Systems: Triazines

Under solid-liquid phase transfer conditions both primary and secondary alcohols react with 2,4,6-trichloro-1,2,5-triazine to give the corresponding mono or dialkoxy derivatives depending on the reagent molar ratios [94SC2153]. A simple synthesis of thiadiazolo[2,3-e]-l,2,4-triazines (79) is the reaction of the triazinone (78) with alkyl thiocyanates and polyphosphoric acid [93CHE125]. The related thiadiazolopyrimidines (81) are produced via the intermediate thiadiazole (80) and diketones [93CHE981]. o Me'~N"NH'

Rl

o Me- ~J~N.N

cio; .~I~-NN~_ SR

N-N

H R= Me. Ph. PhCH2

(78) (79) (80) (81) The triazine (82) reacts with c~-haloketones in aqueous sodium hydroxide to give the products (83). These compounds dehydrate to yield (84) not the isomeric (85) [93JHC293]. H O,~,, N,r~_ $

CIO-1200R ~ aq NaOH

HN

OH

H

S

(82)

(8;))

HN.N,, .N

R

S

,.\t ~

(S4) FIN"

R

(85)

6-Methyl-3-methylthio-l,2,4-triazin-5(2H)one and phenacyl bromide react to yield 3-methylthio-2-phenacyl-l,2,4-tfiazin-5(2H)-one which with hydrazine hydrate gives 7-methyl-3-phenyl-4H-1,2,4-triazino[4,3-hi- 1,2,4-triazin-8(l H)one (86). The ring system (87) is also obtained in this reaction [92MI1]. H

O

Me

(86)

(87)

Formal [3 +2] cycloadditions of the lr-delocalised singlet vinylcarbene/three-carbon 1,3dipole generated in a reversible ring opening of 3,3-dimethoxycyclopropene with a variety

260

Six-Membered Ring Systems: Triazines

of substituted triazines leads to novel pyrrolo[1,2-d][1,2,4]tdazines, e.g. (88). These compounds protonate at N-2 and alkylate at this position with Meerwein reagents such as DMAD to yield the pyrido[2,1-f]pyrrolo[1,2-d][1,2,4]tfiazine (89)and its 8H isomer [93CB23171. CO,Me M e O 2 C . , ~ ~ CO)Me N.,~/, N.~,/ SMe OMe

SMe OMe

(88)

(89)

The pyrrolotriazine (90) is oxidised in the presence of oxygen, daylight and silica gel, to yield the triazine oxide (91) [93CB2317].

OMe

(90)

(91)

6.3.3.2 Tctrazincs Tetrazines (92) react with pseudoazulenes (93) to yield the novel 14T systems (94) via cycloaddition followed by loss of nitrogen. However, the cyclopenta[d]pyridazines, e.g. (95) only yield azines (96) [93CB2143]. CF~

CF~

II N.~N CF~ I

(92)

/,P"~'N Me

CO2R

CO2R

C(CF3):NN:C

CF.~

(93)

(94)

(95)

(96)

6.3.3.3 Purinr and related compounds An earlier report that 6-acetyl-7-(2-dimethylaminovinyl)pyrazolo[l,5-a]pyrimidine (97) reacts with hydrazine hydrate in acetic acid to give 6-methylpyrazolo [5',l':2,3]pyrimido[5,4-d][1,2]diazepine (98) [93H(36)87] has now been shown to be incorrect. Further NMR spectroscopic study and X-ray crystallography have confLrmed the product to be 7-methyl-6-(pyrazol-3'-yl)pyrazolo[1,5-a]pyrimidine (99) [94JCS(I~)16571.

Six-Membered Ring Systems: Triazines

NMe~

(97)

(98)

261

(99)

Temozolomide (44) undergoes ring opening of the tetrazinone ring in deuteriated phosphate buffer with transfer of the methyl group to phosphate and deuterioxide ions. No deuterium exchange of the methyl group occurs in intact temozolomide [93JCS(CC) 1177]. Purines react with tetra-, tri- and dichloroalkanes in HMPA to yield, regioselectively, the 9-tri-, di-, or chloroenamines (Scheme 13) [94JCS(PI)1089]. X

X 4-

I

i, ii or i i i "~ R

a

X = NH2, PhCH20, Cl; Y - H, NH2' Rs = H, el

l

Reagents and conditions: i, Nail, HMPK ii; KH, HMPA. iii; NaOH, NMc4F, DMF

Scheme 13.

Carbon-carbon bond formation in the purine 6-position can be easily accomplished by palladium catalysed cross coupling between 6-chloropurines and organostannanes without protection of the purine NH function. This provides a very convenient route to cytokinines [94TL3155]. Reactions of 1-aminoadenines with hydroxylamine gives adenine-l-oxides. Alkaline treatment of 1-aminoadenines affords 5-amino-4-(1,2,4-triazol-3-yl)imidazoles (100) which are converted, on treatment with sodium nitrite, to 3H-imidazo[4,5-e]triazolo [1,5-c][1,2,3]triazines (101) (Scheme 14) [94MI1].

H2~N

R

R= Me. D-ribofiu~mosyl. 2-deoxy- D-ribofuranosyl

(loo)

OOl) Schcme 14.

Six-Membered Ring Systems: Triazines

262

The use of 9-substituted guanines as antiviral agents has stimulated much work on the synthesis of such compounds. A novel route provides an easy, low temperature, method. 2-Amino-9-benzyl-6-chloropurine reacts with 1,4-diazabicyclo[2,2,2]octane (DABCO) in DMF at ambient temperature to yield the salt (102). This reacts with hydroxide ion (pHI 1), also at ambient temperature, to yield the guanine. Refluxing (102) with alcohols in the presence of potassium carbonate yields the 6-alkoxy-9-subsfituted guanines in yields up to 72% [94JCS(CC)913]. The 6-aza analogue (103) has been obtained from 5-methylthio-l,2,4-triazine-3,6-diamine in an easy, three step, synthesis [94JCR(S)121]. X H2

H2N~~

CH2Ph

(1o2)

N~ i CH2Ph

(1o3)

A series of analogues of acyclovir, and related guanosine compounds, has been obtained by the alkylation of (104 to 108; R= H) [93JHC1341]. O O O O

H2N~~

N

H2N/~~

~N~?

R

O

N

R= vat. alkylsubs.;Y= CI, NH2 ' X= N. CH

(Io4)

(1o6)

005)

(1o7)

(los)

Several new f-fused xanthines have been prepared in which the extra ring is pyrazino, pyrido, pyrimido, or pyrrolo, using the purine (109) which is subsequently developed to give appropriately substituted compounds for cyclisation. For example, the syntheses of pyrimido-fused (110) and pyrazino-fused compounds (111) are shown in Scheme 15 [94HIC81]. o tc~cthoxypropanc' ,

,

n=O Pr

(109)

n=

Pr

(11o)

I~CICH2COCI 0

NaH/DMF Pr

Pr

(Ill) Scheme 1 5.

Six-Membered Ring Systems: Triazines

263

A study of the nitration of xanthine and its N-methyl derivatives has been carded out. In general 9-unsubstituted, and some 9-methylxanthines, can be effectively nitrated with nitric acid in glacial acetic acid. However, 7-methylxanthine derivatives nitrate best using nitronium tetrafluoroborate [93JHC1221]. The tetrazolopyrimidines (112) can be obtained from 5-aminotetrazole. They react with strong acids to give protonated forms which are readily isomerised to the corresponding 2-azidopyrimidines. However, most reagents cause ring opening of the pyrimidine ring to yield substituted tetrazoles [93JI-IC1267]. N"N;N

R= Et, Bu, Ph, PhCH2

N r~3NH* (112) 9-Vinyladenine (113) reacts with diethyl fumarate photochemically to produce, not 9cyclobutyl-substituted adenine, but the tricyclic products (1 i 4a,b). This is one of the few reported photoreactions of adenine derivatives and involves attack of the vinyl group on the N-3 position of adenine and reaction of the diethyl fumarate on the N-6 and N-9 positions. How the C-8 carbon is lost has not been ascertained [94JHC375]. .NH2

NH2 s H

(a) .....C02Et Co) --.0~I~

(113)

(ll4)

6.3.3.4 Pteridines and related compounds Pterins and 5-deazapterins are readily converted to the 4-deoxy-4-aminoderivatives by reaction with 4-chlorophenylphosphochloridate and 1,2,4-triazole to yield the triazolylpterins (115), followed by the action of aqueous ammonia [93H(36)1883].

N~ Me3CO3NH "N"

X~r, Me

9 .J "N ~

(llS) 1,3-Dimethyl-5,7-dichloro-6-nitropyrido[2,3-d]pyrimidine-2,4-diones react with amines to give either or both chlorine atom substitution. Catalytic reduction of the

Six-Membered Ring Systems: Triazines

264

5,7-disubstituted-6-nitropyrido[2,3-d]pyrimidines gives the triamino products which react with amyl nitrite in acetic acid to yield triazolopyridopyrimidines (116) [93CHE335].

o Rt'N-~ Me

(ll6) 2-Alkylthio[ 1,3,4]thiadiazolo[2,3-c][ 1,2,4]triazines (117) undergo ring opening of the triazine moiety with hydrazine to yield the thiadiazoles (118) [94SL165]. O N.-N

N.~s

N--N 'S"

(ll7)

(ll8)

The pyridazino[4,5-d]pyridazines (119) have been prepared and have been shown to undergo thermal intramolecular [4+2] cycloadditions to yield f-annelated phthalazines (120) [94JHC357]. x~(CH2)nCE~CR

X-O. S, NH~ n---2, 3; R-~ H. Me

(119)

(120)

The 3-substituted-6-amino-2-methylpyrimido [4,5-e] [ 1,2,4 ]triazin- 8-ones ( 121), which are 7-substituted-6-methyl-6-azapterins, have been prepared as potential inhibitors of the enzyme dihydropterin reductase. The thio derivatives are relatively unstable in aqueous solution at near neutral pH and are hydrolysed to the corresponding pteridinone. All of the compounds which were obtained inhibited the enzyme with I~ between 10 and 300 /tM. The pk~ for each of the compounds was also recorded [93H(35)807].

Six-Membered Ring @stems: Triazines O ~N'.NM

265

e

R= Me. OH. NH2, MeS.PhCH2S,HO2CC6H4CH2S

(121) REFERENCES 92AHC(55) 129 92MI1 93CB2143 93CB2317 93CCC 1133 93CHE125 93CHE335 93CHE395

93CHFA80 93CHE593 93CHE981 93EJM569 93H(35)581 93H(35)807 93H(35)955 93H(35)1055 93H(35)1397

H. Wamhoff, J. Dzenis and K. Hirota, Adv.Heterocycl. Chem., 1992, 55, 129. M. M. Heravi and M. Bakavoli, J.Sci.lslamic Repub.lran, 1992, 107; Chem.Abstr., 1994, 121, 108726. U. Reimers and G. Seitz, Chem.Ber.,1993, 126, 2143. G. Frenzen, M. Rischke and G. Seitz, Chem.Ber., 1993, 126, 2317. R. Friary, A. T. McPhail and V. Seidl, Collect.Czech. Chem. Cwmnun., 1993, 58, 1133. S. Sh. Shakurov and M. A. Kukaniev, Chem.Heterocycl.Compd. (Engl. Transl.), 1993, 29, 125. O. A. Burova, N. M. Smirnova and T. S. Safonova, Chem. Heterocycl. Compd. (Engl. Transl.), 1993, 29, 335. A. G. Mayants, V. N. Vladimirov, V. A. Shylapochnikov, L. M. Tischenko, S. S. Gordeichuk and S. V. Mikhailova, Chem. Heterocycl. Compd. (Engl. Transl.), 1993, 29, 395. L. G. Levkovskaya, I. G. Mamaeva, L. A. Seroehkina and T. S. Safonova, Chem.Heterocycl.Compd. (Engl. Transl.), 1993, 29, 480. V. F. Sedova and O. P. Shkurko, Chem.Heterocycl.Compd. (Engl. Transl.), 1993, 29, 593. S. Sh. Shukurov, M. A. Kukaniev, V. M. Bobogaribov and S. S. Sabirov, Chem.Heterocycl.Compd. (Engl. Transl.), 1993, 29, 981. F. Gatta, M. R. Del Giudice, A. Boroni, P. A. Borea, S. Dionisotti and E. Ongini, Eur.J.Med. Chem., 1993, 28, 569. T. Itoh, K. Nagata, M. Okada and A. Ohsawa, Heterocycles, 1993, 35, 581. D. Randles, H. Taguchi and W. L. F. Armarego, Heterocycles, 1993, 35, 807. V. Kepe, M. Kocevar and S. Polanc, Heterocycles, 1993, 35, 955. H. Wamhoff and A. Schmidt, Heterocycles, 1993, 35, 1055. T. J. Delia, M. Baumann and A. Bunker, Heterocycles, 1993, 35, 1397.

266

93H(36)87 93H(36)1883 93HCA1980 93JCS(CC)840 93JCS(CC)1177 93JHC293 93JHC497 93JHC1221 93JHC1267 93]HC 1317 93JHC1341 93JOC6976 93MI1 93M12 93SC3195 93T5277 93TIA595 93ZN(B)1212 94AP533

94CPB806 94H(38)113 94JA391 94JCR(S)121

Six-Membered Ring Systems: Triazines F. Bruni, B. Cosimelli, A. Constanzo, G. Guerrini and S. Selleri, Heterocycles, 1993, 36, 87. E. C. Taylor, S. R. Otiv and I. Durucasu, Heterocycles, 1993, 36, 1883. F. Magirius, A. Linden and H. Heimgartner, Helv. Chim.Acta, 1993, 76, 1980. A. J. Blake, H. McNab, M. Morrow and H. Rataj, J. Chem.Soc. Chem. Commun., 1993, 840. R. T. Wheelhouse and M. F. G. Stevens, J. Chem.Soc. Chem. Commun., 1993, 1177. K. H. Lee, B. R. Huang, Y. L. Chen, D. C. Wei and C. C. Tzeng, J.Heterocycl.Chem., 1993, 30, 293. G. Kangars and W. Watt, J.Heterocycl.Chem., 1993, 30, 497. M. A. Mosselhi and W. Pfleidetgr, J.Heterocycl. Chem., 1993, 30, 1221. T. Kappr and P. Roschger, J.Heterocycl. Chem., 1993, 30, 1267. A. Piskala, J. Gut, P. Fiedler, M. Masojidkova, D. Saman and R. Liboska, J.Heterocyl. Chem., 1993, 30, 1317. B. K. Bhattacharya, T. S. Rao and A. F. Lewis, J.Heterocycl. Chem., 1993, 30, 1341. H. Wamhoff and A. Schmidt, J. Org. Chem., 1993, 58, 6976. T. Suyama, M. Kanai and M.Nakayama, Nippon Kagaku Kaishi, 1993, 952; Chem.Abstr., 1994, 120, 164125. M. Han, X. Sift, Z. Yang, M. Cai and T. Cheng, Chin. Chem. Left., 1993, 4, 771; Chem.Abstr., 1994, 120, 323505. P. Bourgeois, R. Cantegril, A. Ch6ne, J. Gelin, J. Mot'tier and J. Moyroud, Synth. Commun., 1993, 23, 3195. A. M. d'A. Rocha Gonsalves, T. M. V. D. Pinho e Melo and T. L. Gilchrist, Tetrahedron, 1993, 49, 5277. E. C. Taylor, W. B. Young and C. C. Ward, Tetrahedron Left., 1993, 34, 4595. R. Tripolt, F. Belaj and E. Nachbaur, Z.Naturforsch. (B), 1993, 48, 1212. H. Moehrle and M. Pycior, Arch.Pharm.(Weinheim, Ger.),1994, 8, 533. M. Sako, R. Totani, K. Hirota and Y. Maki, Chem.Pharm.Bull., 1994, 42, 806. A. Lorente, P. Gamez and M. del Mar Contreras, Heterocycles, 1994, 38, 113. E. C. Coad, P. G. Apen and P. G. Rasmussen, J.Am. Chem.Soc., 1994, 116, 391. L. C. Hwang, D. C. Wei, C. H. Han, K. H. Lee and C. C. Tzeng, J. Chem.Res. (S), 1994, 121.

Six-Membered Ring Systems: Triazines 94JCR(S)268 94JCS(CC)913 94JCS(CC)1687 94JCS(Pl)1089 94JCS(P2) 1657 94JHC81 94JHC319 94JHC357 94JHC375 94JHC535 94JOC3985 94JOC4950 94MC104

94MC122

94MI1 94SC2153 94SL165 94T6705 94T8085

94TI.207 94TL3155 94TIA563

267

S. Grivas and E. Ronne, J. Chem.Res. (S), 1994, 268. J. A. Linn, E. W. McLean and J. L. Kelley, J. Chem.Soc. Chem. Commun., 1994, 913. Y. Wang, M. F. G. Stevens and W. Thomson, J. Chem.Soc. Chem. Commun., 1994, 1687. R. V. Joshi, M. B. Ksebati, D. Kessel, T. H. Corbett, J. C. Dmch and J. Zemlicka, J. Chem.Soc.Perkin Tram. 1, 1994, 1089. S. Chimichi, B. Cosimelli, F. Bruni, S. Selleri, A. Costanzo, G. Guerrini and G. Valle, J. Chem.Soc.Perkin Trans.2, 1994, 1657. F. Gatta, M. R. Del Giudice, A. Borioni and C. Mustazza, J.Heterocycl. Chem., 1994, 31, 81. R. Mileent, G. Barbier, S. Capelle and J.-P. Catteau, J. tteterocycl. Chem., 1994, 31, 319. N. Hairier and C. Loll, J.Heterocycl. Chem., 1994, 31,357. M. D'Auria and A. Vantaggi, J.Heterocycl.Chem., 1994, 31, 375. G. B. Okide, J.Heterocycl. Chem., 1994, 31,535. H. Wamhoff, C. Bamberg, S. Herrmann and M. Nieger, J. Org. Chem., 1994, 59, 3985. D. L. Boger and M. J. Kochanny, J. Org. Chem., 1994, 59, 4950. Y. A. Azev, I. P. Loginova, O. L. Guselnikova, S. V. Shorshnev, V. L. Rusinov and O. N. Chupakhin, Mendeleev Commun., 1994, 104. A. M. Churakov, O. Yu. Smirnov, Y. A. Strelenko, S. L. Ioffe, V. A. Tartakovsky, Y. T. Struchkov, F. M. Dolgushin and A. I. Yanovsky, Mendeleev Commun., 1994, 122. S. Asano, K. Itano, Y. Yamagata and K. Kohda, Nucleosides Nucleotides, 1994, 13, 1453; Chem.Abstr., 1994, 121, 134076. R. Menieagli, C. Malanga and P. Peluso, Synth. Commun., 1994, 24, 2153. Y. A. Ibrahim, A. H. M. Elwahy and A. M. Samuel, Sulfur Lett., 1994, 17, 165. C. Peinador, M. J. Moreira and J. M. Quintella, Tetrahedron, 1994, 50, 6705. A. Pastor, R. Alajarin, J. J. Vaquero, J. Alvarez-Builla, M. Fau de Casa-Juana, C. Sunkel, J. G. Priego, I. Fonseca and J. SanzAparieo, Tetrahedron, 1994, 50, 8085. A. S. Kiselyov and L. Strekowski, Tetrahedron Lett., 1994, 35, 207. L.-L. Gundersen, Tetrahedron Lett., 1994, 35, 3155. M. Rahmouni, A. Derdour, J. P. Bazureau and J. Hamelin, Tetrahedron Lett., 1994, 35, 4563.

Chapter 6.4 Six-Membered Ring Systems: With 0 and/or S Atoms JOHN D. HEPWORTH and B. MARK HERON UniversRy of Central Lancashire, Preston, UK Introduction This year has seen the publication of major reviews on flavonoids (94MI1) and thio-, seleno- and telluro- pyrans (94AHC179) and their analogous pyrylium salts (94AHC65). Other reviews include those on avermectins and milbemycins (94OPP617), bicyclic compounds related to dehydroacetic acid and triacetic acid lactone (94H585), organoelement derivatives of pyran-2-one (94RCR661), the antimalarial qinghaousu (94ACR211) and reviews on naturally occuring dithiins (93RHC1). Applications of O-heterocyclic compounds include 2,4,6-triphenylpyrylium fluoroborate as an electron transfer photosensitiser (94CRV1063) and spirobenzopyran derivatives in photosensitive artificial membranes (94T4039). Information on pyrans, pyranones and their benzologues is included in two reviews of asymmetric hetero Diels-Alder reactions (94OPP129, 94S535), a survey of the value of o-hydroxyaryl ketones in organic synthesis (94OPP159) and a review of saturated oxygen heterocyeles (94COS23). As always this review is selective and cannot cover all the published material. In particular, this year the large amount of work on polyether antibiotics has been omitted. 6.4.1

6.4.1.1

HETEROCYCLES CONTAINING ONE OXYGEN ATOM

Pyrans

The occurrence of the six-membered cyclic ether unit in natural products ensures that the stereoselective synthesis of pyrans is an area of continued interest. Further examples of the synthesis of 3,4-dihydro-2H-pyrans by the hetero DielsAlder reaction have been reported. The reaction of methyl 2-oxobut-3-enoates with alkenes is catalysed by SnCI4 (94BCJ1912), whilst Eu(fod)3 assists the reaction of similar heterodienes with styrenes (94TL8619) and with vinyl ethers derived from chiral secondary alcohols (94T9037). 2-Oxo-l-sulfonyl-3-alkenes are new heterodienes which offer the advantage of useful manipulation of the sulfonyl moiety (94CL145) and the dienophile 3,4-epoxy-2-methyleneoxolane confers a similar asset on the spiro-linked adducts (94T8035). In all of the above examples good endo-selectivity is observed. This feature is apparent in the reaction of an oxazolidinone derived heterodiene with Z-l-acetoxy-2-ethoxyethene, 268

269

Six-Membered Ring @stems: With 0 and~or S Atoms

but with the additional bonus of facial differentiation control by variation of the Lewis acid catalyst (94SL509). Cyclic ketone acetals undergo fast eycloadditions with heterodienes under microwave irradiation to yield 2-spiro-linked 3,4-dihydropyrans (94JCS(P1)3595). Synthesis of the quassinoid system has been approached by a sequence of DielsAlder reactions in which successive eyeloadditions are made feasible by the previous pericyclic reaction, the so-c~ed diene-transmissive Diels-Alder strategy illustrated below (94JOC5596). B

m

H ,~

H

I~OEt ...._

~~,,,~ICO2Mo Yb(f~

"'~ ~CO2Me

H " H (~O2Mo

"'"OEt

Cyclisation of the Z-isomers of unsaturated 1,5-diols derived from 1,3-dichloropropene via the 1,3-dianion leads to 5,6-dihydropyrans (94T13269) and a carbanion is also involved in the formation of 3,4-dihydropyrans from acyloxysulfones, in which chirality in the original substituted pentan-3-ol is retained throughout the sequence (94JOC2014).

O

0~"-0 ~SO2Tol

~"L"~s'7. ~ ~.~SO,To, TsO~~SO~Tol ~' N.,O J ....O ~OH ' ~ ~ bz . ~ ....O ~ ' ~ ' O

A 6-exo cyclisation of vinyl radicals derived from bromopropenyl ethers through Sm mediation leads to 5,6-dihydropyrans (94TL8445) and V,8-unsaturated ketones undergo a fast halocyclisation on treatment with NBS to give 3,5-dibromo-3,4-dihydropyrans (94TL2619).

Br~I

~SiMe3 f Sml2 =

SiMe3

SiMe3

The intramolecular silyl-modified Sakurai reaction has been used to synthesise a subunit of the antibiotic ambrucitine. The vinylsilane (1) reacts with aldehydes or their acetals in the presence of TMSOTf to give the dihydropyran moiety (94T7141).

Me3Si ~ ~ M e + (l)

RCHO

0.2eq.Me3SiOTf ~ O ~ CH2C12,-78to20~ R Me

270

Six-Membered Ring Systems: With 0 and~or S Atoms

The kinetic resolution of racemic dihydropyrans can be achieved by a Zr-catalysed carbomagnesiation procedure (94JA3123) which can conveniently be linked to a Ru-catalysed synthesis of the pyran substrates (93JA9856). ~

,

(i) Ru-eatalyst (ii) EtMgCI, Zr-catalyst THF, 25 to 70 ~

~t 99%ee (60%)

The value of 6,6'-bi-dihydropyrans in regio- and stereo-selective processes has been extended (94TL769, 773,777, 94TA553, 94S1275). The cobalt carbonyl complexes of 4,5-epoxyhept-6-yn-1-ols undergo a 6-endo ring closure on treatment with a Lewis acid. The reaction is both regio- and stereo-selective and leads to 2-ethynyl-3-hydroxytetrahydropyran derivatives in which the configuration at the propynyl stereogenic centre is retained (94TL2179). However, if prior reaction with Co2(CO)8 is omitted and the terminal substituent is electron releasing, inversion of configuration at this centre is observed (94TL2183).

,co

R~,""

(i) BF3.Et20 = O

"~01

R~--"

(i) Co2(C0)a

HO.,J

(ii) BF3.Et2(3

H H O ~ _,~

fl

Co2(CO)6

The terminal substituent on the allylic chiral acetal (2) also exerts some control on the Lewis acid catalysexl cyclisation to the tetrahydropyran (94CC1953). H ::

O

R3M

O~~,,J~O~

"

TIC]4'

OH

PPh3 ~-~

H +

, , , ~ , V . OH

(2) (B) R3M=SnBu 3 A :B 93:7 R3M = SiMe,3 A : B 37 : 63

Concomitant cyclisation and bromination are achieved during the anodic oxidation of unsaturated a-stannyl ethers in a tetrabutylammonium perchlorate dibromomethane electrolyte (94CC2361).

271

Six-Membered Ring Systems: With 0 and~or S Atoms

Dr

H

oAso: ii c.

au4NCIO4 -e (0.75mF)

C

H

H

Formation of tetrahydropyrans by acid mediated cyclisation of methyl 2-acetoxy(2-alkenoxy)acetates proceeds via the highly electrophilic a-ester oxycarbenium ion. The acid catalyst influences the stereochemistry of the product, SnCI4 favouring the 2,4-trans substituted heterocycle, but formic acid leading to the corresponding cis-compounds. A 2-oxonia Cope rearrangement is involved in the reaction in which stereochemical integrity is preserved (94T7115, 7129).

Cl R2

-

Rl

SnCI4

R3/~o~CO2Me OAe

R2-

~

R3

RI CO2Me

~ R~~ ~~Io2Me

Pyrans result from the intramolecular capture of radicals derived from I]-alkoxyacrylates. The 3-hydroxy function in the product allows a reiterative approach, providing a route to fused bipyrans (94TL129).

,us

o.

H

CO2Et AIBN k~O,,,,~jCO2E t

H

~O ...t~~...,,~CO2E t Iq H

The bis-spiroacetal (3) arises by cyclisation of the lactol derived from 8-valerolactone and the 6-(3-phenylsulfonylpropyl)dihydropyran (94JCS(P1)497).

(i) BuLi,

,">"" "~ "2~

~ S O 2 P h

(iii) RaneyNi

~

O / (3)

6.4.1.2

Chromenes

The synthesis of chromenes through the reaction of phenols with a,13-unsaturated aldehydes has been modified in a variety of ways to improve the value of the route. In the presence of phenylboronic acid, a 1,3,2-benzodioxaborin is formed in high yield which on heating yields the chromene via an o-quinone methide. The robustadial framework has been assembled in this manner (94CJC1866). Hetero-fused derivatives of chromenes result from the reaction of Ti(IV) phenoxides with 3-phenylcinnamaldehyde (94JCS(P1)2591) and the 1,2-addition

Six-Membered Ring Systems: With 0 and/or S Atoms

272

of protected 2,4-dihydroxyphenyl lithium compounds to 3-methylbut-2-enal, citral and famesal yields chromenes (94H759). Reactions of the 3,4-double bond include epoxidation with NaOCI or PhlO in the presence of Mn-salen catalyst (94Tl1827). The 1,3-dipolar addition of diazoalkanes with 3-nitroflavenes yields a pyrazoline at 0 - 5 ~ but a pyrazole at 30- 35 ~ by elimination of HNO2 (94T4623). Cleavage of the O-C2 bond occurs on Birch reduction of 2,2-dimethylchromenes giving mainly 2-(1,3-dimethylbut-2-enyl)phenol (94H991), whilst the cathodic reduction of 3-bromochromenes provides a useful route to o-allenylphenols (94CC1177). Allenes are also formed when 2-substituted 3-bromochromenes are treated with butyllithium (94JCS(P1) 1733). The corresponding 4-bromo compounds behave normally towards butyUithium, providing access to a variety of 4-substituted chromenes (94T2507), a procedure used in a facile synthesis of the rotenoid system (94JCS(Pl)653).

H

H

R:~N~ [~C

R3%~,,~ g

~OAc

~.Br

Ae20

R~~ i

R~ (ii) E+ - ~'~J~"OE

(iii)H20

~

~,IOMe

Br ( i ~

(i),(ii) Rn R2

H O

e (iii),(iv) OMe R9-

X=OorS Reagents:(i) BuLi,0 ~ (ii)2,4-dimethoxybenzonitrile,(iii)BCI3,-10~ (iv)NaOAe,EtOH,A. 6.4.1.3

Chromans

o-Quinone methides feature in a number of chroman syntheses. A range of complex polycyclic chromans have been obtained from tricyclic benzodioxaborins, trapping the methide with allylsilanes or ethyl vinyl ether (94TL3691).

OEt

Ph tIsiMea R I (i) L I/" O"u'O R""~ 0"~

fOEt A

~

(ii)TFA

Six-Membered Ring Systems: With 0 and/or S Atoms

273

A variety of monoterpenes take part in a hetero Diels-Alder reaction with the oxabutadiene derivative formed from 1,3-cyclohexanedione and formaldehyde, giving polyketide terpene frameworks by a one-pot regio-, chemo- and stereoselective reaction. Amongst the products accessible by this route is the oxapropellane (4) (94H661). O

(4) The o-quinone methide derived from 4-hydroxypyrid-2-one and citronellal undergoes an intramolecular Diels-Alder reaction to give the chroman (5) structurally related to the free radical scavenger pyridoxatin and the antiinsectan Leporin A (94TL531). OH

m

u

H i~i

pipefidine, py

+

EtOH,A

O~~"

""Me

"o

"Me

I

I H

""Me

H (5)

The cyclisation of aryl ethers is a well established route to chromans and several variations on this theme have been reported. Prenylphenols result from the Pd-catalysed coupling of iodophenols with 2-methylbut-3-yn-2-ol, reduction of the alkynic function and dehydration. The intermediate hydroxyalkylphenols can also be dehydrated to the chroman (94H1487).

The Cr(II) promoted cyclisation of (2-iodophenyl) alkynyl ethers catalysed by Ni(II) involves activation of the C-I bond and leads to the exo-methylene chroman (94TL 1601).

CrCl2, NiCl2 O/

DMF,25 ~

_~

274

Six-Membered Ring Systems: With 0 and/or S Atoms

An intramolecular oxymercuration is used to control the stereochemistry at C-6 in the formation of some cannabinol analogues (94T2671). HO

OH

OR ~

OR

,

'"

(i) Hg(OAc)2,THF,0 ~ ~ (ii) NaBH4,NaOH : HllC5

HIIC5

e _ ?H

Directed lithiation of chroman-4-ols enables the synthesis of 5-substituted benzopyran derivatives to be achieved and the related preferential lithiation of a 5-methyl group provides a route to the naturally occurring 1,4-dioxaphenalene system (94JCS(P1) 1925). Propargyl ethers (6) undergo an intramolecular Diels-Alder reaction, the adducts (7) readily losing the bridging oxygen atom to give isochromanols (8) (94H1507). Me TsOH ~

KOtBu, BuOH A =

R

I

M

II

e

I

OH (6)

(7)

(8)

Isochromans result from the intramolecular C-H insertion reactions of contributing singlet and triplet states of 2-(alkoxymethyl)phenylcarbenes (94TL1699). The cyclisation of both the 2-aUyl and the 2-prop-l'-enyl substituted 3-(1-hydroxyethyl)naphthalene derivatives (9), (10) leads stereoselectively to the trans-naphtho[2,3-c]pyrans (11), the heterocyclic moiety of some aphid pigments (94JCS(P1)859). The alkylation of 2-acetylnaphtho1,4-quinones also affords the linear naphthopyran system (94SC2563). OR

R (9)

Me

KOtBu~ DMF, " N z ~'

OR

OR~Me ~ I,. t"-~~"'~ ~--~"~O

R

Me

R (10)

R (11) Naphthyldioxolanr derivatives (12) undergo a stereoselectivc isomerisation to the angular naphtho[1,2-c]pyran under Mukaiyama conditions. The stcreochcmistry at the 4- and 5- positions of the dioxolane unit controls that at C-3 and C-4 of the isochroman product (94JCS(P1)865).

275

Six-Membered Ring Systems: With 0 and/or S Atoms

OPri ~ ' i\

OPtl

~

Ti(OPrl)4

-

"

Me~1"~oi ""Me

(12) 6.4.1.4

Pyranones

The enamino diester (13) reacts with 1,3-dicarbonyl compounds under acidic conditions to give substituted pyran-2-ones (94H1705). Me

0 AcOH ~---OCH3 O (13)

Ph/

A synthesis of the plant based amino acid stizolobic acid features an Fe(III)catalysed cleavage of the acid (14) and subsequent rearangement of the resulting butenolide to desaminostizolobic acid (94TL6575).

HO

CO2H

e c. HCI

Fe (III) _ HO" T OMe

AcOOH, AcOi-I -~CO2H O

-.(

~CO2H

110212

(14)

Substituted pyran-2-ones can be conveniently obtained from saturated alcohols by a free radical carbonylation / oxidation process initiated by lead tetraacetate (94JA5473). The cyclisation of 1,3,5-triketones by PPh3 in CC14 has been used to synthesise the two pyran-2-one halves of the marine metabolite onchitriol (94TL9581). The versatility of 5-methylene-4-tosyl-3,4,5,6-tetrahydropyran-2-one, derived from the reaction of ten-butyl bromoacetate with dilithiated 2-(tosylmethyl)-2propen-l-ol and subsequent cyclisation of the &hydroxyester with trifluoroacetic acid, is illustrated by its reaction with nucleophiles and acid catalysed remyangement (94T6603) Nu

s

o

Ts

,../-y, ~t:o

"Is

aqN.~Ac~o~.oJ

Ts

o~.oJ

Ts

276

Six-Membered Ring @stems: With 0 and/or S Atoms

2-Amino derivatives of pyran-4-one are available from arylpropiolate esters by reaction with the lithium enolate of N-acetylmorpholine and cyclisation of the resulting acetylenic [3-ketoamides (94S43).

O Ar

0

OLi 0

ill

_I-i ~

,

L.o

A review of the chemistry of a-oxoketenes includes examples of pyranone and dioxinone ring construction (94S1219). A highly substituted pyran-4-one is formed by the tetramerisation of phenylketene generated by the cathodic reduction of 2-chloro-2-phenylacetyl chloride at low current density (94H1339).

0 Ph\cHCOCI el /

e', Et4N+(~ CH2C12

Ph

Ph

PhCH=C=O] OCOCH2Ph Ph

Equally specialised is the trapping of the vinyl ketene (15) derived by photolysis of the cyclobutenone with siloxydienes (94PJC2429).

OMe o

Ph

CI

o

~C~ CI

hx~ ~

el

Me3SiO CI

"%

o

CI

(15)

Chiral boron complexes derived from tartaric acid derivatives and from i]-aminoalcohols act as mild Lewis acids and asynnnetric catalysts for the reaction of aldehydes (94T979) and methyl glyoxalate (94CC1563) with Danishefsky dienes. The resulting 2,3-dihydropyran-4-ones are obtained in high optical purity.

OMe Rl

~

O R l ~

O v

+ tt ~ R 2

Me3Si

RI

I L--OL~-- ",,R2

RI Aluminium bis(2,6-diphenylphenoxide) behaves not only as a Lewis acid catalyst but also complexes selectively with the less hindered of two aldehydes thereby offering a ehemoselective hetero Diels-Alder reaction (94SIA39).

Six-Membered Ring Systems: With 0 and/or S Atoms 6.4.1.5

277

Coumarins

The Pd-catalysed cyclisation of o-halogenophenyl esters is a feature of several coumarin syntheses. Thus, o-iodophenyl 3-butenoate affords 4-methylcoumarin on treatment with Pd(PPh3)4 and CO (94TL5919), whilst the same system containing added phenylacetylene yields a 3,4-disubstituted coumarin as a result of initial incorI~ration of a 2-(3-phenylethynoyl) unit (94TL5923). More complex examples include this mode of cyclisation in a total synthesis of gilvocarcins (94JA1004) and of racemic dinaphtho[2,1-b:l',2'-d]pyran-4-one (94LA91). Several naturally occurring 6-substituted and 3,6-disubstituted coumarins have been obtained by regioselective Claisen rearrangements and tandem Claisen-Cope rearrangements (94JCS(P1)3095, 3101). 4-Hydroxycoumarin and formaldehyde are a source of the o-quinone methide, 3-methylenechroman-2,4-dione, a good Diels-Alder substrate which yields pyrano[3,2-c]coumarins regio- and chemo- selectively with unsymmetrically substituted alkenes (94JOC5556). The intramolecular [2+2]-cycloaddition of both 4- and 5- allenyloxycoumarin occurs with excellent diastereoselectivity, the asymmetric induction being controlled by the allene moiety, and leads to aUylidenecyclobutanes and an alkynyl oxepane, respectively. The latter has potential for the synthesis of the naturally occuning ellagitannins (94JA6622).

~

oi',...

C,~',.. 'C ~ C ~ C " But

h~

I H "O"

Bu t

o 2

"-O

H 9 0/%-

Ph

Bu t C~H~I

h9

Bu t

=

Ph

Pd-catalysed cyclisations also feature in the synthesis of isocoumarins. Outstanding in this context is the cascade carbopalladation in which the pentacyclic compound (17) is formed in 66 % yield from the acyclic precursor (16). The range of examples given enable the course of reactions involving competing Pd-catalysed processes to be predicted (94JA7923).

278

Six-Membered Ring Systems: With 0 and/or S Atoms

~//,.OH

CO,Pd(PPh3)2CI2 Bu

MeO 2

Me02C" [ [

I ~

(O,~O

NEt3,MeOH =

~ ~

~ ~ # ~

Me02C~~~~ Me02C/ [ ~ ~

(16)

Bu

''~'~

(17)

In the Pd-catalysed reaction of 2-(1-alkenyl)benzoic acids with vinylic halides, competitive formation of dihydroisocoumarins and a phthalide is observed. Production of the latter is eliminated when unhindered cis-l.iodo-l-alkenes, 1-bromo-l-alkenes and more substituted vinylic halides or triflates are used (94SL748).

~ H

+CHRcHxI ~

~,~R+ ~ O

C H 2 R O

2-Styrylbenzoic acids afford 3-phenylisocoumarins by an intramolecular selenolactonisation. Occasionally, loss of the phenylseleno group is not spontaneous and the dihydroisocoumarin results (94JHC145). SePh

NSePh

~

CH=CHPh

R/"~

Ph

Ph

"CO2H

O

O

Dihydroisocoumarins are conveniently obtained from the reaction of aldehydes and ketones with the dianions derived from o-toluic acids, though the products are not always stereochemically pure (94SC779). However, enantiomerically pure dihydroisocoumarins result from the stereoselective reduction of (arene)tricarbonylchromium complexes of homobenzylic ketones by DIBALH, followed by oxidation of the resulting lactols (94CC501).

O

O

DIBALH _

O

.O

R

HCI

R Or(CO)3

O

Six-Membered Ring Systems: With 0 and/or S Atoms

279

The Lewis acid catalysed cyclisation of 4-aroyl-3-methylallyltetrahydropyran-2-ones is stereoselective, giving the trans-fused lactones, which may be partially oxidised according to the nature of the catalyst (94T8445).

HO

Ar ?

Ar HO 7 H

Ar H

H

9

TiCI 4

o

-

Me,, o

0

Mo

0 6.4.1.6

0

"~O Irl II O

Chromones

Fluoroalkyl chromone derivatives can be obtained from the base catalysed reaction between 2,2-dihydropolyfluoroalkanoates and phenols. Initial loss of HF allows Michael addition of the phenol and subsequent cyclisation of the enol ether yields the heterocycle, m-Substituted phenols give the expected mixture of 5- and 7-substituted chromones, whilst dihydroxy aromatic compounds give polycyclic materials (94JFC263). In a more conventional approach Z-3-(aryloxy)polyfluoroalkenoic acids, derived from Michael addition of phenols to polyfluoro2-alkynoic acids, undergo intramolecular Friedel-Crafts acylation to 2-polyfluoroalkylchromones (94JFC25).

O RtCF2CH2CO2Et

Et3N

AtOH

RfC=CHCO2Et PPA "1 OAr 170~

Whereas salicylacetamides cyclise to 4-hydroxycoumarin under either aqueous acidic or basic conditions, trifluoromethanesulfonic anhydride behaves as a neutral dehydrating agent and yields 2-aminochromone derivatives (94SC849).

O R ~~~~J[~

O

O NR2

Tf20 RT

--

R

NR2 A combination of isoxazole and organotin methodologies is utilised in syntheses of flavones and pyrano[3,2-g]chromene-4,6-diones. Cyclisation of the 4,6-bisisoxazolylresorcinol derivative occurs following reductivr isoxazole ring cleavage (94ACS61, 165).

280

Six-Membered Ring Systems: With 0 and~or S Atoms Ar

Ar

~r

a';Oila B:3sn

=

HO"

~

"OH |

(i) H 2, Raney Ni ] (ii) HCI, AeOH O

1

O

Suitably 3-substituted chromones take part in cycloaddition reactions. 3-Acyl derivatives react with 1-alkoxyalkenes in an endo-selecftve fashion to form pyrano[4,3-b][1]benzopyran-10-one derivatives from which a range of chromones and chromanones can be obtained (94T11755). The cycloaddition of 1,3-butadienes to 3-alkoxycarbonylchromones shows high diastereofacial selectivity in the presence of ZnCI2 at room temperature (94H1483). O

~2 ~,

O

~ x

O

%1ZyOR N , ~

O

X

R| H

H

X = OR

Z bR

X = H, Me, OH

2-Methylchromone-3-carbaldehyde N,N-dimethylhydrazone gives the endo-adduct with N-phenylmaleimide from which xanthone derivatives result on treatment with palladised charcoal (94T4905). 3-(2-Bromoaryloxy)propanonitriles yield chroman-4-ones through a Parham cycloacylation and in a similar manner diphenyl ethers afford xanthone derivatives (94JCR(S)82).

. Br rCN oj

O (i) BuLi,- 100 ~

(~) 2o ~ (iii) aq. NH4CI

Six-Membered Ring Systems: With 0 and~or S Atoms

281

Irradiation of a mixture of O-allylsalicyloyl chloride and triethylamine in acetonitrile generates aeyl radicals which undergo intramolecular cyelisation to 3-methylchroman-4-one (94JCS(P2)1545). O

O C!

NEt3, M.e,CN

:

h~)

The stereochemistry of 3-arylidenechromanones influences the course of their reaction with dimethyldioxirane. The E-isomer yields the trans-spirooxirane and the Z-isomer the cis-epoxide (94LA795). However, the 2-phenyl analogues, 3-arylideneflavanones, show greater dependence ola the stereochemistry, only the E-isomer affording an oxirane, the Z-isomer giving a mixture containing 3-aroyl -flavones and -flavanones as a consequence of steric hindrance to oxygen atom transfer (94JOC900). A change in the stereochemistry of 2,2-dimethylchroman-4-one oximes in the reaction medium accounts for the preferential alkyl migration and formation of 1,4-benzoxazepin-4(5H)-ones rather than the expected 1,5-isomer during a Beckmann rearrangement. A 5-substituent in the ehromanone prevents such a change and the 1,5-benzoxazepine derivatives are then obtained by aryl migration (94H305). R

6.4.1.7

H

N

,,OH

HO..

N

O

Flavonoids

Interest in the application of organolead compounds to flavonoids continues, with the synthesis using tin-lead exchange of the protected 8-triacetoxyplumbylflavanone derivative (18) and its use to arylate an allyl benzofuran carboxylate (94JCS(P1)1791). The synthesis of a biflavonoid of the Garcinia species has been accomplished using this methodology and a 3-phenylsulfonyl group to activate the flavanone towards plumbylation so forming the C-3 - C-8" interflavonoid bond (94JCS(P1) 1797). MeO

O

O

MeO Pb(OAe)3

(~8)

~ O M o

282

Six-Membered Ring Systems: With 0 and/or S Atoms

Flavonols can be made in a one-pot reaction carried out in aqueous alkaline conditions. Condensation of an aromatic aldehyde with an aryl methyl ketone is followed by oxidation with H202 and acidification (94T11499). Flavones are hydroxylated at the 3-position by iodobenzene diacetate (94IJC272). o

o ,

MeO

(i),(ii)

ff y

y

+

(iii) M e O ~ o ~ O ~ I..~. I.&_ / Reagents: (i) 5 M KOH, (ii) 35 % H202, 80 ~ (iii) dil. HCl ~ -~O

The absolute configurations of flavan-3-ols and their 4-aryl derivatives can be defined using the ester technique of Dale and Mosher and this should allow the stereochemistry in more complex flavonoids to be established (94T12477).

6.4.1.8

Xanthones

Sodium trimethylsilanethiolate, Me3SiSNa, effectively demethylates aromatic methyl ethers and has been used to cyclise 2,2'-dimethoxybenzophenones to xanthone (94TL3545). Total syntheses of the xanthone antibiotics cervinomycin A1 and A2 involve base catalysed cyclisation of an appropriately substituted 2,2'-dimethoxybenzophenone (94T11729). Application of the Skraup reaction to the four aminoxanthones has led to a range of benzopyranoquinoline derivatives. In the case of the 2- and 3- amino compounds, only the angular tetracycle is formed (94H541).

6.4.1.9

Pyrylium Salts

A reliable one step synthesis of 4-aryl-2,6-diphenylpyrylium salts involves heating benzaldehydes with acetophenone in the presence of either sulfuric or perchloric acid (94OPP101). 2-Amino-3-aroyl-diarylpyrylium salts result from the cyclisation of 8-ketonitriles derived from the Michael addition of aroylacetonitriles to chalcones (94JPR623). The ring opening reactions of pyrylium salts has been extended to include aldehydes as carbon nucleophiles; the product of this base-catalysed sequence is a 2,4,5-triarylbenzophenone (94JPR303). One electron transfer reactions of pyrylium cations and some related systems have been reviewed (94H 1165). A single electron transfer is thought to be involved in the photochemical conversion of the diphenylcyclopropane (19) into the xanthylium salt (20) in the presence of an arene donor such as naphthalene (94CC1681). Ph h't)

, B"HO

naphthalene O ~' (19)

Six-Membered Ring @stems: With 0 and/or S Atoms 6.4.2

283

HETEROCYCLES CONTAINING ONE SULFUR ATOM

6.4.2.1

Thiopyrans and analogues

The high yielding hetero Diels-Alder reaction of thiochalcone, 1,3-diphenylthiabutadiene, with chiral dienophiles shows good endo selectivity especially in the presence of Lewis acids, but the chiral induction is quite variable although chromatographic separation of the diastereoisomers is feasible (94JCS(P1)1359). Enaminothiones, prepared from acetophenones by Vilsmeier methodology, give substituted 2H-thiopyrans on reaction with various dienophiles as a consequence of elimination of dimethylamine (94JPR434). 3-Thioacetyindoles behave in a similar manner and yield thiopyrano[4,3-b]indoles (94H725). 3-Aryl-2cyanothioacrylamides form 4-aryl-4H-thiopyrans on treatment with activated alkynes (94JCS(P1)989). R2

:

//" + Ar

R1

Rt

R

R2

A

RI

bz

s ,~ R3-~

Ar

oyoR NRIR2

toluene

.

NC RIR2N" " S "

CO2R "X

A general synthesis of heterofused 2H-thiopyrans involves the cycloaddition of activated alkenes possessing a good leaving group with heteroaromatic thioketones. The products are themselves dienes with the potential for further elaboration (94S727). Br RO2C~

Br X

X + ~ ~" ~[17

~'

bzA

-~ It

~

CO2R CO2R

k~

.S

-HBr : X

S R

R

R

1,2-Dithiolium salts are cleaved at the S-S bond on treatment with cyclopentadienides and an intramolecular Diels-Alder reaction follows leading to the fairly unstable tricyclic thiopyran (94TL3893).

Six-Membered Ring Systems: With 0 and~or S Atoms

284 R2

Rl

S.[ RI

S+

RI

_._

_R 3

I

/ f f " ~ ~ , * * R2 R3~~S" "Rl

R

The directed metallation of diarylsulfone 2-carboxamides leads to thioxanthone dioxides providing a facile route to this otherwise difficultly accessible system (94JOC6508).

O ~CONEt2

LDA,THF

R--

o~

A general route to isothiochromans involves the reaction of a-thiocarbonyl compounds with 1,2-di(bromomethyl)benzene derivatives (94S363).

OMe

OMe Br

+

, , O HS

Br

OR

NaOR II

~

O

,

OR CH2CI2, MeOH RT, 2h

OMe

OMe

3-Benzoylisothiochromene is oxidised by trityl fluoroborate to the reactive 2-benzothiopyrylium salt (21) which reacts with active methylene compounds even in the absence of base to give the 1-substituted isothioehromene. However, the thiopyrylium salt undergoes a cycloaddition reaction with some conjugated dienes forming thioniaphenanthrenes (22). With nucleophiles, these S-bridgehead tricycles yield 1-allylisothioehromenes (94JCS(P1)3129).

COPh

COPh ~s+ (21)

~

R2

~ C O P h Nu S

Nu 2

( ] ~ ~ _ S + 'COPh

(cOMe)2 ~ C O P h

CH(COMe)2

Six-Membered Ring Systems: With 0 and/or S Atoms

285

Triarylthiopyrylium salts are converted into 2,4,5-triarylthiobenzophenones on reaction with arylacetaldehydes, extending the synthetic utility of pyrylium salts and their sulfur analogues (94S252). 5,6-Polymethylene derivatives of selenopyrylium salts are formed when the related 1,5-diketones are treated with zinc selenide in methanolic HCI (94CHE503).

~ O

~ Ph

ZnSe,HCI MeOH CONTAINING

HETEROCYCLES OXYGEN ATOMS

6.4.3

6.4.3.1

Ph TWO

OR

MORE

Dioxins

Interest in the stereoselective synthesis and the reactions of dioxane derivatives continues. All four stereoisomers of 4-dimethylaminomethyl-2-phenyl-l,3dioxane have been obtained from (S)-(-)-malic acid (94LA1273). The lithium enolate derived from 2-tert-butyl-6-trifluoromethyl-l,3-dioxan-4-one is a source of trans, trans-2,5,6-trisubstituted dioxanes and of 2,6-disubstituted dioxinones. The latter undergo a diastereoselective Michael addition with organocuprates and related species. The various products are precursors of enantiomerically pure trifluoromethyl derivatives of 3-hydroxypropionie acid (94CB565). The reaction of the enolate of the dioxanone with aldehydes gives aldol products lacking the tert-butyl group as a result of reaction of the initial Li aldolate with a second molecule of aldehyde and a subsequent cyclisation - ring opening sequence involving expulsion of pivaldehyde (93CB2739).

But OA.O ~/J~C O

O (i)tBuLi,-78~ (ii)2RCHO F3

(iii) aq. NH4CI

,-

0 ~ I~ R

O

OH CF3 R

Organocuprates add exclusively to the top face of 2-tert-butyl-2,6-dimethyl-1,3dioxin-4-one, but the facial selectivity is reversed in photochemical additions (94JA3312). 0

o

: 1~O~ . BuMt (Bu)2CuL i Bu . ~ ~ ~ .O e

i

~I

i'~O~'Me

o

h~ Me

Me"

0

Me

,But

Detailed nmr studies of 1,3-dioxanes, 1,3-oxathianes, 1,3-dithianes and 1,3,2dioxathianes indicate that the equatorial C5-H bond is weaker and longer than the corresponding axial bond. This feature is attributed to a homoanomeric effect between the l - o x y g e n atom and the equatorial bond (94JA5796, 94JCS(P2)1151).

286

Six-Membered Ring Systems: With 0 and/or S Atoms

(R)-2-Vinyl-l,4-benzodioxane is formed in moderate enantiomeric excess from catechol and Z-but-2-en-l,4-diylbis(methylcarbonate) using a Pd (0) catalyst in the presence of (R,R)-BINAP (94TL6093). The benzologue is similarly obtained from 2,3-dihydroxynaphthalene, which also reacts with 1,2-diiodo aromatic compounds under UUmann conditions to yield annulated 1,4-dioxins (94TL1769). The self condensation of 1-bromo-2-naphthol under basic conditions leads to a dinaphthyl ether which affords 1,4-dinaphthodioxin through a radical ipsosubstitution process (94JCS(P2) 1291). 3,5-Di-tert-butyl-o-benzoqtfmone behaves as a heterodiene in reactions with acylic dienes giving rise to 1,4-benzodioxines (23) (94CC1341). A facile method for the preparation of the pure enantiomers of some 7-hydroxy-2-substituted 2,3-dihydro-l,4-benzodioxins involves resolution of the (R)-(-)-pantolactone derivatives of the 2-carboxylic acid (94TA535). OAc

H toluene, 120 ~

+

sealed tube But

OAc

y

. O f ~ .... But

"OAe (23)

A chiral synthesis of 2,8-disubstituted 1,4,7,10-tetraoxaspiro[5,5]undecane starting from (S)-glycidol and (S)-isopropylideneglycerol and an nmr study of their conformation have been reported (94JCS(P2)1299, 94JOC1907). Macrocycles have been constructed incorporating the 1,3,5,7-tetraoxadecalin moiety and a theoretical study of the condensed dioxane system has been made (94CC1611, 94T9707). 6.4.3.2

Trioxins

Hemiperoxyacetals derived from allylic hydroperoxides yield 6-substituted 1,2,4-trioxanes on sequential treatment with Hg(O2CCF3)2 and NaBH4 (94TL8057). Ph

o M

OX OX X = H, CONHPh, Ae

R ~.

OH O

c.o Hg(O2CCF3)2 NaBH4

O

o

Ph "OX

In a new approach to the artemisinin system, a Lewis acid catalysed Diels-Alder reaction between 6-methylcyclohex-2-enone and hexa-3,5-dien-l-ol yields the hemi-acetal (24) which can be manipulated into the desdimethylartemisinin (94JOC4743).

287

Six-Membered Ring Systems: With 0 and/or S Atoms

H

Mo ~

"

. O

~

Me' O,

e (24)

0

The reaction of artemisinin derivatives with acids (HCI or S iO2) is complex and leads to a variety of products arising from intial opening of the trioxane ring (94H 1497, 94JCS(P1)843). 6.4.4

HETEROCYCLES

SULFUR

CONTAINING

TWO

OR

MORE

ATOMS

6.4.4.1

Dithiins

1,2-Dithiins and some 3-substituted derivatives are obtained from the 1,4-bisaddition of alkylthiols to substituted 1,3-butadiynes and subsequent removal of the thiol protecting group and oxidation of the resulting dithioenolates with iodine (94SL201). This latter oxidative cyclisation is also employed as the final step in the total synthesis of the naturally occurring 8 n-electron antiaromatic 3-(3-buten-l-ynyl)-6-(1,3-pentadiynyl)-l,2-dithiin, thiarubrine B (94JA9403). Rl

II II

(i) Li, NH 3, THF, R2SH

~

KOH, DMF

R1

:

~ R

~SR 2 R2S/

1

~

_-- R !

(ii) 12, KI

~r162 \~....R ! \ / S----S

Rl

The dianions derived from polycyclic hydrocarbons react with $8 to give fused dithiins, though usually contaminated with dithioles or thiophenes (94HA113). Disulfur is trapped by dienes when it is generated by heating alkene adducts of triphenylmethanethiosulfenyl chloride leading to the cyclic tetrasulfide (25). This product is quantitatively converted to the dithiin on treatment with triphenylphosphine (94TL7167).

"'"CI

PPh3

(25)

Interest in the 1,3-dithiane system continues, with an improved procedure for the preparation of the parent compound (94OPP377) and the preparation of new 2-substituted derivatives (94SL547). The carbanion derived from 2-trimethylsilane-l,3-dithiane is bisalkylated by chiral epoxides in the presence of

288

Six-Membered Ring Systems: With 0 and/or S Atoms

a crown ether. Removal of the dithioacetal moiety leads to stereochemically pure 1,5-diols, whilst further elaboration affords the 3-oxo derivatives and 1,3,5-triols (94SL511). However, most attention is focussed on the applications of 1,3-dithiane 1-oxides to asymmetric synthesis. Examples include the formation of ot-aminoketones (94TL2427) and the synthesis of (R)-(-)-2,6-dimethylheptanoic acid (94TL2607). Oxidation of 1,3-dithiane has been investigated and optimum conditions determined for the preparation of trans-l,3-dithiane 1,3-dioxide (94JCS(P1)2363) which is of value as a chiral acyl anion equivalent (94CC1653).

R OH

R

R

OH

R

R

SvS

03

R

O,,.SvS.~o

Reagents:(i) MsCI,py, (ii) Na2S, S, DMF,0ii) LiAIH4, Et20, (iv) (MeO)2CH2,BF3.Et20 Reaction of the carbanion derived from 1,3-dithiane 1,1-dioxide with aromatic nitro compounds results in oxidative nucleophilic substitution of hydrogen rather !hart SNAr displacement of even halogen (94T4913).

F ~ N O 2 SvSO2

xx)..,-SO2

DMF

1,4-Dithiins are formed by the thermolysis of ot-alkylthio derivatives of N-aziridinylimines. Carbene and S-ylides are proposed intermediates. The route can be adapted to produce 1,4-oxathiins (94H1971). 1,4-Dithiins act as alkene precursors, the desulfurisation being both fast and stereospecific as illustrated by a synthesis of muscalure, Z-9-tricosene, in 69% yield from decanal (94T7265).

S/r R~"~H

BuLi,THF,-78 ~ Rtl, 0~

"

S/r

RaneyNi

R~-~R

Ac~)H'RT " R / ~ R '

Ring expansion of acenaphthene ethylenedithioacetal and dehyrogenation of the resulting 1,2-ethylenedithio compound leads to 7,10-dithiafluoranthene, a good It-donor (94TL7051).

s/- s ,. (i) TeCI4,CH2CI2 (ii) DDQ, dioxane

289

Six-Membered Ring Systems: With 0 and/or S Atoms

Further work has been reported on the structural and conformational details of 1,3- and 1,4-dithianes and their oxidised analogues (94CJC1722, 94JCS(P2)1439, 94JCS(P2)2329, 94T10107). 6.4.5

HETEROCYCLES CONTAINING BOTH OXYGEN AND

SULFUR IN THE SAME RING 6.4.5.1.

Oxathiins

o-Thioquinones are generated on heating the 2-phthalimidosulfenyl derivatives of phenols and are trapped by ethyl vinyl ether in a regioselective inverse demand Diels-Alder reaction. However, with dienes, the o-thioquinone behaves as the dienophile and forms a spiro-linked thiopyran (94TL9451). OR R ~ O ~ O R

SNPhth

l

S

S

The acid catalysed cyclisation of 2-(2-hydroxyphenylthio)-2-phenylethanol gives 2-phenyl-l,4-benzoxathiane and not the expected 3-phenyl isomer. The rearrangement is considered to proceed via an episulfonium ion. 3-Aryl-l,4benzoxathianes (26) result from an oxidative reawangement of 1,3-oxathiolanes derived from a cyclohexanone (94JCS(P1)1241).

~ S

R

Ph

Ph

=

+~

'

(ii) BuLl (iii) aq. NH4CI

R

S (26)

Substituted 1,4-dihydrobenzothiin 3-oxides (sultines), which are stable at room temperature, can be obtained from the isomeric 1,3-dihydrobenzo[b]thiophene 2,2-dioxides (sulfones) by reduction and eyelisation. The sulfones are formed by the photolytic reaction of 2-methylbenzaldehydes with SO2 (94TL4743). Theoretical studies of the reaction of dienes with SO2 have been reported (94CC1683, 94JA763, 94JOC8058). R

OH

R

OH

R

o R

R

s..- o R

290

6.4.6 93CB2739 93JA9856 93RCHI 94ACR211 94ACS61 94ACS165 94AHC179 94AHC65 94BCJI912 94CB565 94CC501

94CC1177 94CC 1341 94CC1563 94CC1611 94CC1653 94CC 1681 94CC1683

94CC1953 94CC2361

94CHE503 94CJC1722 94CJC1866 94CL145 94COS23 94CRVI063 94H585 94H661 94H725

94H759 94H 1165 94H1705 94H305 94H541 94H991 94H1339 94H1483 94H1487 94H1497 94H1507 94H1971 94HA113 94IJC272 94JA763 94JA1004 94JA3123

S i x - M e m b e r e d Ring @stems: With 0 and/or S Atoms

REFERENCES J.-M. Lapierre, M. Gautschi, G. Greiveidinger and D. Seebach, Chem. Ber., 1993, 126, 2739. G. C. Fu, S. T. Nguyen and R. H. Grubbs, J. Am. Chem. Soc., 1993, 115, 9856. F. Freeman, M. Aregullin and E. Rodriguez, Rev. Heteroat. Chem., 1993, 9, 1. W.-S. Zhou and Y. A, Acc. Chem. Res., 1994, 27, 211. K. V. Gothelf and K. B. G. Torssell, Acta Chem. $cand., 1994, 48, 61. K. V. Gothelf and K. B. G. T~ssell, Acta Chem. Scand., 1994, 48, 165. L Kuthan, P. Sebeck and S. B6hm, Adv. Heterocycl. Chem., 1994, $9, 179. G. Doddi and G. Ercolani, Adv. HeterocycL Chem., 1994, 60, 65. A. Sera, M. Ohara, H. Yamada, E. Egashira, N. Ueda and J.-l. Setsune, Bull. Chem. Soc. Jpn., 1994, 67, 1912. M. Gautschi, W. B. Schweizer and D. Seebach, Chem. Ber., 1994, 127, 565. R. Thangarasa, L R. Green and T. T. Nadasdi, J. Chem. Soc., Chem. Commun., 1994, 501. N. Bhuvaneswari, C. S. Venkatachalam and K. K. Balasubramanian, J. Chem. See., Chem. Commun., 1994, 1177. V. Nair and S. Kumar, J. Chem. Soc., Chem. Commun., 1994, 1341. Y. Motoyama and K. Mikan~, J. Chem. Soc., Chem. Commun., 1994, 1563. S. Abramson, E. Ashkenazi, I. Goldberg, M. Greenwald, H. Jatzke, M. Vardi, S. Weinman and B. Fuchs, J. Chem. See., Chem. Commun., 1994, 161 I. V. K. Aggarwal, A. Thomas and R. J. Franklin, J. Chem. Soc., Chem. Commun., 1994, 1653. H. Moriwaki, T. Oshima and T. Nagai, J. Chem. Soc., Chem. Commun., 1994, 1681. D. Su:u'ez, X. Assfeld, J. Gonz~lez, M. F. Ruiz-L6pez, T. L. Sordo and J. A. Sordo, J. Chem. $oc., Chem. Commun., 1994, 1683. I. Kadota, K. Miura and Y. Yamamoto, J. Chem. Soc., Chem. Commun., 1994, 1953. J.-I. Yoshida, K. Takada, Y. Ishichi and S. Isoe, J. Chem. Soc., Chem. Commun., 1994, 2361. B. I. Drevko, L. A. Fomenko, M. I. Smushkin, O. I. Zhukov, E. V. Drevko and V. G. Kharchenko, Chem. Heterocycl. Compd. Engl. Transl., 1994, 503. T. Schaefer, J. P. Kunkel, R. W. Schurko and G. M. Bernard, Can. J. Chem., 1994, 72, 1722. S. Bissada, C. K. Lau, M. A. Bernstein and C. Dufresne, Can. J. Chem., 1994, 72, 1866. E. Wada, H. Yasuoka and S. Kanemasa, Chem. Lett., 1994, 145. C. J. Burns, Contemp. Org. Synth., 1994, 1, 23. M. A. Miranda and H. Garcia, Chent Rev., 1994, 94, 1063. M. Moreno-Manas and R. Pleixats, Heterocycles, 1994, 37, 585. S. Koser and H. M. R. Hoffmann, Heterocycles, 1994, 37, 661. M. Murase, N. Nishino, N. Nara, Y. Nakanishi and S. Tobinaga, Heterocycles, 1994, 37, 725. R. Cruz-Aimanza, F. P&ez-Flores and C. Lemini, Heterocycles, 1994, 37, 759. D. FSxcasiu, A. T. Balaban and U. L...Bologa, Heterocycles, 1994, 37, 1165. C. Tanyeli, A. S. Demir, O. Ozarslan, I. Mecidoglu and O. Tarhan, Heterocycles, 1994, 37, 1705. A. L6vai, G. T6th, J. Hal~z, T. Timer, L. Frank and S. Hosztafi, Heterocycles, 1994, 38, 305. H. Fujiwara and I. Okabayashi, Heterocycles, 1994, 38, 541. M. Aniol, P. Lusiak and C. Wawrzeficzyk, Heterocycles, 1994, 38, 991. J. I. Lozano and F. Barba, Heterocycles, 1994, 38, 1339. K. Ohkata, T. Kubo, K. Miyamoto, M. One, I. Yamamoto and K. Akiba, Heterocycles, 1994, 38, 1483. M. Tsukayama, M. Kikuchi and Y. Kawamura, Heterocycles, 1994, 38, 1487. J. K. Baker and H. T. Chi, Heterocycles, 1994, 38, 1497. H.-J. Wu, S.-H. Lin and C.-C. Lin, Heterocycles, 1994, 38, 1507. S. Kim and C. M. Cho, Heterocycles, 1994, 38, 1971. A. J. Ashe, Ill, J. W. Kampf and P. M. Savla, Heteroatom Chem., 1994, 5, 113. O. Prakash, S. Pahuja and M. P. Tanwar, Ind. J. Chem., 1994, 33B, 272. D. Su~rez, T. L. Sordo and J. A. Sordo, J. Am. Chem. Soc., 1994, 116, 763. T. Hosoya, E. Takashiro, T. Matsumoto and K. Suzuki, J. Am. Chem. Soc., 1994, 116, 1004. J. P. Morken, M. T. Didiuk, M. S. Visser and A. H. Hoveyda, J. Am. Chem. Soc., 1994, 116, 3123.

S i x - M e m b e r e d R i n g S y s t e m s : With 0 a n d / o r S A t o m s

94JA3312 94JA5473 94JA5796 94JA6622 94JA7923 94JA9403 94JCR(S)82 94JCS(Pl)497 94JCS(Pl)653 94JCS(Pl)843 94JCS(PI)859 94JCS(Pl)865 94JCS(PI)989 94JCS(PI)I241 94JCS(Pl)1359 94JCS(Pl)I733 94JCS(PI)I791 94JCS(PI)1797 94JCS(PI)I925 94JCS(PI)2363 94JCS(PI)2591 94JCS(PI)3095 94JCS(PI)3101 94JCS(P1)3129 94JCS(P1)3595 94JCS(P2)1151 94JCS(P2)1291 94JCS(P2)1299 94JCS(P2)1439 94JCS(P2)I545 94JCS(F2)2329 94JFC263 94JFC25 94JHC145 94JOC900 94JOC1907 94JOC2014 94JOC4743 94JOC5556

291

M. G. Organ, R. D. J. Froese, J. D. Goddard, N. J. Taylor and G. L. Lange, J. Am. Chem. Soc., 1994, 116, 3312. S. Tsunoi, I. Ryu and N. Sonoda, J. Am, Chem. Soc., 1994, 116, 5473. E. Juaristi, G. Cuevas and A. Vela, J. Am, Chem. Soc., 1994, 116, 5796. E. M. Carreira, C. A. Hastings, M. S. Shepard, L. A. Yerkey and D. B. Millward, J. Am. Chem. $oc., 1994, 116, 6622. T. Sugihara, C. ColOrer, Z. Owczarczyk, L. S. Harring and E.-I. Negishi, J. Am, Chem. Soc., 1994, 116, 7923. E. Block, C. Guo, M. Thiruvazhi and P. J. Toseano, J. Am. Chem. Soc., 1994, 116, 9403. A. A. Vitale, G. P. Romanelli, J. C. Autino and A. B. Pomilio, J. Chem. Res., (S), 1994, 82. M. A. Brimble and C. J. Rush, J. Chem. Soc., Perkin Trans. I, 1994, 497. C. D. Gabbutt, J. D. Hepworth and B. M. Heron, J. Chem. Soc., Perkin Trans. 1, 1994, 653. B. Yagen, Y. M. Pu, H. J. C. Yeh and H. Ziffer, J. Chem. Soc., Perkin Trans. 1, 1994, 843. R. G. F. Giles, I. R. Green, L. S. Knight, V. R. L. Lee Son and S. C. Yorke, J. Chem. $oc., Perkin Trans. I, 1994, 859. R. G. F. Giles, I. R. Green, L. S. Knight, V. R. L. Lee Son and S. C. Yorke, J. Chem. Soc., Perkin Trans. I, 1994, 865. J. Bloxham and C. P. Dell, J. Chem, Soc., Perkin Trans. I, 1994, 989. A. Arnoldi, A. Bassoli, R. Caputo, L. Merlini, G. Palumbo and S. Pedatella, J. Chem. Soc., Perkin Trans. 1, 1994, 1241. T. Saito, T. Karakasa, H. Fujii, E. Furuno, H. Suda and K. Kobayashi, J. Chem. Soc., Perkin Trans. I, 1994, 1359. C. D. Gabbutt, J. D. Hepworth, B. M. Heron and M. M. Rahman, J. Chem. Soc., Perkin Trans. 1, 1994, 1733. D. M. X. Donnelly, B. M. Fitzpatrick and J.-P. Finet, J. Chem. Soc., Perkin Trans. I, 1994, 1791. D. M. X. Donnelly, B. M. Fitzpatrick, S. M. Ryan and J.-P. Finer, J. Chem. Soc., Perkin Trans. 1, 1994, 1797. R. J. Bethune, C. D. Gabbutt, S. G. R. Guinot, J. D. Hepworth and B. M. Heron, J. Chem. Soc., Perkin Trans. I, 1994, 1925. V. K. Aggarwal, I. W. Davies, R. Franklin, J. Maddock, M. F. Mahon and K. C. Molloy, J. Chem. Soc., Perkin Trans. 1, 1994, 2363. J.-L. Pozzo, V. A. Lokshin and R. Guglielmetti, J. Chem. Soc., Perkin Trans. 1, 1994, 259 I. N. Cairns, L. M. Harwood, D. P. Astles and A. Orr, J. Chem. Soc., Perkin Trans. 1, 1994, 3095. N. Cairns, L. M. Harwood and D. P. #,sties, J. Chem. Soc., Perkin Trans. 1, 1994, 3101. H. Shimizu, S. Miyazaki, T. Kataoka, M. Hori and O. Muraoka, J. Chem. Soc., Perkin Trans. I, 1994, 3129. A. Diaz-Ortiz, E. Diaz-Barra, A. de la Hoz, P. Prieto and A. Moreno, J. Chem. Soc., Perkin Trans. I, 1994, 3595. J. Cai, A. G. Davies and C. H. Sehiesser, J. Chem. Soc., Perkin Trans. 2, 1994, 1151. L. Fodani, A. Lugli, D. Nanni and P. E. Todeseo, J. Chem, Soc., Perkin Trans. 2, 1994, 1291. M. Lemaire, G. Jeminet, A. Cuer, J.-G. Gourey and G. Dauphin, J. Chem. Soc., Perkin Trans. 2, 1994, 1299. W. Errington, T. J. Sparey and P. C. Taylor, J. Chem. Soc., Perkin Trans. 2, 1994, 1439. S. Das, C. S. Rajesh, T. L. Thanulingam, D. Ramaiah and M. V. George, J. Chem. Soc., Perldn Trans. 2, 1994, 1545. R. J. Abraham, L. Pollock and F. Sancassan, J. Chem. Soc., Perkin Trans. 2, 1994, 2329. W.-Y. Huang, Y.-S. Liu and L. Lu, J. Flourine Chem,, 1994, 66, 263. K. Tamura, T. lshihara and H. Yamanaka, J. Flourine Chem., 1994, 68, 25. T. lzumi and N. Morishita, J. Heterocycl. Chem., 1994, 31, 145. C. Nemes, A. L~vai, T. Patonay, G. T6th, S. Bores, J. Hal~z, W. Adam and D. Golseh, J. Org. Chem., 1994, 59, 900. M. Lemaire, G. Jeminet and G. Dauphin, J. Org. Chem., 1994, 59, 1907. H. K. Jacobs and A. S. Gopalan, J. Org. Chem., 1994, 59, 2014. R. K. Hayes, G. R. King and S. C. Vonwiller, J. Org. Chem., 1994, 59, 4743. G. Appendino, G. Cravotto, L. Toma, R. Annunziata and G. Palmisano, J. Org. Chem., 1994, $9, 5556.

292

94JOC5596 94JOC6508 94JOC8058 94JPR303 94JPR434 94JPR623 94LA91 94LA795 94LA1273 94MI1 94OPPlO1 94OPP129 94OPP159 94OPP377 94OPP617 94PJC2429 94RCR661 94S43 94S252 94S363 94S535 94S727 94S1219 94S1275 94SC779 94SC849 94SC2563 94SL201 94SIA39 94SL509 94SL511 94SL547

94SL748 94T979 94T2507

94T2671 94T4039 94T4623 94T4905 94T4913 94T6603 94T7115 94T7129 94T7141 94T7265 94T8035 941"8445 94T9037 94T9707 94T10107 94T11499

Six-Membered Ring @stems: With 0 and/or S Atoms

C. Spino, G. Liu, N. Tu and S. Girard, Y. Org. Chem., 1994, 59, 5596. F. Beaulieu and V. Snieclms, J. Org. Chem., 1994, [;9, 6508. D. Sukrez, J. GonvAlez, T. L. Sordo and J. A. Sordo, Y. Org. Chem., 1994, 59, 8058. T. Zimmerman, J. Prakt. Chem., 1994, 336, 303. U. Dietrich, A. Feindt, M. Pulst, M. Weissenfels, D. Greif and W. Cao, J. Prakt. Chem., 1994, 336, 434. T. Zimmermann and R. Radeglia, J. Prakt. Chem., 1994, 336, 623. G. Bringmann, B. Sch6ner, O. Schupp, K. Peters, E.-M. Peters and H. G. yon Schnering, Liebigs Ann. Chem., 1994, 91. W. Adam, J. Hal~z, A. L6vai, C. Nemes, T. Patonay and G. T6th, Liebigs Arm. Chem., 1994, 795. B. Wiinsch, H. Diekmann and G. H6fner, Liebi&sAnn. Chem., 1994, 1273. B. V. Mclnerney and W. C. Taylor in 'Studies in Natural Products Chemistry,' ed. A. U. Rahman, 1994, vol. 15, part C, Elsevier, Amsterdam. T. Bak, D. Rasala and R. Gawinecki, Or&. Prep. Proced. Int~, 1994, 26, 101. T. Oh and M. Reilly, Org. Prep. Proced. Int., 1994, 26, 129. A. Kotali and P. A. Harris, Org. Prep. Proced. Int., 1994, 26, 159. H. K. Patney, Org. Prep. Proced. Int., 1994, 26, 377. T. A. Blizzard, Or8. Prep. Proced. Int., 1994, 26, 617. S. N. Naidoff-Meir and A. Hassner, Pol. J. Chem., 1994, 68, 2429. V. N. Kalinin and O. S. Shilova, Russ. Chem. Rev., 1994, 63, 661. J. Morris and D. G. Wishka, Synthesis, 1994, 43. T. Zimmermann, Synthesis, 1994, 252. Y.-C. Xu, E. Lebeau, G. Attardo and T. Breining, Synthesis, 1994, 363. H. Waldmann, Synthesis, 1994, 535. T. Saito, T. Shizuta, H. Kikuchi, J. Nakgawa, K. I-Iirotsu, H. Ohmura and S. Motoki, Synthesis, 1994, 727. C. Wentrup, W. Heiimayer and G. Kollenz, Synthesis, 1994, 1219. C. Genicot and S. V. Ley, Synthesis, 1994, 1275. K. C. Hildebran, T. L. Cordray, K. W. Chan and C. F. Beam, Synth. Commun., 1994, 24, 779. J. Morris, D. G. Wishka and Y. Fang, Synth. Commun., 1994, 24, 849. V. I. Hugo, Synth. Conunun., 1994, 24, 2563. M. Koreeda and W. Yang, Synlett, 1994, 201. K. Maruoka, S. Saito and H. Yamamoto, Synlett, 1994, 439. L. F. Tietze, A. Montenbruck and C. Schneider, Synlett, 1994, 509. L. F. Tietze, H. Geissler, J. A. Gewert and U. Jakobi, $ynlett, 1994, 511. P. C. Bulman Page, R. D. Wilkes, J. V. Barkley and M. J. Witty, Synlett, 1994, 547. R. C. Larock and H. Yang, Synlett, 1994, 748. Q. Gao, K. Ishihara, T. Moruyama, M. Mouri and H. Yamamoto, Tetrahedron, 1994, $0, 979. C. D. Gabbutt, D. J. Hattley, J. D. Hepworth, B. M. Heron, M. Kanjia and M. M. Rahman, Tetrahedron, 1994, $0, 2507. M. A. Tius, A. Makfiyannis, X. L. Zou and V. Abadji, Tetrahedron, 1994, 50, 2671. J.-I. Anzai and T. Osa, Tetrahedron, 1994, 50, 4039. R. P. K. Kodukulla, S. Hariharan, and G. K. Trivedi, Tetrahedron, 1994, 50, 4623. C. K. Ghosh, K. Bhattacharya and C. Ghosh, Tetrahedron, 1994, 50, 4905. M. Makosza and M. Sypniewski, Tetrahedron, 1994, 50, 4913. D. A. Alonso, C. N~ijeraand J. M. Sansano, Tetrahedron, 1994, 50, 6603. L. D. M. Lolkema, H. Hiemstra, C. Semeyn and W. N. Speckamp, Tetrahedron, 1994, 50, 7115. L. D. M. Lolkema, C. Semeyn, L. Ashek, H. Hiemstra and W. N. Speckamp, Tetrahedron, 1994, 50, 7129. I. E. Mark6 and D. J. Bayston, Tetrahedron, 1994, 50, 7141. R. Caputo, G. Palumbo and S. Pedatella, Tetrahedron, 1994, 50, 7265. P. Pale, J. Bouquant, J. Chuche, P. Carrupt and P. Vogel, Tetrahedron, 1994, 50, 8035. M.-C. Roux, L. Wartski, M. Nierlich, D. Vigner and M. Lance, Tetrahedron, 1994, 50, 8445. G. Dujardin, S. Rossignol, S. Molato and E. Brown, Tetrahedron, 1994, 50, 9037. H. Senderowitz, L. Golender and B. Fuchs, Tetrahedron, 1994, 50, 9707. Y. A. Strelenko, V. V. Shamoshin, E. I. Troyansky, D. V. Demchuk, D. E. Dmitriev, G. I. Nikishin and N. S. Zefirov, Tetrahedron, 1994, 50, 10107. F. Fringuelli, G. Pani, O. Piermatti and F. Pizzo, Tetrahedron, 1994, 50, 11499.

S i x - M e m b e r e d Ring Systems: With 0 and~or S Atoms

94T11729 94T11755 94T11827 94T12477 94T13269 94TA535 94TA553 94TL129 94TL531 94TL769 94TL773 94TL777 94TL1601 94TL1699 94TL1769 94TL2179 94TL2183 94TL2427 94TL2607 94TL2619 94TL3545 94TL3691 94TL3893 94TIA743 94TL5919 94TL5923 94TL6093 94TL6575 94TL7051 94TL7167 94TL8057 94TL8445 94TI.,8619 94TL9451 94TL9581

293

G. Mehta, S. R. Shah, Y. Venkateswadu, Tetrahedron, 1994, $0, 11729. S. J. Coutts and T. W. Wallace, Tetrahedron, 1994, $0, 11755. H. Sasaki, R. Irie, T. Hamada, K. Suzuki and T. Katsuki, Tetrahedron, 1994, 50, 11827. W. Rossouw, A. F. Hundt, J. A. Steenkamp and D. Ferreira, Tetrahedron, 1994, 50, 12477. A. Guijarro and M. Yus, Tetrahedron, 1994, 50, 13269. M. Khouili, S. Lazar, G. Guillaumet and G. Coudert, Tetrahedron Asymm., 1994, S, 535. P. J. Edwards, D. A. Entwistle, S. V. Lay, D. R. Owen and E. J. Perry, Tetrahedron Asymm., 1994, 5, 553. E. Lee, J. S. Tae, Y. H. Chong and Y. C. Park, Tetrahedron Lett.,1994, 35, 129. B. B. Snider and Q. Lu, Tetrahedron Lett.,1994, 35, 531. R. Downham, K. S. Kim, S. V. Lay and M. Woods, Tetrahedron Lett., 1994, 35, 769. A. B. Hughes, S. V. I.~y,H. W. M. Priepke and M. Woods, Tetrahedron Left., 1994, 35, 773. D. A. Entwistle, A. B. Hughes, S. V. Lay and G. Visentin, Tetrahedron Lett., 1994, 35, 777. D. M. Hodgson and C. Wells, Tetrahedron Let/.,1994, 35, 1601. W. Kirmse and D. Schnitzler,Tetrahedron Left.,1994, 35, 1699. J. Hellberg and M. E. Pelcman, Tetrahedron Left.,1994, 35, 1769. C. Mukai, Y. Ikeda, Y.-I. Sugimoto and M. Hanaoka, Tetrahedron Left., 1994, 35, 2179. C. Mukai, Y.-I. Sugimoto, Y. Ikeda and M. Hanaoka, Tetrahedron Lett., 1994, 35, 2183. P. C. Bulman Page, S. M. Allin,E. W. Collington and R. A. E. Cart, Tetrahedron Left.,1994, 35, 2427. P. C. Bulman Page, S. M. Allin,E. W. Collington and R. A. E. Cart, Tetrahedron Left.,1994, 35, 2607. R. Anonioletti,S. Magnanti and A. Scettri,Tetrahedron Lett.,1994, 35, 2619. L.-L. Lai, P.-Y. Lin, W.-H. Huang, M.-J. Shiao and J. R. Hwu, Tetrahedron Left., 1994, 35, 3545. S. Bissada, C. K. Lau, M. A. Bernstein and C. Dufresne, Tetrahedron Left.,1994, 35, 3691. K. Hartke, A. Kraska, W. Massa, S. Molinier and S. Wocadlo, Tetrahedron Lett., 1994, 3$, 3893. G. Attardo, W. Wang, J.-L. Kl'aus and B. Belleau, Tetrahedron Lett., 1994, 35, 4743. M. Catellani, G. P. Chiusoli, M. C. Fagnola, G. Solari, Tetrahedron Lett., 1994, 35, 5919. M. Catellani, G. P. Chiusoli, M. C. Fagnola, G. Solari, Tetrahedron Lett., 1994, 35, 5923. M. Massacrer, C. Goux, P. Lhoste and D. Sinou, Tetrahedron Lett., 1994, 35, 6093. J. E. Baldwin, M. R. Spyvee and R. C. Whitehead, Tetrahedron Lett., 1994, 35, 6575. H. Tani, Y. Kawada, N. Azuma and N. Ono, Tetrahedron Lett., 1994, 35, 705 I. I. A. Abu-Yousef and D. N. Harpp, Tetrahedron Lett., 1994, 35, 7167. A. J. Bloodworth and K. A. Johnson, Tetrahedron Lett., 1994, 35, 8057. L. Capella and P. C. Montevecchi, Tetrahedron Lett., 1994, 35, 8445. G. Dujardin, M. Maudet and E. Brown, Tetrahedron Lett., 1994, 35, 8619. G. Cappozzi, S. Menichetti, C. Nativi and M. C. Simonti, Tetrahedron Lett., 1994, 35, 9451. H. Arimoto, S. Nishiyama and S. Yamamura, Tetrahedron Lett., 1994, 35, 9581.

Chapter 7 Seven -Membered Rings DAVID d. LECOUNT

Formerly of Zeneca Pharmaceuticals, UK 1, Vernon Avenue, Congleton, Cheshire, UK 7.1 Introduction In surveying the literature it is relevant to list a number of interesting reviews which have been published during the period. An important group of compounds which fall within any review of seven-membered heterocyclic compounds is the 1,4-benzodiazepines and which is of fundamental importance in medicinal chemistry. In this context, the quantitative structure-activity relationships of these compounds have been discussed and re-appraised in a comprehensive review by Hadjipavlou-Litina and Hansch <94CR1483> and the synthesis of DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepines has been reviewed <94CR433>. A review of 1,2,4-triazines fused to heterocyclic compounds contains numerous references to triazino-azepines, triazino-diazepines and triazino-triazepines <94AHC207>. Discussions of recent developments in the synthesis of medium-ring compounds <94COS457>, saturated nitrogen heterocycles <94COS95> and saturated oxygen heterocycles <94COS23> contain pertinent references on seven-membered systems as do reviews on the synthetic applications of iminophosphoranes <94S1197> and organometallic complexes <94SIA65>.

7.2 Ring systems containing one heteroatom 7.2.1 Azepines One of the well-established reactions for the synthesis of azepines is the photoinduced ring-expansion of nitrenes derived from phenyl azides, particularly when the azide bears an electron-withdrawing substituent. In most cases a 3-substituted3H-azepine is the final product. In a study of the ring expansion of oazidobenzonitriles in aqueous THF, however, Smalley and co-worker have demonstrated that 7-cyano-3H-azepin-2(H)-ones are formed, in addition to the expected 3-cyano isomer <94T5515>. 2-Azido-5-methyl and 2-azido-4-chlorobenzonitrile behave similarly. 2-Azido-5-chloro-benzonitrile and 2,5dicyanophenylazide give only 7-substituted derivatives. In recent years photolysis of azides in a nitrogen or argon matrix has been studied to elucidate the mechanism of ring expansion. In a recent paper it has been demonstrated that the photolysis of 2,6-dichloro- and 2,6-dibromo-4-azidophenol in low concentration affords the corresponding hydroxydidehydroazepine <94JCS(CC)1695>. At higher concentrations the tautomeric azepino-4-ones are obtained. Most such ring expansion reactions to form 3H-diazepines are carried out in the presence of an amine, an alcohol, an alkoxide or water. It has now been shown 294

Seven-Membered Rings

295

that if the reaction is carried out with methyl 2-azidobenzoate in the presence of enol ethers derived from ketones, intensely coloured 6,8-dialkoxy-8,9dihydropyrano[4,3-b]azepines (1) are formed, together with small amounts of the 3,3'-diazaheptafulvalene (2) <94LA1165>. OMe

_..

C02Me

OR ~

Me02C

R~

(1)

(2)

1,4-Dialkylbenzenes undergo addition/ring expansion reactions with methyl azidoformate to give a mixture of methyl 2,5-dialkyl-lH-azepine-1-carboxylate and the corresponding 3,6-isomers <94JCS(Pl)1753>. The carbomethoxy group may be readily removed by hydrolysis with DBU in xylene to form 3H-azepines. Most interestingly, however, is the behaviour of methyl 3,6-di-tert-butyl-lH-azepin-1carboxylate which in addition also forms 2H- and 4H-azepines. In earlier studies the initially formed 1H-azepines require conversion into 1H-cyclobuta[b]pyrroles prior to removal of the carbomethoxy group by strong base <94H(38)769>. 2,7-Dihydro-lH-azepines have been prepared by the reaction of (Z,Z)-I,6dibromohexa-2,4-dienes with primary amines <94jcs(cc)67>, and the reaction of 3iminoprop- 1-enylamines with pentacarbonyl( 1-methoxyprop-2enylidene)chromium(0) afford 5H-6,7-dihydroazepines in high yield in a stereoselective manner <94JCS(CC)321>. The reaction is considered to proceed via the formation of an aziridine which undergoes an aza-Cope rearrangement followed by a 1,3-proton shift to form the azepine. In earlier reports Sharp and co-workers have described the cyclisation of dieneconjugated nitrile ylides of the general type (3) (Scheme 1), where both A and B are benzene rings, to form benz[c,e]azepines <93JCS(P1)2961>. This w o r k has now been extended to systems where A or B is a heteroaromatic ring, in particular furan, thiophene and pyridine <94JCS(Pl)1193>.

AA[~~

+ --N--C--Ph / H (3)

-~

Ph H

\H

Scheme 1

A number of syntheses of reduced azepines have appeared which often are equally applicable to other ring systems. Thus the cyclisation of the alkynylhydroxylamine

Seven-Membered Rings

296

(4) in toluene affords the nitrone (5) in 81% yield <94JCS(Pl)3379> and Claisen rearrangement of the vinyl substituted ketene aminals (6; R = CH2CHMe 2, CH2OSiButMe2) yields the enantiomerically pure 7-substituted tetrahydroazepin-2ones (7) <92JCS(PI)3397>. 1-Ethoxy-2-(3-N-benzylaminopropyl)ethyne gives N-benzylcaprolactam in high yields on heating at 150 ~ for 3 hours <94SL743> and free radical (n-Bu3SnH/AIBN) cyclisation of the iodo-derivative (8) affords the pyrroloazepine system (9) in a 7endo-trig cyclisation <94TIA031>. R

I O (5)

(4)

I~

//~--O

P

(6)

(7)

N

CO2But

NttAc (8)

O

CO2Bu'

NHAc (9)

A similar catalyst system converts N,N-disubstituted ct-(xanthyl)-acetamides with an alkene substituent into cyclised systems as shown in Scheme 2 <94TL1719>. Bu t

Bu t

/

g

o

~

o

SCOEt Scheme 2 Transition metal catalysis is playing an ever increasing role in the synthesis of heterocyclic ring systems. Grubb's ruthenium catalyst is very effective in enyne metathesis of (10) in which the azepine (11) is formed in high yield <94SL1020> and molybdenum metathesis is used in the preparation of pyrroloazepine derivatives <94TL6005>. Palladium catalysis of the cyclisation of N,N-dimethyl-2-(l'-acetoxy-2'propenyl) benzylamines yields 2,3-dihydro-lH-2-benzazepinium (12) salts (Scheme 3) <94TL2877>. The reaction is very sensitive to the length of the allyl side chain. As it is increased there is greater competition from an alternative cyclisation in which isoindolinium salts are formed.

Seven-Membered Rings

297

Ts TsN

\

/

OTBDMS TBDMSO~

(10)

(11)

OAc

Pd(PPh3)4 e2

(12) Scheme

3

Tietze and Schimpf have demonstrated that the Heck cyclisation of oiodophenethylallylamines is a very viable route to 2,3,4,5-tetrahydro-lH-3benzazepines <94AG(E)1089>. If the reaction is carried out using the propargylamine (13) under reductive conditions, the single isomer (14) is formed <94CB2235>. In this approach problems associated with the regiochemistry of the starting aUylamines is overcome as the cyclisation and formation of the exocyclic double bond take place in one step.

Moo MeO ~

(NCOCF3 /

Meo .L.v A] ~ MeO N....--SiMe3

(13)

(14)

The synthesis of 2,3,4,5-tetrahydro- 1H-2-benzazepine-l,5-diones by the photochemical addition of alkenes to phthalimides has been known for a number of years. More recently this method has been extended to the reaction of Nalkylphalimides prepared from phthalic anhydride and amino acids, with a further example being published during the period under review <94T3627>. 2,3-Dihydro1H-2-benzazepine-l,3-diones have been prepared by the reaction of 2-cyanobenzaldehyde with methyl azidoacetate in the presence of methoxide ion <94JHC1299>.

The Beckmann rearrangement has been a popular method for the synthesis of azepine systems based upon caprolactam. A recent example is the synthesis of 7,8-

Seven-Membered Rings

298

dihydrofuro[3,2-c]azepines <94JHC725> and earlier studies on combining the Beckmann rearrangement in combination with allylsilane tandem cyclisations have been extended to the formation of tricyclic systems <94SL375>. In this way a part structure of cephalotaxine has been prepared (Scheme 4). o

0

o

NOMs

R~Si

.........

O

~H

]]" Scheme 4

An interesting alternative to the Beckmann rearrangement is the rearrangement of spiro oxaziridines formed by the oxidation of imines prepared from cyclohexanones. The rearrangement is regiospecific in that the bond anti to the nitrogen lone pair undergoes migration. The reaction may be carried out photolytically or thermally, the former being the more selective. In more recent studies Suda and co-workers have shown that the selectivity of the thermal reaction may be improved if it is carried out in the presence of Mn(tpp)Cl <94JCS(CC)949>. In addition the regiochemistry of the rearrangement is reversed such that migration syn to the nitrogen lone pair migrates; further the reaction may be carried out on N-phenyl derivatives which was not possible under the conditions previously published. A detailed report on the conformational preferences of hexahydro-2H-azepin-2ones has been published where it has been shown that the preferences are similar to those reported for cyclohexanes <94JOC3020>. The Diels-Alder reaction of benzynes offers a route to the synthesis of fused azepine derivatives. Thus it is possible to convert the furan (15) into the fused system (16) in approximately 50% yield by reaction with LiTMP in THF at -78 ~ <94H(38)31>.

'1 M (15)

(16)

It has been previously shown that the reactive intermediate 5-acetyl-10,11didehydro-5H-dibenz[b,f]azepine prepared by base treatment of 5-acetyl-10bromo-5H-dibenz[b,f]azepine will also undergo reaction with furan and cyclohexadiene <71JMC1839>,<91JOC3906>. This work has now been extended by the

Seven-Membered Rings

299

reaction with pyrrole to furnish 8H-N-methylpyrrolo[3,4,d]dibenz[b,f]azepine <94JHC293>. The ring opening/ring closure of bis epoxides with amines offers a route to polyhydroxylated azepines. The formal reaction is shown in Scheme 5 and this method has been applied to the preparation of enantiopure azasugars derived from D-mannitol and L-iditol <94TL3293>. The ratio of 6-exo-tet cyclisation to 7-endo-tet cyclisation may be controlled by modification of the reaction conditions. OP

P PO

OH

OP OH

Bn

PO

OP

\

/

HO~N.~~

OH

I Bn Scheme 5

DBU is well known in its capacity as a 'non-nucleophilic base' but it is also capable of chemical reactions in its own right. A recent example is the reaction with 2Hheptafluorobut-2-ene to give the tricyclic derivative (17) <94JCS(CC)2055>;reaction of the enamine (18) with DMAD affords the pryrroloazepine derivative (19) as a single isomer in 52 % yield <94TL1185>.

MeO2C

F3C

r.

,-, CO2Me __.~'~l~l~--CO2Me

M eu2ts \

CF2H (17)

(18)

(19)

7 . 2 . 2 0 x e p i n e s and thiapines

What the Beckmann rearrangement is to azepine, so is the Baeyer-Villiger oxidation ~o oxepine chemistry. A recent aerobic catalytic study has shown that yields of up to 95 % can be achieved with benzaldehyde and ruthenium dioxide or manganese dioxide <94SL1037>. The rate of reaction is greatly increased in the presence of lithium perchlorate without any significant loss in yield. Chiral nickel and copper complexes have been demonstrated to oxidise 2-phenylcyclohexanone

Seven-Membered Rings

300

in good yield with an ee of up to 69 % when pivaldehyde is used as the oxygen acceptor <94AG(E)I848>. The regioselectivity of the Baeyer-Villiger reaction has been studied on a number of polyhydroxycylohexanones possessing different substituents on the adjacent carbon atoms. The migratory aptitude of the substituted carbon atoms is reported to be in the order of a carbon substituted with benzyloxy > methoxy > ketal oxygen >> acyloxy ~ methyl <94TL7249>. In model studies aimed at the synthesis of zoapatanol (20), the enol ether (21) has been shown to react with dibromocarbene to afford the oxepane (22) <94"rL3085>.

O

,

y s o.

TMS

O

fl,- O .\ ,,

(20)

(21) '

(22)

In model studies carried out in association with their successful s~ynthesis of (+)2'S,3'R-zoapatanol, Trost and co-workers have shown that the palladium catalysed cyclisation of the epoxide (23) is highly dependent on the hydrogen bonding properties of the solvent (Scheme 6) <94AG(E)2182>. An alternative method for the preparation of hexahydrooxepines is cyclisation of the diazo-phosphonate (24) to (25) with rhodium (II) acetate <94JCS(P1)501>.

BOMOI,,.(

"~

~

-oq

THF cat Pd

o

t'~

BOMO

~

t,,.

cat Pd ~ BOMO 4:1 i-C3H7OH/TI-IF (23)

OH

Scheme 6

Selective epoxidation of the isolated double bond of the a,13-unsaturated ester (26), prepared from citronellal by a Wittig reaction with triphenylethoxycarbonylmethylene, with MCPBA followed by treatment with Na2PdCI4 and tert-butyl hydroperoxide in 50% acetic acid affords the bis-ether (27) <94JCS(CC)903>.

~

~

PO(OEt)2 R

O(OEt)2

~H "

~ . , ~ H , ,H~ COlEt

~[ ````Oi~`'/~-~'~`````` CO2Et

R

.....

OH Nl (24)

(25)

(26)

O

(27)

The allene ether (28) cyclises to the benzoxepine (29) on treatment with PdCI2(PPh3) 2 at 100 ~ <94JOC4730>. The product will undergo Diels-Alder reactions giving access to further fused derivatives (Scheme 7).

Seven-Membered Rings

301

CO2Me

//

CO2Me

PdO2(PPh3)2~

i DMAD iiDDQ

0/

v

~O

(29)

(28)

Scheme 7

Cobalt complexes of tx-alkynylpyranosides undergo acid catalysed epimerisation by a mechanism involving an intermediate acyclic cation. The intermediate in this process may be trapped by nucleophiles to give derivatives which after suitable modification, may be induced to undergo thermodynamically controlled cyclisation to fumish dehydrooxepanes (Scheme 8) <94T12883>. Decomplexation may be readily carried out with iodine.

R'~

I-I §

......

o.

"

o:co /+

C~

--k-

X

R

l: Nu R

R

I u

C~

O)6

TfOH 4-

HO

-R

/

H

X

Co2(C0) 6

X Scheme 8

The conversion of (Z,Z)-l,6-dibromohexa-2,4-dienes into azepines has already been discussed. The reaction may also be used to form 1,7-dihydro-oxepines and 1,7-dihydro-thiapines by reaction with respectively toluene-p-sulphonyl chloride and lithium sulphide <94JCS(CC)67>. 2-Styryl- or 2-vinyl- substituted 4-methylene-l,3-dioxalanes undergo Claisen rearrangements to form 4,5-dihydro-3(2H)-oxepinones (Scheme 9). The rate of reaction is of the order 2-phenyl-2-styryl > 2-phenyl-2-vinyl > 2-tert-butyl-2-styryl > 2-styryl <94TL3111>. The reaction of 6-hydroxyhexanal is reported to undergo a Claisen reaction with isopropenylacetate in the presence of NCS and tin (II) chloride as catalyst to form

302

Seven-Membered Rings

2-acetonyloxepane <94JCS(CC)1123>. If the aldehyde has a 2-pentyl substituent, the resulting 3-pentyl oxepane is formed with 95 % diastereoselectivity. R!

Scheme 9

Epoxides and oxetanes possessing ether substituents in the side chain rearrange in the presence of boron trifluoride etherate to form ring enlarged cyclic ethers <94H(38)2165>. By the appropriate selection of side chain the method may be used to form oxepanes bearing 3-CH2-O-alkyl(or alkenyl) substituents. 4,5-Didehydrotropone, prepared by oxidation of 1-amino[4,5-d]-l,2,3-triazole with lead tetraacetate, undergoes cycloaddition reactions with pyridazine N-oxides <94H(38)957>. Loss of nitrogen by the cycloadduct results in the formation of tropono[4,5-b]oxepines (Scheme 10). The electron deficient nature of the tropolone ring precludes the formation of [4 + 2]n cycloaddition products by the oxepine ring, in contrast to the reactivity of benz[b]oxepines. o

o

I RI

R2

N~N

Ra

RI Scheme 10

Irradiation of the bichromophoric 1-(o-cyanobenzyloxy)-2-(phenyl)-2-butenes (30; R = H, Me, OMe) yields the oxepane derivative (32) <94BCJI769>. The reaction is considered to proceed via cycloaddition of (30) in the excited singlet state between the C=C double bond and the C=N triple bond followed by ring cleavage and recyclisation of the resulting azetine (31) (Scheme 11). The cycloaddition reactions involving heterocyclic systems as diene followed by loss of the heteroatom(s) is a common method for the preparation of homocyclic

Seven-Membered Rings

303

systems. It has been shown, however, that reaction of DMAD with the thienobenzpyran (33) affords the thiapine (34), a reaction which involves the formation of a thianonorcaradiene intermediate <94JCS(P1)2191>.

o o O

(30)

Me (32)

(31)

Scheme 11

E

O

v

NH

O-

E

"-N

(33) E (34)

7.3 Ring systems containing two heteroatoms 7.3.1 Diazepines The reaction of butenolides or o~,13-unsaturated lactams (35; X = O or NBoc) reacts with ethylene diamine to form the reduced chiral 7-(o~-hydroxyalkyl)- and 7-(o~-aminoalkyl)-l,4-diazepin-5-ones (36; X = O or NBoc) (Scheme 12) <94T10701>. Diastereoisomeric ratios in excess of 95 95 are obtained. The reaction may be modified to afford 1,5-benzodiazepin-4-ones and 1,5-benzothiazepin-4ones. /----N

rn~

/--'-N

t~ "

X

R

XH

(35)

(36)

Scheme 12

~a

Seven-Membered Rings

304

The electrocyclisation of diene-conjugated diazocompounds to afford 1H-2,3benzodiazepines has been known for a number of years <84T3095>and more recently asymmetric induction in this cyclisation has been described <88TL6361>. The full paper of this latter work has now been published <94JCS(P1)3149>. The synthesis of 5H-2,4-benzodiazepines derivatives from 4-ethoxycarbonyland 4-cyanobenzo[c]pyrilium salts has been described <93CHE1268>. 1,3-Dipolar cycloaddition reactions of 5,7-dimethyl-1,2-diazepine have been used to prepare a number of heterofused derivatives. Thus reaction with mesitylnitrile oxide gives the tricyclic derivative (37; R = mesityl) and trifluoroacetonitrile oxide affords (37; R = CF 3) <94SC513>. Arylnitrilimines prepared from ethyl arylhydrazono-abromoglyoxylates in the presence of triethylamine afford the triazolodiazepine (38; R = CI, Me), together with a small amount of the triazolopyrrolodiazepine (39; R = CI, Me). Considerable attention continues to be paid to the synthesis of 1,4benzodiazepines. Medazepam and a number of related products have been synthesised from 2-benzoyl aryltriflates <94TL9189> and two syntheses of imidazo[4,5-e][1,4]diazepin-8-ones are reported <94CHE1026>, <94H(38)1007>. 9Hpyrimido[4,5-b][1,4]diazepines may be readily prepared from 4,5diaminopyrimidines and ethyl pyruvate <94T13511>. A number of 2- and 3substituted derivatives may be prepared by this method. 1,4-Benzodiazepin-2,5diones are produced by the reaction of Boc-anthranilic acid and a-aminoacid methyl esters or N-carboxy a-aminoacid anhydrides <94T9051>.

EtO2C'~N~N~ R H3C'~/~

Et

(37)

R ~ ~ I N ~ ( ~'~CO2Et

H3C""-I R ~ ~ I N ~ ( ~'-CO2Et (39)

(38)

Conversion of C3-oximido-l,4-benzodiazepines to a carbamate oxime prior to reduction to the 3-amino-derivative allows the reduction to be carried out under mild conditions <94s505>. This offers a convenient route to a number of new benzodiazepine CCK-B antagonists <94JMC/19>, The synthesis of novel unnatural amino acids containing a 1,4-benzodiazepine side chain is described <94AG(E)I737>. In this way the benzodiazepine has been incorporated into a tripeptide system.

<94JMC722>.

Seven-Membered Rings

305

Tricyclic systems which have been prepared include pyrrolo[1,2-a]thieno[3,2-f] and pyrrolo[ 1,2-a]thieno[3,4][ 1,4]diazepines <94H(38)811>, <94JHC341> The Schmidt reaction and the Beckmann rearrangement of thieno[b]quinolizidinones have been used for the preparation of piperidino[ 1,2-a][ 1,3] or [ 1,4]diazepines <94JHC495>. The mass spectrum fragmentation patterns of a number of 2-(4-substitutedphenyl)- 1,2,3,4-tetrahydro-l,4-benzodiazepin-5-ones and their tetrazolo[1,5-d] derivatives have been reported <94JCR(S)62>. The synthesis of dihydro-l,5-benzodiazepin-2-ones by the reaction of o-phenylenediamines with 13-ketoesters is much improved if the reaction is carried out under microwave irradiation <94TL8373>. A mixture of double bond isomers is apparently frequently obtained, unfortunately an error in the original paper makes the nature of the products unclear. The yields are high and no benzimidazole derivatives are observed. The preparation of 1,5-benzodiazepin-2-ones bearing a 4-(2-hydroxyphenyl) residue by the reaction of 4-hydroxycoumarin with o-phenylendiamines is described <94JHC509> and fluorinated derivatives are obtained by the reaction of o-phenylenediamines with 1-aryl-l-trialkylsilyl-perfluoroalkanols or 1-alkyl-1trialkylsilylperfluoroalkenes <94TIA357>. 4-Amino-lH-1,5-benzodiazepine-3-carbonitrile undergoes ring cleavage when treated with active methylene compounds under basic conditions. In the example shown in Scheme 13, the intermediate nitrile re-cyclises in acetic acid to yield the pyrido[2,3-b][ 1,5]benzodiazepine (40) <94JHC49>. NH 2

NH 2

H RCH2CNIDBU

H

(40) Scheme 13

7.3.2 Dioxepines Shibasaki and co-workers have continued their studies into asymmetric Heck reactions and have successfully arylated the 1,3-dioxepine (41) in good yield with up to 75 % ee <94TL1227>. Further conversion of the product (42) affords the asymmetric y-butyrolactone (43) (Scheme 14). The asymmetric lactones (44), readily formed from cyclohexane diol and methyl cyclohexanone-2-carboxylate are readily alkylated to furnish the derivatives (45) in

Seven-Membered Rings

306

a D.s. of over 90 % <94H(37)413>. These products may be readily converted into chiral cyclohexanone carboxylates (46) (Scheme 15). Ar ArOTf

Pd-(S)-BINAP

ovo

#Ar

..

v

o~o

(41)

o

(42)

(43)

Scheme 14

0

0

0

0

"~--

(46) (44)

(45) Scheme 15

Novel dibenzo[d,f][1,3]dioxepines have been prepared from 2,2'-biphenol <94TL9327>. Thus reaction with 2-chloroacrylonitrile affords dibenzo[d,f][1,3]dioxepin-6-acetonitrile and with diethyl bromomalonate the product is diethyl dibenzo[d,f][ 1,3]dioxepin-6,6-dicarboxylate.

7.4 Ring systems containing two different heteroatoms

Electrolysis of the proline amides (47a) and (47b) in an undivided cell using platinum foil electrodes gives the pyrrolooxazepinones (48a) and (48b) in approximately 50 % yield <94TL6989>. Both oxidisation and cyclisation take place during the electrolysis and the cyclisation reaction is highly diastereospecific, with only the bridgehead isomer with S-configuration being observed. No other diastereoisomer was detected by NMR. 1-Cyclopropyl-3,4-dihydro-6,7-dimethoxy-2-methyl-isoquinoline-N-oxide, when heated in a mixture of mesitylene and butyronitrile, is reported to undergo a Meisenheimer rearrangement to give 1-cyclopropyl-4,5-dihydro-7,8-dimethoxy-3methyl- 1H-2,3-benzoxazepine <94TL2409>. N-(2-hydroxymethylphenyl)pyrrole is amenable to selective o~-methylation and the metallated derivative may be trapped with aldehydes, ketones and carbon dioxide <941"2071>. Cyclisation of the new products affords an efficient synthesis of

Seven-Membered Rings

307

4-substituted-4H,6H-pyrrolo[ 1,2-a] [4,1 ]benzoxazepines. N-Boc- 11Hdibenz[b,f][1,4]-oxazepine undergoes lithiation in the 11-position and this lithiated derivative too may be trapped by a number of electrophiles in yields of up to 97 % <94H(38)601>. t-BocI-IN

O

Rn

t-BocHN/,,

O

R~

R2

x......O"~-"~

OH

H

(47a; R 1 = H, R2 = CO2Me)

(48a; R1 = H, R2= CO2Me)

(47b; R 1 = COgMe' R2 = H)

(48b; RI = COgMe, R2 = H)

Intramolecular cycloaddition of an azide to an acetylenic bond offers a route to the synthesis of [ 1,2,3]triazolo[ 1,5-a][4,1]benzoxazepines (Scheme 16) <94H(38)291>. Considering the ready availability of the starting material (isatoic anhydrides and propargyl alcohols) this offers an attractive route to these compounds.

R2

[ N3

oyII

0

A v

Rt

U o-) R O

Scheme 16

A further application of 1,3-dipolar additions to the synthesis of seven-membered rings is cycloaddition to the C=N double bond of 1,5-benzothiazepines. In an extension of their investigations into the cyclofunctionalisation of heterocyclic imine systems, Chimirri et al. have demonstrated that the cycloaddition of benzonitriloxide to 1,5-benzothiazepines affords 3a,4-dihydro-l-phenyl-5H[1,2,4]oxadiazolo[5,4-d]benzothiazepines <94H(38)2289>. The reaction is regiospecific and yields only one isomer (Scheme 17). R

R

R2 Scheme 17

A dynamic 13C-NMR study of 3-hydroxy-l,5-benzoxathiepine in solution has shown that three conformations are possible for the oxathiepine ring, a "chair" with a pseudo-axial hydroxy group, a "boat" with a pseudo-equatorial hydroxy group,

308

Seven-Membered Rings

and a "chair" with a pseudo-equatorial hydroxy group <94JHC1151>. The AG# values for the transitions are 37.0 KJmo1-1 (177 K) and 41.2 KJmo1-1 (186 K) respectively. Single crystal X-ray determination shows a chair conformation with the hydroxy group in the pseudo-equatorial configuration. Tricyclic systems as compounds of potential pharmacological interest prepared by conventional cyclisation procedures include thienoaneUated [1,4]benzoxazepines <94JHC1053>, pyrido[1,4] and [1,5]benzoxazepines and thiazepines <94JMC519>, and 1H- and 2H-pyrazolo[3,4-c][2,1]benzothiazepines <94JHC93>. A number of 1,4-benzoxazepin-5[4H]-ones and-4[5H]-ones have been prepared by the Beckmann rearrangement of 2,2-dimethyl-4-chromanone <94H(38)305>.

7. 5 Ring systems containing 3 or more heteroatoms When heated with N-phenylbenzimidoyl chloride, 5-phenyltetrazole is converted into 3,4,5-triphenyl-l,2,4-triazole. If the reaction is carried out under phase transfer conditions, 1-imidoyl- and 2-imidoyl-tetrazoles are formed, which upon heating in a number of solvents, or in the absence of solvent, the product of the reaction is 2,5-diphenyl-3H-1,3,4-benzotriazepine <94ACS596>. The reaction is solvent dependent in that the highest yields are obtained in benzonitrile. In pyridine or DMF the triazole is formed as a secondary product. 4-Substituted 8-amino-4,5-dihydro-3H-pyrrolo[3,4-f]-l,3,5-triazepin-6-ones (51) are formed by the reaction of the formamidine (49) in an excess of aldehyde or ketone in the presence of DBU <94JCS(Pl)3571>. The intermediate product is the tautomer (50), which rearranges when dissolved in alcoholic solvents (Scheme 18). An alternative route to (51) is via the formamidate (52). Reaction of 1-(2-aminobenzenesulphonyl)pyrrole (53; n = 2) with the ethoxy hemiacetal of ethyl glyoxylate gives the pyrrolo[1,2-b][1,2,5]benzothiadiazepine dioxide (54; R = H, n = 2), which has been converted into the antidepressant tiaaptazepine (55) <94JHC867>. A similar reaction of (53; n = 2) with diethyl oxaloacetate fails to give the expected product (54; R = CH2CO2Et, n = 2) but the synthesis is successful when the reaction is carried out with (53; n = 0), affording (52; R = CH2CO2Et, n = 0) which may be oxidised to (54, R = CO2Et, n = 2) with MCPBA <<94SC2685>. DCC treatment of the thiourea (57; X = CH, N), prepared from the amine (56) by reaction with benzoylisothiocyanate followed by base hydrolysis, affords the tetracyclic derivatives (58) which are claimed to possess considerable antitumour activity in vitro <94H(38)1213>. In an alternative synthesis, (58) may be prepared by methylation of the thiourea group in (57) with methyl iodide followed by treatment with K2CO3 in DMF. The imino-tautomer structure is base upon NMR and infrared spectroscopic evidence.

Seven-Membered Rings

309

H H--~

CN

N

RI Nil

CN tt

H~N

(49)

OEt H.~\

(50)

H N

R

R~

CN NH

~N~O

CONI~

R2 (52)

(51) (Scheme

18)

N-- Et

(-'NMo

R

~sIN~/on

~SnNN~

(53)

(54)

~ ~

NH2 (56)

N

(55)

NHC(S)NH2 (57)

NH (55)

Two reports on pentathiepines have been published. In the first, pentathiepino[6,7-b]indole (59) has been prepared by the reaction of isatin with P4SI0 <94TL5279>. In a second paper the NMR spectrum of the natural product varacin (60) is discussed 94TL7185>. It had been previously noted that the NMR spectrum of the side chain was unusually complex, which was attributed to

310

Seven-Membered Rings

restricted rotation of the side chain. Evidence is now presented which indicates that a high energy barrier to inversion of low energy chair conformations of the polysulphide ring in asymmetrically substituted benzopentathiepins is responsible for the complexity of the NMR spectrum <94TL7185>. Derivatisation of varacin with a chiral auxiliary provides diastereoisomeric products which may be separated by fractional crystallisation. ,,S--'S s

H

S'~ /

(59)

MeO-

x~-

v

-NH2

(60)

7.6 References

71JMC1839 84T3095 88TL6361 91JOC3906 93CHE1268 93JCS(P1)2961 94ACS596 94AG(E) 1089 94AG(E) 1737 94AG(E) 1848 94AG(E)2182 94AHC207 94BCJ 1769 94CB2235 94CHE1026

B. P. Das, D. W. Boykin, J. Med. Chem. 1971, 14, 1839. I. R. Robertson, J. T. Sharp, Tetrahedron 1984, 16, 3095. A. J. Blake, M. Harding, J. T. Sharp, Tetrahedron Lett. 1988, 29, 6361. H. C. Axtell, W. M. Howell, L. G. Schmid, M. C. Cann, J. Org. Chem. 1991, 56, 3906. S. L. Bogza, Y. A. Nikolyukin, Chem Heterocycl. Cmpd. 1993, 29, 1268. K. E. Cullen, J. T. Sharp, J. Chem. Soc., Perkin Trans. 1 1993, 2961. G. Koldobskii, S. Ivanova, I. Nikonova, A. Zhivich, V. Ostrovskii, Acta Chem. Scand. 1994, 48, 596. L. F. Tietze, R. Schimpf, Angew. Chem. Int. Ed. Engl. 1994, 33, 1089. J. Mulzer, F. Schrtider, A. Lobbia, J. Buschmann, P. Luger, Angew. Chem., Int. Ed. Engl. 1994, 33, 1737. C. Bolm, G. Schlongloff, K. Weickhardt, Angew. Chem. Int. Ed. Engl. 1994, 33,1848. B. M. Trost, P. D. Greenspan, H. Geissler, J. H. Kim, N. Greeves, Angew. Chem, Int. Ed. Engl. 1994, 33, 2182. E. S. H. El Ashry, N. Rashed, A. Mousaad, E. Ramadan, Adv.Heterocycl. Chem. 1994, 61, 207. H. Sakuragi, T. Koyama, M. Sakurazawa, N. Yasui, K. Tokumaru, K. Ueno, Bull. Chem. Soc. Jpn. 1994, 67, 1769. L. F. Tietze, R. Schimpf, Chem. Ber. 1994, 127, 2235. G. D. Kalayanov, 1~. I. Ivanov, L. V. Grishchuk, Chem. Heterocycl. Cmpd. 1994, 30, 1026.

Seven-Membered Rings

311

C.J. Bums, Comp. Org. Synth. 1994, 1, 23. J. Steele, Comp. Org. Synth. 1994, 1.95. M.C. Elliott, Comp. Org. Synth. 1994, 1,457. D.E. Thurston, D. S. Bose, Chem. Rev. 1994, 94, 433. D. Hadjipavlou-Litina, C. Hansch, Chem. Rev. 1994, 94, 1483. K. Kato, H. Suemune, K. Sakai, Heterocycles 1994, 37, 413. H. Kotsuki, T. Nobori, T. Asada, M. Ochi, Heterocycles 1994, 38, 31. 94H(38)291 L. Garanti, G. Molteni, G. Zecchi, Heterocycles 1994, 38, 291. 94H(38)305 A. L6vai, G. T6th, J. Hal~isz, L. Frank, S. Hosztafi, Heterocycles 1994, 38, 305. 94H(38)601 T.J. Hagen, M. F. Rafferty, J. T. Collins, D. J. Garland, J. J. Li, M. B. Norton, D. B. Reitz, S. Tsymbalov, B. S. Pitzele, E. A. Hallinan, Heterocycles 1994, 38, 601. 94H(38)769 K. Satake, H. Saitoh, M. Kimura, S. Morosawa, Heterocycles 1994, 38, 1994. 94H(38)811 I. Rault, S. Rault, M. Robba, Heterocycles 1994, 38, 811. 94H(38)957 N. Kakusawa, M. Imamura, J. Kurita, T. Tsuchiya, Heterocycles 1994, 38, 957. 94H(38)1007 P.K. Bridson, Heterocycles 1994, 38, 1007. 94H(38)1213 B.-W. Jin, S.-H. Cho, Heterocycles 1994, 38, 1213. 94H(38)2165 A. Itoh, Y. Hirose, H. Kashiwagi, Y. Masaki, Heterocycles 1994, 38, 2165. 94H(38)2289 A. Chimin'i, R. Gitto, S. Grasso, P. Monforte, M. Zappal~t, Heterocycles 1994, 38, 2289. 94JCR(S)62 P.T. Kaye, M. J. Mphahlele, J. Chem. Res. (S) 1994, 62. 94JCS(CC)67 J.G. Walsh, P. J. Furlong, D. G. Gilheany, J. Chem. Soc. Chem. Commun. 1994, 67. 94JCS(CC)321 J. Barlunga, M. Tom,is, A. Ballesteros, J. Santamaria, F. L6pezOrtiz, J. Chem. Soc., Chem. Commun. 1994, 321. 94JCS(CC)903 N. Balu, S. V. Bhat, J. Chem. Soc., Chem. Commun. 1994, 903 94JCS(CC)949 K. Suda, M. Sashima, M. Izutsu, F. Hino, J. Chem. Soc., Chem. Commun. 1994, 949. 94JCS(CC) 1123 Y. Masuyama, Y. Kobayashi, Y. Kurusu, J. Chem. Soc., Chem. Commun. 1994, 1123. 94JCS(CC)1695 I.R. Dunkin, A. El Ayeb, M. A. Lynch, J. Chem. Soc., Chem. Commun. 1994, 1695. 94JCS(CC)2055 R.D. Chambers, A. J. Roche, A. S. Batsanov, J. A. K. Howard, J. Chem. Soc., Chem. Commun. 1994, 2055. 94JCS(P1)501 C.J. Moody, E.-R. H. B. Sie, J..J. Kulagowski, J. Chem. Soc., Perkin Trans. 1, 1994, 501. 94JCS(P1) 1193 H. Finch, D.H. Reece, J. T. Sharp, J. Chem. Soc., Perkin Trans. 1 1994, 1193. 94JCS(P1)1753 K. Satake, R. Okuda, M. Hashimoto, Y. Fujiwara, H. Okamoro, M. Kimura, S. Morosawa, J. Chem. Soc., Perkin Trans 1, 1994, 1753. 94COS23 94COS95 94 COS457 94CR422 94CR 1483 94H(37)413 94H(38)31

312

94JCS(P1)2191 94JCS(P1)3149 94JCS(P1)3379 94JCS(P1)3397 94JCS(P1)3571

94JHC49 94JHC93 94JHC293 94JHC341 94JHC495 94JHC509 94JHC725 94JHC867 94JHC1053 94JHC 1151 94JHC1299 94JMC519

94JMC719

94JMC722

94JOC3020 94JOC4730 94LA 1165 94S505 94S 1197 94SC513

Seven-Membered Rings

E. Nyiondi-Bonguen, E. S. Fondjo, Z. T. Fomum, D. Dtipp, J. Chem. Soc. Perkin Trans. 1 1994, 2191. A. J. Blake, M. Harding, J. T. Sharp, J. Chem. Soc., Perkin Trans. 1, 1994, 3149. M. E. Fox, A. B. Holmes, I. T. Forbes, M. Thompson, J. Chem. Soc., Perkin Trans. 1 1994 3379. P. A. Evans, A. B. Holmes, K. Russell, J. Chem. Soc., Perkin Trans. 1. 1994, 3397. M. J. Alves, O. K. AI-Duaij, B. L. Booth, A. Carvalho, P. R. Eastwood, M. F. J. R. P. Proen~a, J. Chem. Soc., Perkin Trans.1, 1994, 3571. Y. Okamoto, Y.Zama, K. Takagi, Y. Kurasawa, T. Aotsuka, J. Heterocycl. Chem. 1994, 31, 49. J. A. Diaz, S. Vega, J. Heteterocycl. Chem. 1994, 31, 93. R. A. Bennett, M. C. Cann, J. Heterocycl. Chem. 1994, 31, 293. A. Daich, J. Morel, B. Decroix, J. Heterocycl. Chem. 1994, 31, 341. S. Marchalin, B. Decroix, J. Heterocycl. Chem. 1994, 31, 495. M. Hamdi, O. Grech, R. Sakellariou, V. Sp6ziale, J. Heterocycl. Chem. 1994, 31,509. E. C. Cort6s, E. C. Romero, A. D. Taylor, J. Heterocycl. Chem. 1994, 31, 725. G. Stefancich, R. Silvestri, E. Pagnozzi, M. Artico, J. Heterocycl. Chem. 1994, 31,867. I. Laimer, T. Erker, J. Heterocycl. Chem. 1994, 31, 1053. G. Cerioni, C. Floris, G. Marongiu, G. Navarra, F. Sotgiu, J. Heterocycl. Chem. 1994, 31, 1151. A. S. Kiselyov, K. Van Aken, Y. Gulevich, L. Strekowski, J. Heterocycl. Chem. 1994, 31, 1299. J.-F. F. Li6geois, F. A. Rogister, J. Bruhwyler, J. Damas, T. P. Nguyen, M.-O. Inarejos, E. M. G. Chleide, M. G. A. Mercier, J. E. Delarge, J. Med. Chem. 1994, 37, 519. G. A. Showell, S. Bourrain, J. G. Neduvelil, S. R. Fletcher, S. B. Freedman, J. A. Kemp, G. R. Marshall, S. Patel, A. J. Smith, V. G. Matassa, J. Med. Chem. 1994, 37, 719. M. G. Bock, R. M. DiPardo, E. V. Mellin, R. C. Newton, D. F. Veber, S. B. Freedman, A. J. Smith, S. Patel, J. A. Kemp, G. R. Marshall, A. E. Fletcher, K. L. Chapman, P. S. Anderson, R. M. Freidinger, J. Med. Chem. 1994, 37, 722. A. Matallana, A. W. Kruger, C. A. Kingsbury, J. Org. Chem. 1994, 59, 3020. S. Ma, E Negishi, J. Org. Chem. 1994, 59, 4730. W. Ttickmantel, Justus Liebigs Ann. Chem. 1994, 1165. S. Bourrain, G. A. Showell, Synthesis 1994, 505. P. Molina, M. J. Vilaplana, Synthesis 1994, 1197. M. El Messaoudi, A. Hasnaoui, J.-P. Lavergne, Synth. Commun. 1994 24, 513.

Seven-Membered Rings

94SC2685 94SL375 94SL465 94SL743 94SL1020 94SL1037 94T2071 94T3627 94T5515 94T9051 94T10701 94T12883 94T13511 94TL 1185 94TL1227 94TL1719 94TL2409 94TL2877 94TL3085 94TL3111 94TL3293 94TL4031 94TL4357 94TL5279 94TL6005 94TL6989

313

R. Silvestra, E. Pagnozzi, G. Stefancich, M. Artico, Synth. Commun. 1994, 24, 2685. D. Schinzer, E. Langkopf, Synlett. 1994, 375. J. C~impora, M. L. Panaque, E. Carmona, Synlett. 1994, 465. D. I. MaGee, M. Ramaseshan, Synlett. 1994, 743. A. Kinoshita, M. Mori, Synlett. 1994, 1020. T. Inokuchi, M. Kanazaki, T. Sugimoto, S. Torii, Synlett. 1994, 1037. M. Schlosser, F. Faigl, Tetrahedron 1994, 50, 2071. M. R. Paleo, D. Domfnguez, L. Castedo, Tetrahedron 1994, 50, 3627. K. Lamara, A. D. Redhouse, R. K. SmaUey, J. R. Thompson, Tetrahedron 1994, 50, 5515. M. Akssira, M. Boumzebra, H. Kasmi, A. Dahdouh, M.-L. Roumestant, Ph. Viallefont, Tetrahedron 1994, 50, 9051. J. Bohrisch, H. Faltz, M. Piitzel, J. Liebscher, Tetrahedron 1994, 50, 10701. S. Tanaka, N. Tatsuta, O. Yamashita, M. Isobe, Tetrahedron 1994, 50, 12883. M. Melguizo, A. Stiachez, M. Nogueras, J. N. Low, R. A. Howie, G. Andrei, E. De Clercq, Tetrahedron 1994, 50, 13511. S. Jiang, Z. Janousek, H. G. Viehe, Tetrahedron Lett. 1994, 35, 1185. Y. Kogi, M. Sodeoka, M. Shibasaki, Tetrahedron Lett. 1994, 35, 1227. J. Axon, L. Boiteau, J. Boivin, J. E. Forbes, S. Z. Zard, Tetrahedron Lett. 1994, 35, 1719. T. S. Bailey, J. B. Bremner, D. C. Hockless, B. W. Skelton, A. H. White, Tetrahedron Lett. 1994, 35, 2409. M. Grellier, M. Pfeffer, G. van Koten, Tetrahedron Lett. 1994, 35, 2877. G. Pain, D. DesmaEle, J. d'Angelo, Tetrahedron Lett. 1994, 35, 3085. J. Sugiyama, K. Tanikawa, T. Okada, K. Noguchi, M. Ueda, T. Endo, Tetrahedron Letters 1994, 35, 3111. L. Poitout, Y. Le Merrer, J.-C. Depezay, Tetrahedron Letters 1994, 35, 3293. L. Colombo, M. D. Giacomo, G. Papeo, O. Carugo, C. Scolastico, L. Manzoni, Tetrahedron Lett. 1994, 35,4031. B. Dondy, P. Doussot, M. Iznaden, M. Muzard, C. Portella, Tetrahedron Lett. 1994, 35, 4357. J. Bergman, C. StAlhandske, Tetrahedron Lett. 1994, 35, 5279. S. F. Martin, Y. Liao, H.-J. Chen, M. Piitzel, M. N. Ramser, Tetrahedron Lett. 1994, 35, 6005. F. Cornille, Y. M. Fobian, U. Slomczynska, D. D. Beusen, G. R. Marshall, K. D. Moeller, Tetrahedron Lett. 1994, 35, 6989.

314

94TL7185 94TL7249 94TL8373 94TL9189 94TL9327

Seven-Membered Rings

B. S. Davidson, P. W. Ford, M. Waahlman, Tetrahedron Lett. 1994, 35, 7185. N. Chida, T. tobe, S. Ogawa, Tetrahedron Lett. 1994, 35, 7249. K. Bougrin, A. K. Bennani, S. F. T6touani, Tetrahedron Lett. 1994, 35, 8373. G. A. Kraus, H. Maeda, Tetrahedron Lett. 1994, 35, 9189. R. E. Johnson, E. R. Bacon, Tetrahedron Lett. 1994, 35, 9327.

Chapter 8 Eight-Membered and Larger Rings GEORGE R. NEWKOME University of South Florida, Tampa, FL, USA 8.1 INTRODUCTION In 1994, numerous reviews and monographs appeared covering diverse subjects in the area of macroheterocyclic chemistry. The various topics include: catalysis by metal ions <93CSR221 >, perfluoro macrocycles <94MI216>, lanthanide macrocyclic complexes <94CSR235>, enzyme models <94RTC343>, phosphorus-containing macrocycles and eryptands <94CR1183>, new porphyrin isomers <94AG(E)1348>, synthesis of aza-crown macrocycles <93MI 1, 93MI611>, template synthesis <94AG(E)375>, [ ln]orthocyelophanes <94MI765>, host-guest chemistry <94COS(4)259>, bis- and oligo(benzocrown ether)s <94CR939>, metallomacrocycles <94CR280, 94CSR235>, carriermediated transport through liquid membranes <94CSR75>, molecular recognition <93CSR388, 94PAC679, 92JCC7, 93PAC2329>, molecular modeling studies on molecular recognition <92JCC7>, TTF crown ethers <94CSR41>, template effect <93CSR221>, crown ether containing polymers <94PPS233, 94PPS(5)871>, catenanes/rotaxanes <94AG(E)803, 94PPS000>, supramolecular structures <94AG(E)803, 94CSR41, 94CR280, 94CI(1) 14>, phenanthroline crown ethers <94CCR229, 94CSR237>, and oxiranes and oxetanes in cationic cyclooligomerization <93T8707>. Because of spatial limitations, only meso- and macrocycles possessing heteroatoms and subheterocyclic rings are reviewed; in general lactones, lactams, and cyclic imides have been excluded. In view of the delayed availability of some articles appearing in 1993, several have herein been incorporated. 315

316

Eight-Membered and Larger Rings

8.2 CARBON-OXYGEN RINGS Chiral O-macrocyclic molecular receptors continue to attract interest in view of their potential to resolve and/or quantify enantiomeric materials. Cycloinulohexaose (1) is a -(2 ~ l)-linked cyclohexaose of fructofuranose, produced from inulin by cycloinulooligosaccharide fructanotransferase and possesses a chiral 18-crown-6 ether core. The one-step disulfonylation of I afforded capped chiral molecular pockets <94TL5661>; where as the permethylated cycloinulohexaose and-heptaose, with various metallic cation guests have been characterized <94JOC2967>. Enantiomeric recognition of organic ammonium cations <94TA1549, 94JOC6539, 94CC711>, crown ethers derived from Dglucose <94TL3629>, and photoionopheres prepared from R,R-(+)-tartaric acid <94CJC 1246> have been prepared. HOTXr-CH20H ~--~.OH HO W r'

.m :)

~10..

9

oo

~ 0 0 HOH2c,HO,,'O~,,..,,0..,,,J

.o

HOI"~C~o H

H c

~L~'~"~'J~" ' 0/-"'~0 "-"~_

~'~'~"~n~ J # 0Y0 . ~ 2

3

An allosteric carrier consisting of three crown ether subunits in which conformational information is transferred through the two biphenyl linkages has been prepared <94JOC2939>. New synthetic approaches to large (30 - 72membered) crown ethers and perfluoro-O-macroeycles <94JA5172> have been reported. Diederich and coworkers have prepared two novel cyclophane receptors shaped by two naphthylphenylmethane spacers and have shown that these cyclophanes bind steroids <95T401>. O-Macrocyr carceplexes, which are spherical shells that can entrap guest molecules, have been designed and shown to be remarkably efficient encapsulators <94JA369>. Other molecular ethereal cavities have been prepared <94TL6555, 94AG(E)1503, 94JA4810, 94JCS(P 1)995, 94JCS(P 1) 1009>. The synthesis of a new bis(crown ether)enediyne (2) via a Pd-catalyzed coupling procedure has been described <94TL3501>. The readily available octamethyltetraoxaquarterene with benzyne gave the tetraadduct 3, as a single isomer but could not be transformed to the corresponding [ 1.1.1.1 ]-paranaphthalenaphane <94T9113>.

Eight-Membered and Larger Rings

317

8.3 C A R B O N - N I T R O G E N RINGS

In general, macrocyclic polyamines have been synthesized by one of several procedures: N-alkylation; lactam or imine formation, followed by reduction; or a Michael-type addition. Metal templation can assist this process, or in many cases the resultant complex can be isolated. A simple synthetic preparation of C-functionalized polyazamacrocycles from the corresponding cyclic peptide has been described <94TL3687>. Large polyaza-macrocycles have been created: the "largest expanded" porphyrin <94AG(E)1509>, "new giant size" azamacrocycles (e.g. 4) <94TL2337, 94CC1119, 94JOC7508>, first synthesis of single "strapped cyclam"-porphyrins <94TL3714>, cyclospermi(di)nes <94TL8609>, and macrocycles possessing rigid linkers, such as the diphenylmethane subunit. A pseudorotaxane, built from a macrocyclic cyclophane containing two aromatic n-acceptors and an acyclic molecule containing three aromatic n-donors, has been reported <94CC 181>. A novel tetraammonium macrotricyclic spherical molecule has been prepared and shown to encapsulate fluoride ion <94TL8393>. Even larger cage-type cyclophanes, constructed with two rigid 2,11,20-triaza[3.3.3]para-cyclophane units and three chiral bridging components, were prepared and studied <94TL 13601>. A new and efficient preparation of cyclic carbodiimides (e.g., 5), involving the reaction of C,C-bis(aryliminophosphoranes) connected by aliphatic bridges with Boc20 in the presence of DMAP is described <94JOC7306>; incorporation of heteroatoms into the tether connecting the aromatic rings is also shown.

Me~.N

" J.',,,'q

~.N~N3 .-

C ~ 3 Me --

C C 'N '!~

4

8.4 CARBON-OXYGEN/CARBON-NITROGEN (CATENANES) In 1960, van Gulick pointed out that the symbol of the International Olympics was structurally related to a pentacatenane, to which he offered the trivial name of"olypiadane" <93NJC619>. Thirty four years later, Stoddart et al. reported <94AG(E)1286> the first molecular compound comprised of a linear array of five interlocked rings and thus the generation of the [5]catcnanc (6). More importantly, self-assembly of this [5]-catenane from the eight

Eight-Membered and Larger Rings

318

components in just two steps was possible by the inclusion of"sufficient molecular recognition into the constituent molecular components".

I

~

,A (-x n

Li-b-{~--

o

I

I ' ~-~i

~o_

o.9-" <.o,_,o o,_,o_> 8

The solid state self-organization of a self-assembled [2]-catenane <94CC2475, 94M1159>, the two step self-assembly of [4]- and [5]-catenanes <94AG(E)433>, and the highly selective translation isomerization of [2]catenanes <94CC2479> has been reported. 8.5 CARBON-SULFUR RINGS The synthetic routes to S-macrocycles have been rather limited; generally allyl, alkyl or benzyl halides have been treated with mercaptides in the presence of cesium ion. Thus, dithiametacyclophanes with triple bonds <94CB 1533>, dithiacyclophanes <95T787>, dithia[3.3 ](1,3)(1,4)cyclophanes <94JOC3381>, thiacrown ethers <94TL2095, 94IC2448, 94JCS(P2)1309>, phthalocyanines with peripherally fused tetrathiamacrocycles <94HCA 1616>, ditopic thiacyclophanes <94JCS(P1)1883, 94IC2663>, and symmetric octathio bis(calix[4]arene) cages (7) OR <94JOC4313> exemplify the Ro 9 OR process. The intermolecular cyclization of 1,3-bis(2-bromoethyl)adamantano with thioacetamido using high dilution s/ s' conditions gave 8 in 34% as well as the trimer and disulfide analogue < <94CB 1327>. Criteria to judge the degree of structural preorganization in the study of known and the design of new thiocrown ethers have been RO reported <94JCS(D)2243>. IR

,> ,!

9

Eight-Memberedand LargerRings

319

8.6 CARBON-SELENIUM RINGS Treatment of 2,5-dimethyl-2,5-dichloro-3-hexyne and 2,7-dimethyl2,5-dichloro-3,5-octyne with Na2Se deposited on A1203 gave 3,4,7,8-tetraisopropylidene- 1,2,5,6-tetraselenaoctane (20%) and 2,5,7,10-tetraisopropylidene1,6-diselenacyclodeca-3,8-diyne (10%), respectively; the X-ray structure of the later confirmed the assignment <94TL8779>. 8.7 CARBON-SILICON RINGS The multiple Pd(0)-catalyzed coupling reactions of 9-borobicyclo[3.3.1 ]nonane adducts of allylsilanes and bromobenzenes were used to prepare unusual silametacyclophanes <94OM3728>; for example, methyltriallylsilane and 1,3,5-tribromobenzene afforded 4-methyl-4-sila[34'~~

(9). 8.8 CARBON-GERMANIUM RINGS Although a variety of di- and tetragermemacrocycles possessing from 10- to 44-membered rings has been reported <92JCS(P2)2217>, the recent synthesis of halo or phenyl substituted 1,8-digermacyclotetradecanes has lead to the first germamacrocycles with anion transport capability <94JCS(P2)1549>. 8.9 CARBON-OXYGEN/CARBON-NITROGEN-OXYGEN RINGS (CATENANES) The absorption, emission, and excitation spectra as well as the luminescence quantum yields and lifetimes of the emitting excited states of a [3]-catenand, comprised of a central 44-membered ring possessing two 1,10phenanthroline subunits interlocked with two 30-membered rings each with one 1,10-phenanthroline subunit, and its metal complexes have been evaluated <94JA5211 >. Complexes of catenanes possessing two interlocking 30membered rings with 2,9-diphenyl-1,10-phenanthroline subunits have been structurally and electrochemically studied <94IC3498>. The self assembly of an optically active [2]-catenane possessing a chiral hydrobenzoin subunit on one of the components has been made to order <94TL4835>.

8.10 CARBON-OXYGEN/CARBON-NITROGEN-SULFUR RINGS (CATENANES) The template directed construction of two new [2]-catenanes possessing bisparaphenylene-34-crown-10 interlocked with tetracationic

320

Eight-Membered and Larger Rings

cyclophanes containing either one or two 2,5-disubstituted thiophene subunits in addition to two bipyridinium subunits, has been reported <94S 1344>. 8.11 (CARBON-NITROGEN-OXYGEN)" RINGS

8.11.1 (CARBON-NITROGEN-OXYGEN)"(n=l) RINGS The N-attachment of monoaza crown ethers to diverse molecules has been readily accomplished. Fullerene-azacrown ethers were formed by simply stirring one equivalent of the azacrown with a toluene solution of C6o at ambient temperature for 48 h <94CC397>. Whereas the preparation of bis-pyrazolyl methane bis-azacrown was via an alkylation in the presence of silver ion, the resultant polyheterotopic molecular receptor showed negative allosteric cooperation with Zn(II) <94TL 1295>. Azacrown ethers have been attached to numerous molecules and reported to possess novel characteristics, such as: with substituted phenyl groups, the assembly of ordered bilayer membranes <94CC1965>, with cryptand spirobenzopyrans, highly sensitive and selective signaling receptors <94AG(E)I 163>; with N-side arms (amides or esters), cation transport <94JA690, 94JA3087, 94JA6832>; and with phenols, enhanced completion especially with alkaline-earth cations <94JCS(P 1) 1489). The related bibracchial lariat ethers have been prepared by similar procedures and shown to give rise to high affinity, fluorescent probes for potassium <94JCS(P2) 1615>, to complexes possessing two <94JCS(D)3325> or more <94TL7779> metal cations, and to molecular boxes as well as aggregates via H-bonded associations <94JA6089> when the side arms are terminated with adenine or thymine. Poly(oxa-aza)macrocycles, as "compartmental" macrocyclic receptors, have been reported <94IC617, 94TL8469, 94CC881, 94AJC 115, 94JCS(P2)815>. Circular dichroism spectroscopy has proven useful in the case of lariat ethers with chiral appendages <94TL681>. The one-step synthesis of 1,3-calix[4]-bis(diazabenzo) crown ethers, which combined a calix[4]arene unit with two diazabenzo crown ethers, in a highly symmetric manner has been demonstrated <94TL8369>.

A bis-porphyrin infrastructure has been incorporated within a rigid azaether framework and shown to accept two catalytic metal ions in an isolated environment <94T11339>. 8.11.2 (CARBON-NITROGEN-OXYGEN) n (n>l) RINGS (CATENANES) The elegant synthesis of the first doubly interlocked [2]-catenane (10) was based on the three-dimensional template effect of Cu(I); the concept

Eight-Membered and Larger Rings

321

utilizing double-stranded multimetallic helicoidal complexes is depicted below <94JA375>. A doubly interlocked [2]-catenane and its topological stereoisomer have been studied by FAB-and ESIMS <94CC2257>. The synthesis and characterization of interlocking basket handle porphyrins in which the subunits are assembled by means of the Cu(I) complex of phenanthroline subunits within the framework was reported <94TL3289>.

o

10

8.12 CARBON-SULFUR-OXYGEN RINGS A stable and convenient sulfur transfer reagent, benzyltriethylammonium tetrathiomolybdate {(C6H5CH2NEt3)2MoS4}, has been used in the synthesis of a variety of dithia-r ethers and medium to large (7 - 20-membered) rings possessing the disulfide linkage <94JOC 1354>. Sulfone crown ether 11 has been prepared (26% overall yield) in six-steps and in alkaline aqueous buffer it was shown to cleave supercoiled DNA <94TL 1023>. An improved synthesis of 1,4,7,10-tetraoxa- 13,16-dithiacyclooctadec- 14-en14,15-dicarbonitrile has been reported and shown to complex Hg(II) in the solid state only through the O-donor atoms <94CC1751>. Oxadithia-m-cyclophanes have been prepared and transformed to the corresponding S,S,C-Pd-complexes, which behave as metalloreceptors, selectively binding substrate molecules <94CC1848, 94IC4351>. 3,3'-Crown ether-bridged 2,2'-bithiophene (12) has been prepared and shown to form self-assembled complexes with paraquat; the Pd-r cross-coupling of the organozinr derivative of 12 with 2,5dibromo-3-decylthiophene afforded (>98%) a novel macrocyclir polymer <94JA9347>.

322

Eight-Membered and Larger Rings

"1 o 11

o ~ . . . j O ~ . / o.) 12

8.13 CARBON-NITROGEN-SULFUR RINGS

The preparation and characterization of new thionitrites from cysteamine and mercaptoethanol have been reported <94JOC7019>; in general the dithiaalkanedial was treated with a diamine, followed by sodium borohydride reduction of the intermediate cyclic diimine. Novel complexes of macrocycles composed of two 1,10-phenanthroline moieties connected by a single carbon or nitrogen atom possess poor water solubility; whereas, the complexes of his(l, 10-phenanthroline)[2,1,10,9-bcdef2', 1', 10',9'-ijklm][ 1,8]dithia-[3,6,10,13]tetraazacyclotetradecine, prepared from 9-chloro- 1,10phenanthroline-2(1H)-thione with base, were water soluble <94CSJ 1147>. The synthesis, absolute configuration, chiroptical properties and H-bonding of helical-chiral strained [2.2]cyclophane possessing an unsubstituted nitrogen in the bridge have been noted <94CC 1361>. 8.14 CARBON-OXYGEN-PHOSPHORUS RINGS

The synthesis of a new bis(phosphotriester) macrobicyclic polyether cryptand, O=P[O(CH2)20(CH2)20(CH2)20]3P=O, called phosphocrypt, has been described <94JOC7695>. The synthesis of four 1,1 '-binaphthyl-based macrocyclic bisphosphane ligands (e.g., 13), in both racemic and optically forms, has been reported <94CB 1411>; their square planar cis-P2-Metal (Ni & Pd) complexes have also been established <94CB 1411, 94HCA409>. 8.15 CARBON-NITROGEN-SILICON RINGS

The synthesis of macrocycle 14, composed of two 2,2'-bipyridine subunits interconnected by two CH2SiCH2 moieties, was prepared from bislithio salt of 4,4'-dimethyl-2,2'-bipyridine and the commercially available dichlorodiphenylsilane <94TL7233>; the crystal structure was also reported.

Eight-Membered and Larger Rings 8.16

323

C A R B O N - N I T R O G E N - S U L F U R - O X Y G E N RINGS

Cyclization of 1,8-diamino-3,6-dioxaoctane with 1,8-diiodo-3,6-dithia4,4,5,5-tetrafluorooctane gave 1,4-dithia-7,16-diaza- 1O,13-dioxa-2,2,3,3-tetrafluorocyclooctadecane in 30% yield, which upon further treatment with the diiodo compound produced cryptand 15 <94IC6123>.

13

14

15

8.17 CARBON-NITROGEN-SULFUR-OXYGEN/CARBONNITROGEN-OXYGEN RINGS (CATENANES) Since tetrathiafulvene (TTF) is well known to be a good electron donor (reversibly oxidized at 0.30 V vs SCE) as well as the inherent chemical stability of its cation radical, it was incorporated into a macrocycle possessing the 2,9diphenyl-l, 10-phenanthroline subunit, previously described by Sauvage and his coworkers; the Cu(I) [2]-catenate was synthesized and characterized <94TL4339>. 8.18 CARBON-NITROGEN-PHOSPHORUS-OXYGEN RINGS Although imines have generally not been included in the Chapter, there, however, needs to be one exception. Majoral and his coworkers utilized the previously unknown thioxobis( l-methylhydrazino)phosphoranyl azide in the preparation of macrocycles, cryptands and spherands, such as 16. All compounds are isolated in a pure form and are colorless to yellow stable solids. 8.19 CARBON-METAL RINGS

Ph S Me.,N..~P'CN,Me H ~!~ H /'13 Ph S ~I=c'\ Me,,I~P":wMe

=~

h=

I.I,C=N N~C: H M~p~P~31~Me 16

The template effect observed in the synthesis of carborane-supported macrocycles, mercuracarborands, as well as their characterization and host-guest

Eight-Membered and Larger Rings

324

complexes have been described <94JA7142>. It has been shown that the cyclic pentameric perfluoroisopropylidene-mercury {[(CF3)2CHg]5 } is capable of forming complexes with [PPh4]§ (X') <93JOMC 19>. The synthesis of the first diosma[7.7]cyclophanes, possessing four metal a bonds, has been achieved via bis cationic alkylation of Na2[Os(CO)4] with the bis(trifluoromethanesulfonates in dimethyl ether; the related diferracyclophanes were accessible by a similar procedure <94AG(E)321 >. 8.20 CARBON-NITROGEN-METAL RINGS

Stang and Cao have reported the novel preparation and characterization of platinum- and palladium-based cationic, tetranuclear, macrocyclic complexes __ 8 9

N

N

f"~o ~0 / L,, o

OCt. Phz "~o,,,"co oc," I'~ PhzP CO

19 8 "OSO=CF3

17

/N

I

cI--F~d--Cl

cI--Pd--CI

/

~_ ~ . , . , c , _ ,

~ i--,,~~.,~

0 18

~_

Eight-Memberedand Larger Rings

325

(17), via a self-assembly process <94JA4981>. The related reaction o f cisP2Pt(-C6H4CN)z with cis-PzPt (or Pd) (OSO2CF3) 2 gave the related mixed, neutral-charged, tetranuclear Pt-Pt and Pt-Pd macrocyclic complexes in excellent yields <94OM3776>. Complexation o f cis or trans meso-dipyridyl porphyrins by cis or trans substituted metal ions [Pd(II) or Pt(II)] o f square planar coordination afforded a self-assembly o f multiporphyrin arrays (18) o f square planar architecture

8.21

CARBON-PHOSPHORUS-OXYGEN-METAL

RINGS

The first example o f a metalla crown ether with trans-coordinated Pdonor groups has been reported <94OM 1542> by the photoisomerization of the known cis-Mo(CO)4{Ph2P(CH2CH20)4CH2CH2PPh2-P,P'} to yield 19; reaction conditions were shown to be critical, with highest yields (45%) occurring when the reaction was conducted in THF under nitrogen for 12 minutes.

8.22 REFERENCES 92JCC7 92JCS(P2)2217 93CC1848 93CSR221 93CSR383 93JOMCI9 93M1611 93NJC619 93PAC2329 93T8707 94AG(E)321 94AG(E)375 94AG(E)433 94AG(E)803 94AG(E) l 163 94AG(E)1286 94AG(E)1348 94AG(E)1503 94AG(E)1509 94AG(E)1625 94AJC1155

G. Wipff, J. Coord. Chem. 1994, 27, 7. A. Aoyagi, K. Tanaka, I. Ziemane, & Y. Takeuehi, J. Chem. Soc., Perkin Trans 2, 1992, 2217. J. E. Kickham & S. J. Loeb, J. Chem. Soc., Chem. Commun. 1994, 1848. R. Cacciapaglia & L. Mandolini, Chem. Soc. Rev. 1993, 221. T. H. Webb & C. S. Wilcox, Chem. Soc. Rev. 1993, 383. V. B. Shut, I. A. Tikhonova, F. M. Dolgushin, et al., J. Organomet. Chem. 1994, 443, C 19. K. E. Krakowiak, J. S. Bradshaw, & R. M. Izatt, Synlett 1993, 611. N. Van Gulick, New J. Chem. 1993, 17, 619. H.J. Schneider, T. Blatter, A. Eliseev, et al., Pure Appl. Chem. 1993, 65, 2329. J. Dale, Tetrahedron 1993, 49, 8707. E. Linder, W. Wassing, R. Fawzi, & M. Steimann, Angew. Chem. Int. Ed. Engl. 1994, 33, 321. R. Hoss & F. V0gtle, Angew. Chem. Int. Ed. Engl. 1994, 33, 375. D. B. Amabilino, P. R. Ashton, A. S. Reder, et al., Angew. Chem. Int. Ed. Engl. 1994, 33, 433. G. Wenz, Angew. Chem. Int. Ed. Engl. 1994, 33, 803. M. Inouye, Y. Noguchi, & K. Isagawa, Angew. Chem. Int. Ed. Engl. 1994, 33, 1163. D. B. Amabilino, P. R. Ashton, A. S. Reder, et al., Angew. Chem. Int. Ed. Engl. 1994, 33, 1286. J. L. Sessler, Angew. Chem. Int. Ed. Engl. 1994, 33, 1348. P. R. Ashton, D. Joachimi, N. Spencer, et al., Angew. Chem. Int. Ed. Engl. 1994, 33, 1503. J. L. Sessler, S. J. Weghorn, V. Lynch, & M. R. Johnson, Angew. Chem. Int. Ed. Engl. 1994, 33, 1509. B. R. Peterson & F. Diederich, Angew. Chem. lnt Ed. Engl. 1994, 33, 1625. I. M. Atkinson, L. F. Lindoy, O. A. Matthews, et al., Aust. J. Chem. 1994, 47, 1155.

326

94CB1327 94CB 1411 94CB1533 94CC181 94CC397 94CC711 94CC881 94CC 1119 94CC1361 94CC1751 94CC1965 94CC2257 94CC2313 94CC2475 94CC2479 94CCR229 94CI14 94CJC1246 94COS259 94CR280 94CR939 94CR1183 94CSJ 1147 94CSR41 94CSR75 94CSR235 94CSR327 94HCA409 94HCAI616 941C617 94IC2448 94IC2663 941C3498 941C4351 941C5541 941C6123 94JA369

Eight-Membered and Larger Rings

K. Mlinaric-Majerski, D. Pavlovic, M. Luic, & B. Kojic-Prodic, Chem. Ber. 1994, 127, 1327. M. Widhalm & G. Klintschar, Chem. Ber. 1994, 127, 1411. Y. Dai, H. Kolshom, & H. Meier, Chem. Ber. 1994, 127, 1533. P. R. Ashton, D. PhUp, N. Spencer, et al., J. Chem. Soc., Chem. Commun, 1994, 181. S. N. Davey, D. A. Leigh, A. E. Moody, et al., J. Chem. Soc., Chem. Commun. 1994, 397. K. Naemura, S. Takeuchi, M. Asada, et al., J. Chem. Soc., Chem. Commun. 1994, 711. C. Bazzicalupi, A. Bencini, A. Bianchi, et al., J. Chem. Soc., Chem. Commun. 1994, 881. C. Bazzicalupi, A. Bencini, V. Fusi, et al., J. Chem. Soc., Chem. Commun. 1994, 1119. D. Mtlller, M. Nieger, & F. V0gtle, J. Chem. Soc., Chem. Commun. 1994, 1361. J. W. Sibert, S. J. Lange, C. Stem, et al., J. Chem. Soc., Chem. Commun. 1994, 1751. Z. Tai, X. Qian, L. Wu, & C. Zhu, J. Chem. Soc., Chem. Commun. 1994, 1965. C. Dietrich-Buchecker, E. Leize, J.-F. Nierengaxten, et al., J. Chem. Soc., Chem. Commun. 1994, 2257. C. M. Drain & J.-M. Lehn, J. Chem.Soc., Chem. Commun. 1994, 2313. D. B. Amabilino, P. R. Ashton, J. F. Stoddart, et al., J. Chem. Soc., Chem. Commun. 1994, 2475. D. B. Amabilino, P. R. Ashton, G. R. Brown, et al., J. Chem. Soc., Chem. Commun. 1994, 2479. A. Harriman, V. Heitz, J.-C. Chambron, & J.-P. Sauvage, Coord. Chem. Rev. 1994, 132, 229. D. R. Smith, Chem. Ind. (London) 1994, 14. T. M. Fylcs & V. V. Suresh, Can. J. Chem. 1994, 72, 1246. J. D. Kilbum & H. K. Patel, Contemp. Org. Syn. 1994, 1 (4), 259. F. C. J. M. van Veggel, W. Verboom, & D. N. Reinhoudt, Chem. Rev. 1994, 94, 280. H. An, J. S. Bradshaw, R. M. Izatt, & Z. Yan, Chem. Rev. 1994, 94, 939. A.-M. Caminade & J. P. Majoral, Chem. Rev. 1994, 94, 1183. M. Hirai, K. Shinozuka, H. Sawai, & S. Ogawa, Bull. Chem. Soc. Jpn. 1994, 67, 1147. T. J~rgensen, T. K. Hansen, & J. Becher, Chem. Soc. Rev. 1994, 41. H. C. Visser, D. N. Reinhoudt, & F. de Jong, Chem. Soc. Rev. 1994, 75. F. Amaud-Neu, Chem. Soc. Rev. 1994, 23, 235. P. G. Sammes & G. Yahioglu, Chem. Soc. Rev. 1994, 23, 327. M. Widhalm, G. Kalchhauser, & H. Kahlig, Helv. Chim. Acta 1994, 77, 409. A. G. Gtlrek & O. Bek~oglu Heir. Chim. Acta 1994, 77, 1616. A. AndrOs, C. Bazzicalupi, A. Bencini, et al., Inorg. Chem. 1994, 33, 617. J. J. H. Edema, J. Buter, F. S. Schoonbeek, et al., Inorg. Chem. 1994, 33, 2448. B. de Groot, S. J. Loeb, & G. K. H. Shimizu, Inorg. Chem. 1994, 33, 2663. C. O. Dietrich-Buchecker, J. Guiihem, & J.-M. Kern, Inorg. Chem. 1994, 33, 3498. J. E. Kickham & S. J. Loeb, Inorg. Chem. 1994, 33, 4351. C. F. Martens, R. J. M. K. Gebbink, M. C. Feiters, et al., Inorg. Chem. 1994, 33, 5541. H. Plenio, Inorg. Chem. 1994, 33, 6123. R. G. Chapman, N. Chopra, E. D. Cochien, & J. C. Sherman, J. Am. Chem. Soc. 1994, 116, 369.

Eight-Membered and Larger Rings

94JA375 94JA690 94JA3087 94JA4810 94JA4981 94JA5007 94JA5172 94JA5211 94JA6089 94JA6832 94JA7142 94JA9347 94JCS(D)2243 94JCS(D)3325 94JCS(Pl)995 94JCS(Pl)1009 94JCS(Pl)1489 94JCS(PI)I883 94JCS(P2)815 94JCS(P2)1309 94JCS(P2)1549 94JCS(P2)I615 94JOC1354 94JOC 1694 94JOC2186 94JOC2939 94JOC2967 94JOC3381 94JOC4313 94JOC6539 94JOC7019 94JOC7306 94JOC7508 94JOC7695 94M1216 94M1765 94M 1159 94OM1542

327

J.-F. Nierengarten, C. O. Dietrich-Buchecker, & J.-P. Sauvage, J. Am. Chem. Soc. 1994, 116, 375. Q. Xie, Y. Li, G. Gokel, et al., J. Am. Chem. Soc. 1994, 116, 690. Y. Li, G. Gokel, J. Hern~mdez, & L. Echegoyen, J. Am. Chem. Soc. 1994, 116, 3087. M. J. Gunter, D. C. R. Hockless, M. R. Johnston, et al., J. Am. Chem. Soc. 1994, 116, 4810. P. J. Stang & D. H. Cao, J. Am. Chem. Soc.1994, 116, 4981. J. Mitjaville, A.-M. Caminade, R. Mathieu, & J.-P. Majoral, J. Am. Chem. Soc. 1994, 116, 5007. T.-Y. Lin, W.-H. Lin, W. D. Clark, et al., J. Am Chem. Soc. 1994, 116, 5172. N. Armaroli, V. Balzani, F. Barigelletti, et al., J. Am. Chem. Soc. 1994, 116, 5211. O. F. Schall & G. W. Gokel, J. Am. Chem. Soc. 1994, 116, 6089. Y. Li & L. Echegoyen, J. Am. Chem. Soc. 1994, 116, 6832. X. Yang, C. B. Knobler, Z. Zheng, & M. F. Hawthorne, J. Am. Chem. Soc. 1994, 116, 7142. M. J. Marsella, P. J. Carroll, & T. M. Swager, J. Am. Chem. Soc. 1994, 116, 9347. G. A. Forsyth & J. C. Lockhart, 3'. Chem. Soc., Dalton Trans 1994, 2243. D. Wang, H. Xiang, G. Wang, et al., J. Chem. Soc., Dalton Trans 1994, 3325. M. J. Gunter & M. R. Johnston, J. Chem. Soc., Perkin Trans I 1994, 995. M. J. Gunter, M. R. Johnston, B. W. Skelton, & A. H. White, J. Chem. Soc., Perkin Trans I 1994, 1009. N. G. Lukyanenko, V. N. Pastushok, A. V. Bordunov, et al., J. Chem. Soc., Perkin Trans I 1994, 1489. L. R. Hanton & H. Sikanyika, J. Chem. Soc., Perkin Trans I 1994, 1883. C. Bazzicalupi, A. Bencini, A. Bianci, et al., J. Chem. Soc, Perkin Trans 2, 1994, 815. J. C. Lockhart, D. P. Mousley, G. A. Forsyth, et al., J. Chem. Soc., Perkin Trans 2 1994, 1309. S. Aoyagi, K. Tanaka, & Y. Takeuchi, J. Chem. Soc., Perkin Trans 2 1994, 1549. R. Crossley, Z. Goolamali, & P. G. Sammes, J. Chem. Soc., Perkin Trans 2 1994, 1615. A. R. Ramesha & S. Chandrasekaran, J. Org. Chem. 1994, 59, 1354. M. C. Bheda, J. S. Merola, W. A. Woodward, et al., J. Org. Chem. 1994, 59, 1694. H. W. Gibson, M. C. Bheda, P. Engen, et al., J. Org. Chem. 1994, 59, 2186. A. M. Costero & M. Pitarch, J. Org. Chem. 1994, 59, 2939. Y. Takai, Y. Okumura, T. Tanaka, et al., J. Org. Chem. 1994, 59, 2967. Y.-H. Lai, A. H.-T. Yap, & I. Novak, J. Org. Chem. 1994, 59, 3381. M. T. Blanda & K. E. Griswold, J. Org. Chem. 1994, 59, 4313. Y. Li, L. Echegoyen, M. V. Martinez-Diaz, et al., J. Org. Chem. 1994, 59, 6539. B. Roy, A.d.M. D'Hardemare, & M. Fontecave, J. Org. Chem. 1994, 59, 7019. P. Molina, M. Alajarln, & P. S~inchez-Andrada, J. Org. Chem. 1994, 59, 7306. C. Bazzicalupi, A. Bencini, V. Fusi, et al., J. Org. Chem. 1994, 59, 7508. C. B. Allan & L. O. Spreer, J. Org. Chem. 1994, 59, 7695. R. J. Lagow, T. Y. Lin, H. W. Roesky, et al. ACS Syrup. Set. 1994, 555, 216. W. Y. Lee, Synlett 1994, 765. D. B. Amabilino, J. F. Stoddart, & D. J. Williams, Materials 1994, 6, 1159. G. M. Gray & C. H. Duffey, Organometallics 1994, 13, 1542.

328

94OM3728 94OM3776 94PAC679 94PPS000 94PPS233 94PPS871 94RTC343 94S1344 94T2095 94T9113 94T11339 94T13601 94TA1549 94TL681 94TL1023 94TL1295 94TL2337 94TL3289 94TL3501 94TL3629 94TL3687 94TL3719 94TL4339 94TL4835 94TL5661 94TL6555 94TL7233 94TL7779 94TL8369 94TL8393 94TL8469 94TL8609 94TL8779 95T401 95T787

Eight-Membered and Larger Rings

W. R. Kwochka. R. Damrauer, M. W. Schmidt, & M. S. Gordon, Organometallics 1994, 13, 3728. P. J. Stang & J. A. Whiteford, Organometallics 1994, 13, 3776. W. Verboom, D. M. Rudkevich, & D. N. Reinhoudt, Pure/lppl. Chem. 1994, 66, 679. H. W. Gibson, M. C. Bheda, & P. T. Engen, Prog. Polym. Sci. 1994, 000. U. Tunca & Y. Yagci, Prog. Polym. Sci. 1994, 19, 233. M. Komiyama, Prog. Polym. Sci. 1994, 18, 871. A. M. Reichwein, W. Verboom, & D. N. Reinhoudt, Rec. Tray. Chim. PaysBas 1994, 113, 343. P. R. Ashton, J. A. Preece, J. F. Stoddart, et al., Synthesis 1994, 1344. J. J. H. Edema, J. Buter, & R. M. Kellogg, Tetrahedron 1994, 50, 2095. F. H. Kohnke, M. F. Parisi, F. M. Raymo, et al., Tetrahedron 1994, 50, 9113. H.-Y. Zhang, J.-Q. Yu, & T. C. Bruice, Tetrahedron 1994, 50, 11339. O. Hayashida, S. Matsuura, & Y. Murakami, Tetrahedron 1994, 50, 13601. K. Naemura, T. Mizo-oku, K. Kamada, et al., Tetrahedron: Asymmetry, 1994, 5, 1549. D. Gu, B. D. Kenney, B. W. Brown, Tetrahedron Lett. 1994, 35, 681. S. M. Kerwin, Tetrahedron Lett. 1994, 35, 1023. J. C. Rodriguez-Ubis, O. Juanes, & E. Brunet, Tetrahedron Lett. 1994, 35, 1295. V. Panetta-Le Mer, J.-J. Yaouanc, & H. Handel, Tetrahedron Lett. 1994, 35, 2337. M. Momenteau, F. Le Bras, & B. Loock, Tetrahedron Lett. 1994, 35, 3289. B. KOnig & H. ROtters, Tetrahedron Lett. 1994, 35, 3501. N. S. Mani & P. P. Kanakamma, Tetarhedron Lett. 1994, 35, 3629. K. W. Aston, S. L. Henke, A. S. Modak, et al., Tetrahedron Lett. 1994, 35, 3687. B. Boitrel & R. Guilard, Tetrahedron Lett. 1994, 35, 3719. T. Jorgensen, J. Becher, J.-C. Chambron, & J.-P. Sauvage, Tetrahedron Lett. 1994, 35, 4339. P. R. Ashton, I. Iriepa, M. V. Reddington, et al., Tetrahedron Lett. 1994, 35, 4835. M. Atsumi, M. Mizuochi, K. Ohta, & K. Fujita, Tetrahedron Lett. 1994, 35, 5661. R. G. Janssen, W. Verboom, J. P. M. van Duynhoven, et ai., Tetrahedron Lett. 1994, 35, 6555. C. Kaes, M. W. Hosseini, R. Ruppert, et al., Tetrahedron Lett. 1994, 35, 7233. E. Graf, M. W. Hosseini, & R. Ruppert, Tetrahedron Lett. 1994, 35, 7779. S. Wenger,.Z. Asfari, & J. Vicens, Tetrahedron Lett. 1994, 35, 8369. M. A. Hossain & K. Ichikawa, Tetrahedron Lett. 1994, 35, 8393. C. Bazziealupi, A. Bencini, A. Bianchi, et al., Tetrahedron Lett. 1994, 35, 8469. G. Brand, M. W. Hosseini, & R. Ruppert, Tetrahedron Lett. 1994, 35, 8609. R. Gleiter, H. R0ckel, & B. Nuber, Tetrahedron Lett. 1994, 35, 8779. B. R. Peterson, P. Wallimann, D. R. Carcanague, & F. Diederieh, Tetrahedron 1995, 51,401. U. K. Bandarage, L. R. Hanton, & R. A. J. Smith, Tetrahedron 1995, 51, 787.

SUBJECT INDEX

330

Subject Index

Acridinium salts, 205 Alkoxypyrazoles, 13 Alkyl substituted 3-nitropyridines, 207 Alkyl-2-arylpyrroles, 108 Alkylidene butyrolactones, 137 Alkylpyrrole-3-carboxylates, 109 Amino pyrrolones, 9 Amino-2, 6-diethylpyridine, 195 Amino-7-quinoline carbaldehyde, 215 Aminopyrroles, 4 Acyclovir, analogues, 262 Antibacterial agents, 236 Artemisinin, 287 AJyl-4-quinolone, 215 Arylpyridines, 201 Avermectins, 268 Azaoxindoles, 112 Azepines, 294 Azetidinones, 72 Aziridines, 58, 59 Baeyer-Villeger oxidation, 299 Beckmann rearrangement, 298 Benzo [ b ] furans, 140 Benzo [b ] carbazole diones, 111 Benzodioxane, 287 Benzodioxole-2-thiones, 166 Benzodioxoles, 165, 166, 167 Benzodithioles, 171 B e n z o f u r ~ , 247 Benzofuro-2H-thiapyrans, 132 Benzothiazepine, 307 Benzotriselenoles, 174 Benzotrithiole 2-oxides, 174 Benzoxathiole S-oxides, 173 Benzoylisothiochromene, 285 Bidihydropyrans, 270 Biflavonoid, 281 Bipyridine, 216 Bithiophene, 321 Boretanes, 70 Bromo-2-methoxy-6-methylpyridine, 208 Bromochromenes, 272 Bromoindole, 114 Butoxycarbonylisoindole, 113 Butyl-2-methylpyridine, 200 Butyldimethylsilyl-3-1ithioindole, 113 Butyldimcthylsilylindol ylzinc chloride, 114

Carbazole alkaloids, 121 Carbazoles, 122, 123 Carbolines, 124, 206 Carbomethoxy vinyl indoles, 108 Carceplexes, 316 Catenanes, 315, 317, 319 Cephalotaxine, 298 Cervinomycin, 282 Chiral (salen)Mn(III)catalysts, 44 Chiral nickel and copper complexes, 300 Chiral piperidine, 203 Chloro-2,6-dimethylpyridine-N-oxide, 208 Chloropyridine, 210 Chloropyrroles, 109 Chroman-4-ols, 274 Chroman-4-ones, 280 Chronmn, 272 Chromenes, 271 Chromone, 278 Claisen rearrangement, 277 Cope elimination, 68 Coumarins, 277 Cross-coupling reaction, 86 Cryptands, 315 Cyclic hydroxamic acids, 218 Cyclization of indoles, 119 Cycloaddition reaction, 83, 227 Cycloinulohexaose, 316 Cyclophanes, 316 Cyclopropane, 74 Darzens-type reaction, 59 Deaza-5-thiapterins, 249 D~7~guanine, 248 Dehydrotryptophan, 116 Diaminopyrroles, 7 Diarylpyrroles, 108 Diazetidines, 69 Diazoamides, 74 Dibromopyridine, 208 Didehydrotropone, 302 Diels-Alder reaction, 122, 123, 195 Dihydro-2 I-I-pyrans, 268 Dihydro-2-pyridone, 198 Dihydrobenzo[b]thiophene, 290 Dihydrofuraldehydes, 137 Dihydroisocoumarins, 278 Dihydropyrans, 269

Subject Index Dihydropyridines, 204 Dihydrothiophene- 1, l-dioxide, 94 Dinaphthodioxin, 287 Dioxanes, 286 Dioxaphenalene, 274 Dioxathianes, 286 Dioxepine, 305 Dioxetanes, 69 Dioxin-4-one, 286 Dioxinones, 286 Dioxins, 286 Dioxiranes, 56 Dioxolan-2-ones, 1,3, 165, 166 Dioxolan-4-ones, 1,3, 165, 166, 167 Dioxolane-2-thiones, 1,3-, 166 Dioxolanes, 1,2-, 173 Dioxolanes, 1,3-, 165, 166 Diphenyl-4-pyridylcarbinol, 205 Dithiacyclophanes, 318 Dithianes, 286, 288, 290 Dithiatanes, 69 Dithiins, 288 Dithiol-2-ones, 1,3-, 168, 169 Dithiol-3-ones, 1,2-, 174 Dithiolanes, 1,2-, 173 Dithiolanes, 1,3-, 168, 171, 172 Dithiolanetrithione, 1,3-, 170 Dithiole-2-thiones, 1,3-, 168, 169 Dithiole-3-thiones, 1,2-, 173, 174 Dithiole-2-selenones, 1,3-, 168 Dithioles, 1,2-, 173 Dithioles, 1,3-, 168, 169, 170, 171 Dithiolium salts, 1,3-, 168 Eburnamonine, 122 Electrocyclic reaction, 89, 90 Electrophilic amination, 233 Ellagitannins, 277 Epoxides, 43 Flavanoids, 268 Flavones, 279 Flavonols, 282 Fluoropyrrole-2-carboxylate esters, 109 Folic Acid, 249 Friedel-Crafls reaction, 91,118 Friedlander condensation, 215 Fructofuranose, 316 Fullerene, 181

331

Furan-,g-oligothiophenes, 132 Furanoacetylene phytoalexins, 133 Furo-2H-thiapyrans, 132 Fused bipyrans, 271 Fused xanthines, 262 Germamacrocycles, 319 Gilvocarcins, 277 Glycidyl acetates, 55 Grubbs' ruthenium catalyst, 296 Halocinnolines, 227 Halogenated thiophene, 85 Hammick reaction, 209 Hapalindole 0, 124 Heck reaction, 111,297, 305 Hegedus-type cyclization, 117 Heteroarylpyrroles, 108 Heterocyclization, 88 Hexahydropyridazines, 227 Histamine H2-receptor antagonist, 236 HIV-I reverse transcriptase inhibitors, 236 Hydrodesulfurization (HDS), 83 Hydroxy-2-pyridone, 212 Hydroxy-7-azabenzotriazole, 211 Hydroxybenzofurans, 141 Hydroxypyranones, 131 Hyellazole, 123 Imidazo [4, 5-b.] naphthyridine, 253 Imidazopyrazolopyrimidine, 255 Indole, 3H-, 106 Indole-3-car~xylates, 108 Indoles, reactions of, 123 Indolones, 120 Indolylpalladium(II), 116 Intramolecular ene reaction, 235 Isatins, 112 Isobenzofuranophane, 141 Isochromanols, 274 Isochromans, 274 Isocoumadns, 277 Isoquinolines, 213 Isothiochromans, 285 Isoxazoles, 179 Isoxazolidines, 181 Isoxazolines, 181 Ketipin acid dilactone, 139 Ketoiminato Mn(III) complex, 48 Lariat ethers, 320

332

Subject Index

Lentignosine, 219 Lewis-acid catalyzed rearrangement, 54 Lithiation reactions, 238 Lithiofuran, 130 Lithioindole synthon, 113 Lithiothiophene, 85 Lupinine, 218 Lutidine, 196 Lysergic acid, 125 Macrocycles, 315 Metal halogen exchange, 233 Metalloporphyrins, 44 Methosycarbazoles, 122 Methoxy-6-methylpyridine, 208 Methyl-5, 6-dimethylenepyrimidone, 235 Methylchroman-4-one, 281 Methyleneazetidines, 65 Methylenechroman-2, 4-dione, 277 Methylenefurans, 138 Methylenetetrahydrofurans, 135 Methylquinolinium ion, 214 Milbemycins, 268 Minaprine, 229 Mitsunobu cyclization, 73 Molecular recognition, 315 Monomorine, 118 N-Aminopyridinium salt, 217 N-arylpiperidones, 219 N-substituted azaaromatics, 205 Naphthopyran, 274 Naphthyridine, 205 Nazarov q,'clization, 124 Nicolas-type complexes, 52 Nitroflavenes, 272 Nitropyridine, 207 Nitroso-l, 3, 5-triazine, 256 Obafluorin, 68 Oligothiophene, 96, 98 Oppolzer camphor sultam, 58 Ortho-~rected metalation, 229 Oxadiazoles, 189 Oxadithiolanes, 1,3,4-, 174 Oxapmpellane, 273 Oxathianes, 286 Oxathietanes, 70 Oxathiins, 289 Oxathiolan-2-ones, 1,3-, 173

Oxathiolan-5-ones, 1,2-, 174 Oxathiolan-5-ones, 1,3-, 166, 172 Oxathiolane S, S-dioxides, 1,2-, 174 Oxathiolanes, 1,3-, 172 Oxathioles, 1,3-, 172 Oxazetidines, 70 Oxaziridines, 57 Oxazoles, 184 Oxazolidines, 187 Oxazolidinones, 53, 187 Oxazolines, 184 Oxazolinones, 184 Oxetanes, 66 Oxindoles, 112 Oxoketenes, 276 Pentacatenane, 317 Pentathiepin, 309 Pentathiepino [6, 7-b_]indole, 309 Pentazine, 247 Peracid oxidation, 49 Perfluoro macrocycles, 315 Perfluoroalkyipyrroles, 120 Pesticides, 239 Phenanthroline crown ethers, 315 Phenoxy pyrazolones, 15 Phenyl 3-pyridazinyl ketones, 228 Phenyl-l, 4-benzoxathiane, 290 Phenylisocoumarins, 278 Phosphetes, 71 Phosphocrypt, 322 Phosphoranylidene pyrazol ones, 12 Photochemical coupling, 86 Photoionopheres, 316 Phthalazinones, 229 Polyazamacrocycles, 317 Polyfluoroalkylchromones, 279 Porphyrin, 320 Pyran, 270 Pyrano [4, 3-b_][ 1] benzopyran, 280 Pyranoindolones, 121 Pyranones, 275 Pyrazines, 237 Pyrazolones, 14 Pyrazoles, 16 Pyrazolopyrimido [a ] isoquinolines, 251 Pyrazolopyrimidophthalazine, 251 Pyrazolopyrimidopyrimidines, 251

Subject htdex

Pyridazine tritlates, 228 Pyridazines, 226 Pyridazino [4, 5-d__]pyfidazine, 264 Pyridazinone, 228 Pyridine N-oxides, 210 Pyridine, 196 Pyridine-2,6-carbaldimines, 216 Pyridinecarbonitriles, 197 Pyridinium ylides, 204 Pyrido 4-ones, 246 Pyrido pyrimido pyridines, 250 Pyridones, 197, 217 Pyridothienopyrimidines, 252 Pyridylphosphines, 204 Pyrimidinediones, 234 Pyrimidines, 230 Pyrimidinylzinc halides, 233 Pyrimido [ 1,6-a_]benzimidazoles, 254 Pyrrole, reactivity, 107 Pyrrole-2-carboxylates, 107 Pyn'oleacetate esters, 118 Pyrroles, 3, 100 Pyrrolo [1, 2, 4] triazines, 260 Pyrrolo [2,3-b ] pyridines, 199 Pyrrolo[ 2,3-b ]pyrroles, 7 Pyrrolooxazepinone, 306 Pyrrolyl-3-carbinols, 123 Pyrylium salts, 268, 282 Qinghaousu, 268 Quinazolin-4(3H)-ones, 232 Quinazolines, 230 Quinolines, 202 Quinone methide, 271 Quinoxalinones, 238 Reaction with pyrroles, 120 Reformatsky reaction, 67 Regioselective metallation, 130 Ring expansion, 231 Ring transformation, 232 Rosefuran, 134 Rotaxanes, 315 Rotenoid. 272 Schenck reaction, 49 Selenophene, 84,89,98 Selenopyrans, 268 Selenopyrylium, 286 Sharpless asymmetric dihydroxylation, 43

333

Silacyclobutenes, 71 Silametacyclophanes, 319 Silanonenes, 71 Singlet oxygen, 69 Solenopsin A, 218 Solid-state photocyclization, 68 Spiro-~- lactams, 75 Spiro-azetidines, 65 Spirobenzopyran, 268 Spirosultones, 70 Stereoselective carbonylation, 74 Substituted 2-aminopyridine, 196 Substituted furans, 134 Substituted indolizines, 217 Sulfur ylides, 50 Supramolecular structures, 315 Synthesis ofvinylindoles, 120 Synthesis ofvinylpyrroles, 120 Tandem radical cylization, 125 Tellurophene, 98 Telluropyrans, 268 Tetrahydro- IH-3-benzazepine, 297 Tetrahydrofurans, 136 Tetrahydropyran, 270 Tetrahydropyrroloquinoline, 111 Tetraoxaporphyrin-dication, 131 Tetrathiafulvalenes, 169, 170 Tetrazine-N-oxides, 246 Teucriumlactone, 53 Thiadiazolotriazines, 259 Thiazetidines, 70 Thienothiophene, 99 Thienyl pyrrole-3-carboxylates, 108 Thietanes, 66 Thietes, 68 Thiophene, 82 Thiophene-l, 1-dioxide, 95 Thiopyrano [ 4, 3 -b ] indoles, 284 Thiopyrans, 268, 283 Thioquinones, 290 Thioxanthone dioxides, 285 Tortuosamine, 212 Tosyl- 3-azetidinone oxime, 64 Triarylthiopyrylium, 286 Triazine - 2 ( I H ) - thiones, 244 Triazine -N - oxides, 245 Triazinylpyridinium betaine, 258

334

Subject Index

Triazolo [ 5, 1 -i ] purine, 255 Triazolo [ 1,5-a ] pyridine ring system, 199 Triazolo [ 4, 3 - _a] pyridines, 248 Triazolo [ 4, 3 -b_] pyridazines, 248 Triazolo - 1, 3, 5 - triazine, .257 Triazolodiazepine, 304 Tribactams, 76 Trifluormethylated furans, 135 Trifluoromethylpyri~zines, 226 Trihalomethyl - 2 - pyrimidinones Trimethylbenzofurans, 139 Trinitroazetidine (TNAZ), 64

Trioxanes, 287 Trioxins, 287 Trioxolanes, 1, 2, 4-, 174 Trisubstituted furans, 130 Tropono [ 4, 5 - b ] oxepine, 302 Tryptamines, 117 Varacin, 309 Vinylindole, 122 Xanthone, 282 Xanthylium salt, 282 Yuehchukene, 124