Progress in Heterocyclic Chemistry. Volume 7

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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


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


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


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


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


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


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.


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


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


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


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


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


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


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


[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.


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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,


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


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


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


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


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


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


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


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%)


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


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


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


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


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


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
5:1) . Treatment of malonate 71 with various olefins and managanese (III) acetate produces 72. Examples of intramolecular cyclization are also reported . 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) .

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 .

C

,CN

a

~

H2N"

CN

CN~

S"

NH2

Eq. 16 ,>S N "~N

O2 7S

76

94


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 . Sequential treatment of 3,4diaminothiophene with phenyl isothiocyanate and tfimethylsilyl chloride in pyridine produces thienothiadiazole 76 . Tetrathiafulvalene ~-electron donors 77 and 78 are both produced from the tosyl hydrazone of tetrahydrothiophen-3-one . A simple four step synthesis of [l]benzothieno[3,2-b]furan 79 starts with methyl thiosalicylate .

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) . 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 . The preparation of dihydrothienooxazole 80 requires the careful control of the reaction time and temperature as well as the reactants molar ratio . 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 . 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 . A similar strategy is used to prepare hexahydroindene and octahydronaphthalene ring systems 84 . 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 . An example of a 3-substituted sulfolene-


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 . 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 . 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 . The 2,5-disubstituted thiophene1,1-dioxide 89 reacts with piperidine at 100 "C to form the piperidine adduct 90 . 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- . 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 . 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$ . /

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 . 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 . $

/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 . 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 . Extended electron delocalization is also present in the &cation 101; largely through the two i-PrS-C-C-C-SPr-i moieties . 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 .


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 . 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) . 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) and 5-hydroxy (106) 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 . 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) . 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 .

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 . 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 , carboxyalkyl or alkyl mercaptan containing benzothiophenes , and polythiophenes 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) .


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 . 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 . 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 or novel monomers, such as 112 . 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 . R O R

111

CN

R = SMe 112

S

CN

,......,.

NG

0"

NC

CN R

113

114

R = t-Buor Me 115

R

100


A series of benzobithiophene derivatives are electron accepters in chargetransfer complexes. Of the three isomers reported, 114 is the most stable and soluble . [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 . 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 .

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

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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


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

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104


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. An extensive discussion of ~ f f - and if-sandwich complexes of pyrrole and other heterocyclic analogs of cyclopentadiene appeared. . 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. 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, while using the MP2/6-3]G* level indicates a difference of 2.2 kcal/mol. Nakajima and coworkers used PM3 and AMI semiempirical calculations in an effort to understand reactivity patterns for pyrrole and simple methyl derivatives. 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%. . ~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. 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. 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.

Five-Membered Ring Systems: Pyrroles

108

A number of 2-aryl and 2-heteroarylpyrroles were obtained starting with 1-propargylbenzotriazole. 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. 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. 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. 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. 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. 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. 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.

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. The reaction requires an electron-


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. 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. 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. 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


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. 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. 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. 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. 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.


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. 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. 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. 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


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. 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. ~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. 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.

114


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. 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. 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. 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. 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. This procedure was applied to coupling of 6-bromoindole with 4-fluorophenylboronic acid and proceeded in 90% yield. 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. ,/'-~ 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. 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. 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%


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. 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 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. H H I I Oa:~N~:::O ~c~~ Pd(OAc)2 HOAc 84

I

H

I

H

85

HI

HI


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. 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. 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. 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


An investigation of the reactivity of N-magnesiopyrrole toward =-bromoesters has shown that good yields of pyrroleacetate esters can be obtained. 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. 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. ~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. Radicals are generated by the Fe(II)-H202DMS0 system which involves iodine abstraction by methyl radicals. 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)


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. 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. 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. 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.


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. 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. 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. 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. 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. "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. 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. 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


122

by reaction of indoles with methyl orthoacetate Modest yields of 4-methoxycarbazoles can be obtained with reactive dienophiles such as dimethyl acetylenedicarboxylate. 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.

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. 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. 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. . Tetrahydrofurans of type 10 are available from ethyl-6-acetyloxy-2-aikenoates with sodium ethoxide . 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 . 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 . Me3Si.

Me3Si.

Intramolecular acylation of y-acyloxysuifones leads to 2,3-dihydrofurans . 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 . 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 . ?-Substituted ?-butyrolactones of high enantiomeric purity can be obtained from aldehydes by the following sequence of reactions . 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 . 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 . 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 . 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 . 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 . 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 . y-Z-Alkylidenbutenolides are available from y-bromoq3,y-unsaturated acids . A versatile method for the preparation of 2-substituted 4-trimethylsilylfurans starting from allyltrimethylsilansand acid chlorides was reported . Ring closure of y-hydroxyketones, which were prepared by a reductive ring opening of dihydroisoxazols, yields furans . Furans can be also obtained by a rutheniumcatalyzed cyclization of hydroxyenones and by base-assisted cyclization of l-[3[hydroxy(substituted methyl))]propargyl]benzotriazoles . 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 . Cyclization of 13- and u allylic alcohols with base yields furans . Allenes and lalkynyl-2,3-epoxyalcohols may also serve as starting materials . A molybdenum carbonyl complex promotes the cycloisomerisation of l-alkyn-4-ols to 2,3-dihydrofurans. Chromium and tungsten carbonyls give metal carbenes . 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 . 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 . 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 . An alkynol is an intermediate in this reaction. Examples of the newly developed tetrahydrofuran synthesis via radical and anionic cyclization were reported . Examples of free radical cyclization were published . A short enantioselective synthesis of (+)-nonactic acid and (-)-8-epi-nonactic acid induced by a chiral sulfoxide group was described . Compound 13 can be prepared by an enzyme-triggered ring closure . enzyme .,,~0

CMezOH

12

13

2,4-Disubstituted tetrahydrofurans are available from the fluorinated sulfoxide 14 .

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 . 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 . 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


138

this procedure . The synthesis of rac.-dihydrosesandn was reported . ct-Suifonyl-s-acetylenic ketones on treatment with ButOK and Pd(dppe) may give furans . Probably palladium carbenoids are involved in this reaction.

ii. Pd(dppe)

Divalent palladium-catalyzed cyclization of allylic alkynoates yields a-alkyliden-y-butyrolactones .

o o.r

The use ofbisphosphine ligands as chiral modifiers in the Rh(1)-catalyzed Diels-Alder reaction of 15 was studied . 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 .

~.~

..CO = cot.

I

16

Dihydrofuraldehydes were prepared by an intramolecular silyl nitronate olefin cycloaddition with subsequent acidic workup .

~ 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 . 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 . A new route to 2(SH)-furanones via ruthenium-catalyzed oxidative cyclocarbonylation was reported .

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 .

"['he synthesis of tetrasubstituted furans fi'om photocycloaddition of' conjugated acetylenic ~-diketones with alkenes was reported . 4-Hydroxy-2-cyclobutenone on treatment with lead tetraacetate gives 5-acetoxy-2(SH)-furanones and 5-alkyliden-2(SH)-furanones . Photolysis of a cyclobutanone in the presence of methanol was reported to give a 2-methoxytetrahydrofuran . 6,6-Disubstituted furo[3,4-c]isoxazoles were prepared by intramolecular 1,3-dipolar cycloaddition of nitrones . An efficient synthesis of furanopyrone 17 starting with D-glucose was reported . 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 .

//~.J

"

o

Oge

OMe

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

C v

O

LDA

"C02Bu t

HBoc

The reaction of arylethoxymethylene iron complex 18 with alkynoates produces furans in 19-80% yield . 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


pentadienyl)iron(H) dicarbonyl with carbonyl compounds was reported . *

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 . The preparation of the highly reactive ketipin acid dilactone (19) was reported .

o@o 2-Substituted cycloaikanoylfurans are available from cycloalkanones and 2,5-dihydro-2,5-dimethoxyfuran . 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 . Several known methodologies were applied for the preparation of novel furans, e.g., cycloaddition of carbonyl ylides with alkenes , addition of cyclic rhodium carbenoids to alkynes , and furans from oxazoles . A versatile access to 4,6,7-trimethylbenzofurans is possible through one-electron oxidation of mesityl-substituted enols .

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 . A versatile route to methyl 3-benzofuranylacetate employs the Heck reaction between 2-iodophenol and 2,5-dihydro-2,5-dimethoxy~ran . 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 . The successful use of flash vacuum pyrolysis for


141

the preparation of benzo[b]furans starting with stabilized phosphorans was reported . 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 . 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 . The occurrence of a dihydrobenzo[b]furan during the in-situ generation of a 3-(13-hydroxyalkyl)benzyne was observed . The oxymercuration-reduction procedure of an o-ailyl substituted phenol was proved to be valuable for the synthesis of (-)aplysin . Benzofuranones were generated by an oxidative cyclization of 2'-hydroxychalcones with TI(HI) . 2H[ 1]Benzopyrans and benzofurans were prepared by Clalsen rearrangement of aryl propargyl ethers and allyl aryl ethers . For a CsF-mediated Clalsen rearrangement of aryl propargyl ethers see . 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 . Highly functionalized benzo[b]furans are available in a Pd(0)/Cu(I) catalyzed reaction from iodophenols and trimethylsilylacetylene . Cyclization of dimedone with alkynes in the presence of Hg(lI)acetate in DMSO afforded tetrahydrobenzofurans . A facile synthesis of linear and angular 2-methylfurobenzopyranones by Pd assisted oxidative cyclization of allyl substituted phenols was reported . Dihydrobenzofurans were prepared by a three component Pd catalyzed cyclization-carbonylation anion capture process .

'

oc

CO, NoBPh4

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

OTf

PhONe, MeOH -0

R

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


142

arrangement of 4-hydroxy-2-cyclobuten-l-ones . 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 . 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 . The total synthesis of corianddn, an antiviral agent with benzofuran structure, was reported . The well known lactonization of olefins mediated by Mn(III) was carried out under ultrasonic irradiation at low temperatures . New approaches to the synthesis of rotenone were reported . Benzo[c]furans have remained a field of active research, especially as trapping agents for unstable alkenes (and related compounds) and as synthons for the construction of complex molecules . The reaction of furofurans, thienofurans, furobenzofurans, benzothienofurans and furoindoles were investigated . [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 . The preparation of an iptycene by a Diels-Alder reaction was reported . The unusual stability ofN-methyl maleinimide cycloadducts was studied by computational methods (MP2/6-31G*//HF/6-31G*) . 5.3.4MISCELLANEOUS

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


143

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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

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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

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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)

_

~

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.

(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


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)


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


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].


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].


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 "


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


~ ~

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)


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


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


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


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

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94CL I 107 94CL1833

transient

~e (182)

Me ~'-'N

94CC 1525

only

NN.

M

94CC201

used,

Me /N

5.4.8

GeCI 2 was

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94JMC(37)158

161

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94M!(4)2441

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

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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


[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


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


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


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

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


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 |


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].


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.


~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)

~ ..

"~...~

.

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) . An alternative method for the preparation of hexahydrooxepines is cyclisation of the diazo-phosphonate (24) to (25) with rhodium (II) acetate .

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) .

~

~

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 ~ . 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) . 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 . 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 . 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


2-acetonyloxepane . 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 . 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 . 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) . 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


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 .

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) . 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


304

The electrocyclisation of diene-conjugated diazocompounds to afford 1H-2,3benzodiazepines has been known for a number of years and more recently asymmetric induction in this cyclisation has been described . The full paper of this latter work has now been published . The synthesis of 5H-2,4-benzodiazepines derivatives from 4-ethoxycarbonyland 4-cyanobenzo[c]pyrilium salts has been described . 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) . 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 and two syntheses of imidazo[4,5-e][1,4]diazepin-8-ones are reported , . 9Hpyrimido[4,5-b][1,4]diazepines may be readily prepared from 4,5diaminopyrimidines and ethyl pyruvate . 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 .

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 . This offers a convenient route to a number of new benzodiazepine CCK-B antagonists , The synthesis of novel unnatural amino acids containing a 1,4-benzodiazepine side chain is described . In this way the benzodiazepine has been incorporated into a tripeptide system.

.


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 , 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 . 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 . 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 . 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 and fluorinated derivatives are obtained by the reaction of o-phenylenediamines with 1-aryl-l-trialkylsilyl-perfluoroalkanols or 1-alkyl-1trialkylsilylperfluoroalkenes . 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) . 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 . 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


306

a D.s. of over 90 % . 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 . 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 . 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 . N-(2-hydroxymethylphenyl)pyrrole is amenable to selective o~-methylation and the metallated derivative may be trapped with aldehydes, ketones and carbon dioxide

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