Progress in Heterocyclic Chemistry. Volume 16

PROGRESS IN HETEROCYCLIC CHEMISTRY Volume 16 Related Titles of Interest Books BRANDSMA: Synthesis of Acetylenes, A...

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PROGRESS IN

HETEROCYCLIC CHEMISTRY Volume 16

Related Titles of Interest

Books

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

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

BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) PHYTOCHEMISTRY TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS

PROGRESS IN

HETEROCYCLIC CHEMISTRY Volume 16 A critical review of the 2003 literature preceded by two chapters on current heterocyclic topics Editors

GORDON W. GRIBBLE

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

JOHN A. JOULE

Department of Chemistry, The University of Manchester, Manchester, UK

2004

ELSEVIER Amsterdam - Boston - London - New York- Oxford - Paris ,San Diego - San Francisco - Singapore - SydneyTokyo

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9 2004 Elsevier Ltd. All rights reserved. This work is protected under copyright by Elsevier Ltd., and the following terms and conditions apply to its use: Photocopying Single photocopies of single chapters may be made for personal use as allowed by national copyright laws. Permission of the Publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes, resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use. Permissions may be sought directly from Elsevier's Rights Department in Oxford, UK: phone (+44) 1865 843830, fax (+44) 1865 853333, e-mail: [email protected]. Requests may also be completed on-line via the Elsevier homepage (http:// www.elsevier.com/locate/permissions). In the USA, users may clear permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone: (+1) (978) 7508400, fax: (+1) (978) 7504744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service (CLARCS), 90 Tottenham Court Road, London WIP 0LP, UK; phone: (+44) 20 7631 5555; fax: (+44) 20 7631 5500. Other countries may have a local reprographic rights agency for payments. Derivative Works Tables of contents may be reproduced for internal circulation, but permission of the Publisher is required for external resale or distribution of such material. Permission of the Publisher is required for all other derivative works, including compilations and translations. Electronic Storage or Usage Permission of the Publisher is required to store or use electronically any material contained in this work, including any chapter or part of a chapter. Except as outlined above, no part of this work may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the Publisher. Address permissions requests to: Elsevier's Rights Department, at the fax and e-mail addresses noted above. Notice No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. First edition 2004 Library of Congress Cataloging in Publication Data A catalog record is available from the Library of Congress. British Library Cataloguing in Publication Data A catalogue record is available from the British Library.

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Contents

Foreword

vii

Editorial Advisory Board Members

viii

Chapter 1: Lamellarins: Isolation, activity and synthesis Pablo Cironi, Fernando Albericio, and Mercedes Alvarez, Biomedical Research

Institute, Barcelona Scientific Park, University of Barcelona, Barcelona, Spain.

Chapter 2: Radical additions to pyridines, quinolines and isoquinolines

27

David C. Harrowven and Benjamin J. Sutton,

School of Chemistry, University of Southampton, Southampton, UK.

Chapter 3: Three-membered ring systems

54

Albert Padwa, Emory University, Atlanta, GA, USA and Shaun Murphree, Allegheny College, Meadville, PA, USA.

Chapter 4:

Four-membered ring systems

82

Benito Alcaide, Departamento de Quimica Org6nica I, Facultad de Quimica,

Universidad Complutense de Madrid, Madrid, Spain and Pedro Almendros, Instituto de Quimica Org6nica General, CSIC, Madrid, Spain.

Chapter 5: Five-Membered Ring Systems Part 1.

Thiophenes & Se, Te Analogs

98

Venkataramanan Seshadri, Fatma Selampinar, Gregory A. Sotzing

University of Connecticut, Storrs, CT, USA.

Part 2.

Pyrroles and Benzo Derivatives

128

Tomasz Janosik and Jan Bergman, Department of Biosciences at Novum,

Karolinska Institute, Novum Research Park, Huddinge, Sweden, and SOdertOrn University College, Huddinge, Sweden and Erin T. Pelkey, Hobart and William Smith Colleges, Geneva, NY, USA.

Part 3.

Furans and Benzofurans

]56

Xue-Long Hou, Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key

Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China, Zhen Yang, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, Department of Chemical Biology, College of Chemistry, Peking University, Beij'ing, China Kap-Sun Yeung, Bristol-Myers Squibb Pharmaceutical Institute, Wallingford, CT, USA, and Henry N. C. Wong, Department of Chemistry, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, The Chinese University of Hong Kong, Hong Kong, China and Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, Shanghai, China.

vi

Part 4.

With More than One N Atom

198

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

Part 5.

With N & S (Se) Atoms

228

Mark G. Saulnier, Upender Velaparthi and Kurt Zimmermann,

Bristol Myers Squibb Company, Walling)Cord, CT 06492-7660, USA.

Part 6.

With O & S (Se, Te) Atoms

272

R. Alan Aitken, University of St Andrews, UK.

Part 7.

With O & N Atoms

283

Stefano Cicchi, Franca M. Cordero and Donatella Giomi,

Universith di Firenze, Italy.

Chapter 6: Six-Membered Ring Systems Part I.

Pyridines and Benzo Derivatives

309

Daniel L. Comins and Jason Dinsmore, Department of Chemistry,

North Carolina State University, Raleigh, NC, USA and Sean O'Connor, A TK Thiokol, Inc., Brigham City, UT, USA.

Part 2.

Diazines and Benzo Derivatives

347

Michael P. Groziak, California State University at Hayward, Hayward, CA, USA.

Part 3.

Triazines, Tetrazines and Fused Ring Polyaza Systems

385

Carmen Ochoa, Pilar Goya and Cristina G6mez,

Instituto de Quimica M~dica (CSIC), Madrid, Spain.

Part 4.

With O and/or S Atoms

405

John D. Hepworth, James Robinson Ltd., Huddersfield, UK and B. Mark Heron,

Department of Colour and Polymer Chemistry, University of Leeds, Leeds, UK.

Chapter 7: Seven-Membered Ring Systems

431

John D. Bremner, Department of Chemistry, University of Wollongong,

Wollongong, NSW, Australia.

Chapter 8: Eight-Membered and Larger Ring Systems

451

George R. Newkome, The University of Akron, Akron, OH, USA.

Index

469

~ Vll

Foreword

This is the sixteenth annual volume of Progress in Heterocyclic Chemistry, and covers the literature published during 2003 on most of the important heterocyclic ring systems. References are incorporated into the text using the joumal codes adopted by Comprehensive Heterocyclic

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

The first, by Mercedes /klvarez, Pablo Cironi, and Femando Albericio

covers 'Lamellarins: Isolation, activity and synthesis' a significant group of biologically active marine alkaloids. The second, by David Harrowven and Benjamin Sutton, discusses the increasingly important topic of 'Radical Additions to Pyridines, Quinolines and Isoquinolines'. The remaining chapters examine the recent literature on the common heterocycles in order of increasing ring size and the heteroatoms present. This year, following a consultation exercise involving members of the Editorial Board, and partly in the interest of getting the Volume published as soon as possible after the end of the year being reviewed, the Index is less comprehensive than formerly. It now includes only systematic heterocyclic ring system names. Thus, wherever a pyrrole is discussed, that would be indexed under 'pyrroles'; wherever

'pyrido[3,4-b]indoles' are mentioned an indexed entry under that

name will be found; similarly 'aceanthryleno[1,2-e][1,2,4]triazines', 'azirines', '2H-pyran-2ones', 'l,2,4-triazoles' etc. etc. are listed.

But, subjects like'4-ethyl-5-methylpyrrole', '5-

acylazirines', '6-alkyl-2H-pyran-2-ones', '3-alkylamino-l,2,4-triazoles', are not listed as such in the Index. 'Diels-Alder reaction' or 'Heck coupling' etc., are also not indexed. We are delighted to welcome some new contributors to this volume and we continue to be indebted to the veteran cadre of authors for their expert and conscientious coverage. We are also grateful to Derek Coleman of Elsevier Science for supervising the publication of the volume. We hope that our readers find this series to be a useful guide to modem heterocyclic chemistry. As always, we encourage both suggestions for improvements and ideas for review topics.

Gordon W. Gribble John A. Joule

viii

Editorial Advisory Board Members Progress in Heterocyclic Chemistry 2 0 0 3 - 2004 PROFESSORY. YAMAMOTO(CHAIRMAN)

Tohoko University, Japan

PROFESSOR D. P. CURRAN

PROFESSOR G.R. NEWKOME

PROFESSORA. DONDONI

PROFESSORR. PRAGER

University of Pittsburgh USA

University of Akron USA

University of Ferrara Italy

Flinders University Australia

PROFESSOR K. FUJI

PROFESSORR.R. SCHMIDT

Kyoto University Japan

PROFESSORT.C. GALLAGHER

University of Bristol UK

PROFESSORA.D. HAMILTON

Yale University USA

University of Konstanz, Germany PROFESSOR L. TIETZE

Georg-August University Germany

PROFESSORS.M. WEINREB

Pennsylvania State University USA

PROFESSORM. IHARA

Tohoku University Japan

Information about membership and activities of the International Society of Heterocyclic Chemistry (ISCH) can be found on the World Wide Web at http://webdb, unigraz, at/~kappeco/ISHC/index, html

Chapter 1

Lamellarins" Isolation, activity and synthesis Pablo Cironi, Fernando Albericio, Mercedes Alvarez Biomedical Research Institute, Barcelona Scientific Park-University of Barcelona, 08028 Barcelona, Spain [email protected], [email protected], [email protected]

1.1

INTRODUCTION

The lamellarins constitute an important group of natural products isolated from marine invertebrates such as sponges, molluscs and tunicates with structures without precedents in natural or synthetic compounds. They are characterized for possessing important biological activities. The aim of this review is to provide an overview of the work published since the isolation of the first group of lamellarins <85JA5492> from the marine prosobranch mollusc Lamellaria sp, until the beginning of 2004.

1.2

I S O L A T I O N AND STRUCTURE

More than thirty lamellarins have been characterized since the isolation of the first group of lamellarins A-D <85JA5492>. The structure of lamellarin A was established by X-ray crystallographic analysis <85JA5492>, as was that of lamellarin E <88JOC4570> isolated together with lamellarins H-G from the marine ascidian Didemnum chartaceum collected in the Indian Ocean on the atoll of Aldabra. Six new polyaromatic alkaloid lamellarins I-M, the triacetate of lamellarin N, and four known alkaloids lamellarins A-C were isolated from the marine ascidian Didemnum sp <93AJC489>. Since molluscs from the family Lamellariidae had been described as specific predators of colonial ascidians, it was speculated <85JA5492> that the lamellarins mollusc had most likely sequestered the alkaloids from a colonial ascidian food source. The re-isolation of lamellarins A-D, which had been previously obtained from the prosobranch mollusc Lamellaria sp. supported this idea. The presence of lamellarins in molluscs, tunicates and sponges gives rise to speculations about the role of symbiotic organisms associated with the invertebrates and represents a target for new investigations <95AJC1491>. The first pyrrole non-fused alkaloids of the family were lamellarins O and P isolated from a marine sponge Dendrilla cactos <94AJC 1919>. Later on, from a specimen of Dendrilla cactos collected in Australia <95AJC1491> two new pyrrole derivative lamellarins Q and R were isolated. A new pentacyclic alkaloid, lamellarin S together with the known lamellarin K were isolated from a tunicate Didemnum sp. <96AJC711 >. Lamellarin S was the first example that demonstrated atropoisomerism with a positive [Ct]D, which can indicate an enantiomerically enriched mixture. Repeated optical rotation measurements of lamellarin S over several months suggested slow racemization with a half-life calculated to be ca. 90 days. The first sulfates of lamellarins, the 20-sulfate derivatives of lamellarins T-Y, were extracted from an unidentified

2

P. CironL F. Albericio and M. Alvarez

ascidian from the Arabian Sea <97T3457>. From the same organism the non-esterified lamellarins T-X were also isolated. Later, from the ascidian Didemnum chartaceum, the 20sulfated lamellarins B, C, and L, the 8-sulfated lamellarin G plus a non-sulfated compound, lamellarin Z were identified <99JNP419>. An investigation of the prosobranch mollusc Corioeella hibyae <99MI39> provided two known compounds; lamellarins C <85JA5492> and U <97T3457>. A n e w ester, lamellarin c~ 20-sulfate <99JMC1901> was isolated from an unidentified ascidian collected from the Arabian Sea. From a purple unidentified Didemnum sp (other than D. chartaceum) lamellarin [3 was identified <02MI 163>. Structures of pentacyclic lamellarins Unsaturated

A C E

Ra

R1 R2

RR 7 ~

F G I I aeet.

J

O R5~R4~-~R30

K K triacet.

L L triaeet. S

T Tsulf. U U sulf.

V V sulf. Y sulf.

a7

R1

R2 Z

RR 6 ~ R4~

O

Saturated B D H M N

W X o~

R3

R4

R5

OH H

OMe OMe OH OH H OMe OMe H OH OAc H H H OMe OMe H H OMe OMe H H H

OMe OMe OH OMe OMe OMe OMe OMe

Rl OMe OMe OMe OMe OH OMe OMe OMe OMe OMe OMe OMe OH OMe OMe OMe OMe OMe OMe OMe OH OH

R2 OH OH OH OH OMe OH OAc OH OH OAc OH OAc OH OH OSO3Na OH OSO3Na OH OSO3Na OSO3Na OMe OH

OMe OMe OH OMe

OMe H H OH H OH OMe OH OH OH OSO3Na H

OMe OMe OMe OMe

OH OH OH OH

H

H H H H

H H H

H H H

H H H H OH OH H H H

R6

R7

R8

OMe OMe OMe OMe OMe OMe OMe OMe OH OMe OMe OMe OMe OMe OH OMe OMe OMe OMe OMe OH OMe OAc OMe OH OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OH OH OMe OH OH

OMe OMe OH OMe OH OMe OMe OMe OMe OMe OH OAc OH OH OMe OH OH OH OH OH OH OH

OH OH OMe OMe OMe OMe OMe OMe OH OAc OMe OMe OH OMe OH OMe OMe OMe OMe OMe OH OMe

OMe OH OH OMe OMe OMe OMe OMe

OH OH OH OH OMe OMe OMe OMe

OMe OMe OH OMe OH OH OH OH

The structures of the lamellarins, except for A and E, were established by a combination of 1H and 13C N M R analyses using heteronuclear correlation techniques. New procedures for differentiation of H M B C at two- and three-bond correlation <96TL363> in combination with ADEQUATE experiments <96JMR282> and with O~l-refocused 1,1-ADEQUATE < 9 6 J M R 2 9 5 > experiments were developed for a comprehensive identification of 2JcH and 3JcH

Lamellarins : Isolation, activity and synthesis

3

correlations. The distinction between 2JcH and 3JcHconnectivities facilitates the assignment of complex structures. The apparent biogenetic origin of these metabolites is from two, three or more tyrosine and/or Dopa units and the relationship between them is clear. Looking at the structures, two important groups of lamellarins can be recognised. The most important group in number possess a common pentacyclic structure linked to a new phenyl ring. The differences between the members of this group are in the number and positions of OH/OMe substituents on the benzene rings and in the oxidation level of ring D. This ring can be saturated or unsaturated and/or hydroxylated. Structures of lamellarin pyrrole derivatives

HO.

OH HO

HO

HO/x__ BrBr OH Br-~\ //3 ~( ~ ~ ' 7--- Br

,OH

HO

Br

~

~

Br

HO

OH

O

@

OH

OH

OH

Lukianol A

Ningalin B

OH

Polycitone A

Structures of related natural products

HO

OH

HO.

OH

Me ~R

Lamellarin O R = H Lameilarin P R = OH

~.~OH

Me H Lamellarin Q

OH

HO

+

OH Lamellarin R

Less numerous is the group of lamellarins in which the pyrrole is not fused to another aromatic ring, known as pyrrole derivatives. These alkaloids are probably tyrosine derived metabolites, structurally closer to the lukianols <92HCA1721>, ningalines <97JOC3254>, polycitones and polycitrines <94JOC999> than to the pentacyclic lamellarins. Chemical transformations between these groups of natural products have been described. Thus, dimethoxylamellarin O was transformed into the enol-ether lactam (ring B of pentacyclic lamellarins) and after cleavage of methoxy groups gave lukianol A <95JOC6637>. The open diaryl pyrroles were also chemically transformed into the pentacyclic alkaloids, for instance ningalin B into lamellarin G trimethyl ether <03TL4443>. Again, the ease of chemical

4

P. Cironi, F. Albericio and M./ilvarez

transformation between compounds of these families could indicate their close biogenetic origin. Lamellarins O and P displayed a double family of signals corresponding to the aromatic carbon ortho to the phenolic functions, presumably due to the restricted rotation that generates chirality in these molecules <94AJC 1919>.

1.3

ACTIVITY

While for the pyrrole derived lamellarins and related compounds no activity has been described, several pentacyclic lamellarins show important cytotoxic activities. Lamellarin D at a concentration of 19 ~tg/ml caused a 78% inhibition of cell division in the fertilized sea urchin egg assay while lamellarin C caused 15% inhibition but lamellarins A and B were inactive <85JA5492>. Lamellarins I, K and L present significant cytotoxicity against P338 and A549 cultured cell lines and lamellarins K and L also exhibit immunomodulatory activity <93AJC489>. The effects of several members of the family of lamellarins on the growth of several tumor cell lines and on P-glycoprotein (P-gp) mediated multidrug resistance (MDR) was tested <96MI677>. The use of lamellarins either alone against MDR tumors or in combination with other anti-tumor drugs as effective treatments against MDR cells has been described <97WO01336> after testing an important group of natural lamellarins and derivatives. A nonnatural lamellarin derivative proved to have an important potency as a MDR reversal agent causing hypersensitivity towards vinblastine in the HCT/VM 46 MDR cell line <00JOC2479>. Lamellarin N tested in the NCI on a cell-line panel showed some selectivity towards the melanoma cell lines SK-MEL (LCs0 1.87 x 10-7 M) and UACC-62 (LCs0 9.88 x 10-6 M). Several lamellarins were tested as HIV-1 integrase inhibitors and the a 20-sulfate displayed a very favorable therapeutic index <99JMC 1901 >. Lamellarin a 20-sulfate inhibits integrase terminal cleavage activity with an IC50 of 16 ~tM and strand transfer activity with an IC50 of 16 l,tM and possesses a low toxicity with an LDs0 of 274 ~tM whereas other sulfated lamellarins (lamellarin U 20-sulfate and lamellarin V 20sulfate) were toxic in the 100 ~tM range and lamellarins T and N without the sulfate ester were more toxic. The site of action of lamellarin a 20-sulfate was mapped and it was postulated that it binds to a site composed of multiple integrase domains. A molecular modeling analysis suggested that the planar chromophore of lamellarin D can intercalate between a DNA base pair and that the appended methoxyphenol substituent oriented at a right angle with respect to the main chromophore may serve as a hook to trap proteins <03CR7392>. DNA binding measurements by absorbance, fluorescence, and electric linear dichroism spectroscopy showed that lamellarin D is a weak DNA binder that intercalates between the double helix. Topoisomerase I was efficiently trapped on DNA by lamellarin D in P388 and CEM leukemia cells. The results identify lamellarin D as a novel lead candidate for development of topoisomerase I-targeted antitumor agents. <04BMC 1697, 04WO014917>

1.4.

SYNTHETIC STRATEGIES

From a synthetic point of view, lamellarins are rather complex molecules. In the literature, there are described several approaches, which fall into two main synthetic categories: (i) by pyrrole formation as the key step of the synthesis and (ii) by transformation of a pre-existent pyrrole derivative through cross-coupling reactions. Although and due to the structural

Lamellarins: Isolation, activity and synthesis

5

characteristics of these kinds of molecules, most of the syntheses have been carried out in solution, recently some synthesis carried out in solid-phase has also been described.

1.4.1 SOLUTION STRATEGY 1.4.1.1 Pyrrole ring formation approaches Fiirstner et al. synthesized lamellarin O dimethyl ether following their previous research on carbon-carbon double bond formation from carbonyl compounds by catalytic titanium coupling reactions <94JOC5215, 95JA4468>. A new titanium-mediated approach to pyrrole synthesis, based on the cyclization of a 3-acylamino-enone, was reported <95JOC6637>.

R1

R1

.-,

r" "?r O 1. v NH R2.~_~O

Iow-valenttitanium

=

...

R2 H

In order to adapt this strategy to the synthesis of lamellarin O dimethyl ether, a 3unsubstituted keto-enamine 4 was prepared by hydrogenolysis of precursor isoxazole 3.

O

H202, NaOH

Ar'~-~Ar

98%

1

O O

~ Ar

r 2. NH2OH.HCI,

2

Ar = p-MeOC6H4 Ar, Ar ~O

Ti-graphite

NHR 4R=H 5 R =

52%

Ar. Ar P; ~ ~N )~/ H2 (1 atm), Pd (5%)

1. BF3.Et20

Ar.

67% (both steps) ~OMe

Ar

OMe H

O

r 91%

94%, (7):(E)- 11

3 K2CO3},-

Ar, Ar ~/OMe O

6 FOrstner intermediate

".~/F~O ~ O

OMe

CIOCCOOMe' Py 73% (Z):(E) = 2.5:1

lamellarin O dimethyl ether

Intermediate 3 was readily prepared from commercially available 4,4'-dimethoxychalcone 1 which by standard oxidation conditions afforded the epoxy ketone 2 in high yield. Compound 2 underwent a clean pinacol/pinacolone-type rearrangement with an excess of BF3"Et20. The crude 1,3-keto-aldehyde thus formed was trapped by hydroxylamine leading to isoxazole 3 in good yield. Reductive cleavage of its N-O bond gave the desired keto-enamine 4 (as a ~ 1:1 mixture of the (E)- and (Z)-isomers). Acylation of this mixture with oxalic acid half acid chloride half methyl ester afforded the coupling precursor 5. The (Z) isomer was used for the subsequent titanium-induced ring closure. Upon treatment with preformed Ti-graphite (TIC13: CsK =1:2) <93AG(E)164> in DME, compound 5 bearing three different carbonyl groups

6

P. CironL F. Albericio and M. ,4lvarez

underwent a chemo- and regioselective oxo-amide coupling reaction with formation of pyrrole 6 in good yield without the ester group interfering. N-Alkylation of 6 with 4-methoxyphenacyl bromide 7 proceeded smoothly affording lamellarin O dimethyl ether in 15% overall yield. In work aimed at achieving a regiocontrolled preparation of unsymmetrical 2,3,4trisubstituted pyrroles, Gupton and Sikorski <98T5075, 99T14515> tested the condensation of different substrates (9, 10, 11) with glycine methyl ester, glycine ethyl ester and Nmethylglycine ethyl ester under acidic (HOAc), neutral (DMF) and basic conditions (Nail, DMF). The Firstner intermediate 6 was obtained when glycine methyl ester reacted with chloropropeniminium salt 10 (basic conditions, 77% yield) or with the [3-chloroenal 11 (neutral conditions, 82% yield), but no attempt at lamellarin synthesis was published. MeO

OMe

OMe

MeO

MeO

OMe MeO

OMe

MeO.,,T.. OMe

POCl3 ~

/N\

91%

w

/

8

H20 = THF

/ PF6

9

1 Glycine methyl Nail ester 77%

10

A similar approach was described by Kim et al. <01MI 1403> to build the Firstner synthon from the vinylogous amide 9, previously described, and the commercially available dimethyl aminomalonate hydrochloride as building block for pyrrole systems. The cyclocondensation reaction between the vinylogous amide 9 and dimethyl aminomalonate hydrochloride was performed in acetic acid at room temperature to yield the presumed intermediate 12 via an acid-catalyzed nucleophilic substitution reaction. The mixture was then diluted with additional acetic acid and heated under reflux to facilitate the intramolecular ring closure and the loss of the methoxycarbonyl moiety to produce the desired pyrrole. Formation of lamellarin O dimethyl ether was achieved as in the Firstner approach <95JOC6637>.

\N /

HOAc

Ar = p-MeOCsH4 9

,.

K2003 MeO2C

CO2Me 12

]

60%

90%

lamellarin O dimethyl ether

__J

Following on from their previous work on the biomimetic synthesis of marine natural products, Steglich et al. proposed a biomimetic lamellarin synthesis in which an oxidative dimerization of an arylpyruvic acid and condensation of the resulting 1,4-dicarbonyl compound with a suitable 2-arylethylamine would be the key steps of the synthesis. Thus, the synthesis of lamellarin G trimethyl ether was achieved by coupling two molecules of 3-(3,4dimethoxyphenyl)pyruvic acid and the appropriate 2-phenylethylamine <95T9941, 97AG(E)155>. The use of a mixture of two different arylpyruvic acids afforded the unsymmetrical lamellarin L <00MI1147>.

Lamellarins: Isolation, activity and synthesis

7

The 1,4-dicarbonyl compound 15, a key intermediate for pyrrole ring formation, was obtained in a one-pot procedure by oxidative coupling, for the symmetrically substituted pyrroles <97AG(E)155>, or a deprotonation of ethyl ester 13 with sodium hydride and reaction of the resulting enolate with tx-bromoketone 14 <00MI1147>. The 1,4-dicarbonyl compound 15 thus formed was directly transformed into the pyrrole 17 by adding the amine 16 at room temperature. Secondary reactions interfered in the coupling between 13 and 14 performed with the lithium enolate <97AG(E)155> instead of the sodium enolate. A mixture of coupling products was observed due presumably to bromine exchange between the two coupling partners with the n-BuLi used for the enolate generation. A selective nucleophilic substitution on the methyl ester group of 17 on treatment with NaCN in 1,3-dimethyl-3,4,5,6tetrahydropyrimidin-2(1H)-one (DMPU) <74HCA987> afforded the monocarboxylic acid 18 leaving the ethyl ester group unchanged. Subsequent oxidative lactonization of the carboxylic acid 18 with lead tetracetate, <67JCS(C)1639> in refluxing benzene furnished the lactone 19 in 97% yield. As reported before, <97AG(E)155> this reaction forms exclusively the desired regioisomer by attack of the carboxy radical at the ortho position which carries no adjacent alkoxy substituent. Hydrolysis of the ethyl ester group was achieved by treatment of 19 with 40% aqueous KOH, and removal of the ethanol by distillation. The Pd(0)-catalyzed Heck cyclizations of bromide 20 proceeded with concomitant decarboxylation, a reaction type hitherto not observed in Heck reactions. Treatment of 21 with A1C13 in dichloromethane removed the isopropyl protecting groups <97CC2259, 98JOC9139> and afforded lamellarin L in almost quantitative yield.

co2,

V

0

1. Nail OMe Oi-Pr 2. B ~ oCo2Me 13

1,= ~ "OMe Oi-Pr

MeO' ~ O/-PrOMe Oi-Pr //~.~" ~'\ // 0 ~ 2 Et ?

\

~)

o,-Prl"Pr~

OMe

16

I i-PrO" ":/ ) \ OMe I NH2 I~ L EtO2C--~O O/~-CO2Me ~ Molec.Sieves A ) 5 3 (4 %

"~ "Oi-Pr OMe NaCN,~,. 17 R=Me DMPU 18 R = H 98%

~-

15

. ,., Oi-PrMeO ,.,. ,., Meu~N /~Ul-I-'r ~

1

O ~ R Pb(OAc)4R 97% r ?

Br-.~

ar

\

~

MeO

OR1

O CH3CN'PPh3, ~ NEt3, Pd(OAc)2 O 97% M e O ~

Br-~~ "~ "Oi-Pr OMe 40%aq.K O , ~ 19 R=Et then p-TsOH 20 R = H 80%

R1 0 ~ "

OMe OR1

~ '0

, R = Me : lamellarin G trimethyl ether AlCl3[_~ 21 RI=i-Pr 96% lamellarinL, R1 = H

Boger et al. developed a common strategy useful for the synthesis of related natural products and analogues <99JA54>. Their approach employs an aza Diels-Alder reaction <86CRV781, 89PHC30> using as diene the dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate 25 to

8

P. CironL F. Albericio and M. Alvarez

assemble the substituents onto a six-membered 1,2-diazine core followed by a reductive ring contraction reaction <84JOC4405>. This method provided a tetrasubstituted pyrrole, a five membered heteroaromatic system, assembled by a [4 + 2] cycloaddition reaction followed by a ring contraction.

A•r

RO2C

Ar ~

I-Ar

Ar

Zn Ar'k~Ar DielsAlder N-N reduction , ~>MeO2C~(~ ~CO2Me , > MeO2C---( / \~)~CO2Me CO2R N-N N=N

H

Pd(0) '~~>

Ar

+ ArOTf

or

R3Sn - - SnR3 + 2 ArBr

Significantly, the oxygenation pattern found in the two aryl groups, as in 24, would be expected to increase the nucleophilic character of the acetylene and improve what is a typically poor reactivity of alkynes toward 1,2,4,5-tetrazine derivatives <65CB1435> for an inverse electron demand Diels-Alder cycloaddition.

BnO--~

~

22

BnO--@l

Pd(PPh3)2CI2, Cul, Et3N

N-N

BnO---~

~

~~~--OBn

OBn

~~---~ MeO2C

N-N

BnO.

OBn

Zn, HOAc ~ ~ 7 72% ~ ' ~ 2Me MeO2Cf\ N~CO2 Me H

26

TFA~29 R=CO2H

Br

~o

OBn

0

30 R = H

HO

H2, Pd/C Me 100% "

25

BnO

OBn

K2CO3 ~ OMe

~

,,. oo%

-

// \\

_

MeO2Cf\N~CO2Me 28

27

BnO

LiOH 76% "

N TM

85%

24

75%

23

BnO

Me02C --.~/ \~--C02Me

L-~ O

OH OMe L ~0 1

97%

Me

lamellarin O

OMe

OMe

The acetylene 24 was allowed to react with 1,2,4,5-tetrazine 25 to give the desired pyridazine 26 in excellent yield. Zinc reductive ring contraction followed by N-alkylation of

Lamellarins: Isolation, activity and synthes•

9

the resulting pyrrole 27 with commercially available 4-methoxyphenacyl bromide 7 gave the pentasubstituted pyrrole 28. The symmetrical diester 28 was subjected to a selective hydrolysis with LiOH to provide the monoacid 29 which by decarboxylation afforded the appropriately substituted and functionalized pyrrole core 3t1 found in lamellarin O. This key intermediate could be quantitatively converted into lamellarin O by catalytic hydrogenolysis of O-protecting groups or, more simply, by conducting a TFA treatment of 29 or 30 at more elevated temperatures. Later, <00JOC2479> working on the synthesis of the natural product ningalin B, based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to pyridazine to pyrrole) the same group synthesized 36 a lamellarin derivative with a 7-membered ring instead of 6. The synthesis of the product 34 was achieved by N-alkylation with the phenethyl bromide 32 then subsequent MOM deprotection with concomitant lactonization provided lactone 34. Selective conversion of the methyl into the carboxylic acid 35 was achieved by reaction witn LiI. Attempts to promote decarboxylation under acidic conditions resulted in either no reaction (neat TFA) or Friedel-Crafts acylation (neat Eaton's acid <73JOC4071>) giving 36 in 66% yield.

MeO OMe OMeOMe MeO~Me ~ OMe ~ ~ K2003 ~lOOJOMe ~ \~_/ HCI-EtOAc '%__/ \ 95% = R-~N _ // ~ OMOM 94% 0 MeO2C~\N~CO2Me MeO2C~\N~CO2Me H 31 33

M e O ~

Br

OMe

32

;

P205,MeSo3HMe~O OMe OMeOMe 66% - O ~ N ~ ' O MeO~ MeO

36

MeO

MeO

OMe

OMe Lilt---34 R=CO2Me 80%1---35 R CO2H

O

A different methodology was used by Iwao and co-workers to achieve the first total synthesis of the pentacyclic lamellarins D and H <97T5951>. The strategy was also used to produce a small library of 10 compounds for cytotoxicity evaluation in an effort to examine their structure-activity relationships <02JNPS00>. The common pentacyclic lamellarin skeleton was constructed by N-ylide mediated pyrrole ring formation and subsequent lactonization. The precursor 40 was obtained by a condensation of the known benzylisoquinoline 37 and the substituted benzoate 38 followed by N-alkylation with ethyl bromoacetate. Benzylisoquinoline 37 required for the synthesis of lamellarins was prepared according to a well known procedure <71JPS1634, 61T46>. The 4-benzyloxy-3-methoxy-6methoxymethoxybenzoate 38 was readily obtained by a four-step synthesis from methyl 2,4dihydroxybenzoate in 49% overall yield <97T5951>. Metalation of benzylisoquinoline with LDA was chosen and gave better results than other tested bases on condensation with 38 to give 39 as a tautomeric mixture. Construction of the

l0

P. CironL F. Albericio and M..~lvarez

lamellarin framework from the mixture of 39a and 39b involves: i) quaternization with haloacetate, ii) removal of the MOM protecting group, and iii) pyrrole ring formation and subsequent lactonization. Although the three-step sequence can be operated virtually in a onepot procedure, high temperature or prolonged reaction times decreased the yield of 42. The synthesis of lamellarin D was accomplished by hydrogenolysis of the benzyl groups of 42 over

BnO

B n O ~

MeO~---~~

N

38

B n O ~

MeO~~~ N >- M e O ~ O

LDA 63%

BnO~

37 Q Br

MeO~.~.~

I ~ / 0 0 2 Et

BrCH2CO2Et M e O . . ~ @ O

"

BnO/X"--~ ~

"~

39b MeO"

OBn

RO

R

1

RO~

.

OMOM "~

OBn

R10

0

~

OR

Et3N

~ ./J ..1...OR " 3-~o BnO" ""~ ~ ~ (3steps) MeO"

M e O ~ - ~ ' ~ ' t N'H M e O ~ O

~/OMOM

39a MeO"

B n O ~

==

'~ OBn

40 R = MOM cat. HCI F-L_~ 41 R=H

~

0

H2, r-- 42 R = Bn, R1= Me Pd(OH)2/CI-=- lamellarin D R = H, R1 = Me 82% larnellarinH R=H, RI = H

BBr3 68%

Pearlman catalyst <67TL1663>. Cleavage of both methyl and benzyl ether linkages in 42 using six molar equivalents of boron tribromide afforded lamellarin H. In a similar approach, Ruchirawat et al. <01TL 1205> first prepared an o-mesyloxyphenacyl Br

MeO

MeO

OMs R'~'~ ~ K2CO3

MeO" v

"1

.. . .. ... . .. . R= (~Me

OMe R

R

Me

I~

Ms

DMF, POCI3

63% MeO" ~ MeO

M

OMeR

=

R

e

e OM R

MeO

~

O

~

46 R1 = OMs KOH 47 R1 OH 77% series a 81% series b

~

R Pd(OAc)2, PPh3'

or

=e

e

O 45

MeO ~

OMe R

R

K2CO 3, PhBr

R1 ~ =_

=e M

80%

v 43

MeO~ . - ~ . ~ ~ ~ 48

HO

80%

= M

eO

MeO~ ~ . .

,,

N' ~-

'

O,' 0

49 R = H (from series a) larnellarin G trirnethyl ether, R = OMe (from series b)

Lamellarins: Isolation, activity and synthes&

11

bromide 44a as one of the building blocks, which was further condensed with 3,4dihydropapaverine hydrochloride 43 in the presence of potassium carbonate and acetonitrile as solvent. The expected mesyloxy pyrrolo[2,1-a]isoquinoline 45a was produced presumably due the intramolecular reaction of the derived enamine from the isoquinolinium salt and the ketone as found in the Knorr pyrrole synthesis <99T6555>. The introduction of the formyl group on the pyrrole ring to give 46a was accomplished by Vilsmeier reaction, using DMF in phosphorus oxychloride at room temperature. The O-mesyl protecting group in the derived aldehyde intermediate was easily removed by heating with potassium hydroxide in ethanol to give 47a. Finally, an oxidation of 47a with manganese dioxide in dichloromethane yielded the lamellarin derivative 49 presumably via the hemiacetal intermediate 48a. The same approach was applied again to the synthesis of lamellarin G trimethyl ether as shown in series b. The first three steps proceeded as expected, however the oxidation of compound 47b with manganese dioxide gave lamellarin G trimethyl ether in a disappointing yield (20%). The by-product was found to be the quinone derivative 50 formed by the preferred oxidation of the electron-rich phenolic ring. For this reason the oxidation was carried out with bromobenzene, palladium acetate and triphenylphosphine using DMF as the solvent and potassium carbonate as the base. Lamellarin G trimethyl ether was formed in 80% yield.

50 Later developments from the same group brought some changes <03TL1363> to their previous routte. One of the drawbacks of the previous sequence was the use of a mesyl protecting group, which added two synthetic steps. A better approach was found using a hydroxyl protecting group on the phenacyl bromide synthon that can act as a directing group for the remote deprotonation at the C-2 position of the pyrrole as well as being the source of the lactone group in the subsequent lactonization of the resulting anion without the need for a separate formyl group equivalent. This strategy was pioneered by Snieckus and termed DreM (for directed remote metalation) <99AG(E)1435>. The directing group is typically a carbonate or a carbamate group. Alternatively, the intermediates 53 or 54 could be selectively brominated at the 2-position <02T6373> of the pyrrole to give the bromo compounds 55 or 56 which could undergo metal-halogen exchange to provide an anion similar to the one from the DreM strategy after initial remote deprotonation. Reaction between the benzyl-3,4-dihydroisoquinoline hydrochloride 43 with the carbamates 52a and 52b in the presence of NaHCO3 afforded the pyrrole carbamates 54a and 54b in 91 and 81% yields, respectively. The carbonates 51a and 51b were also coupled with 43 under similar conditions to give the pyrrole carbonates 53a and 53b in 72 and 60% overall yields. Lamellarin 49 was synthesized with just 35% yield after some exploratory work on the DreM methodology. In addition to the low yields, the DreM/cyclizations reactions were not highly reproducible and partial deprotonation of the starting material was frequently found. A more direct way to generate the C-2 pyrrole anion would be via metal-halogen exchange and require the C-2 halo pyrrole. To this end, the pyrroloisoquinolines 53a, 53b, 54a and 54b were

12

P. CironL F. Albericio and M. /ilvarez

selectively brominated with N-bromosuccinimide (NBS) to give the bromo pyrroles 55a, 55b, 56a and 56b in excellent yields (> 95%). Subsequent lithium-halogen exchange of carbamates using tert-BuLi, gave only the 2-(N,N-diethyl)amido-pyrroles 57a and 57b in virtually quantitative yield. Other attempts to achieve ring closure of these amido-pyrroles failed <99AG(E)1435>. However, lithium-halogen exchange of carbonates 55a and 55b with tertBuLi, proceeded smoothly to give the desired lamellarins 49 and lamellarin G trimethyl ether in 72 and 67% yields, respectively.

o Br O ~ O'Jt"x

MeO.~. MeO'- ~ MeO" ~

OMe R

R

~--'~'R

"]

MeO. ~ ~ ~

MeO

NHQC( ~

J

a

,Me

NaHCO3

M

51 X = OEt, 52 = NEt2 a R = H or b R = OMe

v

43

~O x e

O

DreM

~

53 X = OEt, 54 X = NEt2

M-halogen exchange

[

bromination MeO

MeO

OMe R

R

MeO

OMe R

M-halogen H ~exchange Me "~J/~\N/~CONEt2 57

lamellarins

R

o~X b

56 X = NEt2

55 X = OEt,

Recently, <04AG(E)866> Ruchirawat et al. proposed a more convergent strategy which envisioned that the lamellarin skeleton could arise from condensation of the benzyldihydroisoquinoline with a Michael acceptor, such as 61 or 62, which essentially would install the lactone or the ester group on the 2-position. Since imines, which exist in equilibrium with their enamines, have been shown to react with 13-

R40

R50

OR6

R30

R40 B

R

3

R50 0

~

'

OBn

T

o 58

R40

59

A~,

R30

R20~ R10~

OR5 /OR6

+ 60

N+ O2N

60

~,OR5 /OR 6

O 61

O2N

CO2R 62

Lamellarins: Isolation, activity and synthes&

13

nitrostyrene to give the corresponding pyrroles <99TL4177>, it seemed that Michael addition of an enamine derived from a benzyldihydroisoquinoline with a powerful Michael acceptor, followed by ring closure and aromatisation might provide a more direct route to the lamellarin alkaloids than previous methods. Modelling the Michael addition/ring closure reaction, a simple D-nitrostyrene and 3,4dihydropapaverine hydrochloride were reacted under basic conditions resulting in complete consumption of both starting materials but gave no desired product. The ester nitrostyrenes are more powerful Michael acceptor than the simple nitrostyrenes due to the additional electronwithdrawing effect provided by the ester group; this allows the ester nitrostyrenes to react under milder reaction conditions. Consequently, the authors planned to use a coumarin derivative as the ester nitrostyrene which would offer a significant advantage in that the structure already contained the lactone moiety. Unfortunately, such a reaction gave the desired lamellarins in only 5-6% yields. These results prompted the use of an acyclic ester nitrostyrene like 62. From the structure of compound 59, it was apparent that the desired lactone moiety could be formed by unmasking the benzyloxy-protected phenol by hydrogenolysis and subsequently initiating base-mediated lactonization.

R10

X

~CHO

EtO2CCH2NO2 B n O ~ O B n Et2NH.HCl . ,,. . ,..,II I NO2

BnO\ ~ / O B n .~ .~I 65; 3 steps=

R20 / ~

MeO'- -"7-- - - - C H O

63 X=OBn, R I = R 2 = M e

MeO/~x'~""x~

66

CO2Et

67

64 X = R2 = H, R 1= Me 65 X = R 1= H, R2 = Me 63-65, 7 steps

R30"~'~

M e O ~ N

R10~1 ~ X

R40 ~ x

R50 / ~

f/ \~L

NaHCO3,67 M e O . . ~ x OBn 70% "~/ / ' ~ \ N / - ' - C O 2 E t

R~ O ~ ~ ~ . J X

~ R40

OR6

Nail M e O ~ N . ~ O 93%

RI 0 ~ X

68 X = OBn, R1 = R3 = Me, R4 = Bn 70 X = OBn, R1 = R3 = Me, R4 = Bn 69 X = H , R I = R 3 = B n , R 4=Me ~ - 71 X = H , R I = R 3 = B n , R 4=Me H2, Pd/C

,~~ RSo

OR6

0

Lamellarins K LamellarinsL

72 X = OH, R1 = a 3 = Me, R4 = H 73 X = R1 = R3 = H, R4 = Me

The Michael addition/ring-closure reaction of the imines 68 and 69 with the ester nitrostyrene 67 proceeded smoothly in refluxing anhydrous acetonitrile in the presence of NaHCO3 to give pyrroles 70 and 71. The syntheses were completed by subjecting pyrroles 70 and 71 to hydrogenolysis to give compounds 72 and 73 quantitatively, followed by base-mediated lactonization with sodium hydride in dry THF to produce lamellarin K in 93% and lamellarin L in 87% yield over two steps. Lamellarins K and L were successfully prepared in three steps in 65% and 61% overall yields, respectively.

14

P. CironL F. Albericio and M. Alvarez

Iwao et aL developed a short and flexible route to 3,4-diarylpyrrole marine alkaloids applying a new strategy to the synthesis of lamellarin G trimethyl ether and related marine compounds <03TL4443>. The synthetic strategy involved two key reactions: i) Hinsberg-type condensation <95S795> of the aminodiacetates 75 with dimethyl oxalate to produce 3,4dihydroxypyrrole-2,5-dicarboxylates 76, and ii) palladium-catalyzed Suzuki cross-coupling of the bis-triflate derivatives 77 with arylboronic acids. 2-Arylethylamines 74a and 74b were alkylated with methyl bromoacetate in acetonitrile in the presence of NaHCO3 to give the aminodiacetates 75a and 75b. Condensation of 75a and 75b with dimethyl oxalate using NaOMe as a base afforded 3,4-dihydroxypyrrole-2,5dicarboxylates 76a and 76b in modest yields. This pyrroles were converted into the bis-triflates 77a and 77b in good yields. R10 NH2

OR 1

MeO2C~N~CO2Me MeO2C (CO2Me)2 MeONa =R 49%

BrCH2CO2Me, NaHCO3 =~ R OMe 74a R = H 74b R = OMe

91%

MeO CO2Me MeO. _ ~

L,, ""l

78

B(OH)2

Pd(PPh3)4,Na2CO3

/

[ ~

OMe

78%

=~ 79

R OMe

75a 75b

76a R = R 1= H

(0F3SO2)20 86%

76b

R = OMe, R1= H

R = H, R1= Tf 77b R = OMe, R1= Tf 77a

The bistriflate 77b was coupled with 1 equivalent of 3,4-dimethoxyphenylboronic acid 78 to give the mono-arylated 79 in 78% yield, accompanied by 11% of the di-arylated product. The second cross-coupling, of 79 with 4,5-dimethoxyphenylboronic acid 80, was found to be somewhat inefficient due to rapid decomposition of the boronic acid 80 under the coupling conditions. However when the reaction was carried out using excess (2.0 equiv) of 80 and 8% of Pd(PPh3)4, the coupling product 81 and its lactone 82 were obtained in 58 and 12% yields, respectively. Elimination the O-MOM protecting group of 81 by treatment with hydrochloric acid in methanol caused at the same time lactonization to give 82 with an excellent yield. Alkaline hydrolysis of 82 methyl ester followed by heating with p-TsOH produced the acid 83 which by Cu20-mediated decarboxylation in hot quinoline afforded permethyl ningalin B 84. The ring closure of 84 to furnish the lamellarin G trimethyl ether was cleanly effected by application of Kita's oxidative biaryl coupling conditions <98JOC7698> with good yield. Examination of a straightforward ring closure of 83 to lamellarin G trimethyl ether through a Pd(II)-mediated decarboxylative cyclization <97AG(E)155, 00Mill47> also afforded the same lamellarin G trimethyl ether in 65% yield, accompanied by 12% of 84. The ring closure was found to be regioselective at C-6 of the pendant aromatic ring. This novel cyclization may proceed via initial decarboxylative palladation <02JA11250> of the pyrrole ring, followed by electrophilic palladation of the electron-rich aromatic ring and reductive elimination of Pd(0).

Lamellarins: Isolation, activity and synthesis

MeO

,

MeO :M' O e OMOM

MeO2Cf\ N~CO2Me

MeO2CJ\N~-CO2Me -

B(OH)2 ~ T ~OMOM

M~O"'f"

OMe

OMe

.o

+

OMe

L

OMe

811

OMe OMe OMe MeO

MeO2C.~ N ~ "

~

Pd(PPh3)4,Na2C03 OMe

79

MeO

15

0

0

OMe I 82

conc. HCI 90%

OMe OMe OMe

"1

O

OMe

0

HO2C-~ N~"~~ O ~N~ O MeO ?Me OMeoM e 1. KOH 400/0 L..... O Cu20' quinoline L.~ 0 Phl(OCOCF3)2' ~ ~ / 76% -

~J i~L

93%

-

"~\OMe

~

_

I~

'~

OMe 83 I

L

"OMe

. ...~\ ~ MeU " ~

OMe Pd(OAc)2,MeCN

84

2-%

86% M e O ~ O

l

N

\~

lamellarin G trimethyl ether

65% A new, convergent and straightforward approach was first developed by Banwell et al. <97CC2259> in their total synthesis of the parent ring-system lamellarin K. The pivotal step in their approach to lamellarin ring systems involves construction of the central pyrrole moiety via an intramolecular [3 + 2] cycloaddition of an isoquinoline-based azomethine ylide to a suitably tethered bisarylacetylene, a hitherto unknown process. The reaction sequence leading to the alkyne 85 involved a palladium-mediated cross-coupling reaction between the appropriate alkynylzinc chloride and the aryl iodide <97CC2259>, or a Sonogashira crosscoupling between the corresponding arylacetylene and the aryl iodide <02BMC3285, 03OL2959>. The bis-aryl acetylene 85 was subjected to a Baeyer-Villiger reaction using mCPBA as oxidant. The resulting formate ester 86 was readily hydrolysed to the phenol 87 with excellent yield. DCC-mediated condensation of the phenol and ot-iodoacetic acid then provided ester 88 which was used for the quaternization of 3,4-dihydro-6,7-dimethoxy-5isopropoxyisoquinoline 89 to give the salt 90. This last compound was not isolated but immediately treated with Htinig's base. The resulting mixture was heated at reflux in 1,2dichloroethane to bring about the cycloaddition followed by in situ aromatisation to give lamellarin K triisopropyl ether 91. Treatment of this last compound with A1C13 resulted in the formation of the target compound lamellarin K. Applying the same methodology they also synthesized other pentacyclic lamellarins with the isoquinoline core in the dihydro form or in the oxidized form using," for the oxidation step, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) <98WO50365>.

16

P. CironL F. Albericio and M. Alvarez

I-- MeO

Oi-Pr

MeO

,_Pro-

MeO~

OMe

-

o,-Pr

/ R

m-CPBA I NaHCO3 I

M e O ~ 89

I

-

N

"~ l

85 R= CHO 92% two steps --- 86 R = OCHO ' s7 R = OH -I NH3, MeOH

ICH2COOH, DCC DMAP 97% I

OMe

MeO.

MeO~,~ O/-Pr

O./N(~I~=

O

_

90

= 88 R = OCOCH21 Oi-Pr

MeO

.

\

OH

.Oi-Pr

re"ux M e o M e O

X.--,

MeO

, OH

\

,0,96O, o O

MeO

O

OH

O/-Pr 91

lamellarin K

Using a similar strategic procedure Faulkner et aL <02BMC3285> synthesized and evaluated 20-sulfate analogues of lamellarin ct. OM e /

-

P

r

MeO O

OM e

.OiPr

BCI 3

92

.OR

RO

~ 93%

MeO ~ . . ~ . ~ ~ ~

MeO

O

Me

MeO ~ j ~ ~

O

DMF-SO3 r--I_ 9 3 R = H 83% - 94 R = SO3Na

Lamellarins I and K were also synthesized by Guiti~n et aL <01S1164> with a new approach based on the 1,3-dipolar cycloaddition of a nitrone to an alkyne. The key cycloaddition step yielded an isoxazoline which rearranged to afford the central pyrroloisoquinoline core. N-Oxides 96a and 96b were obtained from dihydroisoquinolines 95a and 95b, which were prepared using standard isoquinoline alkaloid synthetic procedures. Reduction of the imine double bond 95 with sodium borohydride, followed by a non-optimised oxidation with sodium tungstate <90JOC1736>, afforded N-oxides 96. The key intermolecular cycloaddition step was carried out by heating a mixture of nitrone 96 and alkyne 97 at high temperature in a sealed tube. Under these conditions compounds 99 were obtained in moderate yields. The cycloaddition appears to produce the expected regiochemistry and form the isoxazoline 98, which upon heating undergoes rearrangement <96T12049, 70CB3196> to the corresponding pyrroles 99. Finally, lamellarins I and K were obtained from 99a and 99b respectively, by removal of the isopropyl protecting groups <98JOC9139> with concomitant acid-catalyzed lactonization.

Lamellarins: Isolation, activity and synthesis

OR M e O ~ MeO~-~

OR M e O ~

OR O-~OMe MeO~ ~- "' ~- ~- - % OCO2Et\ ,, vMe

98a 98b

.CO2Et

,_PrO~[ ~ OM, 120~ "

96a R = Me 96b R = H

95a R = Me 95b R = H

MeO/"--~ ~OkPr

Oi-Pr

96% MeO 2. H202,Na2WO4=MeO'~~ 45% RO" "~

N

]7

MeO----~\ /> MeO.

~ ~

OR

OR

"OMe

MeO ~'/ \~)

"71 "/ ~"h-'/\N/~'CO2Et MeO~ ~ / ~ ' y 99a OR 99b

OR

MeO

MeO----~~ I

II

M e O ~

....

~_ N

\0

O

lamellarin I, R = Me lamellarin K, R = H

1.4.1.2 Approaches starting from the pyrrole core At about the same time as the Steglich report, Banwell et aL published a convergent synthesis for the open lamellarin systems: lamellarin O, lamellarin Q, lukianol A and some more highly oxygenated congeners <97CC207, 99WO67250>. In each case, the key synthetic step involves Stille <86AG(E)508, 92S803> or Suzuki <94PAC213> or Negishi <87OS67, 93CRV2117> cross-coupling reactions of readily available pyrrole-2-carboxylic ester derivatives with the appropriate arylstannane, -boronic acid or-iodide. The pivotal dibromopyrrole 102 required for all the syntheses was prepared from pyrrole itself using procedures developed by Muchowski and co-workers <90JOC6317>. Thus, the Ntriisopropylsilyl derivative of pyrrole 100 was subjected to reaction with NBS in THF to prepare the tribromo-derivative 101, which by reaction with PhLi followed by C1CO2Me afforded the previously unreported compound 102. Stille cross-coupling of pyrrole 102 with the t-BuMe2Si (TBDMS) protected stannane using Pd(PPh3)2C12 as catalyst gave the expected product 103. Elimination of N- and O-silyl protecting groups of 103 with Bu4NF afforded lamellarin Q. The synthesis of lamellarin O followed very similar lines. Thus, compound 102 was desilylated and the resulting pyrrole 104 coupled with the arylstannane. In this manner, the two-fold coupling product 105 was obtained. Reaction of this with 4-methoxyphencaylbromide in the presence of base then gave the N-substituted pyrrole which was deprotected with Bu4NF to afford lamellarin O. Two-fold cross-coupling of pyrrole 104 with p-MeOC6H4B(OH)2 under standard Suzuki conditions afforded lamellarin Q dimethyl ether. This route was shown to be more efficient than Ftirstner's route <95JOC6637>. Stille and Suzuki cross-coupling reactions failed when the authors tried to obtain the monoarylated pyrrole under different conditions. As a consequence, these types of coupling reactions would not seem to be useful in providing access to differentially di-arylated pyrrole systems

18

P. CironL F. Albericio and M. .4lvarez

that would be required for the synthesis of the more complex lamellarins. This limitation was overcome by regioselective lithiation of compound 102 followed by transmetallation and Negishi cross-coupling reaction. HO R1

R1

3x

~

TBDMSO~--~/k--SnMe 3

-

Ar

R2 Pd(PPh3)2Cl2 (10 mol%)9

66%

Si~Pr3

BrB ~ ;

H

78%

,.,r

3x T B D M S O ~ - - S n M e 3

Bu4NF(10 mol%), then 0.5 M aq. HCI

~N,,>L---CO2Me ~

98%

Me

9

Si~Pr3

100 R 1 = R2 = H NBS ]91% R1 R2 = = Br PhLi then I _ _ _ . 101 9 ~ ~ R 1 R CICO2Me = Br, 2 = CO2Me 99% Bu4NF (10 mol%), then 0.5 M aq. HCI

Ar

~''

OH

H

103

lamellarin Q HO\ _ ~~

Ar, ~

-

Ar

1. p-MeOC6H4COCH K2CO3, Bu4NCl _

_ / OH (~-~ (~,,N,~CO2Me

CO2MePd(PPh3)2CI2 (10 mol~ - \ N / ~CO2Me 2. Bu4NF (10 mol% ), 66% H then 0.5 M aq. HCI 104 105 83% 3x M e O - ~ -

B(OH)2

I Pd(PPh3) , sat. aq. Na2CO3 MeO

OMe

OMe lamellarin O

Me H lamellarin

Q dimethyl

ether

Thus, reaction of 102 a t - 7 8 ~ with PhLi afforded the mono-lithio-derivative 106 which was transmetallated with ZnC12 to give the organozinc 107. This last species was, in tum, cross-coupled with the aryl iodide 108 to give the mono-arylated pyrrole 109. Compound 110 was subjected to a further lithiation-transmetallation sequence and the intermediate 111 then cross-coupled with aryl iodide 112. This material was desilylated using Bu4NF thereby affording the target pyrrole 113. A similar reaction sequence where compound 107 was coupled with aryl iodide 112 and the resulting mono-arylated pyrrole subject to metallation and coupling with aryl iodide 108 afforded, after deprotection, the isomeric system.

Lamellarins: Isolation, activity and synthesis

OMe

MeO/ ~

MeO~j/OMe

BrR ~

, lo8 R2 Pd(PPh3)4_ ~

1

,

OMe 1, ~OTBDM OMe S

~OMe

19

MeO

MeO

.OMe

~ 11l H O ~ O M e Pd(PPh3)4

CO2Me 69% from 102 ~..NJ~----CO2Me 2. Bu4NF (10 mol%), ti then 0.5 M aq. HCI Si Pr3 ~;iipr3 68% 102 R'= Br - - 109 R2= Br PhLi I ~ 106 R1= Li BuLi L_~ 110 R2= Li ZnCll = 107 R1= ZnCl ZnCl[ ~_111 R2= ZnCl

"-..N/"--CO2Me H 113

A similar approach was used by Liu et aL <00JOC3587> for the synthesis of 2,3,4trisubstituted-lH-pyrroles with 1-protected 3,4-bis-(trimethylsilyl)-lH-pyrroles as pivotal precursors. They introduced the 1-(N,N-dimethylaminosulfonyl) protecting group for enhancing the acidity of the pyrrole ot proton and also stabilizes an ortho-lithium through coordination with its nitrogen or oxygen atoms. These factors therefore combine to facilitate formation of the a-carbon anion. The lithium salt, generated with n-BuLi, reacted with methyl chloroformate to give the sulfonamide 115. The mono-ipso-iodination of 116 was achieved with iodine and silver (I) trifluoroacetate. Steric and electronic factors played an important role in controlling the regioselecvity, C-4 is more nucleophilic as well as less sterically hindered. Suzuki reaction between 116 and p-methoxyphenylboronic acid gave 117, which was also allowed to undergo an ipso-iodination followed by another slightly modified Suzuki crosscoupling reaction with p-methoxyphenylboronic acid to yield the symmetrical compound 119. Deprotection of 119 with Bu4NF led to 120 but in a low yield. An alternative deprotection method using Mg in MeOH at room temperature gave a much higher yield of 120. Finally, Nalkylation of 120 with p-methoxyphenacyl bromide 7 was accomplished to furnish lamellarin O dimethyl ether. The regioselective methodology would be also suitable for the synthesis of unsymmetrical open lamellarin derivatives.

Me3Si'., __5/SiMe3
n-BuLi

SO2NMe2 114 I SiMe3

e3Si~ S i M e 3 1 \N/--Li

Me3Si~SiMe3 / ClCO2Me 58% ~-

SO2NMe2J

\N / ~CO2Me 12, CF3CO2Ag 100% I SO2NMe2 115

Ar ,

ArB(OH)2,Pd(PPh3)4 Ar'Nf; /SiMe3 2M Na2CO3 12,CF3CO2Ag .// \L CO2Me = \ N Z -~CO2Me " \N / ~CO2Me I 98% 78% I I SO2NMe2 SO2NMe2 SO2NMe2 118 116 117 Ar = C6H4-p-OMe Ar~Ar BF

ArB(OH)2, Pd(PPh3)4 Ar \ Ar, Ar / Ar 2M Na2CO3 ~ Mg~ 95% " <"N">L''CO2Me 85% = \N / ~'CO2Me I SO2NMe2 H 119 120

OMe

K2003

\N / ~'CO2Me

90% OMe

lamellarin 0 dimethyl ether

20

P. CironL F. Albericio and M. Alvarez

A cross-coupling methodology was also used by Banwell et al. to build the lamellarin framework around the pyrrole core 122 using Negishi and double-barrelled Heck-type reactions to establish key carbon-carbon bonds from 121 <99AJC755>.

oub,e-barre,,ed

Heck cyclization '

'

O

:> (

O

Br

121

122

Following the procedure described by Bailey et al. <71OS100, 72JOC3618> the authors synthesized 124, then treated with iodine in the presence of silver trifluoracetate and the 4iodinated product 125 <97AG(E)1442> thereby obtained was hydrolyzed with potassium carbonate in aqueous dimethyl sulfoxide to give the previously unreported acid which was later transformed into the acid chloride 126 by standard methods and reacted with o-bromophenol 127 to give the ester 128. Treatment of this last compound with tosylate 129 resulted in Nalkylation and the formation of the trisubstituted pyrrole 130 which contains two tethered arylbromide units required for the projected double-barrelled Heck cyclizations studies. Prior to conducting such studies, compound 130 was subjected to a Negishi cross-coupling reaction <87OS67, 93CRV2117> with phenylzinc chloride 131. No complications associated with coupling between organometallic 131 and the brominated carbon centers within compound 130 was reported in that coupling. This result is testimony to the chemoselectivity usually found with the Negishi cross-coupling reaction which is useful for selective coupling reactions with iodides in the presence of bromides.

H

I '2'Ag+ ~ R1 82%123 R 1= H

H

1. K2003, I Me2SO'H2O~ COCCI32. (COCl)2, DMF,92% H

125

" IOH 127 COCI 92% = H

126

80%~124 RI= COCI3 I~-~r/~L"~ ~

~znc1131 ~ B r ~

K2CO3, DMF 89% LOZ, ..

Pd(PPh3)2CI2 DMF,95%

Br..~ 129 LJ

O

Br

O 128

N

O

Br 130

121

Based on the application of three iterative halogenation/cross-coupling reaction sequences Handy et aL developed a modular synthesis of the lamellarin G trimethyl ether <04JOC0000>.

Lamellarins: Isolation, activity and synthesis

21

Bromopyrrole ester 132 (prepared in three steps from pyrrole) was protected with t-butyl carbamate to afford 133 prior to the first coupling to avoid extensive dehalogenation. Coupling with boronic acid 78 proceeded cleanly to afford monoaryl compound 134 in good yield. It is worth nothing that a modest excess (2-3 equiv) of the boronic acid was required. The use of only 1.2 equivalents of the boronic acid afforded lower yields of compound 134, along with some homocoupling of bromide 133. Treatment of 134 with an equimolar amount of Nbromosuccinimide led cleanly to selective halogenation at the C5 position. The second coupling with boronic acid 136 was then carried out under standard Suzuki coupling conditions to afford 137. Dihydroisoquinoline ring was closed in a two step procedure: formation of the tosylate followed by intramolecular alkylation of the pyrrole nitrogen. As their expected, on the basis of the previous halogenation, the final halogenation also proceeded cleanly at C3 to afford bromide 139. Several attempts to achieve the lamellarin G trimethyl ether failed due a the thermal sensitivity of the boronic acid 140. Finally, an excess of the boronic acid added slowly increased the yield of the final step producing lamellarin G trimethyl ether in 46% yield (overall yield after 11 steps: 9%).

(BOC)20

~

BOC I

CO2Et DMAP

Br/

BOC

.

93% ;r

BOC I

s:r co et

7o%

oo%

/

MeO

OMe

132

MeO

OMe

OH MeO" ~ f B OC 13sHOv~l~-~ JL ~..LOMe MeO~ ' ~ ~ C O 2 E t (HO)2B" ~ "OMe

MeO.~~'J~ IT"~ 1 MeO~L'~ ~

pd(PPh3)4,Na2CO3 ~ 1. TsCI, Pyr ,. ~ , ,/ 54% "~ 6/ ~1 % \ \ / / ~ 2. Nail, D M S O ~ MeO

OMe

MeO

137

.~

leO

O

N

jOMe Me

OMe ()Me "OMe

lamellarin G trimethyl ether

NBS

~

~ OH . . ~ B~o.,2

CO2Et \"X

OMe 138X=H 139 X = Br

MeOe ~UM

140

Pd(PPh3)4. ' .Na2CO3,~ 46%

22 1.4.2

P. Cironi, F. Albericio and M. Alvarez

S O L I D - P H A S E SYNTHESIS

The solid-phase mode offers several attractive features over and in comparison to classical solution synthesis: molecules are synthesized while covalently linked to the solid support, thus facilitating the removal of excess of reagents, soluble side products and solvents. Furthermore, solid-supported reactions can be driven to completion through the use of excess of reagents. Finally, physical manipulations are easy, rapid and amenable to automation facilitating the preparation of libraries of compounds. Although this strategy has been applied widely for the preparation of biomolecules, such as peptides and oligonucleotides, and more recently for the preparation of simple organic molecules, only very few total syntheses of complex organic molecules have been attempted. The following syntheses of lamellarins carried out in solidphase mode illustrate very well the suitability of this approach for the preparation of complex natural products. The first solid-phase strategy was developed in order to improve and optimise conditions for application to a combinatorial chemistry process <03OL2959>. A hydroxy polystyrene resin, Merrifield-OH or Wang-OH, was used as the starting solid support. The key steps in this synthesis were the Baeyer-Villiger reaction on the solid phase <02TL9437>, which converted the aldehyde group of 143 into a formate and the intramolecular cycloaddition of the dihydroisoquinolinium salt 146 to give the anchored pentacyclic system. Hydrolysis of the formate group gave phenol 144. The anchored lamellarin was achieved in a process similar to Banwell's work. Cleavage of 147 with AIC13 in dry dichloromethane gave lamellarins U and L in 10 and 4% overall yield, respectively. It is possible to obtain diversity in the solid phase synthesis of lamellarins by modifying the conditions of cleavage <04T0000>. The selection of different Lewis acids as a cleavage/deprotection method in the solid-phase synthesis of 147 can produce several analogues, which, after purification, can be submitted for biological evaluation.

Lamellarins: Isolation, activity and synthesis

23

Using another approach, starting from the pyrrole core <04TL0000> syntheses of lamellarins Q and O were also achieved. In this work, the methyl N-(triisopropylsilyl)-3,4dibromopyrrole-2-carboxylate 102 was used as the initial scaffold. Banwell et al. <97CC207> used the dibromopyrrole 102 in an elegant convergent synthesis of several compounds from this family of marine alkaloids (shown above). After several attempts, the strategy showed below was the most convenient one. In this case, 4-iodophenol was attached to the resin under basic conditions through the phenoxy anion, which displaces the chlorine of the resin <99TL9085>. Treatment with NaOMe was also carried out in order to cap any residual reactive chloromethyl groups. The organometallic compound 107 was employed in a Pd(0)-catalysed Negishi cross-coupling reaction with the resin-bound iodophenol 148 to achieve 149 in quantitative yield. The second aromatic ring was introduced by a Suzuki cross-coupling reaction between 149 and the corresponding arylboronic acids. It was found that the best conditions establish with Pd(PPh3)4, Na2CO3 solution as the base in dimethoxyethane or in dioxane as solvent. Preparation of lamellarins Q and O required the use of p-hydroxyphenylboronic acid with a suitable hydroxy protecting group for the introduction of the second aryl substituent. After the Suzuki cross-coupling, it was possible to achieve the N-deprotection, the O-deprotection and the cleavage in one step giving the desired lamellarin Q. For the preparation of lamellarin O, the triisopropylsilyl group was removed from 150b with NH4F at reflux for 6 h. N-Alkylation of 152a with 7 was investigated under different experimental conditions <02OL2633>. The use of excess Nail or LDA as a base in dry THF under reflux gave, after cleavage with A1C13, moderate yields of the N-alkyl derivative 154a. Similar N-alkylation results were obtained starting with the O-isopropoxyprotected derivative. Cleavage of 153b also with A1C13 afforded mixtures of lamellarin Q and O. Using for the second cross-coupling reaction arylboronic acids with different substituents several lamellarin derivatives were prepared. At the same time different alkylation agents afforded lamellarin O derivatives.

24

P. CironL F. Albericio and M..4lvarez

These precedent syntheses have shown that is possible to circumvent one of the main drawbacks usually attributed to the solid-phase mode, which is the lack of control of the reactions taking place on the supl~ort. Thus, the "in situ" monitoring of all reactions in real time, using FT-IR (KBr pellets), C gel-phase NMR and 13C MAS-NMR, made possible a full and an accurate control of the progress in these syntheses <04QSAR61 >.

1.5

CONCLUSIONS

Lamellarins are a family of sea natural products with a broad therapeutic profile. Thus, currently several of them are in advanced pre-clinical phase testing for the treatment of different tumors. Syntheses of this family of molecules have been possible only by the use of the most modem synthetic protocols, mainly cross-coupling reagents and cycloadditions. Furthermore, the application of solid-phase methodology for the synthesis of lamellarins is essential for the preparation of libraries of analogues, for speeding up the process of discovering good drug candidates.

Lamellarins: Isolation, activity and synthesis

1.5

25

REFERENCES

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26 97T5951 97WO01336 98JOC7698 98JOC9139 98JOM165 98T5075

98WO50365 99AG(E)1435 99AJC755 99JA54 99JMC 1901 99JNP419 99T14515 99T6555 99TL4177 99TL9085 99WO67250 00JOC2479 00JOC3587 00MI1147 01MI1403 01S1164 01TL1205 02BMC3285 02JA11250 02JNP500 02MI163 02OL2633 02T6373 02TL9437 03CR7392 03OL2959 03PHC140 03TL1363 03TL4443 04AG(E)866 04BMC1697

04JOC0000 04QSAR61 04T0000 04T0000 04WO014917

P. Cironi, F. Albericio and M. Alvarez

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27

CHAPTER 2

Radical Additions to Pyridines, Quinolines and Isoquinolines David C. Harrowven and Benjamin J. Sutton

School of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK [email protected]

2.1

HISTORICAL OVERVIEW

Radical additions to pyridines and related heteroaromatic ring systems have a long and chequered history. The earliest reported example dates back to 1893 when Mohlau and Berger examined the thermal decomposition of benzene diazonium chloride in pyridine <1893MI1196>. Periodically the reaction was revisited but a combination of low yields and poor selectivity limited its synthetic appeal <63AHC131>. Interest was rekindled in the 1960's with seminal publications from the groups of Dou <66BSF3815> and Minisci <68TL5609>. They found that chemical yields and regioselectivities were each improved when reactions were conducted in an acidic medium. The range of radical intermediates giving the reaction was greatly extended with this discovery <73S1, 74AHC123, 76TCC1, 80MI65, 84CHEC-I293, 96CHECII84>, which in turn led to an increased awareness of the reaction's potential. Indeed, in recognition of his enormous contribution to the field, radical additions to protonated heteroaromatic bases are generally referred to as Minisci reactions. One of the main drawbacks of the intermolecular reaction is that to achieve good yields and selectivity it is frequently necessary to run reactions to low conversion rates or use the heteroaromatic base in vast excess. Such a limitation does not apply when conducting reactions intramolecularly and in recent times much attention has been focussed on such variants. A number of synthetically useful ortho-cyclisation and ipso-substitution reactions have been uncovered providing new routes condensed heteroaromatic ring systems and substituted pyridines. Reactions can be effected at neutral pH and may occur to each of the carbon centres in the pyridine ring system. As these recent advances have not been summarised previously, much of this review will be devoted to the intramolecular reaction.

2.2

INTERMOLECULAR RADICAL ADDITIONS

2.2.1

Additions to Pyridines and Quinolines

Many early accounts dealt with the addition of phenyl radical to pyridine. Mohlau and Berger, for example, showed that heating benzene diazonium chloride in pyridine led to the formation of 2-phenylpyridine in 18 % yield, together with a trace of 4-phenylpyridine <1893MIl196, 1893MI1994>. Similar results were attained when heating various phenyl radical sources in pyridine. These include dibenzoyl peroxide <29RTC993, 48JCS2213,

28

D.C. Harrowvenand B.J. Sutton

58AJC200>, phenylazotriphenylmethane <34LA145, 49JCS3181>, 1-phenyl-3,3dimethyltriazine <43 JCS441 >, acylphenylnitrosamine <40JCS372, 52JCS4657, 51JCS2323>, lead tetrabenzoate <54JCS2747>, diphenyliodonium hydroxide <47JA2253> and phenyl iodosobenzoate <56JCS1475>. Likewise, the photolysis of triphenylbismuth <63AHC131>, electrolysis of benzoic acid <39HCA970> and the decomposition of diazonium salts with hydroxide <40JCS349> have been used to generate phenyl radicals in the presence of pyridine (Scheme 1). In each of the aforementioned examples, overall yields were typically less than 30% based on the phenyl radical source and below 5% based on pyridine. Regioselectivity was also poor, though many early reports suggested otherwise. Reassessments of the isomer distribution using spectroscopic methods led Hey e t al. <55JCS3963, 60JCS3787> and Dannley and Gregg <54JA2997> to conclude that each method gave a similar product distribution with 2-, 3- and 4-phenylpyridine being formed in a ratio of ca. 55 : 30 : 15.

-.~

PhN2Cl, A PhN2Cl, NaOH (PhCO2)2, A (PhCO2)2, by Ph--N =N--CPh3, A

Ph ~__~[ph.] pyddine~ ~

PhN=NNMe2, HCI PhN(NO)Ac Pb(OBz)4, A

Ph= + ~ p h 1

Ph21OH, A Ph3Bi, hv PhCO2H, electrolysis

Isomer distribution

~ 55

+

2

:

~ 30

3

:

~ 15

Yield w.r.t. Ph': 5-25%. Yield w.r.t pyridine: below 5%. Scheme 1

Various substituted pyridines have been examined in the reaction, as indeed have various radical intermediates. These results have been collated in earlier reviews <63AHC131, 74AHC123, 84CHEC-I293> and there seems little merit in repeating them in full here. In almost every case, product yields were low and selectivity poor, making them redundant for synthetic purposes. Some illustrative examples are highlighted in Schemes 2 to 7, together with an indication of the regioisomeric ratios reported. Notably, quinoline was a particularly poor substrate for the reaction <58AJC200>, giving products derived from addition to each of its seven carbon centres (Schemes 3 and 5). Moreover, when dibenzoyl peroxide was used as a source of Ph', oxidation of quinoline to its N-oxide was noted, adding a further complication and inefficiency. By contrast, pyridine N-oxide proved to be a good substrate for the reaction <61JCS 18> and displayed a marked preference for addition at C2 (Scheme

7).

17

4

10-30% <67CJC509> <64CZ458> Scheme 2

Me

16 62

5

6

35% <70JCS(C)2169> M~31 Scheme 3

24

? 10

7

Radical Additions to Pyridines, Quinolines and Isoquinolines

29

20 "~ 8

Me" - 56 ~ 5 24% <67CJC509>

12 20 ~

16

9

Ph" ~ pi"30/3 <58AJC200>

6

Scheme 4

14 6

10

Scheme 5

23

~'~ 11

Me" ~38 13% 64 <70JCSC2169> M <67CJC509>

~

Ph"

~-

12

13

h/~7 " 60 <61JCS18> P 14

Scheme 6

Scheme 7

More recently, Hasebe and Tsuchiya found that the photochemical decomposition of oxime esters provides a reasonably efficient method of alkylating pyridine when the latter is employed as the solvent <86TL3239>. The reaction gives all three regioisomers and the proportion of each was influenced to some extent by the nature of the radical intermediate. Thus, while the homobenzyl radical gave the C4 addition product as a minor constituent, both cyclopentyl radical and cyclohexyl radical gave C2 and C4 addition products in almost equal proportion (Scheme 8).

O 15

Ph

hv pyridine R"

ph~ .

MeCO~ . c-pentyl" c-hexyl"

R

R I

R 16

17

18

53% 35% 40% 42% 42%

11% 11%

16% 20%

15% 12% 15%

31% 40% 38%

Scheme 8

Russell et al. looked at the issue of regioselectivity during a study of the thermal decomposition of organomercurials in pyridine <85JOC3423>. In most cases the ratio of C2 to C4 addition products w a s - 2 : 1. However, when irradiations were carried out in the presence of DABCO, selectivity was enhanced for additions involving 2 ~ and 3~ radicals yet worsened for additions of 1~ radicals (Scheme 9). Yields were determined using a variety of methods (GC, 1H NMR and isolation) and unusually, no products derived from attack at C3 were observed.

30

D.C. Harrowven and B.J. Sutton Product RalJo 1 6 : 1 8 with and without added DABCO t-Bu 6.0:1 1.4:1 /-Pr 3.1:1 1.6:1 n-Bu 1.9:1 2.4:1 R

pyridine 66-98%

19

R

16

18

Scheme 9

Curiously, concentration has also been found to influence the regiochemical course of such reactions. In the addition of phenyl radical to 4-methylpyridine, for example, Dou et al. <68TL953> found that at high dilution in nitrobenzene reactions were biased towards C2 addition. At higher concentrations, however, C3 addition predominated (Scheme 10).

6

nitrobenzene

6

11

Ph

20 0.0009 M 0.0097M 0.029 M

21 56 : 44 43:57 38:62

Scheme 10 2.2.2

Additions to Pyridinium and Quinolinium Salts

Dou et aL <66BSF3815, 68TL953, 71BSF2612> went on to show that radical additions to pyridines, when conducted in acidic media, displayed enhanced selectivity towards C2 (Scheme 11). Indeed, regioselectivities were close to those observed for pyridine N-oxide, making the reaction more viable for synthetic purposes. Minisci et aL <68TL5609> confirmed these findings and went on to uncover some intriguing solvent effects <87JOC730>. In benzene, product ratios were largely unaffected by the nature of the radical intermediate leading to a-~3 : 1 ratio of 2- and 4-substituted pyridines. In water, however, highly reactive radical intermediates such as Ph" and Me" showed a strong preference for addition to C2 whereas 2 ~ and 3~ radicals favoured addition to C4 (Scheme 11). R

H 22

H 23

H

24

H 25

In benzene

R = Ph Me n-Bu /-Pr t-Bu

70 73 74 73 71

6 0 0 0 0

24 27 26 27 29

In water

R = Ph Me n-Bu /-Pr t-Bu

64 62 56 32 23

4 0 0 0 0

32 38 44 68 77

Scheme 11

Radical Additions to Pyridines, Quinolines and Isoquinolines

31

Minisci subsequently used and developed a host of methods to generate carbon centred radical intermediates in the presence of pyridinium salts and has highlighted these in a number of review articles <73S1, 74AHC123, 76TCC1, 80MI65; see also 84CHEC-I293, 96CHECII84>. Thus, only a selection of methods are presented here. In general, intermolecular radical additions to pyridinium salts are complicated by the susceptibility of C2, C4 and C6 towards radical addition. As a consequence, regioselectivity is often poor when each of these positions is unsubstituted. Similarly, multiple additions can prove troublesome in such circumstances, as the products too are often susceptible to the reaction.

O

+

4

O 10 equiv.30% H202 --CO2Et 10 equiv.FeSO4 H2SO4,H20,CH2CI2 26

2Et "N- "CO2 Et 27, 25%

+

CO2Ejt +

CO2Et 28, 4%

29, 34%

Scheme 12

To minimise the formation of poly-substitution products, many of the methods developed employ the heteroaromatic base in vast excess. The ethoxycarbonylation of pyridine with ethyl pyruvate, hydrogen peroxide and Fe(II) salts, provides a typical example. In a preliminary study, yields of 58% and 34% were reported for the C2 and C4 addition products, 27 and 28 respectively. However, these were based on recovered pyridine and no indication was given as to the excess used <73TL645>. Later, Heinisch and Lrtsch revisited the reaction <86T5973> and found that useful yields could be attained at near quantitative conversion, by using a two-phase solvent system and employing the radical source in excess (Scheme 12). When the same reaction conditions were applied to 4-methylpyridine 11, ester 30 was formed in 53% yield with recovered starting material accounting for much of the outstanding mass balance (Scheme 13).

~.~ 11

+

O 10 equiv.30% H202 -"'IL'CO2Et 10 equiv.FeSO4 H2SO4,H20, CH2CI2 26

CO2Et 30, 53%

Scheme 13

Similar problems arise with quinolinium salts as both C2 and C4 are susceptible to radical addition. Where either of these positions is blocked by a substituent, reactions often proceed in high yield. For example, Minisci et al. have described a useful method of formylating heteroaromatic bases which begins with an iron(II) promoted reduction of t-butyl hydroperoxide <86JOC536>. The t-butyloxy radical thus produced abstracts a hydrogen atom from 1,3,5-trioxane 34 giving intermediate 33. Union of 33 and the quinolinium salt 35 next produces radical cation 36, which is oxidised to 32 by iron(III) (Scheme 14).

32

D.C. Harrowvenand B.J. Sutton

c+

~ 40 equiv. 1,3,5-trioxane t-BuOOH, CF3CO2H cat. FeSO4, CH3CN ~reflux, 5 h C

31

32, 84%

ot-BuOH

CF3C

O

t-BuOOH " ~ f - F e ( l l ) , ~

\,,Buo

~ H"

1,3,5-tnoxane

~

~'~

Fe(lll) J

I"

.

CF3CO2- H

CF3CO2

35

36

OvO

Scheme 14

The reaction works well because both the site of hydrogen atom abstraction (34 ~ 33) and the site of radical addition to the heteroaromatic base (33 + 35 ~ 36) are well defined <86JOC536>. Likewise, addition of 1,3,5-trioxane 34 to 2-methylquinoline 37 is an efficient process since radical additions to quinolinium salts are heavily biased towards C4 when C2 bares an alkyl substituent (Scheme 15). ~ 40 equiv. 1,3,5-1rioxane 2.3 equiv, t-BuOOH CF3CO2H, cat FeSO4 CH3CN, reflux

37

CF3CO2"

H

38, 61%

Scheme 15

By contrast, quinoline gives a mixture of C2 and C4 addition products (Scheme 16), while the use of 1,3-dioxolane as a formyl equivalent leads to mixtures derived from hydrogen atom abstraction at C2 and C4 of the saturated heterocycle (Scheme 17). Interestingly, these reactions only work well when iron(II) is used catalytically. At higher concentrations, the iron(III) salts produced oxidise trioxanyl radical 33 to the corresponding cation, thereby killing the reaction. ~ 40 equiv. ],3,5-tdoxane 2.3 equiv, t-BuOOH ..~

.

.

.

.

.

.

.

.

.

t-

~ 0 . . ~

+ ~

0

Radical Additionsto Pyridines, Quinolinesand Isoquinolines

1.7equiv,t-BuOOH CF3CO2H,cat.FeSO4 1,3-dioxolane,reflux " 31

33

I O + F C

C 41,57%

~H 42,

O

28%

Scheme 17

Double addition proved to be a major complication in the addition of cyclooctyl radical to 4-cyanopyridine (Scheme 18). Indeed, it was only by stopping the reaction prematurely that the ratio of mono-adduct 45 to bis-adduct 46 could be improved. In the example illustrated, recovered 4-cyanopyridine accounted for 36% of the product mixture <86JOC4411 >.

CN ~'~ H

+

[~

43

(PhCO2)2 CF3CO2H,A

CN

CN

~,

44

+

)

45, 39%

46, 19%

Scheme 18

In the aforementioned example, the alkyl radical was generated by hydrogen atom abstraction from cyclooctane 44. Its symmetry and use in vast excess, ensured that only one alkyl radical intermediate was given in appreciable amounts. Such a tactic is useful, but places a severe limitation on the number of substrates able to give the reaction cleanly, e.g. cycloalkanes, 1,4-dioxane, 1,3,5-trioxane, methanol etc. Minisci developed an ingenious method to counter that limitation involving iodine atom transfer from an alkyl iodide to a phenyl (or methyl) radical <84TL3897, 86JOC4411>. He reasoned that the rate of iodine transfer from a 2~ iodide to Ph" ( k - 109 Mls "1) was approximately three orders of magnitude greater than the typical values for both hydrogen atom abstraction from an alkane and the addition of Ph" to a protonated pyridine (k-~ 106 M-isl). Consequently, thermal decomposition of dibenzoyl peroxide in the presence of i-PrI leads to the formation of i-propyl radical, and it is this species which adds to the pyridinium salt as opposed to the phenyl radical (Scheme 19).

~

CN

+ /~

CN (PhCO2)2, /CF3CO2H ~ i cat. Fe(lll),MeCN,reflux

47

~

p,. Phi

CF3CO H

43

/ CN

48,

-Pr + i _ P r , ~ i . P r 49, 24% 48%

i-Pr" ...... ~~~N~i_pr H 50

Scheme 19

CN

34

D.C. Harrowvenand B.J. Sutton

Homolytic heteroaromatic substitution reactions of this type have also been effected using organotin hydrides and organosilanes as radical mediators (Scheme 20). Reactions employing tributyltin hydride or tris(trimethylsilyl)silane were inefficient when less than a full equivalent of AIBN was used. Indeed, AIBN appears to function as both an initiator and a hydrogen atom acceptor for rearomatisation of the heteroaromatic ring <93JOC4207, 94BCJ2522>.

~Br+

R3MH CF3CO2H 1 equiv.AIBN PhH,reflux

[ ~ 31

51

Bu3SnH (TMS)3SiH

44% [+ 56%recovered31] 87% [+ 13%recovered31]

Scheme 20

Importantly, reactions could be achieved using triethylsilane and diphenylsilane, both of which are considerably cheaper than tris(trimethylsilyl)silane and have lower toxicity than tributyltin hydride. As the silicon to hydrogen bond in these reagents is stronger than in the more conventional mediators, AIBN was no longer effective as an initiator. Rather, tbutyloxy radical had to be employed to abstract the hydrogen atom from the silane. Various methods for its generation were explored. These included the iron(III) promoted decomposition of t-butyl hydroperoxide and the thermally induced scission of t-butyl peroxyoxalate. Hydrogen peroxide in acetone was also effective as both initiator and oxidant in some cases <93JOC4207>. Intramolecular radical translocations provide a further means of generating alkyl radical intermediates. For example, when quinoline was treated with sulfuric acid, 1-hexanol, sodium peroxydisulfate and catalytic silver(I) nitrate, the product mixture attained comprised of recovered quinoline (66%) and the alkylated quinolines 52 (14%) and 53 (14%) <76T2741>. A series of redox reactions initiate the sequence, oxidising Ag(I) to Ag(II). This, in tum, oxidises alcohol 54 to alkoxy radical 55, setting the stage for an intrarnolecular hydrogen atom abstraction. Addition of the resulting carbon centred radical 56 to quinolinium sulfate, followed by rearomatisation, completes the sequence (Scheme 21). For further uses of peroxydisulfate as a promoter of radical reactions see <83ACR27>.

6

~ O H , Na2S208,cat AgNO3 H2SO4,MeCN,H20

C

~ . ~ O

H+ ~

52, 14%

Ag2*+ SO42-+SO4"- ,, ~ O H 54

0

"

" ~

55

Scheme 21

H

53, 14%

Ag*+ 82082~

O

O

H

Radical Additionsto Pyridines, Quinolines and Isoquinolines

35

A method of effecting the cyclohexenylation of lepidine 31 has also been described by the Minisci group <86TL3187>. Dibenzoyl peroxide was used to trigger the process, which is believed to begin with the addition of PhCO2" to the alkene. The resulting alkyl radical intermediate 59 then adds to the quinolinium salt 35 giving 60. Oxidation to 62 and elimination of benzoic acid reinstates the alkene, giving 57 on work-up (Scheme 22).

cd

2.9 eq uiv. (PhC 02) 2 Cl:3cr'~v,, .H,_ c-hexene " reflux, 40 h

+ 31, 43% 57, 41% '~

31

CF3COOH///

1/2 (PhCO2)2 PhCO2" ~ c-hexene ~ "

",~, 4

~

PhCO

H

H 58

~

--~ PhCO2H

_H + PhCO2" v 61

6O

PHCO262

Scheme 22

The reaction worked well when run to c a . 50% conversion, but has yet to be scoped as a general method for the alkenylation of heteroaromatic bases. One further example was examined involving the union of 1-methylcyclohexene and lepidine 31. In that case, elimination of benzoic acid was less favourable and the only product identified was adduct 63, formed in an unspecified yield (Scheme 14). A related metal-catalysed procedure has been described and its effectiveness is also influenced by the nature of the substrates to be coupled <83JCS(P2)531>.

2.9 equiv. (PhCO2)2 :}1

1-methylcyclohexene CF3CO2H, reflux

}1,

63

Scheme 23

36 2.2.3

D.C. Harrowvenand B.J. Sutton

Ipso-SubstitutionReactions

The preceding discussion has, by implication, suggested that radical ipso-substitution reactions with heteroaromatic bases are rare. A few examples have been uncovered. For example, irradiation of 2-cyanoquinoline in acidic ethanol led to hydroxyethylation of the heterocycle with loss of the cyano-group (Scheme 24) <73BCJ942, 74BCJ942>. Similarly, 2-cyanopyridine has been transformed into 2-(1-hydroxyethyl)-pyridine in 30% yield by this method when run under conditions of high dilution <75CC241>.

hv EtOH

~ C N

.COH 65, 35%

64

(54%in acidicethanol) HCN

,/

~

I CNl" IC CN.CHI. 67

66

68

69

Scheme 24

It is interesting to contrast this substitution reaction with a complementary method for achieving the hydroxyalkylation of pyridines and quinolines developed by Minisci et al. <85T617>. They found that addition of hydroxylamine-O-sulfonic acid to an acidic solution of 4-cyanopyridine in methanol containing catalytic iron(II) sulfate, gave 2-(hydroxymethyl)4-cyanopyridine 70 on work-up (Scheme 25). No products derived from ipso-substitution of the cyano-function were observed.

CN

CN

@

FeSO4,H3N+OSO3"- '

~

H2SO4,MeOH,H20 47

1

H3N+"+ SO42-+ F

CN

M e O ~ NH4+

H ~H2OH 43

CN

H

72

+ 47, 64%

70, 28%

H3N+OSO3-+ Fe2+

CN ~J~

OH

~ O H

-H'"r

CN

H

Scheme 25

73

/

H 71

Radical Additions to Pyridines, Quinolines and Isoquinolines

37

These contrasting results suggest that the two reactions follow different mechanistic courses. The photo-induced ipso-substitution reactions are believed to involve the photoexcitation of the heteroaromatic. The excited quinoline 66, for example, abstracts a hydrogen atom from ethanol to give 67 and hydroxyethyl radical 68. Union of these to 69 is followed by loss of HCN, giving 65 (Scheme 24). In the iron(II)-catalysed decomposition of hydroxylamine-O-sulfonic acid, there is good evidence to suggest that amino radical cation is generated and that this abstracts a hydrogen atom from methanol. The resulting carbon centred radical adds to pyridinium salt 43 giving radical cation 72. Loss of a proton and oxidation with Fe(III) completes the sequence, giving pyridinium salt 71 and recycling the metal catalyst in the process (Scheme 25). Ipso-substitution has been shown to occur when 2,4-dicyanopyridine 74 and tetrabutyltin are irradiated at 254 nm, with butylated cyanopyridines 75 and 76 being formed in 42% and 34% yield respectively <92TL3201>. It has been suggested that the reaction proceeds by an electron transfer from tetrabutyltin to the photo-excited pyridine 77, as indicated in Scheme 26.

CN ~

CN ~~,]N ~ 77

/

74

*

CN

CN

Bu4Sn' MeCN hv'~ ~~'ININ~ + ~'~L ~ + 74, CN Bu CN 75,42% 76, 34% ~HCN ~HCN

CN Bu4Sn'H+. u" + ~ C -

Bu

Bu3Sn+

H 78

FBu CN CN 79

20%

CN 1 Bu

H CNJ 80

Scheme 26

The scope of the reaction has yet to be established and may prove rather limited. When applied to 4-cyanopyridine, for example, the main product was 2-butyl-4-cyanopyridine 81 (Scheme 27). With lepidine trifluoroacetate 35, 2-n-butyllepidine 82 was formed in 25% yield (Scheme 28).

Bu4Sn,hv MeCN 47 Scheme 27

~ Bu 81, 77%

CF3CO2- H 35

Bu4Sn,hv MeCN 82,25%

B

Scheme 28

Tiecco et al. found that 4-acylpyridines were prone to ipso-substitution reactions with 3 ~ alkyl radical intermediates such as 1-adamantyl and bicyclo[2,2,2]octyl radical <76CC329>. They reasoned that the reaction began with an electron transfer from SO4"-to the heteroaromatic base leading to radical cation 87. Addition of Ad" to C4 then gave acetate 88,

38

D.C. Harrowven and B.J. Sutton

which underwent hydrolytic deacylation to provide 85 (Scheme 29). At low conversion rates, both 85 and 89 were formed, showing that addition of Ad" to C2 and C4 of 4-acylpyridine 83 were competitive processes. Indeed, with most alkyl radical intermediates addition to C2 predominates. The authors commented that 'This new SR reaction of nitrogen-containing heterocycles seems to be peculiar to those containing a 4-acyl group. With other substituents (CN, CO2Me, C1, Me and OMe) only substitution at the 2-position was observed.' Ad

Ad

cat Ag(I) d

83 SO4"-v ~

84 SO42-

85, 20%

86, 50%

Scheme 21 -C

0

Ad"

83

Ad" d

87

88

89

Scheme 29

2.2.4

Radical Halogenation

Radical chlorination of pyridine has been achieved in reasonable yield <96CHECII84>, with photolysis of a carbon tetrachloride solution of pyridine and chlorine facilitating efficient t~-chlorination <67JHC375>. Bromination has been effected in the vapour phase with BrC1 and gives mainly 2-bromopyridine. By contrast, when Br2 was used both 2- and 3-bromopyridine were given in roughly equal quantity <67JHC377>.

2.2.5

Radical Silylation

Applications of the reaction in medicinal chemistry have begun to surface, in particular for the preparation of camptothecin derivatives. Sawada et al. were the first to use an intermolecular radical addition to the embedded quinoline within camptothecin as a means of introducing alkyl substituents to C7 <91CPB 1446, 91 CPB2574, 91CPB3183>. Later, Curran et al. showed that silyl radicals too could be added to camptothecin 90 but that addition occurred to both C7 and C12 <03BMC451>. The two products, 91 and 92 respectively, were each given in low yield with recovered starting material accounting for much of the outstanding mass balance (57%). Nonetheless, functionalisation of the natural product in this way was deemed preferable to the total synthesis of such analogues (Scheme 30).

Radical Additions to Pyridines, Quinolines and Isoquinolines

N

0 ,~

TBDMS-H (t-BuO)2, t-BuSH dioxan e, reflux 36h

39

y•[ ~x

N

O

91, X = TBDMS, Y = H, 20% 92, X = H, Y = TBD MS, 10%

90 Scheme 30

2.3

I N T R A M O L E C U L A R RADICAL ADDITIONS

2.3.1

Cyclisations to Pyridinium and Isoquinolinium Salts

The problem of having to use either the radical precursor or radical acceptor, or both, in vast excess limits synthetic applications of the Minisci reaction. Intramolecular radical additions to pyridines are, by their very nature, devoid of such constraints. Many early attempts to effect radical cyclisations to pyridines met with failure <37JCS835, 37JA2079, 49JCS1311, 54JCS2471>. Hey et al. were the first to observe the reaction, but the yields attained were pitiful <49JCS3164, 54JCS4263>. In the early 1960's, Abramovitch described a successful Pschorr type ring closure to a pyridine <60CJC2273>. As the radical donor was attached to the pyridine through C3, cyclisation of 93 led to ring closure to both C2 and C4 of the proximal pyridine giving 95 and 96 respectively (Scheme 31). As expected, cyclisation to C2 predominated.

NH2 I

NaNO2, dil. HCl 0-5 ~

Cl- N2+

I

"]

30 min

93

94 J i. urea ii. Cu, RT

I

I

95, 47%

96, 25%

Scheme 31

A year later, Herz and Murty examined the Pschorr cyclisation of dihydroazastilbene 97 <61JOC418> and found that the yield of benzo[h]isoquinoline 99 was extremely low (Scheme 32). These results are in line with the expected preference for radical additions to pyridinium salts, with addition to C2 being more efficient than addition to C4, which in turn is more efficient than addition to C3.

40

D.C. Harrowven and B.J. Sutton H2

NaNo2,

dil. H2SO4, 3 oc

+

then Cu 97

98, ~15%

99, --5%

S c h e m e 32

Subsequently, Abramovitch et aL employed the Pschorr cyclisation of 100 in a synthesis of benzo[c]phenanthridine 102 <63CJC2265>. The key step involved addition of an aryl radical to C3 of an isoquinoline and proceeded in good yield (Scheme 33). Notably, no products derived from cyclisation to the pendent arene were observed [see also Scheme 56].

NaNO2

-~~

i. urea

dil. HCI, 0 o~

!,.

ii. Cu, RT

~ N

~+NH 100

101

102,

50%

S c h e m e 33

Murphy and Sherbum <90TL1625, 90TL3495, 91T4077> went on to show that alkyl iodides 103, 105 and 119 each underwent Minisci type cyclisation on treatment with tributyltin hydride, forming five, six and seven membered rings respectively. The reaction displayed good tolerance of alkyl substituents on the pyridine and in each of the cases examined cyclisation was followed by rearomatisation (Schemes 3 4 - 37). To achieve good yields it was necessary to employ 1.2 molar equivalents of AIBN, indicating a dual r61e for that reagent. Indeed, it acts as both a radical initiator and an oxidant. With less than a full equivalent of AIBN, ionic reactions were observed leading to spirocycle formation <90CC1069>. Unsurprisingly, the attempted macrocyclisation of iodide 121 failed (Scheme 37). R"

RR~R' ~

ll

R"

R'

Bu3SnH RR~R' AIBN,MeCN~

II

THF,A

I-

\

/

103 R = R' = R" = H 104, 65% 101 R=Me, R'=R"=H 108,65% 111 R'=Me, R=R"=H 112,67% 115 R"=Me, R=R'=H 116,58% S c h e m e 34

RII

R' I~ ~ 1 105 109

113 117

Bu3SnH AIBN, MeCN THE, A

!- L,v/j

R = R'= R" = H R=Me, R'=R"=H

106, 60% 110,58%

R'=Me, R=R"=H 114,67% R"= Me, R = R'= H 118,58% S c h e m e 35

It is worth noting that cyclisations involving the addition of pyridinium radical intermediates to alkenes provide an alternative method of synthesising such ring systems <97TL5383>. As the reactions of pyridine and pyridinium centred radicals are beyond the scope of this review, the interested reader is directed to the following lead references <88BSF67, 85TL6001, 93TL5653, 94TL5301>.

Radical Additions to Pyridines, Quinolines and Isoquinolines a

a

.

(CH2)51 119 123 125

127

t!

Bu3SnH ~. ~ ~ AIBN, MeCN THF, A I-

I

R = R' = R" = H R=Me, R'=R"=H R'=Me, R=R"=H R"=Me, R = R ' = H

41

O

Bu3SnH r AIBN' MeCI~ (CH2)lol THF, A I

120, 58% 124, 58% 126, 66% 128, 79%

121

G

II (CH2)gCH3 122, 30%

Scheme 37

Scheme 36

A related reductive cyclisation has been developed by Sch~fer et aL in which the cathodic cyclisation of N-(oxoalkyl)pyridinium salts led to indolizidine and quinolizidine derivatives <95AG(E)2007, 03EJO2919>. Electrolyses of the pyridinium salts were carried out in a divided beaker-type cell at a mercury pool cathode under constant current, using 1 M aqueous sulfuric acid as the electrolyte. In this way, cyclisation of cyclopentanone 129 to the isomeric quinolizidines 130 and 131 was achieved in high yield and with excellent diastereoselectivity (Scheme 38). The stereochemical course of the reaction with cyclohexanone 133 was not as well defined, with three of the four possible diastereoisomers being given in a ratio of 10 : 21 : 26 (for 134, 135 and 136 respectively).

e-, H+ Br

OH

OH

)n 1 M H2SO4~

+

+

O n= 0 n= 1

133, n = 1

H'lK

130, 68% 134, 14%

131,5% 135, 30%

2e-, H+

HH OH

137

138

IFH"

e

139

"~ R

129, n = 0

OH

OH

~

OH

e

140

141 Scheme 38

On

132, 0% 136, 37%

42

D.C. Harrowvenand B.J. Sutton

The reaction was shown to be triggered by protonation of the ketone and reduction to 139. Cyclisation of the carbon centred radical to the pyridinium ring next produced radical cation 140. Addition of a second electron then gave enamine 141, which underwent reversible protonation to iminium salt 138. Further cathodic reduction completes the sequence (Scheme 38). Interestingly, such cyclisations appear to be reversible as the product mixtures attained better reflect a reaction under thermodynamic control than one under kinetic control <03EJO2919>. A new method of preparing pyrazolopyridines from N-azinylpyridinium N-aminides has been developed by Alvarez-Builla et al. <02SL1093> and features a radical addition to a pyridine. Initially, attempts to convert aminide 142 into pyrazolopyridine 143, through the slow addition of tris(trimethylsilyl)silane and AIBN to a refluxing acetonitrile- benzene solution of the two components, was thwarted by a competitive reduction of the N-N bond. Indeed, aminopyridine 144 was formed as the major product in 60% yield. However, through the simple expedient of adding potassium carbonate to the solution of aminide 142, that reduction pathway was almost completely shut down and the yield of pyrazolopyridine 143 was elevated from 2% to 56% (Scheme 39). CI

2 equiv. (Me3Si)SiH

142

2 equiv. AIBN MeCN, Phil K2CO3, 80 ~ 24 h

CI H2N

143, 56%

144, 5 %

Scheme 39 The reaction has also been used to synthesise pyridopyrazolepyrazine 146 (Scheme 40). Here too, adding potassium carbonate to the solution of aminide 145 proved to be crucial for achieving a successful cyclisation reaction.

BryN C,

,N/L~.N m

145

2 equiv. (Me3Si)SiH 2 equiv. AIBN MeCN, Phil K2CO3, 80 ~ 24 h

Scheme 40

2.3.2

Cyclisations to Pyridines

The addition of an aryl radical intermediate to a pyridine featured as a key step in a total synthesis of the alkaloid toddaquinoline by Harrowven and Nunn <98TL5875, 00TL6681, 01T4447>. Thus, cyclisation of azastilbene 148 using tributyltin hydride and AIBN, led to both the desired product, toddaquinoline methyl ether 149, and an unwanted regioisomer 150 (Scheme 41).

Radical Additions to Pyridines,Quinolines and Isoquinolines

~

43

.OMe

.OMe Bu3SnH

D,

+

15 mol% AIBN PhMe, 80 ~ 4 h O k.--O

148

N -'~ Me 150, 29%

149, 29%

Scheme 41

Notably, when the same cyclisation was carried out using sodium cobalt(I)salophen, the reaction became selective for toddaquinoline methyl ether <00TL6681>. This apparent dichotomy was attributed to the formation of a Lewis acid- Lewis base complex between cobalt(II)salophen and the pyridine moiety. Loss of bromide from the radical anion 151 generates aryl radical 152 which adds to the proximal pyridine giving 153. Dehydrocobaltation to toddaquinoline methyl ether 149 completes the sequence (Scheme 42). Notably, as the pyridine ring is activated by complexation to the Lewis acidic Co(II), the cyclisation is more akin to a Minisci reaction. Consequently, cyclisation to C6 is promoted in this case <01 T4447>.

Nacosao0en N~OM

THF, RT

Nx~,,,.OM e 149,61%

148

[Co]~

O'.O

_J~".O l-'-Na+

e

~[Co] Ill

-NaBr

O..1

MeO~ 151

152

153

Scheme 42

The same group went on to show that radical cyclisations to C3 of a pyridine were also favourable at neutral pH <01TL9061, 03OBC4047>. Thus, on treatment with tributyltin hydride and AIBN, azastilbene 154 underwent cyclisation to benzo[f]quinoline 155 in 47% yield (Scheme 43), while the corresponding reaction with iodide 157 gave benzo[h]isoquinoline 159 in near quantitative yield (Scheme 44). (

.

0

O

/--0 Bu3SnH AIBN PhMe, A 155, 47%

154

Scheme 43

44

D.C. Harrowven and B.J. Sutton

In the latter case an important halogen effect was uncovered. While iodide 157 gave benzo[h]isoquinoline 159 on treatment with tributyltin hydride under standard radical forming conditions, the corresponding bromide 158 gave trans-azastilbene 156. Alkene isomerisation occurs through the reversible addition of tributyltin radical to the alkene, a process that outpaces carbon to bromine bond homolysis in this instance. A range of conditions were examined for the cyclisation of iodide 157 to benzo[h]isoquinoline 159. Tris(trimethylsilyl)silane and tributylgermanium hydride were each as effective as tributyltin hydride, circumventing the need to employ toxic organotin reagents <03OBC4047>. One downside of these alternative radical mediators is their high cost. Samarium(II) iodide also gave the reaction, albeit in reduced yield (Scheme 44).

I

Bu3SnH, AIBN 9

see below

PhMe, 80 ~

~

X

\--N ~ 157, X = I 158, X = Br

156, 97%

159

Bu3SnH, AIBN, PhMe, 80 ~ (Me3Si)3SiH, AIBN, PhMe, 80 ~ Bu3GeH, AIBN, PhMe, 80 ~ Sml2, THF, HMPA, RT hv, MeCN, Quartz cell, RT (Bu3Sn)2, by, MeCN, Quartzcell, RT

98% 99% 97% 75% 23% 24%

Scheme 44

'Catalytic' tributyltin hydride methodologies were also studied, with sodium borohydride used as a co-reductant <03OBC4047>. In all cases examined, the yield for cyclisation of 157 to 159 was reduced substantially. This was due, in part, to the low solubility of sodium borohydride in toluene which made it necessary to employ either THF or ethanol as the reaction solvent. Unfortunately, their use promoted alkene isomerisation and substantial quantities of trans-azastilbene 156 were formed as a by-product (Scheme 45).

0.25 equiv. Bu3SnH 1.4 equiv. NaBH4 0.2 equiv. AIBN 157

Toluene, 9 80 ~ EtOH, 9 reflux THF, 9 reflux

o

159 9% 48% -

156 52% 72%

Scheme 45

Further investigation showed that the tether conjoining the pyridine to the aryl radical precursor played a significant rrle in determining the course of such reactions <01TL9061, 03OBC4047>. Thus, while in the aforementioned examples reactions favoured orthocyclisation via a 6-exo/endo-trig pathway, the corresponding alkanes gave products derived

Radical Additions to Pyridines, Quinolines and Isoquinolines

45

from cyclisation to both the ortho- and ipso-carbon centres. With dihydroazastilbene 160, for example, the products of reduction 166 and ortho-cyclisation 161 were accompanied by a product of rearrangement 162. It is believed that its formation arises from ipso-cyclisation of 163 to spirocycle 167. Scission of the newly created ring then gives alkyl radical intermediate 168. Ortho-cyclisation to 165, followed by aromatisation, provides dihydrobenzo[/]isoquinoline 162 (Scheme 46).

~..O

o

Bu3snH. 5 mol%AIBN PhMe, 80 ~ 40 h

~,~N

160

161,

Bu3Sn" - Bu3Snl

31%

162, 18%

/ #

cyclisation~

163

~

Bu3SnH - Bu3Sn"

164

isation

rearrangement.." .."

<00~,

or~o-

cyclisation

s S

>~N fragmentati~ O ipso-

cyclisalJon 166, 31%

165

-"

"

168

167

Scheme 46

Again, the reaction could be effected with tributyltin hydride, tris(trimethylsilyl)silane and tributylgermanium hydride, though only the product of reduction, 166, was given with samarium(II) iodide. A similar outcome was noted for dihydroazastilbene 169, with the products of reduction 172, ortho-cyclisation 170, and ipso-cyclisation and rearrangement 171, each formed in similar quantity (Scheme 47).

AIBN ' PhMe,A 169

+

N

N~ / 170, 33%

171, 27%

172,

35%

Scheme 47

Contemporaneously, Zhang and Pugh <01TL5613, 03T3009> uncovered a related rearrangement leading to azacoumarins. Thus, treatment of ester 173 with

46

D.C. Harrowvenand B.J. Sutton

tris(trimethylsilyl)silane and AIBN, initiated an ipso-cyclisation of aryl radical 175 to C2 of the pendent pyridine generating spirocycle 176. Scission of the newly formed ring, next gave the carbonyloxy radical 177. An ortho-cyclisation and ejection of methoxy radical furnished azacoumarin 174 in an impressive 75% yield (Scheme 48). 0

Br

(TMS)3SiH 10 mol% AIBN Phil, reflux

OMe

IL

174,75%

173

(TMS)3Si"/- (TMS)3SiBr / O

N~,

0

~

OMe ioso

0,. OMe

'

MeO"

C02"ortho

" N'~OMe

176

175

~

0 N

177

178

Scheme 48 Earlier, Motherwell et al. had observed an ipso-substitution reaction at C3 of a pyridine during studies on the radical induced rearrangement of homopropargyl arenesulfonates <92CC1067, 97H523>. They found that tributyltin radical would add to the terminal alkyne in 179 leading to vinyl radical 181. Cyclisation to the pyridine and ejection of the sulfonyl radical then gave 183, which underwent a second cyclisation and elimination sequence to give dihydrooxathiindioxide 180 (Scheme 49). The yield for the cascade was disappointing at just 24%. However, an analogous rearrangement of a homopropargyl arenesulfonate attached at C8 of a quinoline was also reported and proceeded in a more satisfying 57% yield.

0 tO

0 0

,O~/

1 equiv. Bu3SnH 1 equiv. AIBN Phil, reflux syringe pump

179

180,24%

Bu3Sn/

f

o,p

S'o

N~Bu3Sn"

ipso

Bu3Sn

~~o2

9

m

'<,N~

181

02

182

183

Scheme 49

184

Radical Additions to Pyridines, Quinolines and Isoquinolines

47

A different course was followed when sulfonate 185 was treated analogously <97TL137>, with ortho-cyclisation to C2 of the pyridine predominating (Scheme 50). With the corresponding sulfonamide 187, products derived from both ortho-cyclisation to C2 and ipso-cyclisation to C3 were furnished, 188 and 189 respectively (Scheme 51). Curiously, neither of these cyclisation modes was observed with the homologous sulfonamide 190 <97TL141>. Rather, ortho-cyclisation to C4 occurred leading to biaryl 191 and dihydropyridine 192 (Scheme 52).

o,,:o

~ S ' O ' ~

Bu3SnH

~,BN PhH, refluxr" syringe pump

'S-o

IL__/~ .. "N- "~.

185

186, 43%

Scheme 50

O,vp

H /N

o,,,9 Bu3SnH AIBN, Phil, reflux syringe pump

+

=t

188, 33%

187

Cyo 189, 29%

Scheme 51

I

Bu3SnH AIBN, Phil, reflux syringe pump

190

Me 02 191, 55%

NMe H

192, 24%

Scheme 52

2.3.3

Cyclisations to Quinolines

A study of the cyclisation of aryl radical intermediates to quinolines uncovered some striking differences in the reactivity profile of quinolines and pyridines towards radical intermediates <01TL2907, 02T3387>. Most notably, cyclisations involving quinolines were generally more efficient when the heterocycle and radical precursor were conjoined using a saturated tether. Moreover, in each case products derived from ortho-cyclisation were observed irrespective of the nature of the tethering chain or its point of attachment to the quinoline (Schemes 53 - 55).

48

D.C. Harrowven and B.J. Sutton

O

5 equiv. Bu3SnH

O

0.6 equiv. AIBN PhMe, 80 ~ 72 h

193

194, 42%

I NaOAc H2NNHTSaq. THF 172 h, 88%

f

_/%

i...~!

~-~(~

o--~ o

1.2 equiv. Bu3SnH 0.1 equiv. AIBN PhMe, 80 ~ 24 h

195

196, 70% Scheme 53

As with the pyridine series, competing alkene isomerisation proved to be a significant problem within the azastilbene series. It was especially prominent when aryl bromides were employed as radical precursors. For example, exposure of the bromide analogue of 193 to tributyltin hydride and AIBN returned the starting material as a mixture of cis- and transisomers. Alkene isomerisation was most pronounced when the alkene was conjoined at C4 of the quinoline. In this case, even carbon to iodide bond homolysis was slow by comparison (Scheme 54). O-.--k

1.4 equiv. Bu3SnH 0.1 equ iv. AI BN PhMe, 80 ~ 24 h

,, ~

A

197

~

~

> ~-""

+

198, 35% 199, 55%

H2NN HTs NaOAc aq. THF 72h, 87% ~

1.4 equiv. Bu3SnH 0.2 equiv. AIBN PhMe, 80 ~ 48 h

ii

200

201,67% Scheme 54

By way of contrast, when attached at C3, no alkene isomerisation was observed with iodide 202 and it was only a minor side reaction with the corresponding aryl bromide. With two ortho-cyclisation pathways available to the radical intermediate, it is perhaps

Radical Additions to Pyridines, Quinolines and Isoquinolines

49

unsurprising that 202 gave a mixture of 203 and 204, while 205 gave both 206 and 207. Notably, in each case there was a clear preference for cyclisation to C4 of the quinoline (Scheme 55).

Bu3SnH

m

+

10 mol % AI BN PhMe, 80 ~ 18 h 202

204, 38%

203, 57%

H2NNHTs NaOAc aq. THF reflux, 72 h

f'-O Bu3SnH

+

10 mol% AI BN PhMe, 80 ~ 36 h 205, 59% 207, 23%

206, 51%

Scheme 55

2.3.4

Cyclisations to Isoquinolines

Recently, Sit et al. extended the reaction to isoquinolines in an elegant synthesis of the dopamine agonist, (+)-dinapsoline 210 <02JMC3660>. The key step of the synthesis was a tributyltin hydride mediated cyclisation of aryl bromide 208 to pentacycle 209, a procedure that could be scaled up to 100 g of starting material at a time. The authors commented that the 'tributyltin hydride and AIBN combination was by far the most efficient reductive system for generating the free radical species for cyclisation'. Acetic acid (or trifluoroacetic acid) was added to the reaction medium to aid removal of the tin by-products. No comment was made as to whether the acid played any further r61e, such as protonation of the heteroaromatic base. OH O ~---OL--.O ~ " / ~ " ~ N

3.7 equiv. Bu3SnH

3 steps

1 equiv. AIBN PhH, reflux ~

N

H

50

D.C. Harrowvenand B.J. Sutton

carbon tether, only products of reduction and alkene isomerisation were observed (Schemes 57 and 58). When conjoined through C3 or C4 however, ortho-cyclisation to C4 and C3 respectively proceeded efficiently within both the azastilbene and dihydroazastilbene series (Schemes 59 - 62).

Bu3SnH

Bu3SnH~

O PhMe,A ~

PhMe,A O 2-0 212, 96%

213

214, 60%

Scheme 57

Scheme 58

/--O O

/-'--O o

[ ~ ~ 215

Bu3SnH AIBN -~ PhMe, A Scheme 59

Bu3SnH AIBN PhMe,A 216, 63%

/'--O

Bu3SnH I AIBN PhMe,A

N

219

2.3.5

Scheme 61

~,+

220, 80%

217

Scheme 60

•••[•1 N

221

218, 66%

Bu3SnH PhMe,A

Scheme 62

NI~ ~ Y

222, 71%

Cyclisations Involving Nitrogen Centred Radicals

While greatest attention has been focussed on reactions involving carbon centred radical intermediates, it is perhaps appropriate to close with an unusual cascade sequence wherein the addition of a nitrogen centred radical to a pyridine features. Nanni et al. observed such a reaction when treating imine 223 with di-iso-propyl peroxydicarboxylate (DPDC) in the presence of diethyl azodicarboxylate 224 <89CC757>. Thermal decomposition of the peroxydicarboxylate first gave iso-propyloxy radical, which abstracted a hydrogen atom from the imine to give 226. Union with diethyl azodicarboxylate 224 was followed by cyclisation of the resulting radical 227 to C2 of the adjacent pyfidine leading to 228. Aromatisation,

Radical Additions to Pyridines, Quinolines and Isoquinolines

51

through the formal loss of a hydrogen atom, gave the pyridotriazine ring system 225 (Scheme 63).

, ~ MeO

+ EtO2c,,N,,N,,CO2Et N•R H 22.3

/-PRO"l -/-PrOH

DPDC Phil, 60 ~

224

MeO

N"N"cO2Et I CO2Et 225, 27-47%

/

I~~I~N~ R

LMeo" "N-

CO2Et

226

227

MeO/k~N-"k',,N,"N-CO2Et CO2Et 228

Scheme 63

2.4

CONCLUDING REMARKS

Thus, radical addition reactions provide a useful means of functionalising pyridines, quinolines and isoquinolines, particularly when it is reasonable to employ the heteroaromatic base in excess. Intramolecular variants of the reaction are devoid of that limitation and have been widely exploited in the synthesis of nitrogen-containing heteroaromatics. The mildness of the reaction conditions have found favour in natural products total synthesis and medicinal chemistry programs. These bare testament to the reactions worth and have raised its stature from academic curiosity to useful synthetic tool.

2.5

REFERENCES

1893MIl196 1893MI1994 29RTC993 34LA145 37JA2079 37JCS835 39HCA970 40JCS349 40JCS372 43JCS441 47JA2253 48JCS2213 49JCS1311 49JCS3164 49JCS3181 51JCS2323 52JCS4657 54JA2997 54JCS2471 54JCS2747 54JCS4263 55JCS3963

R. M6hlau, R. Berger, Ber. Deut. Chem. Ges. 1893, 26, 1196. R. M6hlau, R. Berger, Ber. Deut. Chem. Ges. 1893, 26, 1994. J. Overhoff, G. Tilman, Rec. Tray. Chim. 1929, 48, 993. H. Wieland, Liebigs Ann. Chem. 1934, 514, 145. C.R. Noller, R.O. Denyes, J.W. Gates, W.L. Wasley, J. Am. Chem. Soc. 1937, 59, 2079. T. Richardson, R. Robinson, E. Seijo, J. Chem. Soc. 1937, 835. F. Fichter, H. Stenzl, Helv. Chim. Acta 1939, 22, 970. J.W. Haworth, I.M. Heilbron, D.H. Hey, J. Chem. Soc. 1940, 349. J.W. Haworth, I.M. Heilbron, D.H. Hey, J. Chem. Soc. 1940, 372. J. Elks, D.H. Hey, J. Chem. Soc. 1943, 441. R.B. Sandin, R.K. Brown, J. Am. Chem. Soc. 1947, 69, 2253. D.H. Hey, E.W. Walker, J. Chem. Soc. 1948, 2213. H.S. Forrest, R.D, Haworth, A.R. Pinder, T.S. Stevens, J. Chem. Soc. 1949, 1311. D.H. Hey, J.M. Osbond, J. Chem. Soc. 1949, 3164. W.J. Adams, D.H. Hey, P. Mamalis, R.E. Parker, J. Chem. Soc. 1949, 3181. B. Lythgoe, L.S. Rayner, J. Chem. Soc. 1951, 2323. D.H. Hey, J. Stuart-Webb, G.H. Williams, J. Chem. Soc. 1952, 4657. R.L. Dannley, E.C. Gregg, Jr., J. Am. Chem. Soc. 1954, 76, 2997. D.H. Hey, D.G. Turpin, J. Chem. Soc. 1954, 2471. D.H. Hey, C.J.M. Stirling, G.H. Williams, J. Chem. Soc. 1954, 2747. R.A. Abramovitch, D.H. Hey, R.D. Mulley, J. Chem. Soc. 1954, 4263. D.H. Hey, C.J.M. Stirling, G.H. Williams, J. Chem. Soc. 1955, 3963.

52

D.C. Harrowven and B.J. Sutton

56JCS1475 58AJC200 60CJC2273 60JCS3787 61JCS18 61JOC418 63AHC131 63CJC2265 64CZ458 66BSF3815 67CJC509 67JHC375 67JHC377 68TL953 68TL5609 70JCS(C)2169 71BSF2612 73BCJ942 73S1 73TL645 74AHC123 74BCJ942 75CC241 76CC329 76T2741 76TCC1 80MI65 83ACR27 83JCS(P2)531 84TL3897 84CHEC-I293 85JOC3423 85T617 85TL6001 86JOC536 86JOC4411

D.H. Hey, C.J.M. Stirling, G.H. Williams, J. Chem. Soc. 1956, 1475. K.H. Pausacker, Aust. J. Chem. 1958, 11,200. R.A. Abramovitch, Can. J. Chem. 1960, 38, 2273. P.J. Bunyan, D.H. Hey, J. Chem. Soc. 1960, 3787. K.H. Pausacker, J. Chem. Soc. 1961, 18. W. Herz, D.R.K. Murty, J. Org. Chem. 1961, 26, 418. R.O.C. Norman, G.K. Radda, Advan. Heterocycl. Chem. 1963, 2, 131. R.A. Abramovitch, G. Tertzakian, Can. J. Chem. 1963, 41, 2265. K. Schwetlich, R. Lungwitz, Chem. Ztg. 1964, 4, 458. H.J.M. Dou, B.M. Lynch, Bull. Soc. Chim. Fr. 1966, 3815. R.A. Abramovitch, K. Kenaschuk, Can. J. Chem. 1967, 45, 509. M.M. Boudakian, F.F. Frulla, D.F. Gavin, J.A. Zaslowsky, J. Heterocycl. Chem. 1967, 4, 375. M.M. Boudakian, D.F. Gavin, R.J. Polak, J. Heterocycl. Chem. 1967, 4, 377. H.J.M. Dou, G. Vernin, J. Metzger, Tetrahedron Lett. 1968, 953. F. Minisci, R. Galli, M. Cecere, V. Malatesta, T. Caronna, Tetrahedron Lett. 1968, 5609. K.C. Bass, P. Nababsing, J. Chem. Soc. C 1970, 2169. G. Vemin, H.J.M. Dou, J. Metzger, Bull. Soc. Chim. Fr. 1971, 2612. N. Hata, T. Saito, Bull. Chem. Soc. Jpn. 1973, 46, 942. F. Minisci, Synthesis 1973, 1. R. Bemardi, T. Caronna, R. Galli, F. Minisci, M. Perchinunno, Tetrahedron Lett. 1973, 645. F. Minisci, O. Porta, Advan. Heterocycl. Chem. 1974, 16, 123. N. Hata, I. Ono, S. Matono, H. Hirose, Bull. Chem. Soc. Jpn. 1974, 47, 942. T. Furihata, A. Sugimori, J. Chem. Soc., Chem. Commun. 1975, 241. M. Fiorentino, L. Testaferri, M. Tiecco, L. Troisi, J. Chem. Soc., Chem. Commun. 1976, 329. T. Caronna, A. Citterio, L. Grossi, F. Minisci, K. Ogawa, Tetrahedron 1976, 32, 2741. F. Minisci, Top. Curr. Chem. 1976, 62, 1. F. Minisci, A. Citterio, Adv. Free Rad. Chem. 1980, 6, 65. F. Minisci, A. Citterio, C. Giordano, Acc. Chem. Res. 1983, 16, 27. C. Arnoldi, A. Citterio, F. Minisci, J. Chem. Soc., Perkin Trans. 2 1983, 531. G. Castaldi, F. Minisci, V. Tortelli, E. Vismara, Tetrahedron Lett. 1984, 25, 3897. E.F.V. Scriven, Comp. Heterocycl. Chem., I sl edn. 1984, 2, 293. G.A. Russell, D. Guo, R.K. Khanna, J. Org. Chem. 1985, 50, 3423. A. Citterio, A. Gentile, F. Minisci, M. Serravalle, S. Ventura, Tetrahedron 1985, 41,617. K. Shankaran, C.P. Sloan, V. Snieckus, Tetrahedron Lett. 1985, 26, 6001. C. Giordano, F. Minisci, E. Vismara, S. Levi, J. Org. Chem. 1986, 51,536. F. Minisci, E. Vismara, F. Fontana, G. Morini, M. Serravalle, C. Giordano, J. Org. Chem.

86T5973 86TL3187 86TL3239 87JOC730 88BSF67 89CC757 90CC 1069

G. Heinisch, G. LOtsch, Tetrahedron 1986, 42, 5973. E. Vismara, M. Serravalle, F. Minisci, Tetrahedron Lett. 1986, 27, 3187. M. Hasebe, T. Tsuchiya, Tetrahedron Lett. 1986, 27, 3239. F. Minisci, E. Vismara, F. Fontana, M. Serravalle, G. Morini, J. Org. Chem. 1987, 52, 730. V. Snieckus, Bull. Soc. Chim. Fr. 1988, 67. R. Leardini, D. Nanni, A. Tundo, G. Zanardi, J. Chem. Soc., Chem. Commun. 1989, 757. J.A. Murphy, M.S. Sherbum, J.M. Dickinson, C. Goodman, J. Chem. Soc., Chem. Commun. 1990, 1069. J.A. Murphy, M.S. Sherburn, Tetrahedron Lett. 1990, 31, 1625. J.A. Murphy, M.S. Sherbum, Tetrahedron Lett. 1990, 31, 3495. S. Sawada, S. Okajima, R. Aiyama, K. Nokata, T. Furuta, T. Yokokura, E. Sugino, K. Yamaguchi, T. Miyasaka, Chem. Pharm. Bull. 1991, 39, 1446. S. Sawada, K. Nokata, T. Furuta, T. Yokokura, T. Miyasaka, Chem. Pharm. Bull. 1991, 39, 2574. S. Sawada, S. Matsuoka, K. Nokata, H. Nagata, T. Furuta, T. Yokokura, T. Miyasaka, Chem. Pharm. Bull. 1991, 39, 3183. J.A. Murphy, M.S. Sherburn, Tetrahedron 1991, 47, 4077. W.B. Motherwell, A.M.K. Pennell, F. Ujjainwalla, J. Chem. Soc., Chem. Commun. 1992, 1067. F. Minisci, F. Fontana, T. Caronna, L. Zhao, Tetrahedron Lett. 1992, 33, 3201. F. Minisci, F. Fontana, G. Pianese, Y.M. Yan, J. Org. Chem. 1993, 58, 4207. D.C. Harrowven, Tetrahedron Lett. 1993, 34, 5653. H. Togo, K. Hayashi, M. Yokoyama, Bull. Chem. Soc. Jpn. 1994, 67, 2522.

1986, 51,4411.

90TL 1625 90TL3495 91CPB 1446 91CPB2574 91CPB3183 91T4077 92CC 1067 92TL3201 93JOC4207 93TL5653 94BCJ2522

Radical Additions to Pyridines, Quinolines and Isoquinolines

94TL5301 95AG(E)2007 96CHECII84 97H523 97TL137 97TL141 97TL5383 98TL5875 00TL6681 01 T4447 01TL2907 01TL5613 01TL9061 02JMC3660

02SL1093 02T3387 03BMC451 03 EJO2919 B-03MI001 03OBC4047 03T3009

53

D.C. Harrowven, R. Browne, Tetrahedron Lett. 1994, 35, 5301. R. Gorny, H.J. Sch/ffer, R. Fr6hlich, Angew. Chem., Int. Ed. Engl. 1995, 34, 2007. D.L. Comins, S.P. Joseph, Comp. Heterocycl. Chem., 2"d edn. 1996, 5, 84. E. Bonfand W.B. Motherwell, A.M.K. Pennell, M.K. Uddin, F. Ujjainwalla, Heterocycles 1997, 46, 523. M.L.E.N. da Mata, W.B. Motherwell, F. Ujjainwalla, Tetrahedron Lett. 1997, 38, 137. M.L.E.N. da Mata, W.B. Motherwell, F. Ujjainwalla, Tetrahedron Lett. 1997, 38, 141. A.P. Dobbs, K. Jones, K.T. Veal, Tetrahedron Lett. 1997, 38, 5383. D.C. Harrowven, M.I.T. Nunn, Tetrahedron Lett. 1998, 39, 5875. D.C. Harrowven, M.I.T. Nunn, N.J. Blumire, D.R. Fenwick, Tetrahedron Lett. 2000, 41, 6681. D.C. Harrowven, M.I.T. Nunn, N.J. Blumire, D.R. Fenwick, Tetrahedron 2001, 57, 4447. D.C. Harrowven, B.J. Sutton, S. Coulton, Tetrahedron Lett. 2001, 42, 2907. W. Zhang, G. Pugh, Tetrahedron Lett. 2001, 42, 5613. D.C. Harrowven, B.J. Sutton, S. Coulton, Tetrahedron Lett. 2001, 42, 9061. S.-Y. Sit, K. Xie, S. Jacutin-Porte, M.T. Taber, A.G. Gulwadi, C.D. Korpinen, K.D. Burris, T.F. Molski, E. Ryan, C. Xu, H. Wong, J. Zhu, S. Krishnananthan, Q. Gao, T. Verdoorn, G. Johnson, J. Med. Chem. 2002, 45, 3660. A. Nufiez, A.G. de Viedma, V. Martinez-Barrasa, C. Burgos, J. Alvarez-Builla, Synlett 2002, 1093. D.C. Harrowven, B.J. Sutton, S. Coulton, Tetrahedron 2002, 58, 3387. W. Du, B. Kaskar, P. Blumbergs, P.-K. Subramanian, D.P. Curran, Bioorg. Med. Chem. 2003, 11,451. J. Heimann, H.J. Sch/ffer, R. Fr6hlich, B. Wibbeling, Eur. J. Org. Chem. 2003, 2919. B.J. Sutton, Ph.D. Thesis, Southampton, 2003. D.C. Harrowven, B.J. Sutton, S. Coulton, Org. Biomol. Chem. 2003, 1, 4047. W. Zhang, G. Pugh, Tetrahedron 2003, 59, 3009.

54

Chapter 3

Three-Membered Ring Systems Albert Padwa

Emory University, Atlanta, GA 30322 chemap @emory.edu

Shaun Murphree

Allegheny College, Meadville, PA 16335 smurphre @alle gheny.edu

3.1

INTRODUCTION

As the smallest heterocycles, three-membered rings offer an uncommon combination of reactivity, synthetic flexibility, and atom economy. This chapter surveys a selection of the most recent advances among the most common three-membered ring systems composed of carbon, oxygen, nitrogen, and sulfur. Emphasis is given to novel synthetic methods and new insights into existing methodologies for the selective construction and controlled reaction of the title compounds reported in the past year's literature. While not the exclusive focus of this minireview, well-represented themes in the literature include asymmetric techniques and environmentally compatible reagents. The organization of the chapter is similar to that of previous years.

3.2

EPOXIDES

3.2.1

Preparation of Epoxides

This past year's literature has shown extraordinary activity in this realm. Perhaps the most firmly entrenched methodology for the preparation of chiral epoxides is the metallosalen mediated epoxidation of unfunctionalized alkenes (the Jacobsen-Katsuki epoxidation), which has been recently reviewed <03SL281 >. It is widely accepted that this reaction proceeds through an oxo intermediate, and that the observed enantioselectivities depend upon the electronic stability of this species. For example, Jacobsen found empirically that electron-donating substituents in the 5 and 5' positions of catalyst 1 gave better enantioselectivities <91JA6703>. More recent

Three-Membered Ring Systems

55

density functional theory calculations support Jacobsen's original hypothesis that the correlation is due to an electronic stabilization of the intermediate oxo species and therefore a late transition state leading to the epoxidation <03JOC6202>.

0 R

R

\t-Bu

t-BJ

Catalysts of this type can be used not only for the enantioselective generation of epoxides from alkenes, but also for the hydrolytic kinetic resolution (HKR) of racemic epoxides, particularly the terminal variety. For example, the cobalt(III)salen complex 2 catalyzed the enantioselective hydrolysis of racemic hexene oxide 3 in the presence of 0.5 equivalents of water to provide the (R)-enantiomer in 99% ee. Here, the inorganic ligand was found to be important for catalyst activity and selectivity, with the conventional acetate ligand giving inferior results <03TL5005>.

/

.

O

2 (0.3 mol%) 0.5 eq H20

rac-3

5h

~

O

_OH H 4

+

~ ~

46% yield (92% of max) 99% ee (R)-3

A similar HKR strategy for the resolution of terminal epoxides has been reported using an easily recoverable heterogenous polymeric catalyst prepared from polyfunctional aldehydes derived from hydroquinone and chloroglucinol. Mixtures of the di- and tri-aldehydes provided cross-linked structures of the type shown in the idealized structure 5. The polymeric catalyst gave high yields and ee' s--sometimes better than the corresponding homogeneous catalyst. For example, racemic epichlorohydrin 6 could be resolved in 50% yield and 98% ee. The recovered catalyst could not be reused, presumably due to the sensitivity of the ester linkages toward hydrolysis <03TL7081>.

56

A. Padwaand S. Murphree

The oxidation of alkenes represents the largest segment of preparative methods for epoxides, and here the various methods can be characterized largely by two key components: the oxygen carrier (or catalyst) and the terminal (stoichiometric) oxidant. Hydrogen peroxide is frequently used in the latter role, and a variety of metal catalysts facilitate the transfer of oxygen to the alkene, from coordination complexes to zeolites to soluble metal oxides, as illustrated by the tungstate-catalyzed epoxidation of 1-dodecane 7 using the Noyori conditions <97BCSJ905>, and the reader is directed to a timely and concise review on the topic of such metal-mediated oxygen transfers <03CR2457>. This methodology has also been applied to the epoxidation of lipophilic alkenes (e.g., 9) in ionic liquids, with epoxidation components being provided via an aqueous phase, and reaction products (e.g., 10) being extracted into a pentane layer <03OL3423>. Na2W04 30% H202 7

[C H3(n-CsH17)3N]HSO4

(99%) 8

Three-Membered Ring Systems

[ ~ ~

57

H202/ Me4NHCO3/ MnSO4 ~ O [bmim][BF4]

9

(95%)

10

Oxone (2KHSO5 + KHSO4 + K2SO4 ) is also frequently employed as a stoichiometric oxygen source, since it is readily available and stable. Oxone can be activated toward oxygen transfer by catalysts as straightforward as simple amines. If chiral amines are used a modest asymmetric induction is observed, as shown in the conversion of 1-phenylcyclohexene 11 to the corresponding epoxide 13 in the presence of (S)-2-(diphenylmethyl)pyrrolidine 12 and Oxone, which yielded enantiomeric excesses in the 20-50% range. Here the oxygen atom is not believed to be transferred via an N-oxide, but rather directly from the Oxone reagent through the pyrrolidinium salt of peroxysulfate. Thus, proper buffering is key to the success of the protocol <03JA7596>.

Ph {~

12

H

Oxone pyr / NaHCO3 MeCN / H20

11

91% yield 52% ee

Ph

13

A more common method for effecting the asymmetric delivery of oxygen from Oxone is by an intermediate transfer to an appropriate ketone precursor to form a chiral dioxirane species, which then provides an asymmetric environment about the electrophilic oxygen atom. There exists an interesting diversity of architectural approaches for such epoxidations reported in the literature. For example, the chiral oxazolidinone-equipped ketone 14, prepared in six steps from D-glucose <03JOC4963>, is effective in promoting the asymmetric epoxidation of cisdisubstituted and terminal olefins. In recent studies involving the epoxidation of cismethylstyrene 15, the electronic character of the oxazolidino N-aryl group was found to influence the outcome of the reaction, presumably by modulating the interaction between the catalyst and the aromatic substituent of the substrate <03OL293>.

.O (3"

N-Ar

" --

Ph/=~M e 15

1,

~.~ Oxone

A,

PI'i

Me

16

14

A novel heterogeneous ketone catalyst 17 has been prepared by anchoring an enantiomerically enriched ot-fluorotropinone to KG-60 silica gel. In the presence of Oxone, the resulting

58

A. Padwa and S. Murphree

immobilized catalyst was effective in promoting the epoxidation of trisubstituted and t r a n s disubstituted alkenes with moderate enantioselectivity. A representative case is provided by Emethylstilbene 18, which is converted to the S,S-epoxide in 67% yield and 52% ee <03JOC3232>.

Amines are known to catalyze the epoxidation of alkenes using Oxone and significant levels of asymmetric induction were observed when pyrrolidinium peroxymonosulfate (20) was used as the active oxidizing agent. The chiral amine could be reisolated in > 90% yield when reactions were conducted at -10 ~ indicating that the integrity of the amine was maintained during the oxidation process <03JOC6576>.

~ p h

Ph Cl

HSOs-

21

20

Oxone NaHCO3 pyridine CH3CN / H20

93% yield 46% ee

Cl 22

Ruthenium-based catalysts allow for a remarkable diversity of terminal oxidants, including iodosylbenzene, molecular oxygen, and even water. Effective use of the latter was realized v i a a photochemical oxygenation employing the ruthenium(II)porphyrin catalyst 23 as a photosensitizer and hexachloroplatinate(IV) as an electron acceptor. Thus, norbomene 24 is selectively epoxidized in acetonitrile using water as the oxygen source in the presence of catalyst 23. The mechanism of this unusual conversion is believed to proceed through the formation of a hydroxyruthenium(III) species, which can provide an oxo-ruthenium complex postulated to be the actual oxygen-transfer species. When isotopically labeled water (H2018) is used, the corresponding O18-epoxides are formed <03JA5734>.

N m .R~--N, 24 23

K2PtCl6 H20 CH3CN 420 nm

25

59

Three-Membered Ring Systems

In another protocol using a ruthenium(pyridinebisoxazoline)(pyridinedicarboxylic acid) catalyst 26 and iodosylbenzene as the terminal oxidant, Belier and co-workers <03TL7479> found that the addition of water and protic solvents resulted in a 100-fold acceleration of the epoxidation, presumably due to a ligand dissociation effect that promotes the oxidation of the ruthenium catalyst. Thus, the conversion of trans-stilbene 27 to the corresponding S,S-epoxide 28 required 96 h in anhydrous toluene, but only 1 h in the presence of t-butanol and water. The enantioselectivity of the reaction was not significantly affected (63% and 57% ee, respectively).

i

Phv 27

26 ,11~ Ph Phl(OAc)2 toluene / t-BuOH / H20

1"3

Phi,../"N,., . . . . . iH Ph

84% yield 57% ee

28

26

In terms of practicality, molecular oxygen is a very attractive terminal oxidant. In this arena, a novel N-2'-chlorophenyl-2-pyridinecarboxamide ruthenium complex 29 has been reported to catalyze the efficient epoxidation of cyclic alkenes in the presence of 1 atm of oxygen and isobutyraldehyde, which is believed to coordinate to the catalyst and prevent the formation of unwanted allylic oxidation products. Using this system, cyclooctene 30 is converted to the corresponding epoxide in excellent yield in 9 h at ambient temperature. Interestingly, the reaction is shut down by the addition of 2,6-di-tert-butyl-4-methylphenol, so that a radical mechanistic pathway has been postulated <03CC 1058>.

if"~

CI O

Cl~[~}

cI

:30

02 (1 atm) isobutyraldehyde CICH2CH2CI

97% yield 31

29

As another example of innovation in the oxygen carrier system, a simple self-organizing phenanthroline iron(Ill) ~t-oxo catalyst 32 has been developed and applied to the rapid and efficient epoxidation of a variety of alkenes, including the often recalcitrant terminal olefins. Thus, vinylcyclohexane 33 provides the corresponding epoxide 34 within 5 min at 0~ in 90%

60

A. Padwa and S. Murphree

isolated yield. The protocol uses peracetic acid as the terminal oxidant, which can be prepared from acetic acid and hydrogen peroxide, and the catalyst itself can be generated in situ by combining ferric nitrate with 2 equivalents of phenanthroline in aqueous acetonitrile <03OL2469>. Iron-mediated oxygen transfer is also at play in the chloroperoxidase (CPO) catalyzed epoxidation of simple alkenes, which has the added advantage of providing high enantiomeric excesses. For example, cis-2-heptene 35 is converted to the chiral epoxide 36 in 78% yield. However, the protocol is generally limited to fairly accessible disubstituted alkenes: the more imbedded olefin of cis-3-heptene only undergoes 12% conversion, while the epoxides derived from terminal olefins tend to alkylate the enzyme and serve as suicide inhibitors <03T4701>.

~11

.

H20 O .H2~ / %.~O

h m=;,

CH3CO3H CH3CN 5 min, 0~

33

90% isolated

34

32

--~__/--~__ 35

cPo

H20 2

,~.

~~ _ . ~ O

78% yield

36

There are also many interesting reports on novel and improved methods for the conversion of functionalized olefins. For example, the transition-metal catalyzed epoxidation of allylic alcohols is well established, but some very interesting new methods have been reported which cater specifically to the demanding requirements of industrial processes with respect to robustness and environmental concerns. In one protocol, sandwich-type polyoxometalates (POMs), such as [WZnMnlI2(ZnW9034)2]12-, catalyze the selective epoxidation of chiral allylic alcohols with aqueous hydrogen peroxide under mild conditions. Thus, 4-methylpent-3-en-2-ol 37 is converted to the threo epoxide 38 in 88% yield and 84% de. The diastereoselectivity is highly sensitive to the nature of substitution about the double bond, with trans-pent-3-en-2-ol giving a 1:1 mixture of threo and erythro epoxides under the same conditions. The key intermediate is believed to be a tungsten peroxo complex rather than an oxo-Mn species <03JOC1721>.

Three-MemberedRing Systems

OH

61

[VVZnM n112(ZnW9O34)2]12-

OH 88% yield 84% de

30~ H202 (2 eq) 20~ 6 h 37

38

A polyoxometalate is also at the heart of an enantioselective epoxidation of allylic alcohols using a C-2 symmetric chiral hydroperoxide 39 derived from 1,1,4,4-tetraphenyl-2,3-Oisopropylidene-D-threitol (TADDOL). Thus, in the presence of the oxovanadium(IV) sandwichtype POM [ZnW(VO)2(ZnW9034)2]12- and stoichiometric amounts of hydroperoxide 39, the dienol 40 is converted to the (2R) epoxide 41 in 89% yield and 83% ee. The proposed catalytic cycle invokes a vanadium(V) template derived from the POM, substrate, and hydroperoxide, a hypothesis supported by the lack of enantioselectivity with unfunctionalized alkenes. The catalytic turnover is remarkably high at about 40,000 TON <03OL725>.

Phk Ph PI~yh HO ~ o ' ~ " O O

H

i~,~

OH

[ZnW(VO)2(ZnWgO34)2]12(0.01 moI%) 39 (1.1 eq)

CICH2CH2CI 39

II

40

P h " ~ A . _ OH 89% yield ph~,',,~ 84% ee 41

Modest enantioselectivities have been observed in the titatium-catalyzed epoxidation of allylic alcohols using the camphor-derived hydroperoxide 42 as a stoichiometric oxidant. In the case of chiral substrates with a secondary alcohol moiety, the method also represents a novel kinetic resolution technique. For example, when the racemic cyclohexeno143 was treated with peroxide 42 in the presence of titanium(IV) isopropoxide, the (S)-isomer was preferentially consumed, leading to the formation of epoxide 44 in 48% yield and 38% ee, while the (R)-isomer was recovered in 37% yield and 35% ee. Diastereoselectivity in the reaction was quite high, as only syn-epoxides were observed <03CC1440>. Similar high syn-selectivity was found using diethylzinc in the presence of 1 atm of dioxygen <03JA9544>.

OOH

'

-~L..~./0 42

--ft. (rac)-43

Ti(O-i-Pr)4 CH2C12

+ 0 ;5 " 44

48% yield 38% ee

(R)-43 37% yield

35% ee

Homoallylic alcohols can be asymmetrically epoxidized using a chiral vanadium catalyst equipped with the hydroxamic acid ligand 45, as exemplified in Yamamoto's concise synthesis

62

A. Padwa and S. Murphree

of (-)-ct-bisabolol 48 <03AGE941>. A zirconium-diisopropyl L-tartrate (DIPT) system is also efficient in such chiral epoxidations, as illustrated in the conversion of styrene derivative 49 to the (3S)-epoxide 50 in 93% yield and 89% ee using cumene hydroperoxide (CHP) as a stoichiometric oxidant. Interestingly, the sense of asymmetric induction is governed by the ratio of metal to ligand, which was linked to whether the complex exists as a monomer (as in the 1:2 complex) or a trimer (as in the 1:1 complex) <03OL85>.

Ph

t-l~u OH 45

VO(O-i-Pr)3 (2 mol%) OH

t-BuOOH (1.5 eq) toluene, 0~ 84% yield, 90% de

46

OH 47

CI CI

OH

Zr(O-t-Bu)4, 20 mol% ~ , (L)-DIPT CI ,ll,~ CHP benzene CI" ~ MS 4A

49

48

~ "OH 50

ratio of Zr 9DIPT 1"1 1:2

config

% yield

o~ ee

3R 3s

98 93

73 89

Another class of olefins for which new epoxidation methods are continually investigated is the electron-deficient variety. One recently reported efficient epoxidation protocol for these substrates involves the use of a cationic manganese catalyst 51 and commercially available peracetic acid as a terminal oxidant, as exemplified by the rapid conversion of cyclohexenone 52 to the corresponding epoxide 53 with low catalyst loading <03JA5250>. Alternatively, this reaction could be promoted with ultrasound using hydrotalcite catalysts and excess hydrogen peroxide <03SC2017>. When two types of olefins are present on the same molecule, electronrich double bonds are preferentially oxidized in the former set of conditions, electron-deficient olefins react much more slowly.

63

Three-Membered Ring Systems

M e , , ~ . ' ~ ,Me

0

0 con0,t,ons

(see be low) ~" 52

51

O 53

conditions

yield (isol)

51 (0.1 mol%), CH3CO3H(1.2 eq), CH3CN, 5 min, 22~

88%

H202 (4 eq), hydrotalcite (5 g/mol), CH3CN, ultrasound, 4h

86%

The nucleophilic epoxidation of y-hydroxyvinyl sulfoxide derivatives (e.g., 54) proceeds with complete diastereoselectivity, an effect which has been rationalized by invoking a geometrically constrained chair-like transition state (e.g., 56) <03JOC4797>.

0II

Lr OTBDPS 54

,-Buoo_

0II

THF 90% yield 100% de

PS 55

TBDPSQ H Me.~ i H~~,p-Tol t-BuO~'"oIK .....O 56

Several enantioselective epoxidation methodologies for enones have also been reported. For example, the novel chiral quaternary ammonium salt 57 serves as a phase-transfer catalyst for the high-yielding epoxidation of chalcone 58 with moderately good enantioselectivity <03SC435>. Similarly, the tridentate aminodiether ligand 60 has been used with lithium cumene peroxide to give fair to good enantioselectivities in the epoxidation of certain enones (e.g., 61), presumably through a tetracoordinate lithium complex <03T4549>. A novel multifunctional asymmetric catalyst derived from lanthanum(Ill) isopropoxide, B INOL, and triphenylarsine oxide promoted epoxidation of enone 63 in the presence of t-butylhydroperoxide (TBHP) with excellent enantioselectivity. The resultant epoxide 64 was used as a key intermediate in the total asymmetric synthesis of (+)-decursin 65 <03T6889>.

A. Padwa and S. Murphree

64

r.o

0

- 84

Ph

P

~OMe 57

Ph

rt

58

Me2N

P

Ph

59

60 (20 mol%)

OMe

Ph

60

t-Bu CHP / LiCHP 76% yield

61

O

0

~

91% yield 60% ee

t-Bu

PI~,.,P / O / [ ~

63

57 (10 mol%) NaOCI ~ toluene

La(O-i-Pr)3 BINOL Ph3As=O ,._ TBHP decane / THF 94% yield 96% ee

71% ee

p

t-Bu 62

Oe~ o

O 64

65

The preparation of epoxides is not limited to the addition of oxygen to olefins. Another important general protocol is available through the methylenation of carbonyl compounds. In this arena, the Corey-Chaykovsky synthesis <62JA867> is by now a standard method, but one which is the subject of current innovation. This reaction--like most other methylenations--rely upon an intermediate sulfur ylide to serve as a methylene transfer reagent. Recent reports have shown that dry mixtures of trimethylsulfonium iodide and sodium hydride form a shelf-stable source of "instant methylide" upon treatment with carbonyl compounds in a polar aprotic solvent. Thus, combination of acetophenone 66 with the "instant methylide" reagent in dimethyl sulfoxide resulted in the high-yielding formation of the corresponding epoxide 67 <03SC2135>. The Corey-Chaykovsky epoxidation has also been adapted for use in an ionic liquid medium, such as (bmim)PF6 <03TL3629>. In addition, methylides are conveniently available through a novel thermal decarboxylation of carboxymethylsulfonium betaines. Thus, treatment of the sulfonium bromide 68 with silver oxide affords the corresponding betaine 69, which exhibits a half-life of 5 h in chloroform at room temperature, but can be stored for months neat at < 0~ At elevated temperatures, a rapid decarboxylation provides the methylide 70, which reacts with 2,6-dichlorobenzaldehyde 71 to give the epoxide 72. Not surprisingly, the more electron-deficient aldehydes gave higher yields, with benzaldehyde itself failing to provide any epoxide at all, presumably due to competing thermal decomposition of the ylide 70 <03OL2283>.

Three-Membered Ring Systems

.•

Me3SI/Nail DMSO 5h

.~/J~O

66

/ I I I o Ho~ BF

68, R = n-octyl

65

96% yield

67

____.6~176

Ag20

CH3OH ~

(quant.)

/S

O-

(CH2CI)2

-

69

71 CI

~

CI

70

~/O

72

While this methodology is, in principle, applicable to more highly substituted epoxide derivatives, vinyl epoxides can be tricky to prepare this way due to a potentially facile [2,3]sigmatropic rearrangement of the ylide itself. One workaround to this problem has been found in the use of tetrahydrothiophene 73 as a catalyst, which prevents the rearrangement through geometric means. Thus, treatment of p-chlorobenzaldehyde 75 with allyl bromide in the presence of 2 mol% 73 provides epoxide 76 in 94% yield <03CC2074>. Simple telluronium salts, such as allyldiisobutyl-telluronium bromide 74, exhibit similar utility as catalysts for the synthesis of vinyl epoxides <03TL4137>.

H CI 73

74

II

catalyst (see below)

CI

75

76

catalyst

conditions

% yield

cis / trans

73 (1 mol%)

K2CO3, t-BuOH

94

36/64

74 (2 m o l % )

Cs2CO3,t-BuOH

92

55 / 45

The sulfur ylide approach has also been applied to the asymmetric synthesis of epoxides by using a chiral sulfide template, a protocol which has been the topic of a recent review <03CC2644>. In many cases, the sulfide can be used in catalytic quantities, generating the ylides by reaction with diazo compounds formed in situ through the rhodium-catalyzed fragmentation of tosyl hydrazones. Thus, treatment of benzaldehyde 78 with a slight excess of tosyl hydrazone 79 in the presence of catalytic amounts of rhodium acetate and 20 mol% of the camphor-derived sulfide 77 leads to the formation of the 1,2-diarylepoxide 80 with 89% ee <03JA10926>. However, when the substrate is a heteroaromatic, n-alkyl aliphatic, Gt,13-

66

A. Padwa and S. Murphree

unsaturated, or acetylenic aldehyde, stoichiometric quantities of the preformed chiral sulfur ylide must be used <03AGE3274>.

H

?Me +

~

4_1

Rh2(OAc)4 (1 mol%)

Na+

BnEt;3NCI CH3CN / H20 89%ee

77

3.2.2

78

79

G'-'""O OMe O

80

Reactions of Epoxides

The most common reaction of epoxides in organic synthesis is their ring opening by nucleophiles. Here issues of regioselectivity and scope of the reaction continue to be topics of current interest. Azide is a competent, easily controlled nucleophile in the ring-opening of epoxides, and many methods exist with which to control regioselectivity of the reaction. For example, epichlorohydrin 81 undergoes clean attack by sodium azide at the less substituted oxirane carbon under the catalysis of lithium tetrafluoroborate <03SC999> or samarium chloride hexahydrate <03SC1603>. On the other hand, diethylaluminum azide promotes ring opening at the more substituted position, as exemplified by the conversion of limonene epoxide 83 to the azido alcohol 84, a reaction that proceeds largely with inversion of stereochemistry at the site of nucleophilic attack <03JOC75>. CI/~'~lo

NaN3

catalyst (see below)

~.

C l " ' ~ / " ~ N3 OH

6

81

catalyst

conditions

yield

LiBF4

t-BuOH, reflux, 15 min

93%

SmCI3-6H20

DMF, r.t., 6 h

93%

Et2AIN3

82

HO,,. ),..

83

Three-Membered Ring Systems

67

The same differential behavior can be observed with amine nucleophiles. For example, calcium triflate promotes the aminolysis of propene oxide 84 with benzylamine to give 1-(Nbenzyl)amino-2-propanol 85, the result of attack at the less substituted site <03T2435>, and which is also seen in the solventless reaction of epoxides with heterocyclic amines under the catalysis of ytterbium(III) triflate <03SC2989>. Conversely, zinc chloride directs the attack of aniline on styrene oxide 34 at the more substituted carbon center <03TL6026>. A ruthenium catalyst in the presence of tin chloride also results in an SNl-type substitution behavior with aniline derivatives (e.g., 88), but further provides for subsequent cyclization of the intermediate amino alcohol, thus representing an interesting synthesis of 2-substituted indoles (e.g., 89) <03TL2975>.

O

PhCH2NH2 ~ Ca(Omf)2(0.5 eq) CH3CN

.~H

84

85

PhNH2 ZnCI2(5 mol%) CH3CN

p

Ph/

34

H Ph

OH

93% yield

86

NH2

87

N~/Ph

88

PPh3(15 mol%) SnCI2 dioxane, 180~ 98% yield

Ph 89

The oxygenophile triphenylphosphine catalyzes epoxide ring opening with a variety of nucleophiles, including mercaptans, as exemplified by the reaction of cyclohexene oxide 90 with thiophenol to provide the phenylthioalcohol 91 <03JOC726>. Thiocyanate anion also serves as a competent nucleophile in the presence of the cobalt(II) complex 93, forming adducts of type 92 in very good yields <03BCSJ137>. If indium tribromide is used as a catalyst, these intermediates undergo subsequent cyclization with loss of cyanide to form episulfides (e.g., 95) <03SL396>.

PhS

OH

~~)

PhSH

O

~Bu3P(10m~176 C3HC N~ ~ ) 72% yield

91

NH4SCN

HO

SCN

93(lm~ . CH3CN 93% yield

90

92

68

A. Padwa and S. Murphree

-

-

~

93

.~",,,.~Qv'~ 94

KSCN InBr3 (5 m~ CH3CN 94% yield

95

Carbon-centered nucleophiles can also be used to advantage in the reaction with epoxides. For example, the lithium enolate of cyclohexanone 96 engages in nucleophilic attack of cyclohexene oxide 90 in the presence of boron trifluoride etherate to give the ketol 97 in 76% yield with predominant syn stereochemistry about the newly formed carbon-carbon bond <03JOC3049>. In addition, a novel trimethylaluminum / trialkylsilyl triflate system has been reported for the one-pot alkylation and silylation of epoxides, as exemplified by the conversion of alkenyl epoxide 98 to the homologous silyl ether 99. The methyl group is delivered via backside attack on the less substituted terminus of the epoxide <03OL3265>.

DH 1. LiN(SiMe3)2 2.90, BF3"OEt2 96

98

Me3AI

TESO~ Et3N

CH2Cl2

76% yield 97

93% yield 99

Some noteworthy intramolecular nucleophilic ring openings have been reported in the recent literature, which can be used to prepare functionalized heterocycles of synthetic interest. For example, the highly oxygenated epoxide 100 undergoes rearrangement induced by boron trifluoride etherate, whereby anchimeric assistance from the pendant phenylthio substituent leads to an intermediate episulfonium ion 101 which subsequently suffers 5-exo-tet cyclization to form the tetrahydrofuran derivative 102 <03TL5547>.

Three-MemberedRing Systems

PO

T so

F-0 r

OTMS

OH OH

po

SPh benzene 68% yield

H

69

__

100 (P = TBDPS)

OH Ph

"'OH

101

102

Another fascinating intramolecular process involves the spirocyclic epoxide 103, which carries a pendant azide group. Under the influence of ethylaluminum chloride, this substrate undergoes Lewis acid assisted cyclization followed by an intramolecular Schmidt reaction and subsequent in situ reduction of the intermediate iminium species 105 upon addition of sodium borohydride. This protocol was used as a key step in a novel synthesis of indolizidine alkaloids of pharmaceutical interest <03OL583>. N

O ~ N 3

---~

EtAICI2

103

NaBH4 63% yield (one pot)

104

105

H 106

So far the reactivity of epoxides has involved their use as an electrophile. However, oxiranyl anions can serve as functionalized nucleophiles in their own fight. Thus, the sulfonyl substituted epoxide 107 can be deprotonated with n-butyllithium to provide a stabilized anion which engages in facile SN2 reaction with triflate 108 <03JOC9050>. Other examples of such stabilized epoxide anions include those derived from oxazolinyloxiranes (e.g., 110), which react with nitrones to provide the spirotricyclic heterocycles of type 112. Hydrolysis provides the epoxy amino acids 113, in which the carboxylic acid moiety was provided by the oxazoline nucleus and the amine functionality was derived from the nitrone <03OL2723>. A recent report has demonstrated that oxiranyl anions can also be stabilized by the amide functionality <03H(59)137>.

B n O ~ TolO27~,~j 107

TES-.-O,~o + TfO.. Z

.,,Si''t-Bu

v ~'O" -~t-Bu 108

n-BuLi HMPA~ THF -100~ 81% yield y

BnOv'~

9

OTES ~'"0

T olO 2 S C ~ ' ~ O " ' ~ ~ u Bu 109

70

A. Padwaand S. Murphree

N ~,.

s-BoLi

t-Bu/N~''Ph

~,Ph TMEDA~ Ph

...

_98oc

111~

C~. H ~ h t-Bu"

110

"Ph

~

HO_~

Ph

Ph "eh

"NHt-Bu

112

113

Certain Lewis acids are known to induce an epoxide-aldehyde rearrangement <01TL8129>, and this chemistry has recently been combined in tandem with metal-mediated allylations. For example, epoxides react with tetraallyltin in the presence of bismuth(Ill) triflate to give homoallylic alcohols 116. The reaction involves an initial 1,2-shift to form an aldehyde 115, which is then attacked by the allyl tin species <03TL6501>. A similar but operationally more straightforward protocol is available by combining allyl bromide with indium metal, followed by the addition of epoxide <03TL2911>.

~]'~-'~]O CI

Bi(OTf)3 0H2012

114

~

O CI

Sn(CH2CH=CH2)4 = ~ ~ (one pot) 90% yield CI

115

"~''~

116

Epoxides are known to engage in 1,3-dipolar cycloadditions in the guise of carbonyl ylides under thermal conditions, a behavior which can be facilitated through the use of microwave radiation <03SC1861>. Another type of intramolecular [3 + 2] cycloaddition between an epoxide moiety and a tethered alkynyl group is mediated by a tungsten catalyst in the presence of boron trifluoride etherate, providing a novel synthesis of bicyclic lactone derivatives. Thus, the epoxyalkyne 117 undergoes cyclization to form lactone 118 after aqueous workup <03JOC 1872>. m

c~-_.~--~qTs CpW(CO)3CI BF3"Et20 H20 ,,,,~,Vr -/ Et2NH 670/0overall Cul 117

~,,l~)q 0

.,,

118

Finally, epoxides can be deoxygenated to the corresponding alkenes using molybdenum hexacarbonyl under essentially neutral conditions in refluxing benzene. The mechanism is believed to proceed through initial loss of carbon monoxide followed by a complexation of the molybdenum center with the epoxide oxygen to provide an activated species 120 which collapses to form the alkene (i.e., 121) <03TL2355>. The low-valent titanium catalyst Cp2TiC1, readily available by the in situ reduction of Cp2TiC12 with activated zinc, has also been used for this type of deoxygenation <03TL435>.

Three-Membered Ring Systems

0

71

0 0

0

benzene"

-

95% yield

0

0

119

120

3.3

AZIRIDINES

3.3.1

Preparation of Aziridines

121

As with the epoxides, there are two broad categories of synthetic approach to the aziridine moiety: (a) addition of a nitrogen center onto an existing alkene or (b) addition of a carbon center onto an imine. The reader is directed to an excellent review of both approaches within the context of enantioselective catalytic aziridination <03CR2905>. Illustrative additional offerings from the past year's literature are also included below. The aziridination of olefins is most commonly carried out using a source of nitrene, such as [N-(p-tosyl)imino]phenyliodinane (PhI=NTs), in the presence of some transition metal catalyst, which serves as a nitrenoid carrier. Effective catalysts show remarkable diversity, both in structure of the ligands and the metal centers to which they are coordinated. For example, the tridentate t-Bu3tpy ligand 122 forms a 2:2 complex with silver(I) to provide a novel soluble disilver catalyst which exhibits well-controlled oxidation reactivity as seen in the aziridination of trans-methylstyrene 126 <03JA16202>. The tetradentate pyridyl ligand 124 was found to provide the most efficient catalyst with copper(I) ion in the aziridination of styrene 128, but subtle changes to the ligand structure resulted in striking differences in the properties of the resultant catalyst <03EJIC1711>. The macrocyclic pyridinophane 125 gives rise to an interesting conformationally strained "capped" catalyst that is particularly reactive, converting cyclooctene 130 to the corresponding aziridine 131 in near quantitative yield <03OL259 l>. The chiral copper(I) complexes derived from binaphthyldiimine 123 (BINIM-TC) are effective in the asymmetric aziridination of 3-aryl-2-propen-l-ones (e.g., 132) with excellent enantiomeric excess <03BCSJ189>. t-Bu

N t-Bu

-

~~t.

~

C'N

e

CI

Bu

122 (L 1)

N

el 123 (L 2)

124 (L 3)

125 (L 4)

72

A. Padwa and S. Murphree

[Ag2(L1)2(NO3)](NO3) (2 mol%) . PhI=NTs CH3CN

90% yield

126

127

[CuI(L3)](BF4) (1.7 mol%)

L,~~,~j~ Ts

PhI=NTs CH3CN 128

80% yield

129

[Cul(L4)Cl (5 mol%) PhI=NTs CH2CI2

{ ~

=

{ ~

130

[Cu(MeCN)4]PF6.L2 (10 mol%) Ot-Bu

132

98% yield

131

O Ph

NTs

PhI-NTs CH2Cl2

~

TSo

Ph

Ot-Bu

57% yield 98% ee

133

Other reagents are also employed as nitrene precursors, primarily in an effort to avoid the practical problems associated with PhI=NTs <01TL8089>, such as expense of the reagent and the generation of iodobenzene as a by-product. For example, tosyl azide has been used in combination with the chiral ruthenium(salen) catalyst 134 to effect the enantioselective aziridination of terminal alkynes with very good ee's <03CL354>. Another alternative source of latent nitrene is N-iodo-N-potassio-p-toluenesulfonamide (TsN.KI), a stable crystalline solid obtained from the treatment of toluenesulfonamide with iodine in the presence of potassium hydroxide. When used in combination with copper(I) chloride as a catalyst, simple alkenes undergo aziridination in fair to good yields <03TL575>. Chloramine-T can also be used as a source of nitrogen in the presence of NBS; however, here the mechanism is not believed to proceed through a nitrene species, but rather by initial bromonium ion formation from the alkene, which undergoes subsequent nucleophilic attack by Chloramine-T <03TL989>.

Three-Membered Ring Systems

73

conditions ~ N T s (see below)

135

136

134

conditions

% yield

o~ e e

134 ( 2 mol%)

TsN3, CH2C12

71

87

Me

CuC1 (5 mol%)

TsN.KI, CH3CN

75

rac

C1CH2-

NBS (20 mol%)

Chloramine-T, CH3CN

67

rac

catalyst

]

Exocyclic ot,[3-unsaturated lactones (e.g. 137) have been converted to the corresponding spiroaziridines 138 by treatment with ethyl N-{[(4-nitrobenzene)sulfonyl]oxy}carbamate (NsONHCO2Et) in the presence of calcium oxide <03TL4953>. In a similar vein, a novel chiral carbamate 139 based on Helmchen's alcohol has been applied to the same conditions with moderately good diastereoselectivities, as shown in the aziridination of carboethoxycyclopentenenone 140 <03TL3031>.

NsONHCO2Et

EtO2

(60%yield)

CaO CH2CI2

137

138

0

r ~

NHONs 139

0

140

OEt

139

CaO CH2CI2

0 ~ L 2Et CO2R* 141

86% yield 70% de

74

A. Padwa and S. Murphree

Of course, aziridines can also be synthesized by the ring-closing reactions of appropriately substituted amines. For example, halohydrins of type 142 are converted to N-hydroxy-aziridines 144 by treatment with hydroxylamine derivatives, followed by base-catalyzed intramolecular SN2 reaction of the intermediate 13-haloaminoesters 143 under phase-transfer conditions <03TL3259>. N-Bromoethylimines 146, formed from the reaction of benzaldehyde derivatives (e.g., 145) and 2-bromo-2-methylpropylamine hydrobromide, undergo nucleophilic attack by methoxide, followed by intramolecular displacement of bromide to form N-(txmethoxybenzyl)aziridines 147 <03TL 1137>. HNOH v

~ "C02Me CI

NaOH, CO

HCI/Na2C03 THF 90%

v

142

'"II 'C02Me CI

CN

Bu4NHS04 benzene 65%

CI

143

144

B r ~ "~NH2"HBr

H

2N NaOMe

~..

=..

Et3N CH2CI2 87%

145

C02Me

MeOH 85%

e

146

147

Analogous to epoxides, aziridines can be prepared by the methylenation of imines. In this case, ethyl diazoacetate is the most common source of carbenes. For example, the imine derived from p-chlorobenzaldehyde 148 is converted to the cis-aziridinyl ester 149 upon treatment with ethyl diazoacetate in the presence of lithium perchlorate <03TL5275>. These conditions have also been applied to a reaction medium of the ionic liquid 1-n-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6) with excellent results <03TL2409>. An interesting enantioselective twist to this protocol has been reported, in which a diazoacetate derived from (R)-pantolactone 150 is used. This system was applied to the aziridination of trifluoromethylsubstituted aldimines, which were prepared in situ from the corresponding aminals under the catalysis of boron trifluoride etherate <03TL4011>.

N''Ph

I~h

(see below) ~"

CI

C02Et CI"

148

-,,7

149

Three-Membered Ring Systems

75

conditions

% yield

LiCIO4, CH3CN, r.t., 4.5 h

90

bmimPF6, r.t., 5 h

98

H

O

150

MeO.,.~ NH HO/J'CF3

BF3-OEt

151

3.3.2

MeO~ ~,.~ .,,,,.. "~ "N H LCF3 "

one pot

MeO..,~L.

-" 81% yield 94% de

~/~-,,CO2R (~-F3

152

153

Reactions of Aziridines

Inasmuch as aziridines are strained heterocycles, they can undergo facile ring-opening reactions with various nucleophiles, especially if the aziridine nitrogen is equipped with an electron-withdrawing substituent. For example, the N-tosylaziridine 154 is smoothly cleaved by aniline in the presence of bismuth trichloride to give the diamine 155 <03SC547>. Ceric ammonium nitrate (CAN) catalyzes the ring-opening of 154 with water to afford the amino alcohol 156 in 88% yield <03CL82>.

BiCI3 ~NHTs ~10mo1%) ~ N - - T s "NHPh PhNH2 96% yield 155 154

CAN (10m~176176 H20 CH3CN 88% yield

.~]~OH NHTs 156

Nonactivated aziridines can be prompted to undergo ring-opening reactions under the influence of tris(pentafluorophenyl)borane as a catalyst, as shown by the reaction of hydroxypropylaziridine 157 with benzylamine to give the diaminoalcohol 158. Mechanistic studies suggest the intermediacy of [(C6Fs)aB(OH2)]'H20 formed in situ as a Bronsted acid catalyst <03JOC5160>. In the case of amino aziridines 159, the regioselectivity of the nucleophilic attack can be controlled by the reaction conditions. Thus, the use of a protic acid, such as p-toluenesulfonic acid (pTsOH), leads to the attack of water at the less hindered C-3 position, whereas the aprotic Lewis acid catalyst boron trifluoride etherate leads to a C-2 mode

76

A. Padwa and S. Murphree

of ring opening. Anchimeric assistance from the amino substituent has been invoked as a rationale for the regiochemical changeover <03JOC6407>.

B(C6F5)3 (10 mol%,L PhNH2 CH3CN

NHPh r ~ "~' "~',,/~ N ~ O H H

157

NHBn " ~ ~ N B n 2 OH ~ 160

158

TsOH CH3CN H20 78%

1. BF3.OEt2 OH - ~ ~ N B ~ NBn CH3CN _--- - ~ ~ N B n 2 NHBn 2. NaHCO3 H20 81% 159

161

Aziridines can also be employed as nucleophiles. When one of the carbon atoms in the aziridine ring is equipped with an electron-withdrawing substituent, these substrates can often be cleanly deprotonated and used for subsequent carbanion chemistry. For example, the anion derived from the trifluoromethyl aziridine 162 engages in nucleophilic addition onto benzaldehyde to give the aziridinyl alcohol 163 in 83% yield <03TL6319>. Similarly, deprotonation of the oxazolinylaziridine 164 followed by treatment with methyl iodide gave mainly the methylated product 165 <03TL2677>.

TS /N~ ~CF3

Ts Ou sec'BuLL PhCH0~ ,A ,,,1~, THF " - % _ Ph "CF3

162

163

SO2Ph Me,'A,' sec-BuL.i ,,H TMEDA THF

164

83% yield

Mel

SO2Ph e,"A' M ,,Me

69% yield

165

N-Unsubstituted aziridines can be elaborated by taking advantage of the nucleophilicity of the nitrogen center. One noteworthy example is the palladium-catalyzed arylation of aziridine 166 with p-bromonitrobenzene 167 using a Pd2(dba)3/BINAP system. Best results were obtained using electron-deficient aryl bromides. Aryl chlorides of any type, however, failed to react under these conditions. The aryl-aziridine coupling reaction could also be carried out with arylboronic acids using a copper catalyst <03JOC2045>.

Three-Membered Ring Systems

[ ~

NH +

Pd2(dba)3 (2 m~ j ~ N - - ~ ~.BINAP t-BuONa 96% yield 168

~NO2 Br" ~

166

77

167

NO2

N-Substituted hydroxymethylaziridines undergo an interesting ring expansion in the presence of phosgene, which involves initial nucleophilic behavior of the nitrogen center. Thus, treatment of aziridine 169 leads to the formation of a short-lived bicyclic intermediate 170, which suffers nucleophilic ring opening by chloride to give the chloromethyloxazol-idinone 171 with retention of stereochemistry at both chiral centers. The use of one equivalent of sodium hydride is necessary to prevent the buildup of hydrochloric acid during the reaction, which tends to cause an unwanted ring-opening of unreacted aziridine <03JOC43>. A similar rearrangement to oxazolidinones is known to occur upon treatment of aziridines with di-tert-butyl dicarbonate (tBoc20) <03T677>.

-'L t-Bu ~~'~OH %H

1 9Nail / THF 2. COCI2

169

,,.'"

0

t-Bu

90% yield

~

,' . . . .

0

\ / CI----~" %t-Bu

170

171

Hydroxymethylaziridines of this type can also be induced to engage in a Lewis acid-mediated rearrangement to the corresponding aminocarbonyl compound. Thus, the bicyclic tosylaziridine 172 provided 173 in near quantitative yield when treated with zinc bromide in methylene chloride. The rearrangement involves a stereospecific 1,2-migration of the aryl group. The latter compound was used as a key intermediate in the synthesis of mesembrine <03OL2319>.

H

.OMe

O~~oMe

TBSO,I~

NTs 172

ZnBr2 CH2CI2 98% yield

O . ~ ~

TBSs

v

OMe

"NHTs -'~-~ OMe 173

Finally, when aziridines bear a 2-alkenyl substituent, they can engage in an SN2' reaction with dialkylzinc reagents using copper catalysts. Enantioselectivity can also be induced by including a chiral ligand, such as the binaphthyl phosphoramidite 174. For example, the aziridinyl cyclohexane 175 provided exclusively the trans-l,4 adduct with 83% ee upon treatment with dimethylzinc in the presence of copper(II) triflate and ligand 174 <03TL8559>.

78

A. Padwa and S. Murphree

~ q p ~

0

P~I~..... ' _ h~ P

174

3.4

{~N

-Cbz

174 Cu(OTf)2~ Me2Zn THF

~IHCBz 48%yield 83%ee

175

176

AZIRINES

2H-Azirines are valuable precursors for preparing a wide range of polyfunctional acyclic and cyclic nitrogen containing compounds <02OPP219>. A number of synthetic methods are available for forming 2H-azirines such as intramolecular rearrangements of N-functionalized imines, vinyl azides, isoxazoles and oxazaphospholes. 2H-Azirines have also been prepared by bimolecular reactions between nitriles and carbenes or nitrenes and acetylenes. The most common methods for preparing 2H-azirines are photolysis or thermal extrusion of nitrogen from vinyl azides. This past year an efficient and environmentally friendly method for preparing 2Hazirines was achieved by microwave irradiation of vinyl azides 9 in solvent free conditions <03TL67637>. The Katritzky group reported on a method to synthesize 2-(benzotriazol-l-yl)2H-azirines under mild conditions and also disclosed the first example of a nucleophilic substitution reaction of the 2H-azirine system with organometallic reagents <03JOC9105>.

Bt

TsCI R~...NOH 10%KOH

R2MgBr Bt

177

R2

178

179

Chiral 2H-azirines have been prepared by dehydrochlorination of N-chloroaziridines, Swern oxidation of aziridines and elimination from N-sulfinylaziridines. These reactions require the use of high enantiopure aziridine esters as starting materials <03T2345>. Chiral enriched ethyl 3-methyl-2H-azirine-2-carboxylate was found to act as an efficient alkylating agent for the preparation of a variety of five-membered aromatic nitrogen heterocycles <03TL6277>. Mo.

+ R1NHR2 1..14..,,,CO2Et 180

~" R2H,,~,,CO2Et 181

The reaction of 2H-azirine-3-carboxylates unsubstituted at C2 with diazomethane occurs to produce a 4,5-dihydro-3H-pyrazole derivative 185. This reaction represents an interesting example of the imino group acting as a 2n-component in a 1,3-dipolar cycloaddition reaction <03TL6313>. The process seemingly involves the reaction of 2H-azirine 182 with

Three-Membered Ring Systems

79

d i a z o m e t h a n e to give c y c l o a d d u c t 183 as a transient species which then undergoes a subsequent r e a r r a n g e m e n t to generate allyl azide 184. This c o m p o u n d participates in a second 1,3-dipolar cycloaddition with d i a z o m e t h a n e to give 185.

N~.._./--"'CO2Me CH2N2 ~N~'~ ~- CH2~~--N3 C02Me CH2N2E3~ ~ V V "CO2Me 184 CO2Me N 182

3.5

183

185

REFERENCES

62JA867 91JA6703 97BCSJ905 01 TL8089

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03JOC43 03JOC75 03JOC726 03JOC1721 03JOC1872 03JOC2045 03JOC3049

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80

03JOC3232 03JOC4797 03JOC4963 03JOC5160 03JOC6202 03JOC6407 03JOC6576 03JOC9050 03OL85 03OL293 03OL583 03OL725 03OL2283 03OL2319 03OL2469 03OL2591 03OL2723 03OL3265 03OL3423 03SC435 03SC547 03SC999 03SC1603 03SC1861 03SC2017 03SC2135 03SC2989 03SL281 03SL396 03T677 03T2435 03T4549 03T4701 03T6889 03TL435 03TL575 03TL989 03TLl137 03TL2355 03TL2409 03TL2677 03TL2911 03TL2975 03TL3031 03TL3259 03TL3629 03TL4011 03TL4137

A. Padwa and S. Murphree

G. Sartori, A. Armstrong, R. Maggi, A. Mazzacani, R. Sartorio, F. Bigi, B. Dominguez-Fernandez, J. Org. Chem. 2003, 68, 3232. R. Fernandez de la Pradilla, M.V. Buergo, P. Manzano, C. Montero, J. Priego, A. Viso, F.H. Cano, M.P. Martinez-Alcazar, J. Org. Chem. 2003, 68, 4797. L. Shu, Y.M. Shen, C. Burke, D. Goeddel, Y. Shi, J. Org. Chem. 2003, 68, 4963. I.D.G. Watson, A.K. Yudin, J. Org. Chem. 2003, 68, 5160. L. Cavallo, H. Jacobsen, J. Org. Chem. 2003, 68, 6202. J.M. Concellon, E. Riego, J. Org. Chem. 2003, 68, 6407. W.K. Chan, W.Y. Yu, C.M. Che, M.K. Wong, J. Org. Chem. 2003, 68, 6576. Y. Mori, K. Nogami, H. Hayashi, R. Noyori, J. Org. Chem. 2003, 68, 9050. T. Okachi, N. Murai, M. Onaka, Org. Lett. 2003, 5, 85. L. Shu, P. Wang, Y. Gan, Y. Shi, Org. Lett. 2003, 5, 293. P.G. Reddy, B. Varghese, S. Baskaran, Org. Lett. 2003, 5, 583. W. Adam, P.L. Alsters, R. Neumann, C.R. Saha-M611er, D. Seebach, R. Zhang, Org. Lett. 2003, 5, 725. D.C. Forbes, M.C. Standen, D.L. Lewis, Org. Lett. 2003, 5, 2283. Z.L. Song, BM. Wang, Y.Q. Tu, C.A Fan, S.Y. Zhang, Org. Lett. 2003, 5, 2319. G. Dubois, A. Murphy, T.D.P. Stack, Org. Lett. 2003, 5, 2469. A.N. Vedernikov, K.G. Caulton, Org. Lett. 2003, 5, 2591. R. Luisi, V. Capriati, L. Degennaro, S. Florio, Org. Lett. 2003, 5, 2723. P. Shanmmugam, M. Miyashita, Org. Lett. 2003, 5, 3265. K.H. Tong, K.Y. Wong, T.H. Chan, Org. Lett. 2003, 5, 3423. D.Y. Kim, Y.J. Choi, H.Y. Park, C.U. Joung, K.O. Koh, J.Y. Mang, K.Y. Jung, Synth. Commun. 2003, 33, 435. N.R. Swamy, Y. Venkateswarlu, Synth. Commun. 2003, 33, 547. F. Kazemi, A.R. Kiasat, S. Ebrahimi, Synth. Commun. 2003, 33, 999. K. Bhaumik, U.W. Mali, K.G. Akamanchi, Synth. Commun. 2003, 33, 1603. G. Bentabed, A. Derdour, H. Benhaoua, Synth. Commun. 2003, 33, 1861. U.R. Pillai, E. Sahle-Demessie, R.S. Varma, Synth. Commun. 2003, 33, 2017. J.A. Ciaccio, A.L. Drahus, R.M. Meis, C.T. Tingle, M. Smrtka, R. Geneste, Synth. Commun. 2003, 33,2135. S. Luo, B. Zhang, P.G. Wang, J.-P. Cheng, Synth. Commun. 2003, 33, 2989. T. Katsuki, Synlett 2003, 281. J.S. Yadav, B.V.S. Reddy, G. Baishya, Synlett 2003, 396. L. Testa, M. Akssira, E. Zaballos-Garcia, P. Arroyo, L.R. Domingo, J. Sepflveda-Arques, Tetrahedron 2003, 59, 677. I. Cepanec, M. Litvic, H. Mikuldas, A. Bartolincic, V. Vinkovic, Tetrahedron 2003, 59, 2435. Y. Tanaka, K. Nishimura, K. Tomioka, Tetrahedron 2003, 59, 4549. V.M. Dembitsky, Tetrahedron 2003, 59, 4701. T. Nemoto, T. Ohshima, M. Shibasaki, Tetrahedron 2003, 59, 6889. C. Hardouin, L. Burgaud, A. Valleix, E. Doris, Tetrahedron Lett. 2003, 44, 435. S.L. Jain, B. Sain, Tetrahedron Lett. 2003, 44, 575. V.V. Thakur, A. Sudalai, Tetrahedron Lett. 2003, 44, 989. M. D'hooghe, A. Hofkens, N. De Kimpe, Tetrahedron Lett. 2003, 44, 1137. A. Patra, M. Bandyopadhyay, D. Mal, Tetrahedron Lett. 2003, 44, 2355. W. Sun, C.-G. Xia, H.-W. Wang, B. Tetrahedron Lett. 2003, 44, 2409. R. Luisi, V. Capriati, S. Florio, R. Ranaldo, Tetrahedron Lett. 2003, 44, 2677. B.K. Oh, J.H. Cha, Y.S. Cho, K.I. Choi, H.Y. Koh, M.H. Chang, A.N. Pae, Tetrahedron Lett. 2003, 44, 2911. C.S. Cho, J.H. Kim. H.J. Choi, T.J. Kim, S.C. Shim, Tetrahedron Lett. 2003, 44, 2975. S. Fioravanit, A. Morreale, L. Pellacani, P.A. Tardella, Tetrahedron Lett. 2003, 44, 3031. S. Boukhhris, A. Souizi, Tetrahedron Lett. 2003, 44, 3259. S. Chandrasekhar, C. Narasihmulu, V. Jagadeshwar, K.V. Reddy, Tetrahedron Lett. 2003, 44, 3629. T. Akiyama, S. Ogi, K. Fuchibe, Tetrahedron Lett. 2003, 44, 4011. K. Li, Z.Z. Huang, Y. Tang, Tetrahedron Lett. 2003, 44, 4137.

Three-Membered Ring Systems

03TL4953 03TL5005 03TL5275 03TL5547 03TL6025 03TL6319 03TL6501 03TL6523 03TL6613 03TL7081 03TL7479 03TL8559

81

T. Gasperi, M.A. Loreto, P.A. Tardella, E. Veri, Tetrahedron Lett. 2003, 44, 4953. G.J. Kim, H. Lee, S.J. Kim, Tetrahedron Lett. 2003, 44, 5005. J.S. Yadav, B.V.S. Reddy, M.S. Rao, P.N. Reddy, Tetrahedron Lett. 2003, 44, 5275. M. Sivakumar, B. Borhan, Tetrahedron Lett. 2003, 44, 5547. L.D. Pach6n, P. Gamez, J.J.M. van Brussel, J. Reedijk, Tetrahedron Lett. 2003, 44, 6025. Y. Yamauchi, T. Kawatee, H. Itahashi, T. Katagiri, K. Uneyama, Tetrahedron Lett. 2003, 44, 6319. J.S. Yadav, B.V.S. Redddy, G. Satheesh, Tetrahedron Lett. 2003, 44, 6501. A. Solladi6-Cavallo, P. Lupattelli, L. Jierry, P. Bovicelli, F. Angeli, R. Antonioletti, A. Klein, Tetrahedron Lett. 2003, 44, 6523. P. O'Brien, C.M. Rosser, D. Caine, Tetrahedron Lett. 2003, 44, 6613. Y. Song, H. Chen, X. Hu, C. Bai, Z. Zheng, Tetrahedron Lett. 2003, 44, 7081. M.K. Tse, S. Bhor, M. Klawonn, C. D6bler, M. Beller, Tetrahedron Lett. 2003, 44, 7479. G. Fini, F. Del Moro, F. Macchia, M. Pineschi, Tetrahedron Lett. 2003, 44, 8559.

82

Chapter 4

Four-Membered Ring Systems Benito Alcaide

Departamento de Quimica Org6nica, Facultad de Quimica, Universidad Complutense de Madrid, 28040-Madrid, Spain [email protected] Pedro Almendros

Instituto de Quimica Org6nica General CSIC, Juan de la Cierva 3, 28006-Madrid, Spain iqoa3 [email protected]

4.1

INTRODUCTION

Tremendous advances have been made in the stereoselective synthesis and synthetic applications of strained four-membered ring systems in the past years. However, there is still a lot of new four-membered heterocyclic chemistry being continuously reported. In particular, oxygen- and nitrogen-containing heterocycles dominate the field in terms of the number of publications. Obviously, one Chapter cannot incorporate all the exciting chemistry emanating from research groups active in this area, and so we have concentrated on the more relevant aspects. 4.2

AZETES, AZETINES, AZETIDINES AND 3-AZETIDINONES

A review including the synthesis of 3-azetidinones has been published <03T7631>. Azacyclobutadiene (azete) is a highly reactive and unstable molecule. A base-induced novel condensation reaction of ot-chloro oxime derivatives to furnish alkynyl oximes through an azacyclobutadiene intermediate has appeared <03AG(E)5613>. A novel reaction of N-acyl thiazolidinethione enolates with enolizable aldoxime ethers produced thiazolidinethione azetines 1 with excellent diastereoselectivity <03JA3690>. Subsequent addition of an acyl chloride to these azacyclobutene derivatives leads to the formation of the corresponding N-acyl-Gt,13-disubstituted 13-amino acid derivatives, via selective generation of a cyclic four-membered iminium salt. Azetine derivatives were obtained as minor products on irradiating aryl-substituted N-acyl-otdehydroalanines <03H63 7>. o .OMe N" R.,~H

o

s

s

F "-e ~

+

Key: i) TiCl 4, (-)-sparteine, CH2Cl2,RT. ii) PhCOCl. iii) H20.

7

P h ' ~ NH O

-

S

~j .s

83

Four-Membered Ring Systems

The structure of the natural product gelsemoxonine was revised showing it to be a novel azetidine-containing indole alkaloid <03OL2075>. A diastereoselective approach to the synthesis of 4-trifluoromethylated 2,3-dialkylazetidines 2 was developed via Wittig reaction of a 4-trifluomethylated [3-1actam, followed by alkylation and hydrogenation <03OL4101>. Functionalized enantiopure 2-cyano azetidines 3 were prepared in good yields starting from [3-amino alcohols, by using, as the ring closure step, the intramolecular Michael addition of a lithiated a-amino nitrile <03SL726>. Enantiopure azetidine 2-carboxylic acids 4 were prepared by hydrolysis of the corresponding 2-cyano azetidines, without ring cleavage of the azetidine ring or epimerization. These cyclic amino acids were used for the synthesis of tripeptides <03TA2407>.

R,, F3c

,j.. 2

r,,,, CO2H

C02Et

C02Me 02Bu t

R

i_L

NH2

N/~CN Bn

.

R ~ N , Bn 3

R14"J---NR2 4

Key: i) (a) PhCHO, then NaBH4; (b) BrCH2CN; (c) Swern oxidation, then Ph3P=CHCO2Et. ii) LiHMDS.

The attempted aza-Baylis-Hillman reaction of N-tosylated imines with ethyl 2,3butadienoate or penta-3,4-dien-2-one has been reported to give azetidine derivatives 5 in the presence of DABCO <03OL4737>. The catalytic asymmetric [2+2] cycloaddition of 1methoxyallenylsilane(germane)s with an cx-imino ester afforded 3-methylene-azetidine 2carboxylates 6 in good yields and with excellent enantioselectivities. In addition, the acidcatalyzed ring opening of these azetidines afforded chiral acylsilane(germane)s quantitatively <03OL3691>. The preparation, through a route that employed hydroboration-amination and intramolecular SN2-type substitution reaction from a natural taxoid, taxinine, and biological evaluation of 4-deacetoxy-l,7-dideoxy azetidine paclitaxel analogs, have been described <03BMCL1075>. The stereospecific synthesis of cis-azetidine-2,3-dicarboxylic acid was achieved by RuO4 oxidation of 1-(methoxycarbonyl)-1,2-dihydropyridine <03CPB96>. EWG ArCH=NTs +

/

EWG

i

~N~T s

H

EtO2CH=NTs+

/

OMe

e \~\O MSiMe3

Ar MR3 EtO2C4 Ts 5 (31-99%) 6 (60-92%, 58-97% ee) Key: i) DABCO, CH2CI2, RT. ii) M = Si, Ge, 10 mol% (R)-ToI-BINAP; [Cu(MeCN)4]BF4, THF, RT.

The synthesis of a novel bridged nucleic acid monomer, 3'-amino-3'-deoxy-5-methyl3'-N,4'-C-methyleneuridine 7, was accomplished via a useful and convenient azetidine ring formation under Staudinger conditions <03TL5267>. A library of fused pentacyclic azetidines 8 (72 examples) has been prepared, which incorporate the benzodiazepinequinazolinone moiety of the Circumdatin family of alkaloids <03S1707>. Using molecular mechanics (MM3 force-field)-based methodology, conformational dynamics have been studied for 1-aza-bicyclo[2.2.0] hexane 9 <03JOC3055>. The reaction of N-(alkoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 10 with halonium ion electrophiles gave different rearranged products <03JOC5292>. Stereodefined cxhydroxyalkyl azetidines, prepared in a few steps from enantiomerically pure I]-amino alcohols, are transformed into chloro or methanesulfonyl derivatives 11 in good yields. Heating these compounds induces a stereospecific ring enlargement to give 3-chloro or 3methanesulfonyloxy pyrrolidines <03TL5209>.

84

B. Alcaide and P. Almendros

O .R

"ICIN"

N N OH R 7

x

,J

Ph_

"

O

9

R2

10

11

Bn

"" I

Bn

75-80% Key: X = CI, MsO; i) DMF, reflux.

Several 1-alkyl-2-methylazetidin-3-ones 12 were prepared in good yields by the hydride-induced cyclization of the corresponding [3-bromo-tx,c~-dimethoxyketimines, the resulting 3,3-dimethoxyazetidines being hydrolysed by acid. Imination of these 1,2disubstituted azetidin-3-ones, followed by alkylation under kinetic control resulted in a regioisomeric mixture of 2,4- and 2,2-dialkylated compounds <03T2231>. The ring opening of a mesoionic 1,3-dioxolylium-4-olate, obtained by RhE(OAc)4-catalyzed decomposition of a phenyldiazoacetic anhydride, generated an acyloxyketene, which was trapped in the presence of carbodiimides to give azetidin-3-ones 13 <03TL7945>. The electroreduction of chiral aromatic tx-imino esters prepared from (S) amino acids, such as (S)-valine, (S)-leucine, and (S)-phenylalanine, in the presence of chlorotrimethylsilane and triethylamine afforded stereospecifically mixed ketals of cis-2,4-disubstituted azetidin-3-ones 14 <03JA 11591>. N"R O~ ~ rl R2 MeO II O ~ OR1 ,/---~ MeO~ i Ar2 N~CO2R1 --" ii --" ~N TMSO""~'~'~

L _Br

R2"'~N" Bz R" N/"}--N'R 12 13 14 (>99% de, 85--99% ee) Key: i) (a) NaBH4, MeOH, reflux; (b) 6N HCI, reflux, ii) (a) + e, TMSCI; (b) BzCI, Et3N.

4.3

"R

MONOCYCLIC 2-AZETIDINONES (IS-LACTAMS)

A review on the synthesis of 2-azetidinones and some chemistry of the [3-1actam nucleus have been published <03T7631 >. A review on solid-supported ketenes, including the polymer-assisted synthesis of [3-1actams, has appeared <03AG(E)2340>. A review on chiral amines as catalysts in asymmetric synthesis <03CR2985>, as well as a review on asymmetric synthesis using ketenes <03T3545>, both of them including 13-1actam formation, deserve to be mentioned as well. A chiral tris(oxazoline)/Cu(II) system catalysed the coupling of terminal alkynes and nitrones (Kinugasa reaction) to afford cis-disubstituted [3-1actams 15 with reasonable enantioselectivity <03CC2554>. A new synthetic route to 4-alkoxycarbonyl4-alkyl-2-azetidinones 16 by silver-induced ring expansion of alkoxycyclopropylamines was developed <03JOC6685>. R3 R1 R;,, I /IR 2 CI / N OMe i_~.i/J/_l R'--+ i _o..N,R2 "-~ ,R2 R 1 R 2~ O N'R3 15 (33-98%, 70-85% ee) 16 (75-99%) Key: i) 10 mol% Cu(CIO4)2, 12 mol% ligand, Cy2NH, MeCN. ii) (a) AgBF4, CH2CI2; (b) H20.

H

The benzylic lithiation of substituted acrylamides bearing a [3-electron withdrawing group, followed by 4-exo-trig cyclisation yielded 13-1actams in modest yields <03CC2582>. A series of highly functionalized [3-1actams 18 can be generated on treatment of 1,3-thiazolium-

85

Four-Membered Ring Systems

4-olates (thioisomtinchones) 17 with aliphatic aldehydes, after ring fragmentation of the initial [3+2] cycloadducts <03JOC6338>. The synthesis of trans-2-azetidinone 19, an advanced precursor of thrombin and tryptase inhibitors has been recently accomplished <03JOC2952>. Bn..N.Me Me Bn...~ Ar o==L"s R NH S~ i Ph/"H"H H2N/J~.N~ ' , , , . I~I~C O2Me G + RCHO ~ ' ' O / ~ N,Ar IH O/I/--I~1 i..1 Ph 17 18 19 Key: i) C6H6, reflux. The synthetic utility of a tandem Petasis-Ugi multi-component condensation and 1,3diisopropylcarbodiimide condensation reactions have been employed to prepare libraries of aza-[~-lactams 20 and 21 <03TL6297>. The synthesis of 13-1actams from a N-rhenaimine, as well as the effect of the transition metal on the energetic profile of the Staudinger reaction have been described <03JA3706>. A ruthenium porphyrin-catalysed stereoselective intramolecular carbenoid C-H insertion converted tosylhydrazones to cis-fS-lactams in good yields <03OL2535>. The preparation of [~-lactams that incorporate different dendritic wedges (up to third generation) at the 4-position of the 2-azetidinone ring has been accomplished <03SL1587>. In the presence of Zn/CpETiC12, t~-bromoalkanoates react with imines in one pot to form 13-1actams 22, at room temperature without the need for pre-treatment of the solvent or Zn <03TL2611>. R3 R2 R2 R1 R1 R2 ,R 1 R1

O~N'N'H "~- H2N-N'z i' o ' ~ Nh~ Rk/__CO2H -~ 20

21 R3

N--R4

R2/

I]N"

+ R3CHBrCOOR4 ii-L"

H

o N.

1

22

Key: i) DIPC, dioxane-H20, ii) R3CHO, R4NC, MeOH-H20. iii) Zn, CP2TiCI2 (cat.), THF, RT. The formyl group of an axially chiral chromium complex was transformed into compound 23 by addition of MeLi, radical cyclization and 13-1actam formation <03SL519>. The enantioselective synthesis of substituted [3-1actams was described based upon an improved alkylation of substituted Sch611kopf chiral auxiliaries by tx-haloacetate esters, employing tert-butyllithium as the deprotonating base, and the conversion of the resulting quaternary 2,5-diketopiperazines into the targeted [3-1actams 24 <03SL2398>. Free-radical mediated stannylcarbonylation of azaenynes provides a 4-exo annulation approach leading to ct-stannylmethylene [3-1actams 25 <03JA5632>. The solid phase synthesis of [3-1actams using the Staudinger reaction was reported to be monitored by 19F NMR spectroscopy <03T3719>. ~-Oxohydrazones were used as imine components in the synthesis of functionalised 2azetidinones by the Staudinger cyclization <03T10195>. Pseudomonas cepacia lipase (PS30) was used in hydrolytic resolution of 3-acetoxy-4-aryl-substituted [3-1actams (>97% ee) <03T9147>, while the enzymatic preparation of (3R)-cis-acetyloxy-4-(1,1-dimethylethyl)-2azetidinone, a side-chain synthon for an orally active taxane, was recently achieved <03TA3673>. A stereoselective synthesis of [~-lactams from thio-Michael/aldol tandem adducts has been described, syn-Selective tandem reaction followed by amidation and intramolecular SN2 reaction provided 2-azetidinones 26. While the domino process with aromatic aldehydes provided [3-1actams in diastereomerically pure form, aliphatic aldehydes afforded a mixture of diastereoisomers <03T9931 >.

86

B. Alcaide and P. Almendros

•••'•OMe

MeO,,T

O/~-- N'ph

i,,,,~ 10Me CO2Bn

MeO2C R1

Bu3Sn

R

i _L -"-

o~N'so2Ar 24

23 Key: i) (a) TFA, MeCN-H20; (b) ArSO2CI,/-Pr2NEt; (c) H2, Pd/C, MeOH; (d) EDC, CH2Cl2, RT. ii) CO, Bu3SnH, C6H6, 90 ~ EDC = N-(3-dimethylaminopropyl)-N-ethylcarbodiimide.

N-Protected 3,3-difluoroazetidin-2-ones 27 were obtained in two steps, consisting of a Reformatsky-type reaction for the preparation of N-substituted 3-amino-2,2difluoropropanoates followed by N1-C2 cyclization under basic conditions <03S2483>. The synthesis of NH-3-benzylsulfanyl- and NH-3-phenylsulfanyl-13-1actams 28 via a 4rtconrotatory electrocyclization of 1-benzylsulfanyl- or 1-phenylsulfanyl-2-trimethylsilyloxy3-aza-l,3-dienes has been accomplished <03T9577>. OH O

R

~sp

i R

OBut ~

H

N'L.

"N" H

"OBn 26 (43-59%)

h

F F ii

R ~

ArS.

,,R

"R

H

27 (38-62%)

28

Key: i) (a) Ac20, py; (b) TsOH (cat.); (c) NH2OBn, MeOH; (d) AgClO4, Mel, then K2CO3. ii) (a) BrCF2CO2Et, Zn; (b) t-BuMgCI, Et20.

The asymmetric induction observed during cyclization of N-alkyl-N-chloroacetyl amino acid derivatives to fl-lactams 29, ascribed to chirality memory, is dependent on the substituents on the starting material <03TA2161>, and can be controlled by the appropriate choice of the base and solvent <03SL1007>. The use of bicarbonate salts as viable alternatives to more expensive bases for the in situ generation of ketenes and their synthetic equivalents, has been applied to the catalytic asymmetric synthesis of 13-1actams <03SL1937>. 4-Alkylidene-13-1actams have been obtained by reaction of 4-acetoxy-13-1actams with several diazo compounds in the presence of Lewis acids <03EJO 1765>. The preparation of 4-aryl-4-phosphono-13-1actams 30 by acylation of iminium salts with chloroacetyl chloride followed by phosphite addition and ring closure using sodium hydride has been recently documented <03TL 1619>. An N--O silyl migration has been observed in the chemistry of 1-tbutyldimethylsilyl-4-hydroxymethyl-2-azetidinone <03TL6339>. The stereoselective synthesis of azetidinone 31, a key intermediate to l l3-methylcarbapenem, has been achieved from an aziridine precursor via a three-membered ring opening reaction with cyanide as nucleophile and a tandem 13-1actam formation <03SLl149>. The Lewis acid-catalysed cyclization of 2-aza-3-trimethylsilyloxy-buta-l,3-diene as well as the stereochemical differences with the uncatalyzed cyclization have been documented <03TA993>. A novel family of 2-azetidinone-based heterocycles, 4-pyrazolyl-13-1actams, has been prepared involving a nitrilimine cycloaddition <03TL 1425>.

R OO2R'

R3

I - i _" c ~

-.o

'

N, R1

o 29 Key: i) (a) ClCH2COCl,then P(OR2)3;(b) Nail, THF.

,~r 9 OR2~ F1--P':oR

i -"

O

30

'

/ O"~ H~IN : 31

CO~H

87

Four-Membered Ring Systems

The [Rh2(OAc)4]-catalysed cyclization of ot-diazo-c~-(diethoxyphosphoryl)acetamides has been used for the preparation of trans-~-lactams 32 <03TL6571> <03EJO3798>. A convenient and general method of synthesis of NH-13-1actams via Grubbs' carbene promoted isomerization of the respective N-allyl 13-1actam followed by RuC13catalyzed enamide cleavage has been developed <03TL8693>. The asymmetric syntheses of 2-azetidinones by [2+2] cycloaddition using chiral imines derived from D-(+)-glucose <03T2309>, as well as a chiral acid auxiliary derived from (-)-ephedrine have been reported <03TA453>. Novel enantiopure (i)-(13-1actam)-(Gly)-(i+3) peptide models, defined by the presence of a central cx-alkyl-c~-amino-13-1actam ring placed as the (i+1) residue, have been synthesized in a totally stereocontrolled way by r of suitable N[bis(trimethylsilyl)methyl]-13-1actams. The 13-1actam 33, analogue of melanostatin (PLG amide), has also been prepared, and characterized as a type-II 13-turn in DMSO-d6 solution, and tested as a dopaminergic D2 modulator <03JA16243>.

H 0 X /", . ~ R X../~ RI [I N" i N2 L R 2 - " O/~-N.R1

O,,I~N,. - ~.: O O//

/--I ii

H,

\N4~ 0 N

0

O/17--N'v~N "H 33 (30%) I~1 Key: X = PO(OEt)2. i) 1 mol% Rh2(OAc)4, CH2CI2, reflux, ii) (a) LDA, BrCH2CMe=CH2; (b) H2, Pd/C; (c) n-BuLi, TMEDA, then Me3SiNCO; (d) Li, NH3; (e) Cbz-(L)-Pro-F, NMM; (f) H2, Pd/C. 32

,-TsiMe3 SiMe3

Imines derived from 4-oxoazetidine-2-carbaldehydes were found to be versatile azaDiels-Alder reagents because two reactivity patterns have been observed. These imines led to cycloadducts arising from normal as well as inverse electron-demand [4+2] cycloaddition <03CEJ3415>. The dihydropyridone- and tetrahydroquinoline-[3-1actams 34 and 35 were used for the asymmetric synthesis of indolizidine-type alkaloids <03CEJ5793>. The use of [3lactams as chiral building blocks in organic synthesis is now well established and routine. The 2-azetidinone system has been used as intermediate in the synthesis of eudistomins <03SL738>, cryptophycins <03JOC9687>, dioxocyclams <03JOC8409>, macrocyclic taxoids <03OL3733>, ibotenate analogues <03OBC2670>, a-amino acids <03JOC27>, and ot-alkyl aspartic acids <03TL6145>. R~

R4

.R5

R 6 ~ O M e

\R 4

R ~ 2 H H

2H H w

,v

R~-%O

R3

- H H

r~

0

,.

O/~---N"R, 35

R3: PMPo~N" R, R3=aIIyI O'P[--lq'R,R~ 34

R'HN H ~ O

?

O

Key: i) Danishefsky's diene, 20 mol% Znl2, MeCN. ii) Electron-rich alkene, 20 mol% In(OTf)3, MeCN. iii) (a) L-Selectride, THF; (b) Grubb's carbene, toluene, reflux; (c) MeONa, MeOH. iv) MeONa, MeOH.

4.4

FUSED POLYCYCLIC [~-LACTAMS

The synthesis of the carbapenam-3-carboxylic acid 36 <03JA15746> as well as a study on carbapenem biosynthesis have been documented <03JA8486>. The cephalosporin derivative 37 has been prepared and its use as a novel fluorogenic substrate for imaging 13lactamase gene expression demonstrated <03JA11146>. The nucleus of the carbacephem antibiotic loracarbef has been synthesized in a highly efficient and enantioselective fashion from 2S,3S-2-amino-3-hydroxy-6-heptenoic acid, which was derived from enzyme-catalyzed

88

B. Alcaide and P. Almendros

condensation of glycine and 4-pentenaldehyde. The bicyclic framework of loracarbef was established through sequential Mitsunobu reaction and aldol condensation <03TL5991>. t

~,,,. ~

i ~

H

m

Bn

,uo,c , . , o c c o , , n - o'36

HHHO.

CO2Na

N

-

0

O" "OH

37

0

0

Key: i) (a) NaOH, THF/H20; (b) allyl bromide, CsCO3, THF; (c) TFA; (d) N-methyl-2-chloropyridiniumtriflate,

MeCN; (e) Pd[PPh3]4,sodium p-toluenesulfinate, MeOH.

A method for the enantioselective synthesis of the functionalised carbapenam core 38 from D-serine-derived pyrrolidines has been reported <03JOC187>. Disubstituted pyrrolidines, obtained from the retro Dieckmann reaction of azabicyclo[2.2.1 ]heptan-2-one1-carboxylic acid methyl esters, have been used as starting materials to develop concise syntheses of all four stereoisomers of carbapenam-3-carboxylic acid methyl esters <03JOC2889>. The synthesis of 1-methylcarbapenams 39 by intramolecular attack of lactam nitrogen on a r/3-propargylpalladium complex has been reported <03JOC8068>. Ii ", ..~.., TBSO TBSO O\ ...../,,.N>.,.,,/CO2Me i--~ ~ O T B S

o-

%mu'

38 (20%)

i._~

X

"X

39(71%) Key: i) (a) HCI, MeOH; (b) TBSCI, DMF; (c) AcOH/H20/THF; (d) RuO4, MeCN; (e) N,N-diisopropyl-O-t-

butylisourea, t-BuOH; (f) H2, Pd/C; (g) LiOH, THF/H20; (d) N-methyl-2-chloropyridinium triflate, MeCN. X = OP(O)(OEt)2. ii) 5 mol% Pd2(dba)3, PhCOONa, THF.

3-Alkoxycarbonyl-113-methylcarbapenem 40 has been synthesized using a palladiumcatalyzed C-N bond-forming coupling of vinyl halide and 13-1actam nitrogen <03JOC3064>. (5S)-Tricyclic penems 41 which have been prepared via intramolecular cyclization of penem epoxy amides catalysed by the weak Lewis acid Mg(C104)2, exhibited inhibition of bacterial signal peptidases <03S1732>. Starting from L-ethyl lactate and 4-vinyloxy-azetidin-2-one, the 5-oxacepham 42 was obtained <03T5893>. T B S OH~ H TBSO TBSO H _H _~NHS OAc H0 i X

CO2Et

CO2Et

40 (90%)

Key: X = Br, I. i) 10 mol% Pd(OAc)2, K2CO3, toluene.

O 41 O ~ ~ B n

o~N'~ 42

The Barton photochemical reaction has been applied in the synthesis of 1-dethia-3aza-l-carba-2-oxacephem 43, a novel agent against resistant pathogenic microorganisms <03OBC2461>. A complex cephalosporin derivative incorporating structural features of the peptydoglycan was designed and tested as an inhibitor specific for DD-transpeptidases <03JA16322>. The synthesis of the 4,5-dihydrofuroazetidinone 44 was produced by photorearrangement of 2-(2,4-dimethyl-3-phenyl-2H-isoxazol-5-ylidene)malonic acid diethyl ester <03TL9247>. The lipase-catalysed kinetic resolution of bicyclic 13-1actams, both NH<03OL1209> as well as N-hydroxymethyl <03TA3805>, has been described. The diastereoselective zinc-mediated Barbier-type allylation and propargylation of 3formylcephalosporins has been reported <03EJO 1749>.

89

Four-Membered Ring Systems H

N3 ~ N OH C)" N]

OEt

Bn"~/N~ II i "r--l"JK'O

i --~

Ph Me ~-~__CO2Et

O O,/~.._N.~N

CO2Me

Me--N.,.,~

"O

43 CO2H

EtO2C~ O hv

Me~ !

CO2Et

( Ph 44

"Me

Key: i) (a) CINO, py; (b) hv, 06H6; (c) DEAD-PPh3; (d) H2S, then BnCOCI, py; (e) pig liver esterase.

The titanocene(nI) chloride-induced cyclization of four enantiomerically pure isomeric N-substituted epoxyaldehyde-2-azetidinones has been used as a stereospecific entry to polyfunctionalised carbacephams 45 <03JOC2024>. Enantiopure epoxyalkene-2azetidinones derived from D-glucosamine by Staudinger reaction, gave on treatment with titanocene(III) chloride bi- and tricyclic 13-1actams with high selectivity but with low conversion <03T241>. Bicyclic 13-1actams 46 have been synthesized starting from 2H-A 2thiazolines and Meldrum's acid derivatives <03OBC1308>. Enantioenriched tricyclic ~lactams 48 have been prepared via a copper/phosphaferrocene-oxazoline catalytic intramolecular Kinugasa reaction from nitrone 47 <03AG(E)4082>. MeO~ .,..fl,.~ Ph ~ 6

i

~

O / ~ - N ' ~ CliO ~ Sg

MeO

II

Ph

O"/

ii

- " ~ "OH Sg

O2R2

45 46 Key: Sg = sugar, i) TiCP2CI,THF. ii) CuBr, ligand, (C6Hll)2NMe, MeCN.

Ar 47

48

The Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4oxoazetidine-2-carbaldehydes gave homoallylic alcohols, which have been used for the diastereoselective preparation of fused bicyclic, tricyclic and tetracyclic [3-1actams of nonconventional structure 49 and 50, using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences <03JOC3106>. MeO

H H _OHII

OH

Ph i_~ Me

Ci" N~)n n=1,2

Ph

M

H H OH e O ~

Me

50 (46%)

49 (36-46%) SnPh3

Key: i) Ph3SnH, AIBN, 06H6, reflux, ii) (a) MsCI, Et3N; (b) DBU, 06H6, 190 ~

Thermolysis of 3,4-cis ring-fused 5-spirocyclopropane isoxazolidines in the presence of a protic acid, yielded 3,4-cis ring-fused azetidin-2-ones 51 with concomitant extrusion of ethylene <03JOC3271>. Bicyclic isoxazolidines have been converted into the corresponding 13-1actams by sequential N-O bond cleavage, oxidation and cyclization <03JOC1207>. Intramolecular aromatic nucleophilic substitution has been established as a route for tricyclic [3-1actams 52 <03T5259>. . \N-O

\

i.~

Key: i) TFA, 110 ~

O

O2N O H

51 (60-72%)

O Cl

N

HAr

52

53

90

B. Alcaide and P. Almendros

The polycyclic 13-1actam 53 has been prepared through Staudinger reaction of the corresponding cyclic imine, en route to the synthesis of the spiranic-2-azetidinone-containing alkaloids chartellines <03TL4141>. A diastereospecific synthesis of pentacyclic [3-1actams has been achieved via a 6-exo-trig, 7-endo-dig tandem radical cyclization <03TL1827>. It has been reported that the thermolysis of [3-1actam-tethered enallenyl alcohols gave tricyclic ring structures 54 via a formal [2+2] cycloaddition of the alkene with the distal bond of the allene, while the tin-promoted radical cyclization in 2-azetidinone-tethered allenynes proceeded to provide bicyclic [3-1actams 55 containing a medium-sized ring <03OL3795>. Appropriately substituted bis-[3-1actams, pyrrolidinyl-[3-1actams and piperidinyl-[3-1actams undergo ring-closing metathesis using Grubbs' carbene, to give unusual fused tricyclic 2azetidinones 56 beating two bridgehead nitrogen atoms <03JOC 1426>. 1

R

H H OH R2 O

~_

~ 54

1 H H :OH R"

O

~

D2 --1 H H - OH r~

~2

ii..~ NO

H

CH3

M e O ~

H

'~"T==x

m = 0-2; n = 1-3; X = O, H2 56

55 Key: i) toluene, 220 ~ sealed tube. ii) Ph3SnH, AIBN, C6H6,reflux.

4.5

H~.)m

OXETANES, DIOXETANES AND 2-OXETANONES (I3-LACTONES)

A review on the Patemo-Bfichi reaction of furan derivatives to give oxetanes has been published <03MI1443>. A mechanistic feature for the ketene-alkene cycloaddition reaction to give cyclobutanones including an exclusive formation of an tx-methyleneoxetane has been published <03JA14446>. Photocycloaddition of 5-methoxyoxazoles with aldehydes gave bicyclic oxetanes, which after hydrolysis yielded tx-amino-13-hydroxy esters <03JOC9899>. It has been reported that deletion of the oxetane ring in docetaxel analogs is detrimental to biological activity <03OL5031>. Bicyclic oxetane 57 has been generated via an iodoso compound after oxidation of an iodo TBS ether <03OL4385>. The synthesis of hydroxymethyl branched [3.2.0]bicyclic nucleosides 58 has been achieved using a regioselective oxetane ring formation <03OBC3738>, while 2'-spiro ribonucleosides 59 with an O2'-C2' linked spiranic oxetane has been prepared using selective mesylation followed by base-induced ring closure <03OBC3514>. The fused tetracyclic oxetane 60 was formed via a Paterno-Bfichi reaction <03JOC6611 >. R _H

~ E

I

H

i H

HErO

R10/--1

BnO---i 0 OMe

r R2 57 58 Key: E = CO2Me. i) (a) TBSCI, lutidine; (b) m-CPBA, CH2CI2

59

60

A water soluble fused tetracyclic oxetane resulted by conjugation of arginine-based molecular transporters to taxol <03OL3459>. Uracil oxetane adducts, which are model compounds for the oxetane intermediates generated during the formation of photoproducts or in their photoenzymatic repair, have been synthesized using 1,3-dimethyluracil with carbonyl compounds <03MI357>. Substantial 2H-magnetic isotope effects have been observed on the diastereoselectivity of triplet photocycloaddition oxetane-formation reactions <03JA9016>. The exclusive formation of oxetanes 61, instead of the expected tetrahydrofurans, has been

91

Four-Membered Ring Systems

observed via selenocyclization of a (Z)-2-ene-l,5-diol <03T7365>. The spirocyclic oxetane 62 has been obtained through acid-catalyzed cyclization of an hydroxy epoxide <03JOC4422>. Methylene bridged sugar amino acids bearing an oxetane ring have been prepared <03T2423>. An oxetane D-ring has been fused to the framework of a highly functionalised taxane <03JOC2282>, while 2-(m-substituted-benzoyl)baccatin III analogs have been synthesized and evaluated for antitumor activity <03T1529>. The oxetane indole 63 has been prepared from tryptophan and used as a precursor in the total synthesis of manossyl tryptophan <03CEJ1435>. The selective formation of 2,2-disubstituted oxetanes has been accomplished by directed ring-opening of 1,5-dioxaspiro[3.2]hexanes <03JOC1480>. The preparation and fluoride-induced chemiluminescent decomposition of dioxetanes 64 beating a siloxyaryl moiety has been reported <03T4811>. 1,2-Dioxetanes bearing a phenyl moiety substituted with a methyl having an electron-withdrawing group decomposed on treatment with TBAF to afford yellow light <03CC482>. A novel neolignan incorporating a dioxetane ring, mansoxetane, has been isolated from the heartwood of a plant <03TL6759>. 1,2-Dioxetanones rather than 1,2-dioxetanediones have been postulated as the key intermediates in peroxyoxalate chemiluminescence reactions <03CC794>.

H~~

O-O

HO

PhSe

I,,

OH O--~,,/R 1 H 61

AcO

......

,'

CO2M e 62

~~-~,N~ I H

N3

O ~ - R R R2 63

64

A review on ynolates, including the synthesis of ~-lactones, has appeared <03S2275>. Morita-Baylis-Hillman-type adducts have been converted into ct-alkylidene-13-1actones 65, which on reaction with dimethyltitanocene can be transformed into 3-alkylidene-2methyleneoxetanes <03OL399>. Lactones 66 have been obtained via the cinchona alkaloidcatalyzed dimerization of monosubstituted ketenes <03OL4745>. The PdC12-promoted synthesis of ~-lactones 67 have been achieved via cyclocarbonylation of 2-alkynols <03OL4429>. R1

o

-

,,!

65 66 Key: i) o-Nitrobenzenesulfonyl chloride, ii) Trimethylsilyl quinine, i-Pr2NEt, iii) PdCI 2, CuCI 2, CO.

67

13-Lactones have, for the first time, been prepared by 4-exo-trig radical cyclization <03OL757>. 13-Lactones 68 have been formed through the amine-catalyzed coupling of aldehydes and ketenes derived from Fischer carbenes <03JOC6056>. A mechanistic study of 13-1actone synthesis from epoxides and carbon monoxide has appeared <03AG(E)1273>. The bicyclic lactone salinosporamide A, a highly cytotoxic proteasome inhibitor, has been isolated from a marine bacterium <03AG(E)355>. The total syntheses of (-)tetrahydrolipstatin 69 <03TL2869> <03TL8051> and a-methylomuralide 70 have been accomplished <03JOC2760>. The [3-1actone-containing natural product lipstatin has been shown to be biosynthesised by Claisen condensation of two fatty acid moieties <03JMC4209>. A protic acid-catalysed polymerisation of 13-1actones has been developed for the synthesis of chiral polyesters <03TA3249>. [3-Lactones have been used as building blocks for the preparation of 3-(pyrrol-2-yl)-2-indolones <03JOC6447> as well as ot-methylD-cysteine <03OL 1035>.

92

B. Alcaide and P. Almendros

Ph OMe R

.C.r(CO)5

ph.,~OMe+RCHOi_.. O~O Key: i) DMAP, hv, CO.

O

C B H 1 3 . . . , , ~ / CllH23

O~ /-O7-7"O~ N1/-BuIH

68

69

O

H

NH 70

4.6 DIAZETIDINES, DIAZETINES, OXAZETIDINES, THIAZETIDINES, AND RELATED SYSTEMS The cycloaddition of N-phenyltriazolinedione to a spirocyclic cycloheptatriene featuring a tetrahydropyran ring has been shown to give the 1,2-diazetidine 71 <03OL177>. The thermal decomposition of a series of 1,2-diazetines has been studied <03JOC8643>. 1,3Diazetidines have been prepared by catalytic bond metathesis between carbodiimides and titanium-imido complexes <03CC2612>. A theoretical study on cycloaddition reactions of 2azaallene cations with isocyanates to give 1,3-diazetidin-2-ones has appeared <03EJO 1942>. The synthesis of enantiomerically enriched oxazolin-3-yl[1,2]oxazetidines 72 from nitrones has been recorded <03JOC 10187>. The 4-methyl- 1,2-oxazetidine-4-carboxylic acid moiety of the originally proposed halipeptin structure has been prepared <03TL3067>. The reaction of thiophene-l-imides with 1,2,4-triazoline-3,5-diones afforded 1,2-thiazetidines 73 through rearrangement of the initial [4+2] adducts <03JA8255>. The [1,3,2,4]diazadiboretidine 74 has been prepared via rhodium-mediated dimerization of secondary amine boranes <03JA9424>. Azazirconacyclobutanes 75 have been obtained by the cycloaddition of dialkylallenes with imidozirconocene complex <03JA7184>. A new class of four-membered azapalladacycles has been isolated during exploration of Heck-type processes <03JA1587>.

_•N• ~.,,.O

71

4.7

t

N~ O "~N,p h o

R,,

,Ox

"1--~ e N _ OM t-Bd

R1 S'-N~TS R1~ ~ N ,N -.~O ) ~ N'R2

7'2

(Ox = oxazolin-3-yl)

73

0

2 R1 H ,, R "I~1-13"n ,B-Iq-R 2 H ~ 'RI 74

R~"I--ZrCP2 R/'~N"Ar 75

THIETES, THIETANES, DITHIETANONES, DITHIETES AND [~-SULTAMS

Photochemical reactions of thioamides and thioimides, including thietane ring formation, have been reviewed <03H399>. Spirothietanes 76 have been prepared through the photochemical cycloaddition of monothiosuccinimides to diphenylethylene <03CC2218>. Four-membered sulfonium ion intermediates have been observed <03T3261> <03TL6519>. The insertion of CO into the C-S bond of thietanes to give thiobutyrolactones has been reported <03CC2046>. Bicyclic thietes 77 were obtained from thiohydantoins <03S340>. 1,3-Dithietanones 78 resulted from treatment of geminal pivaloyl xanthates with titanium tetrachloride <03CC1408>. The preparation of [1,2]dithiete-l,l-dioxides 79 has been achieved via rearrangement of propargylic dialkoxy disulfides <03JA14290>. 13-Sultams are the sulfonyl analogues of 13-1actams, and N-acy113-sultams have been shown to be inactivators of 13-1actamases <03BMCL4489>. 13-Sultams 80 have been prepared by cyclization of 13aminocyclohexyl sulfonates <03S1856>. The alcoholysis of 1,2-thiazetidine 1,1-dioxide has been investigated using ab initio and density functional theory <03CPL 13>.

93

Four-Membered Ring Systems

Ph2C'/~-S

Ar\

~'N-Ar

S

S/~~Ar

0 76 4.8

O

O

L--~" s R 78

77

,,R

R 2 ~ R ~O

O=S-Nr--I" b "H 80

79

SILICON AND PHOSPHORUS HETEROCYCLES

A review on the [2+2] cycloreversion of silacyclobutanes (siletanes) has appeared <03CCR149>. The preparation and oxidation of 1-methyl-l-alkylsiletanes 81 has been described <03OL4571>. Computational studies of siletane have been carried out <03JA10759>. 1,1-Diarylsilacyclobutane has been probed as a photochemical precursor of silenes <03JA8096>. 5-Silabicyclo[3.2.0]heptatrienes 82 have been prepared through the reaction of 4-silatriafulvenes with cyclopropenones <03JA9310>. The synthesis of siletes 83 fused to a six-membered zirconacycle from zirconacyclobutene-silacyclobutenes has been reported <03TL677>. Silacyclobutenes have been prepared through the [2+2] cycloaddition reactions of silenes, produced from acylpolysilanes, with acetylenes <03MIl156>. 3A1,2,3,4-Disiladigermetene 84 has been prepared through the [2+1] cycloaddition reaction of disilagermirenes with GeC12 <03JA6012>. The photochemical isomerization of a bicyclic 1,2-dihydro[1,2]disilete has been reported <03CC1200>. A review on the chemistry of organophosphorus compounds, including fourmembered phosphaheterocycles has been published <03AG(E)1578>. The applications of 2,4-bis(p-methoxyphenyl)-l,3-dithiaphosphetane-2,4-disulfide (Lawesson's reagent) in organic synthesis have been reviewed <03S1929>. The reaction of (x-hydroxyketones with phosphorus acid triamides gave tricyclic [ 1,2]oxaphosphetane 2-oxides 85 <03TL6327>.

,.u.e iGe = 81

R

R

.

c,,,=!-!.,,,=i=e,-=u

CP2

82

83

t-Bu2MeSi

84

=o=-,_.o

CI

85

The 2-thia-l-phospha-bicyclo[3.2.0]heptane derivative 86 has been synthesized via the [2+2] cycloaddition of 1,2-thiaphospholes <03EJO512>. Spiranic 1,2-oxaphosphetanes 87 have been prepared from dilithiated phosphazenes <03CC856>. Isolable oxaphosphetanes have been converted via retro [2+2] fragmentation into olefins <03JA1821>. The dimerization of 1-phosphaallenes has been reported to give 1,3-diphosphacyclobutane 88 <03EJO4838>, and the corresponding radical 1,3-diphosphacyclobutane-2,4-diyl has been prepared <03AG(E)3802>. The syntheses of a platina[1,2]diphosphetane 1-oxide <03CC1092> as well as a four-membered Sn2P2 ring have been documented <03CC2608>. Reports on the syntheses of 1,3-ditelluretane 89 <03TL2397> and 1,2-oxastibetanes 90 have appeared <03JA13346>. Reports on the preparation of [1,2,3]oxadigermetanes <03JA12702>, platinaoxetanes <03JA10522>, four-membered tetraboranes <03AG(E)1717>, and distannoxanes <03CC862> have appeared.

R~ S / ~ R 2

O Mes* I 1 R2R1N/LL.~_~x MeO~====K,P~==:~OMe H_

Et2NEGVr ~EWG R3 R 86

87

I~les* 88 Mes*= 2,4,6-tri-t-butylphenyl

/Te 89

Ar

F3C~CF3 ph,,

Ob~

R2 90

94

4.9

B. Alcaide and P. Almendros

REFERENCES

03AG(E)355 03AG(E)1273 03AG(E)1578 03AG(E)1717 03AG(E)2340 03AG(E)3802 03AG(E)4082 03AG(E)5613 03BMCL1075 03BMCL4489 03CC482 03CC794 03CC856 03CC862 03CC1092 03CC1200 03CC1408 03CC2046 03CC2218 03CC2554 03CC2582 03CC2608 03CC2612 03CCR149 03CEJ1435 03CEJ3415 03CEJ5793 03CPB96 03CPL13 03CR2985 03EJO512 03EJO1749 03EJO1765 03EJO1942 03EJO3798 03EJO4838 03H399 03H637 03JA1587 03JA1821 03JA3690 03JA3706 03JA5632

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Four-Membered Ring Systems

03JA6012 03JA7184 03JA8096 03JA8255 03JA8486 03JA9016 03JA9310 03JA9424 03JA10522 03JA10759 03JAl1146 03JAl1591 03JA12702 03JA13346 03JA14290 03 JA 14446 03JA15746 03JA16243 03JA16322 03JMC4209 03JOC27 03JOC187 03JOC1207 03JOC1426 03JOC1480 03JOC2024 03JOC2282 03JOC2760 03JOC2889 03JOC2952 03JOC3055 03JOC3064 03JOC3106 03JOC3271 03JOC4422 03JOC5292 03JOC6056 03JOC6338 03JOC6447 03JOC6611 03JOC6685 03JOC8068 03JOC8409 03JOC8643 03JOC9687 03JOC9899 03JOC10187 03MI357 03MIl156

95

V. Y. Lee, K. Takanashi, M. Ichinohe, A. Sekiguchi, J. Am. Chem. Soc. 2003, 125, 6012. F. E. Michael, A. P. Duncan, Z. K. Sweeney, R. G. Bergman, J. Am. Chem. Soc. 2003, 125, 7184. W. J. Leigh, X. Li, J. Am. Chem. Soc. 2003, 125, 8096. T. Otani, J. Takayama, Y. Sugihara, A. Ishii, J. Nakayama, J. Am. Chem. Soc. 2003, 125, 8255. A. Stapon, R. Li, C. A. Townsend, J. Am. Chem. Soc. 2003, 125, 8486. A. G. Griesbeck, S. Bondock, P. Cygon, J. Am. Chem. Soc. 2003, 125, 9016. Y. Kon, J. Ogasawara, K. Sakamoto, C. Kabuto, M. Kira, J. Am. Chem. Soc. 2003, 125, 9310. C. A. Jaska, K. Temple, A. J. Lough, I. Manners, J. Am. Chem. Soc. 2003, 125, 9424. E. Szuromi, H. Shan, P. R. Sharp, J. Am. Chem. Soc. 2003, 125, 10522. R. Damrauer, A. J. Crowell, C. F. Craig, J. Am. Chem. Soc. 2003, 125, 10759. W. Gao, B. Xing, R. Y. Tsien, J. Rao, J. Am. Chem. Soc. 2003, 125, 11146. N. Kise, H. Ozaki, N. Moriyama, Y. Kitagishi, N. Ueda, J. Am. Chem. Soc. 2003, 125, 11591. M. S. Samuel, K. M. Baines, J. Am. Chem. Soc. 2003, 125, 12702. Y. Uchiyama, N. Kano, T. Kawashima, J. Am. Chem. Soc. 2003, 125, 13346. S. Braverman, T. Pechenick, H. E. Gottlieb, M. Sprecher, J. Am. Chem. Soc. 2003, 125, 14290. T. Machiguchi, J. Okamoto, J. Takachi, T. Hasegawa, S. Yamabe, T. Minato, J. Am. Chem. Soc. 2003, 125, 14446. A. Stapon, R. Li, C. A. Townsend, J. Am. Chem. Soc. 2003, 125, 15746. C. Palomo, J. M. Aizpurua, A. Benito, J. I. Miranda, R. M. Fratila, C. Matute, M. Domercq, F. Gago, S. Martin-Santamaria, A. Linden, J. Am. Chem. Soc. 2003, 125, 16243. M. Lee, D. Hesek, M. Suvorok, W. Lee, S. Vakulenko, S. Mobashery, J. Am. Chem. Soc. 2003, 125, 16322. W. Eisenreich, E. Kupfer, P. Stohler, W. Weber, A. Bacher, J. &led. Chem. 2003, 46, 4209. T. B. Durham, M. J. Miller, J. Org. Chem. 2003, 68, 27. B. P. Hart, S. K. Verma, H. Rapoport, J. Org. Chem. 2003, 68, 18. M. C. Whisler, P. Beak, J. Org. Chem. 2003, 68, 1207. B. Alcaide, P. Almendros, J. M. Alonso, M. C. Redondo, J. Org. Chem. 2003, 68, 1426. R. Taboada, G. C. Ordonio, A. J. Ndakala, A. R. Howell, J. Org. Chem. 2003, 68, 1480. G. Ruano, J. Marti~ifiez, M. Grande, J. Anaya, J. Org. Chem. 2003, 68, 2024. L. A. Paquette, H. Y. Lo, J. Org. Chem. 2003, 68, 2282. P. Saravanan, E. J. Corey, J. Org. Chem. 2003, 68, 2760. A. Avenoza, J. I. Barriobero, J. H. Busto, J. M. Peregrina, J. Org. Chem. 2003, 68, 2889. R. Annunziata, M. Benaglia, M. Cinquini, F. Gozzi, J. Org. Chem. 2003, 68, 2952. A. M. Belostoskii, E. Markevich, J. Org. Chem. 2003, 68, 3055. Y. Kozawa, M. Mori, J. Org. Chem. 2003, 68, 3064. B. Alcaide, P. Almendros, C. Pardo, C. Rodriguez-Ranera, A. Rodriguez-Vicente, J. Org. Chem. 2003, 68, 3106. F. M. Cordero, F. Pisaneschi, M. Salvati, V. Paschetta, J. Ollivier, J. Salatin, A. Brandi, J. Org. Chem. 2003, 68, 3271. T. Prang6, M. S. Rodriguez, E. Sufirez, J. Org. Chem. 2003, 68, 4422. G. R. Krow, G. Li, D. Rapolu, Y. Fang, W. S. Lester, S. B. Herzon, P. E. Sonnet, J. Org. Chem. 2003, 68, 5292. C. A. Merlic, B. C. Doroh, J. Org. Chem. 2003, 68, 6056. M. Avalos, R. Babiano, P. Cintas, F. R. Clemente, R. Gordillo, J. L. Jim6nez, J. C. Palacios, J. Org. Chem. 2003, 68, 6338. J. M. Manley, M. J. Kalman, B. G. Conway, C. C. Ball, J. L. Havens, R. Vaidyanathan, J. Org. Chem. 2003, 68, 6447. M. C. de la Torre, I. Garcia, M. A. Sierra, J. Org. Chem. 2003, 68, 6611. P. Campomames, M. I. Men6ndez, T. L. Sordo, J. Org. Chem. 2003, 68, 6685. Y. Kozawa, M. Mori, J. Org. Chem. 2003, 68, 8068. T. A. Brugel, L. S. Hegedus, J. Org. Chem. 2003, 68, 8409. G. W. Breton, J. H. Shugart, J. Org. Chem. 2003, 68, 8643. R. Vidya, M. Eggen, S. K. Nair, G. I. Georg, R. H. Himes, J. Org. Chem. 2003, 68, 9687. A. G. Griesbeck, S. Bondock, J. Lex, J. Org. Chem. 2003, 68, 9899. R. Luisi, V. Capriati, S. Florio, E. Piccolo, J. Org. Chem. 2003, 68, 10187. Q. H. H. Song, X. M. Hei, Z. X. Xu, X. Zhang, Q. X. Guo, Biorg. Chem. 2003, 31,357. Li, J. Synth. Org. Chem. Jpn. 2003, 61, 1156.

96 03MI1443 03OBC1308 03OBC2461

03OBC2670 03OBC3514 03OBC3738 03OL757 03OL1035 03OL1209 03OL177 03OL2075 03OL2535 03OL3459 03OL3691 03OL3733 03OL3795 03OL399 03OL4101 03OL4385 03OL4429 03OL4571 03OL4737 03OL4745 03OL5031 03S340 03S1707 03S1732 03S1856 03S1929 03S2275 03S2483 03SL519 03SL726 03SL738 03SL1007 03SLl149 03SL1587 03SL1937 03SL2398 03T241 03T1529 03T2231 03T2309 03T2423 03T3261 03T3545

B. Alcaide and P. Almendros

M. D'Auria, L. Emanuele, R. Racioppi, G. Romaniello, Curr. Org. Chem. 2003, 7, 1443. H. Emten~is, M. Carlsson, J. S. Pinker, S. J. Hultgren, F. Almqvist, Org. Biomol. Chem. 2003, 1, 1308. G. H. Hakimelahi, P.-C. Li, A. A. Moosavi-Movahedi, J. Chamani, G. A. Khodarahmi, T. W. Ly, F. Valiyev, M. K. Leong, S. Hakimelahi, K.-S. Shia, I. Chao, Org. Biomol. Chem. 2003, 1, 2461. P. B. Hitchcock, K. Papadopoulos, D. W. Young, Org. Biomol. Chem. 2003, 1, 2670. B. R. Babu, L. Keinicke, M. Petersen, C. Nielsen, J. Wengel, Org. Biomol. Chem. 2003, 1, 3514. N. K. Christensen, A. Katrine, L. Andersen, T. R. Schultz, P. Nielsen, Org. Biomol. Chem. 2003, 1, 3738. K. Castle, C.-S. Hau, J. B. Sweeney, C. Tindall, Org. Lett. 2003, 5, 757. N. D. Smith, M. Goodman, Org. Lett. 2003, 5, 1035. E. Fort6, F. FulOp, Org. Lett. 2003, 5, 1209. L. A. Paquette, P. Webber, I. Simpson, Org. Lett. 2003, 5, 177. M. Kitajima, N. Kogure, K. Yamaguchi, H. Takayama, N. Aimi, Org. Lett. 2003, 5, 2075. W.-H. Cheung, S.-L. Zheng, W.-Y. Yu, G.-C. Zhou, C.-M. Che, Org. Lett. 2003, 5, 2535. T. A. Kirschberg, C. L. VanDeusen, J. B. Rothbard, M. Yang, P. A. Wender, Org. Lett. 2003, 5, 3459. T. Akiyama, K. Daidouji, K. Fuchibe, Org. Lett. 2003, 5, 3691. X. Geng, M. L. Miller, S. Li, I. Ojima, Org. Lett. 2003, 5, 3733. B. Alcaide, P. Almendros, C. Aragoncillo, Org. Lett. 2003, 5, 3795. I. Martinez, A. E. Andrews, J. D. Emch, A. J. Ndakala, J. Wang, A. R. Howell, Org. Lett. 2003, 5, 399. J. Jiang, H. Shah, R. J. DeVita, Org. Lett. 2003, 5, 4101. Y. Gu, B. B. Snider, Org. Lett. 2003, 5, 4385. S. Ma, B. Wu, S. Zhao, Org. Lett. 2003, 5, 4429. J. D. Sunderhaus, H. Lam, G. B. Dudley, Org. Lett. 2003, 5, 4571. G.-L. Zhao, J.-W. Huang, M. Shi, Org. Lett. 2003, 5, 4737. M. A. Calter, R. K. Orr, W. Song, Org. Lett. 2003, 5, 4745. V. Deka, J. Dubois, S. Thoret, F. Gu~ritte, D. Gu6nard, Org. Lett. 2003, 5, 5031. L. D. S. Yadav, S. Singh, Synthesis 2003, 340. A. Grieder, A. W. Thomas, Synthesis 2003, 1707. X. E. Hu, N. K. Kim, L. Grinius, C. M. Morris, C. D. Wallace, G. E. Mieling, T. P. Demuth, Jr., Synthesis 2003, 1732. D. Enders, S. Wallert, J. Runsink, Synthesis 2003, 1856. M. Jesberger, T. P. Davis, L. Barner, Synthesis 2003, 1929. M. Shindo, Synthesis 2003, 2275. S. Lacroix, A. Cheguillaume, S. G6rard, J. Marchand-Brynaert, Synthesis 2003, 2483. Y. Tanaka, T. Sakamoto, K. Kamikawa, M. Uemura, Synlett 2003, 519. A. Carlin-Sinclair, F. Couty, N. Rabasso, Synlett 2003, 726. T. Yamashita, H. Tokuyama, T. Fukuiyama, Synlett 2003, 738. M. A. Bonache, G. Gerona-Navarro, M. Martin-Martinez, M. T. Garcia-L6pez, P. L6pez, C. Cativiela, R. Gonz~ilez-Mufiiz, Synlett 2003, 1007. S. H. Kang, M. Kim, D. H. Ryu, Synlett 2003, 1149. E. Diez-Barra, J. C. Garcia-Martinez, J. Rodriguez-Lopez, Synlett 2003, 1587. M. H. Shah, S. France, T. Lectka, Synlett 2003, 1937. S. Vassiliou, C. Dimitropoulos, P. A. Magriotis, Synlett 2003, 2398. J. Anaya, A. Fern~mdez-Mateos, M. Grande, J. Marti~ifiez, G. Ruano, M. R. Rubio-Gonz~ilez, Tetrahedron 2003, 59, 241. T. Horiguchi, T. Oritani, H. Kiyota, Tetrahedron 2003, 59, 1529. A. Salgado, Y. Dejaegher, G. Verniest, M. Boeykens, C. Gauthier, C. Lopin, K. A. Tehrani, N. De Kimpe, Tetrahedron 2003, 59, 2231. M. Arun, S. N. Joshi, V. G. Puranik, B. M. Bhawal, A. R. A. S. Deshmukh, Tetrahedron 2003, 59, 2309. R. M. van Well, M. E. A. Meijer, H. S. Overkleeft, J. H. van Boom, G. A. van der Marel, M. Overhand, Tetrahedron 2003, 59, 2423. J. Skarzewski, M. Zielinska-Blajet, S. Roszak, I. Turowska-Tyrk, Tetrahedron 2003, 59, 3261. R. K. Orr, M. A. Calter, Tetrahedron 2003, 59, 3545.

Four-Membered Ring Systems

03T3719 03T4811 03T5259 03T5893 03T7365 03T7631 03T9147 03T9577 03T9931 03T10195 03TA453 03TA993 03TA2161

03TA2407 03TA3249 03TA3673 03TA3805 03TL677 03TL1425 03TL1619 03TL1827 03TL2397 03TL2611 03TL2869 03TL3067 03TL4141 03TL5209 03TL5267 03TL5991 03TL6145 03TL6297 03TL6327 03TL6339 03TL6519 03TL6571 03TL6759 03TL7945 03TL8051 03TL8693 03TL9247

97

I. Le Roy, D. Mouysset, S. Mignani, M. Vuilhorgne, L. Stella, Tetrahedron 2003, 59, 3719. N. Watanabe, Y. Nagashima, T. Yamazaki, M. Matsumoto, Tetrahedron 2003, 59, 4811. P. Del Buttero, G. Molteni, A. Papagni, T. Pilati, Tetrahedron 2003, 59, 5259. Z. Kaluza, A. Kazimierski, K. Lewandowski, K. Suwinska, B. Szczesna, M. Chmielewski, Tetrahedron 2003, 59, 5893. P. Van de Weghe, S. Bourg, J. Eustache, Tetrahedron 2003, 59, 7365. G. S. Singh, Tetrahedron 2003, 59, 7631. J. A. Carr, T. F. A1-Azemi, T. E. Long, J.-Y. Shim, C. M. Coates, E. Turos, K. S. Bisht, Tetrahedron 2003, 59, 9147. M. Panunzio, A. Bongini, E. Tamanini, E. Campana, G. Martelli, P. Vicennati, I. Zanardi, Tetrahedron 2003, 59, 9577. A. Kamimura, R. Morita, K. Matsuura, H. Mitsudera, M. Shirai, Tetrahedron 2003, 59, 9931. L. Bianchi, C. Dell'Erba, M. Maccagno, A. Mugnoli, M. Novi, G. Petrillo, F. Sancassan, C. Tavani, Tetrahedron 2003, 59, 10195. B. A. Shinkre, V. G. Puranik, B. M. Bhawal, A. R. A. S. Deshmukh, Tetrahedron: Asymmetry 2003, 14, 453. A. Bongini, M. Panunzio, E. Tamanini, G. Martelli, P. Vicennati, M. Monari, Tetrahedron: Asymmetry 2003, 14, 993. M. A. Bonache, G. Gerona-Navarro, C. Garcia-Aparicio, M. Alias, M. Martin-Martinez, M. T. Garcia-L6pez, P. L6pez, C. Cativiela, R. Gonz~ilez-Mufiiz, Tetrahedron: Asymmetry 2003, 14, 2161. F. Couty, G. Evano, N. Rabasso, Tetrahedron: Asymmetry 2003, 14, 2407. F. A. Jaipuri, D. D. Bower, N. L. Pohl, Tetrahedron: Asymmetry 2003, 14, 3249. R. N. Patel, J. Howell, R. Chidambaram, S. Benoit, J. Kant, Tetrahedron: Asymmetry 2003, 14, 3673. Z. Cs. Gyarmati, A. Liljeblad, M. Rintola, G. B6math, L. T. Kanerva, Tetrahedron: Asymmetry 2003, 14, 3805. T. Yu, L. Deng, C. Zhao, Z. Li, Z. Xi, Tetrahedron Lett. 2003, 44, 677. P. Del Buttero, G. Molteni, T. Pilati, Tetrahedron Lett. 2003, 44, 1425. C. V. Stevens, W. Vekemans, K. Moonen, T. Rammeloo, Tetrahedron Lett. 2003, 44, 1619. S. N. Joshi, U. D. Phalgune, B. M. Bhawal, A. R. A. S. Deshmukh, Tetrahedron Lett. 2003, 44, 1827. D. Rajagopal, M. V. Lakshmikantham, M. P. Cava, G. A. Broker, R. D. Rogers, Tetrahedron Lett. 2003, 44, 2397. L. Chen, G. Zhao, Y. Ding, Tetrahedron Lett. 2003, 44, 2611. J. A. Bodkin, E. J. Humphries, M. D. McLeod, Tetrahedron Lett. 2003, 44, 2869. B. B. Snider, J. R. Duvall, Tetrahedron Lett. 2003, 44, 3067. J. L. Pinder, S. M. Weinreb, Tetrahedron Lett. 2003, 44, 4141. F. Couty, F. Durrat, D. Prim, Tetrahedron Lett. 2003, 44, 5209. S. Obika, J. Andoh, M. Onoda, O. Nakagawa, A. Hiroto, T. Sugimoto, T. Imanishi, Tetrahedron Lett. 2003, 44, 5267. J. W. Misner, J. W. Fisher, J. P. Gardner, S. W. Pedersen, K. L. Trinkle, B. G. Jackson, T. Y. Zhang, Tetrahedron Lett. 2003, 44, 5991. G. Gerona-Navarro, M. T. Garcia-L6pez, R. Gonz~ilez-Mufiiz, Tetrahedron Lett. 2003, 44, 6145. D. Naskar, A. Roy, W. L. Seibel, L. West, D. E. Portlock, Tetrahedron Lett. 2003, 44, 6297. E. E. Nifantyev, M. P. Koroteev, G. Z. Kaziev, I. S. Zakharova, K. A. Lyssenko, L. N. Kuleshova, M. Y. Antipin, Tetrahedron Lett. 2003, 44, 6327. S. G~rard, J. Marchand-Brynaert, Tetrahedron Lett. 2003, 44, 6339. Y. N. Romashin, M. T. H. Liu, B. T. Hill, M. S. Platz, Tetrahedron Lett. 2003, 44, 6519. P. M. P. Gois, C. A. M. Afonso, Tetrahedron Lett. 2003, 44, 6571. P. Tiew, H. Takayama, M. Kitajima, N. Aimi, U. Kokpol, W. Chavasiri, Tetrahedron Lett. 2003, 44, 6759. M. Hamaguchi, N. Tomida, E. Mochizuki, T. Oshima, Tetrahedron Lett. 2003, 44, 7945. A. N. Thadani, R. A. Batey, Tetrahedron Lett. 2003, 44, 8051. B. Alcaide, P. Almendros, J. M. Alonso, Tetrahedron Lett. 2003, 44, 8693. D. Donati, S. Fusi, F. Ponticelli, Tetrahedron Lett. 2003, 44, 9247.

98

Chapter 5.1

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs Venkataramanan Seshadri, Fatma Selampinar, Gregory A. Sotzing University of Connecticut, Storrs, CT, USA sotzing@mail, ires.uconn, edu

5.1.1

INTRODUCTION

This chapter will review novel synthetic routes to thiophenes, selenophenes, tellurophenes and some of their significant derivatives reported over the last one year (Jan-Dec 2003). The subsequent sections will review functionalization of these heterocycles, novel molecules containing these five membered rings and some of their uses.

5.1.2

SYNTHESIS OF THIOPHENES, SELENOPHENES AND TELLUROPHENES

This section will cover new ring closure reactions for the synthesis of thiophenes, selenophenes and also fused ring systems consisting of these heteroaromatics.

5.1.2.1

Ring Closures to Produce Thiophene, Selenophenes and Tellurophenes

Benzo[b]thiophenes have been synthesized by the introduction of a methyl sulfanyl group ortho to N,N-diethylamide followed by ring closure under basic conditions. The amide group serves as a good internal electrophile and the thienone is aromatized by reduction followed by elimination (Scheme 1).

2•1

O

R

R3" " ~

R4

RI~

R1

NEt2 LDA/THF .._

"SMe

(-78~

R

O

NaBH4M / eRI O~H/ R1

10 % NaOH

Reflux, 10 h R4

Scheme 1

R R4

99

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

Several substituted fused thiophenes like benzo[b]thiophene 1, [1]Benzothieno[3,2-b]pyrans 2 and 3 have been synthesized in accordance to this route in >_70 % yield < 03T4767, 03SL1479>.

R2)~N,~

~OMe

1

_ ~ _ 1 ~ ~_~ (~

2

3

"Photo-Bergman" cyclization have been carried out on diethynyl sulfides 4 to produce 3, 4disubstituted thiophenes 5. Matzger reported this as being the first five-membered ring cycloaromatization reaction <03OL2195>. The reaction is found to produce many side products thereby lowering the yield of the desired heterocycle.

hv > . ~ . P h j ~ S ~ " Ph

Ph!~

H S Ph

4

H

> ph~-~ph 5

While cyclohexadiene or y-terpinene (hydrogen donors) gives -~30% of the thiophene, alcohols were found to produce thioesters and acetylenes along with a lower yield of thiophene. The major side reaction reported is the oligomerization of the intermediate thiophene diradical. A one-pot synthesis of substituted 2-arylbenzo[b]thiophene has been described by Kolasa and co-workers.

~A~/

R~

R2 + H S R 4 ~ ~ X R3 X = F, Cl, NO2 R2= H,Ar A=CH, N

K2CO3 DMF,A

R2

~,4

R3

Aromatic nucleophilic substitution of a benzyl thiol to an aromatic ketone, nitrile or aldehyde followed by addition/elimination results in solely the formation of 2-arylbenzo[b]thiophenes 6 <03TL6665>.

1 O0

v. Seshadri, F. Selampinar and G.A. Sotzing

One pot syntheses.

O

O

(i) K2CO3/DMF

RI'~~

O

R2 (ii)Ph-NCS

O R2

p 7

X'CH2-Y 1 K2CO3/DMF . .O~ J~. O

O R1-~2 Ph-HN" "S" Y -~ 8 X = halogen Y = e withdrawing group (-CN, -COOEt)

RI "1/ R2 Ph-HN/~S~Y R1 and R2 = Me, OEt, Ph Scheme 2

Ketene thioacetals 7 have been used to synthesize thiophene with a carbonyl in the 3-position 8 (Scheme 2) <03T1557, 03T2631>. In the reported procedure <03T2631> u-oxoketene dithioacetal is converted to the substituted thiophene 9 upon reaction with diiodomethane in the presence of Zn-Cu. Simple formylation or acetylation of thiophenes only produces the 2- or 5derivatives and, hence, this is a useful technique to produce the 3- or 4- derivatives. This method also has been studied to synthesize substituted selenophenes 10 <03SL855>. MeO.

OMe

O~1 H

CH212/Zn'Cu~ Et20, reflux "-

OHC

SMe

MeS" "SMe

O R1

H

@

O I

R2 e

Na2Se X'CH2-Y

MeS

Y 10

A [3,3] Claisen rearrangement of thiomorpholides has been reported to produce 2,3,5trisubstituted thiophenes 11 <03TL6253>. H

O Ar-'JLCH3

(~~+S

i/'"O ~./X-Br + K2CO3 ~ A r - " ~ N-...~ Microwave, 10 min S 120-130[]3, o-dichlorobenzene

Ar

r . CH3 11

Ar= Phenyl,4-chlorophenyl,4-bromophenyl 4-biphenyl,2-naphthyl,4-methoxyphenyl

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

l 01

Microwave assisted Gewald synthesis of 2-acyl aminothiophenes 13 on solid support has been carried out by Gauvin and co-workers <03SL63>, wherein the solid support was a

Solid phase synthesis of highly substituted thiophene derivatives 15 using a cyclic malonic acid ester resin 14 was also reported. Highly pure thiophene derivatives were reported to have been prepared by this solid phase synthesis <03T4851>. While alkyl or aromatic substitutions on the 13 position to the carbonyl yielded the corresponding 5-alkyl/aryl substituted 2-acyl aminothiophene, acetaldehyde did not produce the corresponding 2,3-disubstituted thiophene.

2-aminothiophene-3-carboxamide synthesized via Gewald's route has been used to synthesize thieno[2,3-b]pyridines 16 and thieno[2,3-d]pyrimidines 17 <03HC459>. In an unprecedented reaction between triethylamine and disulfur dichloride in the presence of DABCO in chloroform, thienopentathiepin 18 and heptathiocane 19 were obtained <03OL1939>.

Ar

R ~S"s

16

17

18

S NEt2

.[ _S_~ NEt2 19

4, 5-Dithenyl[1,3]dithiol-2-one 20-21 have been used to synthesize 6-arylthieno[3,4b]thiophene 22-23 and 2,3,4,5-tetrathiophen-2-ylthiophene 24 < 03JOC7115>.

102

V. SeshadrL F. Selampinar and G.A. Sotzing

S ~

a,b,c R

~

S

R

R=3-thienyl 20 R=2-thienyl 21

R=3-thienyl 22 R=2-thienyl 23

(a) hv, 6 h (b) (i) NaBH4, EtOH (ii) Mel, Na2CO3, rt (c) Mel, D

~~

=O

(i) hv, 5h (ii) AcOH, H202

24

Reactions of 2-trifluoromethylchromones with ethyl mercaptoacetate have been carried out to give trifluoromethyl containing 1,2-dihydrothieno[2,3-c]chromen-4-ones 25-28. Two thieno[2,3-c]coumarins have been prepared from the corresponding sulfoxides using the Pummerer rearrangement followed by aromatization <03T2625>. O CF3

CF 3

R2OOC

s

I ,,r

COOR2

-

S

" 0 R = H or Me 25, 26

0 R = H or Me 27, 28

R1, R3 = H or alkyl R2 = alkyl

29

H

H

30

A similar mercaptoacetate addition reaction to 5-acyl-4,7-dioxo-4,7dihydrobenzo[b]thiophene-2-carboxylates followed by cyclization and oxidation to give benzo[1,2-b:5,4-b ']dithiophene-4,8-dione derivatives 29 has been shown <03H1689>. Nitrogen bridged heterocycles, 3-(benzylthio)thieno[3,4-b]indolizine derivatives 30 have been synthesized and intramolecular arene-arene interactions within these compounds were reported <03CPB75>. The arene-arene interaction leads to significant shifts in the proton NMR signals and red shifts in the absorption maxima. Benzo[c]selenophene 32 has been prepared by the aromatization of dihydrobenzo[c]selenophene 31 following the bromination of the selenium using molecular bromine and a subsequent elimination in the presence of an aqueous or non-aqueous base <03OL2519>. Furthermore, the dialdehyde and dicarboxylic acids on the ot positions of benzo[c]selenophenes have been synthesized.

103

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

So + Br2

~

S

31

r

32

Some porphyrin and octaphyrins consisting of selenium will be discussed later in this chapter. To the best of our knowledge there have been no reports on the synthesis or chemistry of tellurophenes over the last one year.

5.1.2.2 Ring Closures Carried out on Thiophene Starting Materials

The synthesis of tetrasubstituted naphthalenes consisting of thiophene 33 were reported using palladium catalyzed reactions of aryl iodides and intemal alkynes <03JOC6836>.

~ ~-

COOEt COOEt ~ "COOEt COOEt /

33

S S

R1 R

H

R1, R2 - -H, -H -OMe, -H -OMe, -OMe

34

H

35

H ~

R

R2 1

R1, R2 = -H, -H -OMe, -H -OMe, -OMe

36

Thieno[3,2-c] or [2,3-b]carbazoles 34-35 and indolo[3,2-b]benzo[b]thiophenes 36 and derivatives have been synthesized by palladium catalyzed amination and subsequent palladium catalyzed cyclization reactions <03T3737>. While blocking the ~- and 13- position of thiophene gives thienocarbazoles the unsubstituted thiophene undergoes ring-closure on the b face of thiophene to give the indolobenzo[b]thiophenes. One pot borylation of benzo[b]thiophene followed by palladium catalyzed Suzuki coupling with aryl halides to make thienocarbazole compounds have been reported <03TL4327>. 1,3,5,7-tetramethyl-4,8-dihydrobenzo[1,2-c:4,5c']dithiophene-4,8-dione 37 was synthesized from 2,5-dimethyl-3,4-dicyanothiophene and the diones were then converted to the mono- 38 and dithiones 39 in modest yield <03OL 1883>. The monothione has been prepared reproducibly using Davy's reagent in a 42 % yield.

104

14. Seshadri, F. Selampinar and G.A. Sotzing

Me

X

Me

O

Me

Me

~

Me

O

Me

X,Y=O,O 37 S,O 38 S,S

40

39

Increasing the reaction time lead to the formation of the dithione in only very low yield (5 %). Also, the synthesis of 40 has been reported to have been accomplished using the same procedure starting from phthaloyl chloride and 2,5-dimethyl thiophene. Conversion of this to the mono- and di-thiones has been reported to be unsuccessful. Thiophene containing fused 6, 7 and 8 membered ring systems 41-46 have been prepared from in situ generated azomethine imines followed by cycloaddition to N-methyl maleimide and subsequent Pd(0) catalyzed cyclizations <03T(59)445 l>. Me

O...~/N ~ "0 \

H ~ ~ -'~H /S ~.>.(..N.N.co2Me

41

Me

0 N-/.0 \

H~ H /S~N.N.co2Me

42 Me

Me

O ~ Nx~.O I

H H H,,. .N.co2Me

43 Me

I

Me

I

I

o

44

45

N

o

46

Thiophene analogs 47 of isatoic anhydride have been synthesized and their chemical reactivity towards nucleophiles have been studied <03TL 10051 >. Unlike the reaction of isatoic anhydride with a nucleophile wherein both 2-ureidobenzoic acid and 2-carbamoylbenzoic acid are obtained, 6- and 7-arylthieno[3,2-d][1,3]oxazine-2,4-diones have been shown to give only the ureidothiophen carboxylic acid 48.

105

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

o

o

H Nu = Benzylamine, Butanol 47

O~,.Nu 48

Meldrum's acid 50 was found to react with 3,4-bis(bromomethyl)-2,5-dimethylthiophene 49 in the presence of triethylamine to give a C, O-dialkylation product, namely, 1,3,7,7-tetramethyl4H, l OH-6,8,9-trioxa-2-thiabenz[/]azulen-5-one 51. Upon heating this compound in the presence of a catalytic amount of potassium iodide in acetonitrile at 100~ the lactone 52 is produced and heating in butanol led to trapping of the ketene intermediate resulting in 53 <03JOC7455>.

0

.- t.~uO/../

51

5.1.3

O,~C02_t_B u 0

THIOPHENE RINGS, CAGES AND MISCELLANEOUS

5.1.3.1 Conjugated Macrocycles Shape-persistent macrocycles consisting of thiophenes alone or with other aromatic rings have been synthesized.

o

1 16

106

v. Seshadri, F. Selampinar and G.A. Sotzing

A "gigantocycle" with a diameter of 12 nm was synthesized in a 38% yield for the ring closing step wherein thiophenes have been used as the angular unit and the rest of the cycle was comprised of phenylethynyl. The open chain hexadecamer with terminal acetylenic group was cyclized using copper(II) acetate under very dilute conditions to produce the cyclic hexadecamer 54 <03ACI3176>. Bauerle and co-workers have synthesized a macrocycle consisting of 8 thiophenes in conjugation by an oxidatively induced elimination of platinum complexes <03CC948>. The platinum complexes 55 were obtained by reaction of terthiophene with terminal acetylenic groups with cis-Pt(dppp)C12 in the presence of CuI and Et3N. C-C bond formation was effected by oxidatively induced elimination using iodine and the diacetylene bridged thiophene macrocycle 56 was converted to an all thiophene macrocycle 57 by reacting with sodium sulfide.

t-Bu

t-Bu t-Bu

t-Bu

t-Bu

, ph.,.7x..q~ "~\,-,/\-Ph, I uP~ P~ t

t-Bu t-Bu

t-Bu

2eq. 12 ~

h"

h

60~ 24 h

S t-Bu"

55

t-Bu~

t-Bu

t-Bu t-Bu" t-Bu

"t-Bu

56

t-Bu

Na2S9.H20 xylene, ROH

140~ 20 h

t - B u ~ t _ B u 57 5.1.3.2

Porphyrin Analogs

Ravikanth et al <03T6131 > have reported meso- or [3-furyl porphyrins with N3S and N2S2 cores 58-62. Porphyrins have generated a lot of interest as they can be good acceptors for efficient energy transfer in donor-acceptor type architectures.

107

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

0

R

--C N 58-60

61

<,. O

Ph ~ S P

h

~

P

Ph h

Ph"*~~~~ Ph $ ~

Ph Ph

63

62

Meso 3-thienyl octaphenylporphyrin 63 has been synthesized using a modified Adler-Longo reaction <03IC2227>. Dioldithiachlorins 64 and tetraoldithiabacteriochlorins have been synthesized by osmium tetraoxide mediated dihydroxylation reactions. Furthermore, the dioldithiachlorins have been converted to the porpholactones (65), porphyrin-like derivatives in which the peripheral double-bond is replaced with a lactone moiety <03TL7793>. Coremodified porphyrins consisting of sulfur/selenium instead of nitrogen atoms with meso-phenyl substitutions also have been reported and their photophysical properties studied <03JMC3734>.

Ar

OH

Ar OH

Ar

64

Ar

65

108

v. Seshadri, F. Selampinar and G.A. Sotzing

Tetrathiaoctaphyrin 66 and tetraselenoctaphyrin 67 have been synthesized from modified tetrapyrranes by treating with trifluoroacetic acid followed by further oxidation using chloranil <03CEJ2282>.

m-

m-xylyl

m-xylyl

Me

66

Mes 67

Hexylthiophene connected to octaethylporphyrin through a diacetylene linkage has been synthesized and the effect of substituents (like H, Br, CN, CHO, NO2) on the electronic properties were studied <03TL5423>. It was reported that the absorption maxima were greatly influenced by the substitution as they increase the intramolecular charge transfer through the diacetylene linkage. This effect was reported to be more pronounced in the thienyl linked porphyrin in comparison to the phenyl linked ones.

5.1.3.3

Non-Conjugated Macrocycles and Cages

In other reactions, zirconacyclopentadiene-coupled macrocycles 68 were converted to thiophene containing phenyl bridged macrocycle 69 through the I3 positions upon reaction with $2C12 <03JOMC15>. These macrocyles are triangular in shape and the phenyl rings were found to be orthogonal to the thiophene rings.

Me3Si~

Cp2

SiMe3

Me3Si~NMe3 HF,

Me3Si~siMe3 Cp2Zr...~" ~ SiMe3 68

"~ZrCp2 SiMe3

Me3Si~SiMe3 S...~" ~ ~ ' ~ ~ SiMe3 69

S SiMe3

Calix[2]bipyrrole[2]thiophene 70, a non-conjugated thiophene containing macrocycle has been synthesized and was found to have a preference for binding to caboxylate anions. <03JA13646>. Chiral macrocyclic ligands such as N452 and N6S3 containing thiophene rings have been synthesized and their metal binding capabilities studied <03OBC2801>. Thiophene containing cage molecules, trithienylmethanophanes 71-74 have been synthesized and reported to form stable monocations 75-77, dications 78 and dianions 79 <03CL422>.

109

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

R

R R

R= H, OH 3 06H13, Si (OH3)3 71-74

70

R= H, OH 3 06H13, + 75-78

A siloxa-bridged cyclophane 80 consisting of thiophene has been synthesized by reacting 2,5-bis(chlorodimethylsilyl) thienyl with water <03NJC994>.

~

O'Si~S 79

5.1.3.4

~

80

Miscellaneous Derivatives

5-Lithiated-N, N-disubstituted-2-aminothiophene has been reacted with alkyl derivatives of di- and tricarbonic acids and converted to the multicharged methinium compounds 81 by the addition of perchloric acid <03OL2393>. Sexithiophenes coupled through the [3-positions in an alternating 2,2':3,3' regioregular 82-84 way has been synthesized and been shown to exhibit a reliable helical motif <03JA13928>. R2N

NR2

/~S

S-~

Cl

NR2

R2N

NR2 81

Cl

x

-

Cl R2N

Cl

Cl

X

Cl

X = H, Cl, Br 82-84

Both X-ray crystallographic studies and theoretical predictions have been done to show that these sexithiophenes take a helical conformation. Intemal torsional forces between rings have been used to drive the molecule to take a solid state helical conformation. Synthesis of tetrathia[7]-helicene (TH[7]) 85 has been carried out by McMurry coupling of 2-formyl-benzo[ 1,2-b:4,3-

110

V. SeshadrL F. Selampinar and G.A. Sotzing

b']dithiophene followed by a photochemical coupling reaction <03T6481>. Furthermore, the terminal aldehyde of TH[7] 86 and an unexpected cyclized formyl derivative of TH[7] 87 were also reported.

85

86

87

Oligopyrrolic clusters with thiophene spacers 88 have been synthesized and their ability to bind phosphate in the solution phase evaluated <03TL6695>. Tetrathiafulvalene (TTF) analogs consisting of fused thiophenes 89-91 have been synthesized and the mechanism of formation of TTF derivatives from 1,8-diketones has been analyzed <03T8107>. Ph

Ph

s~

S

N

N

S

SCH3

S~'~S

88

SCH3

89

R

R

R

R 90

91

Reaction of 2-thienyl carbonylchloride with ferrocene in the presence of AICI3 (anhydrous) gave the corresponding ketone 92-93, which was coupled with 2- dimethoxyphosphinyl-l,3benzodithiole using Wittig-Homer reaction to yield 94 <03T6353>. The dithienylcarbonylferrocene upon coupling has been reported to give 95 as the major product. s

? ~

o

92

93

94

95

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

5.1.4

5.1.4.1

111

REACTIONS ON THIOPHENES

Photoreactions of Thiophenes

Light induced reactions on thiophenes which exhibit photochromism have been studied (Scheme 4).

F2 F2c~C"cF2

F2 F2c~C"cF2

~'~isible R3

R6

Scheme 4

Thermally stable photoreactions of a thiophene containing molecule 96 have been reported to produce highly conjugated molecules having strong absorbance in the visible region <03T8359, 03CL1078>. While the quantum yield for the photocyclization was 0.0094 the yields for photocycloreversion was reported to be only 0.0026. Three different photochromic systems, which exhibit different colors upon ring closure, have been shown to be capable of displaying a multi-color photochromic effect. Three component single crystals grown from materials with different conjugation lengths were found to exhibit stable colors such as yellow, red and blue in the dark depending on the wavelength of incident light <03JA 11080>.

F2 F2ctC".CF2

F2 F ~ j . ~

~q,,, .,.SMe)~

MSo M'~~MH:-S

Me "~'%',F2 C F2C~c F2 In another work on photoreactions, Yokoyama et al. <03JA7194> have shown diastereoselective photochromism of bisbenzothienylethene. Preliminary studies on racemic mixtures of 97 showed that the R form shows a high preference towards ring closure as a result of steric and electronic interactions. Furthermore, the pure enantiomer was synthesized and shown to undergo thermally stable photoreactions. An example of diastereocyclization in chiral diarylethylene crystals was reported by Irie and co-workers. A diarylethylene consisting of photoreactive thiophenes and a chiral side-chain 98 was shown to exhibit selectivity in the crystalline phase, while there was no selectivity observed in solution <03OL 1769>.

112

v. SeshadrL F. Selampinar and G.A. Sotzing

F2

F2c/C"cF2

H3C

CH3

98

Photochemically, a ring closed product was found to ring-open upon electrochemical oxidation <03JA3404>. Electrochemical ring opening of ring-closed compounds has been shown to occur in 99-102. Photochromism of linear and angular heteroannellated thieno-2Hchromenes have been studied. Opening of the pyran ring in 2H-chromenes upon exposure to light results in a photochromic effect <03T2567>.

F2 F2C."C'cF2

F2 F2c"C'cF2

S

s

~ \

Ar = Ph or Th

Ar = Ph or Th

99, 100

101,102

\

R \

\ ~

103

R

Photochemical 2n-2n cycloaddition of benzo[1,2-b;4,5-b']dithiophene and substituted acetylenes have been used to synthesize cyclobuta[b]thieno[2,3-J][1]benzothiophenes 103 <03JOC8258>. Both disubstituted acetylenes and diynes have been shown to undergo this type of 2n-2n photoaddition and moreover the addition was found to undergo via a syn addition. Photoirradiation of tris(2-benzo[b]thienylmethane) 104 in acetonitrile undergoes a di-n-methane rearrangement to produce a cyclopropane, which upon further irradiation is easily converted to a secondary product, a thiopyran 105 <03TL751>. (i) and (ii) hv, Acetonitrile

104

105

Photoaddition of 3-acetylbenzoxazole-2(3H)-thione with thiophenes was reported to give 106, which was unstable at room temperature and thus underwent an elimination to yield 107 <03HCA3255>. Benzyne intermediates produced by heating diphenyliodonium-2-carboxylate

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

113

have been trapped using thiophenes and possible mechanisms for the formation of the products have been studied. Thiophene and 2-methylthiophene addition to benzyne has been found to give naphthyl phenyl sulfides 108 and halothiophene was found to yield dithienyl sulfides 109 <03JOC70>.

S..~.O 106

5.1.4.2

Me

107

108

109

Diels-Alder and Other Reactions

Thiophene 1-oxides have been shown to undergo syn-n-face see 110 selective Diels-Alder reactions. The oxide was shown to preferentially undergo Diels-Alder reaction with a variety of thioaldehydes, thioketones <03TL5159> and dienophiles <03JA8255>, through the syn-Tt-face to give 111-117. anti-n-face

o

t-gu / s t.Bu~'-]/-~x

IT

x CI X = Me,-(CH2)5-,

syn-n-face

110

S"O t-Bu-..~/I"-I~''x-,~O t_au~X' .--Y O

111,112

X=CH, Y=O X=CH,Y=NMe X=CH, Y=NPh X=N,Y=NPh 113-117

S"O

t-Bu~/1~-/

t_Bu..i,/~ ~ E E = electronwithdrawinggroups (CN, COOMe,SO2Ph,CI)

Nakayama and co-workers have shown that 3, 4-di-tert-butylthiophene 1-oxide can serve as trapping agents for unstable thioaldehydes and thioketones. Benzothiophenium salts 118 have been shown to undergo [4+2] cycloaddition with a number of dienes to give compounds of type 119 <03JOC731>.

Ph '

118

+ OTf-

+

[~

CH2Cl2'reflux ~

~

OTf" Ph le+ H

119

114

5.1.4.3

V. SeshadrL F. Selampinar and G.A. Sotzing

Ring Substitutions

Nitration of benzo[b]thiophene has been achieved by treatment of trimethyl stannyl benzo[b]thiophene with tetranitromethane in the presence of light <03EJOC 1711>. Amination of thiophene halides has been carried out using Pd(dba)2 <03JOC2861>. While the bromo derivatives have been reported to give moderate to high yields the chloro derivatives were found to give only 40-50 % yield.

A phase vanishing acylation method (Figure 1), wherein a dense catalytst (SnCI4) phase is separated from the acylating agent and the substrate to be acylated (thiophene) by a fluorous media was demonstrated <03SL247>. This procedure has also been extended to simultaneous synthesis of different acylated products using a multi-fingered glass apparatus.

5.1.4.4

Precursors for Aryl Coupling

Palladium catalyzed synthesis of 2-substituted 3-thienylboronic acids and esters as well as 3substituted-2-thienylboronic acids and esters starting from halothiophenes have been reported <03JOC9513>. The coupling has been carried out in the presence of P(tert-Butyl)3 as the ligand for palladium and the borylation was found to be tolerant to a variety of functional groups. Arylzinc compounds have been prepared by the reaction of aryl bromides with zinc dust in the presence of cobalt (II) bromide <03JA3867>. This reaction has been applied to aryl rings consisting of both electron donating and electron withdrawing functionalities. Using this method 2- and 3-thienyl bromides have been converted to their corresponding thienylzinc derivatives via this reaction. Also dizinchalide derivatives of thiophenes have been synthesized by this route. 2,5-Bis-(butyltelluro)thiophene has been used as a precursor for preparing symmetrical and unsymmetrical 2,5-bis-(acetylenic) thiophenes in high yields. The bistelluro derivatives were also found to be very stable and could be purified by column chromatograph and stored in a dark container at room temperature for several days <03TL685>.

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

5.1.4.5

115

Aryl Coupling Reactions

1,4- addition of thiopheneboronic acid to a,13-unsaturated carbonyl compounds catalyzed by rhodium has been shown to proceed with high enantioselectivity (Scheme 5) <03H605>. O [~ ~ B(OH)2 [Rh(OH)((S)-binap)2

+

THF/H20(10/1) Scheme 5

Suzuki-Miyaura coupling of trifluoroborates of thiophenes with aryl halides has been carried out in the presence of a palladium catalyst [PdClz(dppf)] using potassium carbonate as the base <03JOC4302>. Highly regioselective direct arylation conditions for 3-esters of thiophene has been reported <03OL301>. Several substituted phenyl bromides have been coupled with 3carboalkoxy thiophene in the presence of Pd(PPh3)4 as the catalyst and potassium acetate as the base. This method provides an alternative direct aryl cross-coupling, which is quite often carried out for e.g. by Suzuki, Stille methods requiring multi-step synthetic steps. Palladium containing perovskite-based catalysts have been used for aryl cross-coupling reactions. These catalysts possess the advantage of self-regeneration under oxidative and reductive conditions while suppressing the formation of metallic Pd-particles which are difficult to separate. The perovskite-based catalysts have been used in Suzuki reactions between aryl halides and boronic acids <03CC2652>. 2-Iodothiophene has been coupled with phenylboronic acid using this catalyst in the presence of a phase transfer catalyst (tetra-n-butylammonium bromide). Amino acid derivatives with heterocycle substitutents are of current research interests owing to known and potential biological activities. Palladium catalayzed Suzuki coupling of thiophene derivatives with halogenated dehydroamino acid has been carried out to prepare 13-substituted dehyrdoamino acid derivatives 120-124 <03TL3377, 03TL6007, 03EJOC 1537>. H

Boc~NI

120, 121

CO2CH 3

H

122

H H3 Boc.NyCO2Me

123

H Boc~Ni~ CO2Me

124

Thiophene halides have been coupled with in situ generated tributyltin enolate of acetone in the presence of a palladium catalyst (Pd2(dba)3) along with 2-dimethylamino-2'diphenylphosphino-l,l'-biphenyl as the phosphine ligand)to give the corresponding arylacetone 125-126 in good yields <03TL8869>.

116

V. SeshadrL F. Selampinar and G.A. Sotzing

••OOEt 125

5.1.4.6

N3

126

127

Miscellaneous Reactions

A regio and stereoselective ring opening of trans ethyl 2-thienyl-glycidate leading to the formation of anti ethyl-i3-thienyl-[3-amino-ot-hydroxy propionate 127 was reported as a result of ring opening of epoxide using sodium azide <03TL5075>. 3,4-di-tert-Butylthiophene-l-oxide prepared from the oxidation of the corresponding thiophene was converted to a 4+4 head-to-head dimer 128 upon refluxing with 2-methylene-l,3-dimethylimidazolidine. This was further oxidized to the dioxide form 129 using dimethyl dioxirane. The dioxide upon refluxing in toluene was converted to 1,4,5,8-tetra-tert-butyl-l,3,5,7-cyclooctatetraene 131 by two-fold extrusion of SO2 from cis- 1-transoid- 1,2-cis-2-3,4,7,8-tetra-tert-butyl-9,10dithiatricyclo[4.2.1.1 ]deca-3,7-diene-9,9,10,10-tetraoxide 130 <03TL7893>.

o.:S. tort-butyl

/

tert-butyl /(,.tert-butyl 128

Toluene, reflux, 45 min -SO2, 100 % ""-

tert-butyl O2S~tert_buty I

O~.

tert-butyl / tert-butyl -

tert-butyl

~~x

S

I~_

129

Toluene, reflux, 88 min \~...tert_butyl -SO2, 100 % "tert-butyl

130

131

Boron trichloride has been shown to be an efficient and selective agent for deprotection of tert-butyl sulfonamides. High yields have been reported for tert-butyl sulfonamides of thiophenes <03TL4523>. Resolution of pure enantiomeric precursors for duloxetine 132, a thiophene based anti-depressant, were reported both by chemoenzymatic methods and by using (S)-mandelic acid. Immobilized lipase from Pseudomonas cepacia was found to give high enantioselectivity and good yields <03TL4783>. Lipase catalyzed kinetic resolution of 3hydroxy-3-(2-thienyl)propanenitrile was carried out by transesterification with vinyl acetate. The (S)-3-hydroxy-3-(2-thienyl)propanenitrile was reported to have been obtained in a 42 % yield (purity >99 %). Classical resolution techniques utilizing (S)-mandelic acid to resolve 3(methylamino)-l-(2-thienyl)propan-l-ol have been described. It is reported that presence of water influences the enantioselectivity and pure S-form with > 99 % ee was obtained by using 2-

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

117

butanol containing 2 equimolar amounts of water as solvent <03TA1631>. Constrained raloxifene analogues 133-134 have been synthesized by using Friedel-Crafls and directed remote metalation reactions <03JOC5992>.

R ~

RO O

O

~

NHCH3

~ ~ ~ ~ ~ - O H

HO 132

,.OH HO" ~ I ' ~ s

133

134

Attempts to use 5-nitro-2-thienyls as reductive triggers for release of drugs have been made. Different drugs like aspirin, prednisolone and its hemisuccinate, O- and iV- linked isoquinolines, nifedipine were linked to 5-nitrothienyl by ether or ester linkages and release of the drug under reductive conditions were tested <03T3437>. Only O-linked 1-(5-nitrothienyl-2ylmethoxy)isooquinolines were found to undergo the nitro group reduction leading to drug release. Release of aspirin and prednisolone hemisuccinate was reported to be not through nitro group reduction but via heterolytic ester cleavage. 5.1.5

OLIGOMERS AND POLYMERS

Heterocycles have played a significant role in conjugated polymers and in the last three decades enormous amount of literature on these molecules has been made available. This section will review some of the recent understandings of this class of conjugated species both in the well-defined oligomeric form as well as in a higher polymeric form.

5.1.5.1 Hyperbranched/Dendrimeric Thiophenes Hyperbranched and dendrimeric materials have attracted a lot of attention owing to their interesting molecular architectures and properties. Oligothiophenes appended to truxene 135141, a polycyclic compound has been synthesized and its emissive properties have been studied as a function of the number of thiophene repeat units <03JA9944>. The oligothiophene functionalized truxene was also polymerized through the terminal thiophenes using ferric chloride to give a hyperbranched structure.

118

V. SeshadrL F. Selampinar and G.A. Sotzing R

R x

R

I

S

, X

135 136 137

139 140 141 R = 06H13

X

n

H

1

Br

2

H

3

Br

4

H Br

5 6

H

7

X

Dendrimer encapsulated pentathiophenes 142-144 have been synthesized. The core pentathiophene and peripheral triarylamines have been shown to simultaneously emit light <03JA13165>. This provides a good model for single layer multichromic organic light-emitting

T5 encapsulated dumbbell shaped dendrimer

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

119

diodes (OLEDs). Synthesis of hyperbranched poly(thiophene-phenylene) has been done and the ionochromic effect, change in color as a function of ions, studied. The hyperbranched polymers have been prepared by Suzuki coupling of 2, 3, 5-tribromo thiophene and 2, 5-dialkoxy-1, 4phenyldiboronic acid <03MA2689>. The ionochromic behavior of the hyperbranched polymers have been compared with that of poly(2,3-thienylene-phenylene) and poly(2,5-thienylenephenylene), also obtained by Suzuki coupling of the 2,3- or 2,5-dihalothiophenes with the phenyldiboronic acid. Poly(carbosilanes) containing thiophenes have been synthesized using Karstedt's catalyst (platinum-divinyltetramethyldisiloxane complex) <03MA5580>. These polymers were found to range from viscous oils to clear tacky solids. 5.1.5.2

Well-defined Oiigomers

Oligothiophenes capped or bridged with different functionalities are reviewed within this section. Different synthetic methodologies towards oligothiophenes have been reviewed by Lukevics et al <03H663>. The number of thiophene repeat units within the oligomers prepared range from 2 to 6.

/--o

S

o

S

145

0

146

Coupling through the B-positions of terminal thiophenes to form cyclic structures have been studied as possible actuators. 145 consisting of azobenzene was synthesized from biscyanoethylsulfanyl quarterthiophene and bis-p-bromomethylazobenzene. The azobenzene can be reversibly switched between an extended trans and a shorter cis configuration photochemically, thus forming the basis of actuation <03JA2888>. A similar molecular actuation concept has been applied to crown annelated oligothiophenes 146, which binds to cations through the oxygens in the ring to give rise to the actuation <03JA1363>. Quarterthiophenes and sexithiophenes consisting of varying lengths of ethyleneoxy units have been reported and conformation changes studied as a result of cation binding. Functional groups like alkyl chains, cyanovinylenes, nitro, arylamino groups on the t~position of terminal thiophenes of the oligomers leads to endcapping, i.e., no further reaction is possible leading to longer chains. These serve as excellent models to understand the property change as a function of chain length, end-groups. Since there are little or no defects as the chain lengths are same these could be highly efficient in devices. Dialkylfluorenyl-oligothiophenes 147-150 <03CM1778>, diarylamino-oligothiophenes 151-159 <03OL1817>, asymmetric and symmetric nitro terthiophenes <03JA2524>, mono- and bicapped tricyanovinyl containing oligothiophenes (bithiophene to sexithiophene) <03CM616, 03OL1535> 160-165 have been synthesized and their optical properties studied.

120

E SeshadrL F. Selampinar and G.A. Sotzing

Ar2N'~~

NAr2 151-156

147-150 Bu ~

CN CN

~ Z

Bu ~ Z

n=1,2

CN

CN CN

X

H H H

160, 161

n

-C(CN)=C(CN)2

12 62 63 ~ 64

65

PhThiophene3NO2 and BrThiophene3NO2 were reported to behave as push-pull systems while symmetric NOEThiophene3NO2 displayed a highly delocalized structure. Bridged oligothiophenes consisting of phosphonate ester end-groups have" been synthesized 166-169. <03OL 1879> Electroactive surfactants such as these have been shown to improve the efficiency of inorganic-organic hybrid solar cells based on CdSe nanoparticles. Also incorporation of electron rich donors like 3,4-ethylenedioxythiophene (EDOT) within the backbone of these surfactants and its effect on the optical properties has been studied.

CH2OR

O x o

~

S

.s.

~

.s.

S~ / " ~ ~ ~

S/~ PO(OEt),

,(3

"O

~

S

~

PO(OEt)2

n = 1, 2 CH2OR X = m-xylyl, 1,9-nonyl 166-169 The effect of systematic displacement of fluoroarenes from the periphery to the core of a quarterthiophene 170-172 on the crystal structure, HOMO-LUMO levels has been studied.

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

121

F F

F~F

F

o

~

o

F

~

170

F

~ /~

F

F

FI F

172

Crystal structure studies indicate that the torsional angle between adjacent outer-rings are about 17.6 ~ and 7.9 ~ with minimum cofacial n-n distances of 3.20 ~ and 3.37 ~ for 170 and 171, respectively <03ACI3900>.

R v

n = 0, I, 2, 4

173-176

R

R = CnH2n+ I n = 4 , 7, 10, 14

177-180

Well-defined oligothiophenes surrounded by bicyclo[2.2.2]octane frameworks 173-176 have been synthesized and their crystal structures, electrochemical, optical properties have been studied. The solid state properties of the oligomers as a function of increasing number of thiophene units have been reported <03JOC8305>. The effect of additional double bonds in between thiophene rings on the ~,max of the oligomers has been studied <03JOC7254>. A plot of number of sp 2 carbons in alternating thienylenevinylene and thienylenebutadiene series was reported to be linear and the AE values converge almost at the same energy levels indicating that additional double bonds do not affect the band-gaps. Unsymmetrical functionalized thienylenevinylene capped 3,3'-bipyridines have

122

v. SeshadrL F. Selampinar and G.A. Sotzing

been synthesized and has been proposed for incorporation into polymer side-chains with possible NLO properties <03TL5879>. Small organic molecules based on EDOT and oligoEDOT have been synthesized and its optical properties, energy levels have been reported. Soluble bi-, ter- and tetraEDOT have been synthesized and the absorption spectrum as a function of chain length has been reported <03JOC5357>. BiEDOT endcapped with dithifulvalenyl groups have been synthesized and found to have strong n-donor properties <03TL649>. Other thiophene containing oligomers that have been synthesized include 2,5-diethynyl-3,4dibutylthiophene substituted multitopic bipyridine ligands and their ruthenium (II) complexes <03CC288>, several oligo(p-phenylene-vinylene-thiophene) and the cyano substituted analogs <03T5193>, mono-, bi-, ter- and quarterthiophene capped with alkyl phenyls and biphenyls <03JA9414>.

5.1.5.3

Conjugated Thiophene Polymers and Copolymers

Synthesis of aryl coupled thiophenes and polymerization of these by conventional procedures leads to new copolymers which have different properties compared to the parent polythiophenes. This oligomeric approach towards building novel copolymers has been used to modify the mainchain and also to incorporate fractional amounts of functionalities in the side chains of the polymer back-bone. Copolymers of azulene and alkyl thiophenes have been synthesized from 177-180 by oxidative polymerization using ferric chloride. Protonation of the polymer using trifluoroacetic acid (TFA) was followed using electronic spectroscopy and electron paramagnetic resonance (EPR) spectroscopy <03MA536>. EPR studies indicate the formation of azulenium cations upon TFA addition and furthermore at higher levels of TFA, doping of the polymer takes place leading to the formation of cation radicals and dications.

016H33

016H33% ~ C N R = Me, n-hexyl 181

182

R ~ C N R" - CN I

Alternating copolymers of fluorene-thieno[3,2-b]thiophene 181 have been prepared by Suzuki coupling and have been shown to exhibit liquid crystalline behavior both by differential scanning calorimeter (DSC) as well as from polarized light microscopy images <03MA4288>. Copolymers have also been chemically/electrochemically prepared from EDOT-alkylThiopheneEDOT <03OL3229>, EDOT-thiazole-EDOT <03CM557>. Alternating poly (hexylthiopheneco-thiazoles) <03MA7986>, and poly(thienylene-co-phenylene) consisting of NLO

123

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

chromophores 182 have been reported <03MA7014>. BisEDOT-bisalkylthiazoles have been synthesized and electrochemically polymerized through the terminal EDOT units <03CM404>. None of the polymers reported in <03MA536, 03OL3229, 03CM557, 03MA7986> and <03CM404> are expected to produce regioregularity owing to the nature of the polymerization techniques employed. Functionalized side chains have been introduced into polythiophenes for specific purposes like chemical sensing, solubility, self-doping etc. An imidazolinium salt of poly(3-alkoxy-4methylthiophene) (183) was found to exhibit good selectivity towards iodide in the presence of a wide range of other anions (F-, CI-, Br, CO32-, HCO3, H2PO4, HPO4, CH3COO, EDTA 4-, SO42, (C6Hs)nB) <03JA4412>. Addition of iodide leads to large bathochromic shifts in the absorption spectrum and as well as quenching of fluorescence. Phosphonic acid functionalized polythiophenes 184-185 with high regioregularity were reported to have been synthesized by Stille coupling and the resultant phophonic acid functionalized polymer was found to be solubilized by addition of tetrabutylammonium hydroxide <03MA7114>. Alkyl-3-thiophene carboxylates were polymerized with >97 % regioregularity through a nickel catalyzed coupling of the Grignard reagent. <03SY2255> Highly regioselective Grignard reagent was prepared by treating the 2, 5-dibromo thiophene carboxylate with i-propyl magnesium bromide at -40~ Covalently linked tetracyanoanthraquinodimethane to thiophene in the 13-position 186 have been reported and the monomers were polymerized using ferric chloride by itself or with 3-alkyl thiophenes <03OL1669>. The donor-acceptor type copolymers were reported to be highly soluble in solvents like chloroform, THF and carbondisulfide. CN O012H25

r H3C

O-(CH2)m-N,(~ Br

, ~ 'n

~"

.PO3H2

r

.PO3H2

184

,~/'~

- Nc ON

~"

~'S~n ~E~'S~ ~~~n 183

~

185

z/

~'S~ 012H25

186

Composites of 3-undecylthiophene/cross-linked polystyrene have been prepared in supercritical carbon-dioxide and characterized <03MA3015>. Solution processable conjugated polymer based on alkylcyclopentadithiophene has been synthesized by ferric chloride polymerization of the cyclopentadithiophene and also via Negishi protocol using a nickel catalyst and Riecke zinc <03CC2548>. Solid state synthesis of PEDOT from 2, 5-dihalo-EDOT has been reported and the in situ sublimation polymerization technique has been used to make thin transparent coatings onto glass/plastic substrates. It was reported that while the dibromo and diiodo were found to polymerize upon heating the dichloro derivative did not undergo any

124

v. SeshadrL F. Selampinar and G.A. Sotzing

transformation. <03JA15151>. Electropolymerization of EDOT in the presence of anionic porphyrin was found to produce nanorod like structures on the electrode <03OL 1395>. 08H1702S,

SO208H17

.

08H1702S

R = H, Ph, Butyl, thienyl, tolyl 187-t90

SO208H17 191

Electropolymerization of terthiophene appended to an organo molybdenum cluster 187-190 was reported and their electrochemical and electrochromic behavior has been studied <03CM825>. Oligothiophenes covalently linked to fullerenes have been synthesized and used as active photovoltaic materials <03CL404>. In another work, fullerenes have been derivatized with polymerizable thienylEDOT and electrochemically polymerized <03MA3020>. Nickel phthalocyanine covalently linked to thiophenes 191 has been synthesized and copolymerized with 3-decylthiophene <03TL8475>. Also the synthesis of triazolephthalocyanine-thiophene has been reported. Bithiophenes were coupled to calix[4]arene scaffolds and electropolymerized to produce alternating quarterthiophene-calix[4]arene structures 192 <03JAl142>. In situ conductivity measurements with and without TFA indicate that the polymers require protonation to be highly conductive. OR

s

N

5.1.6

192

REFERENCES

03ACI3176 03ACI3900

Mayor, M.; Didschies, C.; Angew. Chem. Int. Ed. 2003, 42, 3176. Facchetti, A.; Yoon, M-H.; Stem, C. L. Katz, H. E. Marks, T. J. Angew. Chem. Int. Ed. 2003, 42, 3900.

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

03CC288 03CC948 03CC2548 03CC2652 03CEJ2282 03CL404 03CL422 03CL1078 03CM404 03CM557 03CM616 03CM825 03CM1778 03CPB75 03EJOC1537 03EJOC 1711 03HC459 03H605 03H663 03H1689 03HCA3255 03IC2227 03JA1142 03JA1363 03JA2524 03JA2888 03JA3404 03JA3867 03JA4412 03JA7194 03JA8255 03JA9414 03JA9944 03JA11080 03JA13165 03JA13646 03JA13928

125

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126

03JA15151 03JOC70 03JOC731 03JOC2861 03JOC4302 03JOC5357 03JOC5992 03JOC6836 03JOC7115 03JOC7254 03JOC7455 03JOC8258 03JOC8305 03JOC9513 03JOMC15 03JMC3734 03MA536 03MA2689 03MA3015 03MA3020 03MA4283 03MA5580 03MA7014 03MA7114 03MA7986 03NJC994 03OBC2801 03OL301 03OL1395 03OL1535 03OL1669 03OL1769 03OL1817 03OL1879 03OL1883 03OL1939 03OL2195 03OL2393 03OL2519 03OL3229 03SY2255 03SL63 03SL247 03SL855

V. SeshadrL F. Selampinar and G.A. Sotzing

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

03SL1479 03T1557 03T2567 03T2623 03T2631 03T3437 03T3737 03T4451 03T4767 03T8359 03T4851 03T5193 03T6131 03T6353 03T6481 03T8107 03TA1631 03TL649 03TL685 03TL751 03TL3377 03TL4327 03TL4523 03TL4783 03TL5075 03TL5159 03TL5423 03TL5879 03TL6007 03TL6253 03TL6665 03TL6695 03TL7793 03TL7893 03TL8475 03TL8869 03TL10051

127

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128

Chapter 5.2

Five-Membered Ring Systems" Pyrroles and Benzo Derivatives Tomasz Janosik and Jan Bergman

Department of Biosciences at Novum, Karolinska Institute, Novum Research Park, SE-141 57 Huddinge, Sweden, and SOdertOrn University College, SE-141 04 Huddinge, Sweden [email protected] (T. J.),jabe@cnt. ki.se (J. B.) Erin T. Pelkey

Hobart and William Smith Colleges, Geneva, NY 14456, USA [email protected]

5.2.1

INTRODUCTION

The progress in synthesis and chemistry of pyrroles, indoles, and related fused ring systems are the subjects of this chapter. Due to space limitations, only a selection of the recent advances reported during the period of January-December 2003 has been included in this text. However, several specialized reviews on the chemistry of indoles and pyrroles have appeared during the reporting period of this account, providing more in-depth coverage. An excellent comprehensive review on pyrrole natural products (also including tetramic acid derivatives), written by Gossauer has appeared <03MIl>, as well as a more limited one on the synthetic chemistry involving the pyrrole natural products roseophilin and prodigiosin <03AG(E)3582>. Likewise, the synthetic efforts in the field of the pyrrole-imidazole class of alkaloids have been covered <03S1753>. Further reviews in this area focus on the biosynthesis of biologically active macrocycles, chlorophylls <03NPR327>, and vitamin B12 <03JOC2529>. The chemistry of expanded porphyrins and related systems has been reviewed in detail <03AG(E)5134>. A survey of the chemistry and applications of pyrrolotetrathiafulvalenes, an interesting class of n-electron donors, has been provided <03EJO3245>. The synthesis and chemistry of 3,4-2H-dihydropyrroles (Al-pyrrolines) have also been reviewed <03CHE405>. In addition, a part of a review on new advances in transition metal-catalyzed annulations has been devoted to processes leading to pyrroles <03SL2265>. The isolation and synthesis of indole alkaloids containing a non-rearranged monoterpenoid unit have been reviewed <03NPR216>, as has the synthesis of spiro[pyrrolidine-3,3'-oxindoles] as building blocks for oxindole alkaloids <03EJO2209>.

129

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

Moreover, the synthetic efforts leading to the natural products Gelsemine <03AG(E)36>, and synthetic and biosynthetic aspects of the paraherquamides, brevianides and asperparalines <03ACR127> have been summarized. New indole chemistry developed in the Gribble group during the past few years has also been the subject of an account <03PAC 1417>. A review on the recent progress in indole synthesis on solid phase has also been provided <03T5395>. Furthermore, an account covering indole and isatin oximes has been published <03CHE3>, but unfortunately a number of structures corrected a long time ago are displayed. Thus the product obtained by treatment of N-acetylisatin is not the dioxime 1, but the quinazoline 2 <76TL3611 >.

N..OH

H %-"-0.

1 5.2.2

2

S Y N T H E S I S OF P Y R R O L E S

In an application of the Paal-Knorr pyrrole synthesis, the synthetic equivalents 3 of 1,4ketoaldehydes were prepared by the radical addition of ketones 4 to vinyl pivalate. Treatment of the intermediates 3 with amines gave pyrroles 5 <03SL75>. Other new extensions of this popular pyrrole synthesis include the preparation of a number of pyrroles from hexane-2,5dione and amines under solvent-free conditions in the presence of layered zirconium phosphate or phosphonate catalysts <03TL3923>, and the development of a solid-phase variant of this reaction <03SL711>. Likewise, the preparation of N-acylpyrroles from primary amides and 2,5-dimethoxytetrahydrofuran in the presence of one equivalent of thionyl chloride has also been reported <03S 1959>. I

R2

S

R3

S"LL"oEt ~OPiv peroxide

CICH2CH2CI [~1

SI

S'fl~"OEt

O~oPiv

~

R3

3

R3NH2

.......60-95% ~

4

59-98%

=

R1

A series of 3-pyrrolin-2-ones 6 has been synthesized from the readily available oxamates 7 and dimethyl acetylenedicarboxylate (DMAD) in the presence of PPh3 <03SC2527>. Unexpectedly, the reaction of thioamides with DMAD involving a 1,3-dipolar cycloaddition of an intermediate azomethine ylide provided a new routte to pyrroles <03TL4175>. H

Et

O 7

N'R

DMAD, PPh3 CH2Cl2, rt 75-87%

,.

Et~CO2Me

O~.~N/ ~CO2Me I

R

6

130

T. Janosik, J. Bergman and E.T. Pelkey

Employing a 5-endo-dig cyclization process catalyzed by p-toluenesulfonic- or sulfinic acid, the amino esters 8 were smoothly converted to the pyrroles 9 in refluxing toluene. Both acid catalysts gave comparable results in terms of yield <03SL2258>.

HO, R 1 ~CO2Et R2"~j/ NHTs

RI

TsSO2H (0.5equiv.) _ ~ PhMe,reflux _-. 61-86% R2

CO2Et

i Ts

8

9

The reaction of the amino acid derivatives 10 with various 1,3-dicarbonyl compounds in the presence of base gave the dihydrofurans 11, which in turn underwent conversion into the pyrroles 12 upon treatment with trifluoroacetic acid <03EJO2635>. 0 R 0 Ts, ~ O O O 0S2003,CH3CN R - ~ TFA,CH2CI2 NHBoc Boc"~ Oie +i e / J L ~ . R 78-88% 77-92% Me- "O" "CO2Me M 10 11 12

CO2Me H

Cyclization of the 8-dienamino esters 13 with NBS provides a route to a number of pyrroles 14. In cases where R 2 = H, considerably lower yields were obtained <03S859>.

0

/C02Me

RR1~~~Ji2 3 H

/ ~ 0~ NBS' CH2CI2 5-95%

R3 -= MeO2C"x~"N'~)'~R2 ~t1

13

14

The reaction of the ketene-N,S-acetals 15 with ethyl bromoacetate in the presence of base gave the 1-phenylpyrroles 16. Precursors 15, easily obtained from 1,3-dicarbonyl compounds and isothiocyanetes followed by S-alkylation, may also serve as starting materials for the synthesis of 2-aminothiophenes by reaction with ethyl thioglycolate <03T1557>.

R1 Ph

0

H

0

R2 e

15

BrCH2CO2Et K2CO3

t~l

o

~..R2

acetone

10-98%

"

EtO2C~Nf~SMe Ph 16

The chiral pyrroles 17 were synthesized over several steps by elaboration of amino acids, relying on a pyrrole-ring formation involving the precursors 18 and TosMIC 19 as the key feature <03H(60)791>. Other processes employing cyclocondensation between isocyanidebased reagents such as TosMIC and electron deficient alkynes leading to 3,4-disubstituted pyrroles encompass the syntheses of precursors to tetrabenzoporphyrins <03TL5163>, pyrrolyllactam indolinones <03BMCL1939>, pyrrole C-nucleosides <03SL1619>, and polypyrrole based molecular wires <03JA6870>.

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

131 NHBoc

NHBoc -" R~__/CO2Et

+

Nail, DMSO, Et20

CN~Ts

18

77-98%

19

=

R~CO2Et

H

17

The interesting reaction of cyclopropenes 20 with nitriles mediated by gallium(III) or indium(III) salts offers a new route to isomerically pure pyrroles 21 in low to moderate yields. A mechanistic rationale for this transformation was also provided <03OBC4025>. Likewise, pyrroles 21 have been obtained via a cascade comprising [3 + 2] dipolar cycloaddition of a wide variety of nitriles to the donor-acceptor containing cyclopropanes 22, following dehydration, and isomerization <03OL5099>. R1 ~_ C O 2 E t R;

R2 ~

R3CN'GaCl3 ,.

H

80 ~ 17-51%

20

CO2Et

R1

H

~ R3CN, TMSOTf

R1 RO - - ~ ~

25-98%

R3 21

R2

22

O2Et "

2-Alkenylpyrroles 23, which readily underwent hydrolysis to 24, have been prepared via reaction of enyne-imines 25 or the corresponding enyne-N,N-dimethylhydrazones with the Fischer carbene complex 26. The hydrazones were found to be the more useful synthons, generally giving higher yields <03OL2043>. ,R 1

R3 MeO"

R

R4

H

-Me

R2

=

R3 R1

THF, 60 ~

~4

25

R2

HCl

OMe

R1

9-74% overall "

~4

23

O

24

Cyclic enyne-imines 27 have also been used as precursors to a series of fused pyrroles 28 in a rhodium-catalyzed process with suitable alkenes involving the (2-pyrrolyl)carbenoid intermediates 29 <03OL2615>. R1 ""N" R2

R1 CH2Cl2,rt

=

R1 R2

~

2

18-100% 27

~

R h 29

28

L~X~R 3

A considerable number of pyrroles 30 with alkyl, alkenyl, or aryl substituents were synthesized by spontaneous cyclization of the enyne precursors 31 (when R 4 = H, Ph, CH2OTHP), or upon treatment of 31 with the catalytic system PdC12/KC1 (when R 3 = H), or alternatively, by treatment of 31 with CuC12 (when R 3 # H) <03JOC7853>. Treatment of 7ketoalkynes with amines in the presence of catalytic amounts of platinum dichloride constitutes a new route to 1,2,3,5-substituted pyrroles <03AG(E)2681>. An intramolecular rhodium(II)-catalyzed N-H insertion reaction of ~5-amino-~,,7-difluoro-a-diazo-13-ketoesters has been used for the synthesis of a series of 3-fluoropyrroles <03OL745>.

132

T. Janosik, ,i.. Bergman and E. 7". Pelkey

R2 R1 ~

R3 C u CPdCI2/KCI DMA I 2 4or

=

R1RR2~ , R

31

R4

30

Several thiopropargylimines 32 underwent ring-closure to the pyrroles 33 upon treatment with CuI in hot N,N-dimethylacetamide (DMA). This process involves a propargyl-allenyl isomerization followed by a 1,2-migration of the thio-group in the intermediate allenes <03AG(E)98>.

R3S-, ~//~/'~- NR1 2

Cul DMA,(cat) A

R3~

67-86%

R2

32

I~1

33

The substituted pyrrole 34 has been prepared by halogen-metal exchange in the diene 35, followed by an interesting cyclization induced by TMEDA to provide intermediate 36, which was in turn treated with electrophiles, and oxidized to the final product. Several other similar pyrroles were also prepared in this manner <03EJO771>.

Br Ts Br

1. t-BuLi,Et2O, -78~ 2. TMEDA,-78 ~ to rt

Ts

Ph

. L N ~ , . ~ Li

1. Ph2SiCI2,-78~ to rt dt~x.,. 2. DDQ,CH2CI2

Li

35

81%

Ph Ph/ 'Ph

36

34

A modified mechanism and the stereochemisty for the formation of porphobilinogen 37 from 5-aminolevulinic acid catalyzed by porphobilinogen synthase has been proposed based on experiments starting from (3R)- or (3S)-deutero-5-aminolevulinic acids <03OBC1443>. In a related paper, the synthesis and biological acivity of a new porphobilinogen analogue 38, the most potent inhibitior hydroxymethylbilane synthase discovered to date, was reported <03OBC21 >. The dipyrrinone 39, an useful precursor for the synthesis of bile pigments, has been prepared in large scale in 10% overall yield over eight steps, involving a Barton-Zard pyrrole synthesis as the key step <03SC 1031>.

C02H R ~ . ~ H2N H

/C02 H 37R=H 38 R = Me

/

~ O

39

The pentacyclic pyrrole-containing systems lamellarins U 40 and L 41 have been synthesized on solid phase, involving a [3 + 2] cycloaddition of a 3,4-dihydroisoquinolinium salt with an alkyne as the pyrrole ring-forming key step <03OL2959>. In another application

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

133

of [3 + 2] cycloaddition, the fused pyrroles 42 were prepared by intramolecular reaction of imines generated from the aldehydes 43 and the sarcosine or alanine derivatives 44, followed by dehydrogenation of the intermediate dihydropyrroles 45 <03TL8417>. MeO

OH

OMe OH

v

MeO R

Cso R1

O

~

O 40 R = Me 41R=H

"CHO

MeNOO HH .~3

R2 43

10%Pd/C EtOAc 54-72%

44

R1

R2

=

PhMe, reflux 64-87% R1

R3

~

Me

45

R2

~~~_NI~~ Me R~2

Other new developments in pyrrole synthesis include for example conversion of 4-oxo-1(PhF)proline benzyl ester into the corresponding 4-aminopyrrole-2-carboxylates with suitable amines in the presence of TsOH, and further elaboration thereof into pyrrolo[2,3d]pyrimidines <03JOC6984>, the use of a modification of the Hemetsberger reaction in a synthesis of furo[3,2-b]pyrroles <03TL4257>, a new protocol for conversion of Naryloxazines obtained by Diels-Alder reactions of unfunctionalized dienes with nitroarenes catalyzed by palladium-phenanthroline complexes into 1-arylpyrroles <03JOC460>, preparation of pyrroles and 3-pyrrolines by ring-closing metathesis under microwave irradiation <03TL 1783>, thermally induced formation of 1-naphthylpyrroles by reaction of 1nitronaphthalene with moderately reactive dienes <03TL2943>, and synthesis of Nperfluorophenyl pyrroles, N-polyfluorophenyl pyrroles, and N-fluoroalkanesulfonyl pyrroles by ring-contraction of the corresponding 3,6-dihydro-l,2-thiazine-l-oxides <03T9669>. Pyrroles have also been obtained from three-component condensations between aldehydes or ketones, primary amines, and nitroalkenes <03TL2865>. Treatment of 2-amino-l,l,3tricyanopropene (malonitrile dimer) with aryl amines gave the corresponding 3,5-diamino-1aryl-lH-pyrrole-2,4-carbonitriles <03HC612>. Reduction of 3- and 4-pyrrolin-2-ones with 9borabicyclo[3.3.1]nonane (9-BBN) provides a route to 3-arylpyrroles <03SL2013>. The 1arylpyrroles 46 have been accessed by a reduction of the pyrrolidin-2-ones 47 with sodium borohydride in the presence of iodine, followed by decarboxylation of the intermediates 48, and final aromatization with DDQ <03TL8229>. On the other hand, treatment of 2,2disubstituted pyrrolidines with DDQ in dioxane provides a route to the corresponding 2Hpyrroles <03TL3701 >.

At2 CO2Et

O~"~N'~"\CO2Et AF" 47

AF NaBH4, 12,THF

CO2Et

Ar' CO2Et 48

Ar2 2. DDQ,Phil

77-84%overall "

~r1

CO2Et 46

134

5.2.3

T. Janosik, J. Bergman and E. T. Pelkey

REACTIONS OF PYRROLES

Simple pyrroles have been demonstrated to readily undergo addition to B(C6F5)3 in pentane, toluene, Et20 or CHECI2 to give excellent yields of the corresponding B(C6F5)a-Npyrrole complexes 49, which could be further transformed into the ammonium salts 50 by treatment with triethylamine, thus demonstrating the relatively high acidity of the methylene protons of 49. Likewise, indoles were also shown to undergo these transformations <03JOC5445>. ~

B(C6F5)3 H

quant.

~ H

EtaN H

I - B(C6F5)3

49

quant.

,.

~

+

HNEt3

_1 B(C6F5)3

50

Studies aimed at the synthesis and applications of simple pyrroles which are useful intermediates for more complex pyrrole containing molecules continue to draw attention. Thus for example, 2-bromo-l-(p-toluenesulfonyl)pyrrole has been prepared in 80% overall yield from pyrrole by bromination with 1,3-dibromo-5,5-dimethylhydantoin in the presence of AIBN, followed by N-protection. This robust 2-bromopyrrole derivative was also used in Suzuki couplings to produce various 2-arylpyrroles <03SL1993>. Treatment of ethyl 3,4dimethylpyrrole-2-carboxylate with SC12 gave 3,3'-dipyrrolylsulfides, which were subsequently manipulated to give building blocks for the synthesis of macrocycles containing dipyrromethene units <03CJC988>. During studies on the Suzuki-coupling of 4bromopyrrole-2-carboxylates, dehalogenated material was observed as the major product instead of the desired 4-arylpyrrole-2-carboxylates. This side reaction was suppressed by the use of Boc-protected 4-bromopyrrole-2-carboxylates, which gave 4-arylpyrrole-2carboxylates under the same conditions with concomitant loss of the Boc-group <03TL427>. In another application, a double Suzuki-Miyaura reaction of a pyrrole-3,4-diboronate was utilized as a key step in a synthesis of the marine alkaloid halitulin <03T9239>. Chlorination of 1-methylpyrrole has been explored in some detail using activated substituted Nchlorobenzamides as carriers for the electrophile. The observation of constant selectivity regardless of the substituent of the used carrier, favouring formation of 2-chloropyrrole along with small amounts of 3-chloro- and 2,5-dichloropyrroles, suggests that two different intermediates are in fact formed in this acid-catalyzed process <03T2125>. Direct metalhalogen exchange in an ~t-bromopyrrole has been used as a key step in a synthetic approach towards the lamellarin alkaloids <03TL1363>. A method for regioselective acylation of pyrroles has been developed employing 1-acylbenzotriazoles as acylating agents. Thus pyrroles 51 underwent acylation at C-2 upon treatment with the reagents 52 in the presence of TIC14 to give 53, whereas the use of 1-triisopropylsilylpyrrole 54 under similar conditions gave the corresponding 3-acylated products 55 due to the bulky nature of the TIPS group <03JOC5720>.

135

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

~

TiCI4 CH2CI2, reflux

TiCI4 CH2CI2, rt

COAr

"

21-94%

I

R

i

54-92%

i

R

53 R = H or M e

~

/COAr

52,

52,

TIPS

51 R = H or M e

55

54 R = TIPS

52

Both pyrrole itself, as well as 4,5,6,7-tetrahydroindole underwent N-vinylation with 2cyano-l-phenylacetylene in DMSO in the presence of KOH, while the treatment of 4,5,6,7tetrahydroindole with 2-benzoyl-l-phenylacetylene under the same conditions furnished predominantly a C-vinylated product <03S1272>. Several functionalized 3-vinylpyrroles were prepared by reaction of pyrrole-3-carbodithioates with malonitrile, cyanacetamide, or ethyl cyanoacetate induced by KOH in DMSO <03TL3501 >. Reductive aldol chemistry was investigated for the formation of 2,2-disubstituted-3pyrrolines. Thus for example, Birch-type reduction of pyrrole 56 with lithium di-tbutylbiphenyl (LiDBB) in the presence of bis(methoxyethyl)amine (BMEA), quenching the unreacted LiDBB with 1,2-dibromoethane, treatment with magnesium bromide, and addition of isobutyraldehyde gave a >20:1 mixture of anti-57 and syn-58 <03OBC3749, 03TL1095>. 1. LiDBB,BMEA,-78*C, thenBrCH2CH2Br ~ 2. MgBr2"OEt2 3. i-PrCHO CO2Et =I 72% Boc

~

Boc

'"'OH + 2Et

anti-57

56

t - B u ~ t - B u

Boc

....OH 2Et syn-58

-~i+

LiDBB

H

Meo~N~oMe BM~

Dipyrromethanes, useful building blocks for pyrrole-containing macrocycles, have been prepared in an environmentally benign acid-catalyzed procedure by treatment of pyrrole with ketones in water <03TL3971>. Indium triflate-catalyzed addition of pyrroles to acetylenes has been studied, leading predominantly to 2:1 adducts (i.e. a,a-dipyrromethanes or 13,13dipyrromethanes) depending on the reaction conditions <03CC2454>. The electrophilic substitution reactions of dipyrroheptane have also been investigated <03TL345>. Moreover, a new indium-catalyzed synthesis of dipyrromethanes has been described, exemplified by the synthesis of dipyrromethane 59 from pyrrole and the enecarbamate 60 <03SL417>. InBr (5 mol%) CH3CN, rt

+ H

I Boc

60

NHBoc

78% 59

In an approach employing oxidative radical alkylation, the pyrrole 61 was converted to the corresponding pyrrol-2-acetic acid derivative 62 by treatment with the xanthate 63 in the presence of dilauroyl peroxide (DLP). This procedure was also useful for the alkylation of other heterocyclic systems (e.g. indole) producing ethyl indole-2-acetate <03CC2316>. Alternatively, pyrrole-2-acetic acids have been obtained by treatment of pyrrole with various substituted iodoacetic acids and Na2S203/n-BunNI with propylene oxide as the HI-trap in

136

T. Janosik, 3. Bergman and E.T. Pelkey

methyl t-butylether under irradiation <03TL6853>. Furthermore, treatment of pyrrole with iodonium ylides has been shown to give alkylation at C-2. Thus for example, exposure of pyrrole to a bis(phenylsulfonyl)methylide in the presence of Rh2(OAc)4 gave 2bis(phenylsulfonyl)methylpyrrole <03OL 1511 >.

CHO + EtOI I Me

61

I E s I~ O 63

DLP' refluxCICH2CH2CI

t

69%

O

"

EtO2C

CliO

I Me

62

In a study focusing on the synthesis and reactions of 2-(2-aminoethyl)pyrroles, a preparation of the tricyclic ring-system 64 was accomplished by reduction of the succinimides 65, followed by cyclization of the intermediates 66. Moreover, 2-(2aminoethyl)pyrroles were demonstrated to undergo cyclization with aldehydes to provide 4,5,6,7-tetrahydropyrrolo [3,2-c]pyfidines <03T5265>.

~ R2

N

0

t

~

NaBH4,MeOH, THF,-10*C

~ N t _ ~

OH

R2

65

MsCI,Et3N,or (COOH)2,SiO2

~N ~1

66

O

64

An intramolecular cyclization approach has also been used for the synthesis of the fused pyrroles 67, which were obtained by treatment of the Weinreb amides 68 with t-BuLi. The requisite precursors 68 were prepared by N-benzylation of the pyrrole 69 with the benzyl bromides 70 <03OL 1115>. R1

R 3 ~ B

OMe

r

R1

R1

H O 69 KOH,DMSO = R3/'~R4 ~

R" 70

68

N

t-BuLi,-78 *C

N . O M e 62-87%

O

R

Me

Irradiation of the vinylic pyrroles 71 in benzene or methanol produced the ring systems 72 in low yields via the non-isolable intermediates 73. Subsequent hydrolysis of the carbamate under basic conditions gave the parent fused pyrrole <03JOC7524>. Related photochemistry involving stilbenyl pyrroles was investigated for the preparation of fused indole and isoindole derivatives <03TL7337>. hv

N

Phil or MeOH~

_-.-

2R 71

73

CO2R

72

CO2R

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

13 7

Cations of certain alkylated 2-(guanidinocarbonyl)pyrroles, such as 74 have been shown to take part in efficient complexation of amino acid carboxylates <03OL4579>. A new class of anion-binding calixpyrroles, calix[n]bipyrroles (n - 3 or 4) has been prepared from 2,2'bipyrrole fragments and acetone under acidic conditions <03AG(E)2278>. Surprisingly, it was established that 3,3',4,4'-tetramethyl-2,2'-bipyrrole undergoes cyclization induced by 0.1 M FeCl3 in 1 M HC1 to cyclo[6]pyrrole and cyclo[7]pyrrole, along with the expected cyclo[8]pyrrole <03JA6872>. Both 3,3'- and 4,4'-dimethoxy-2,2'-bipyrroles have been prepared and were evaluated as highly electron-rich model compounds for formation of polypyrrole <03CEJ449>. Pyrroles also undergo PC15-mediated condensation with aromatic aldehydes with concomitant air-oxidation to provide a new route to tetraarylporphyrins in moderate yields <03HCA408>. It is also worth mentioning that several linear octapyrrolic and dodecapyrrolic oligomers of dipyrromethene have been prepared by condensation of building blocks of various lengths <03CJC1668>. The derivatives 75 of TrOger's base have been obtained by reaction of 4-amino-l-methylpyrrole-2-carboxylates with formaldehyde in the presence of HC1, and were also further transformed into various amide derivatives <03TL2083>.

Me ~NH

H

H

H

RO2C~N//N~CO2

74

5.2.4

75

R

Me

SYNTHESIS OF INDOLES

New approaches to the indole nucleus are continuously developed, providing access to indoles which are difficult to prepare using the well established reactions, such as the Fischer indole synthesis. Nevertheless, this classic reaction is still often used for constructing more complex systems, as exemplified by the preparation of 2-(pyrimidin-4-yl)indoles <03CPB975>, or indolo[3,2-b]carbazoles possessing new substitution patterns <03T1265>. The COX-2 inhibitor 76 has been prepared in an efficient manner from the aniline derivative 77 and 2'-bromo-4-chloroacetophenone under basic conditions in N,Ndimethylacetamide (DMA), followed by a saponification of the intermediate ethyl ester 78 <03JOC4104>. Similar results were obtained starting from phenylsulfonyl-protected (E)-2aminocinnamates similar to 77 <03TL7269>.

1.p-CIC6H4COCH2Br DMA,rt C - i ~r . .NHT: O2Et 2. K2CO3, DBU,rt 9 81% 77

/.----CO2R O Cl

,--NaOH,MeOH/H20,8 1 % i/~ -

78 R = Et 76 R = H

x

CI

A series of 1-substituted indolines such as 79 has been synthesized via aryl radical cyclizations of acetophenone imines 80, providing an enantioselective route to indoline aamino acids <03JA163>. Aluminum chloride-induced cyclization of imine precursors derived by condensation of p-anisidine and a-phosphorylated-ct-chloro aldehydes provided 3phosphorylated 5-methoxyindoles <03CHE 1521>.

138

T. Janosik, J. Bergman and E. T. Pelkey

R1

R1

R [ ~ ~ B r N.~ 80

n-Bu3SnH' Phil, 80 *CAIBN

R3

78-86%

Ph

~'-

~ ~ N- -

R2

ph")~R3

79

SmI2 mediated cyclization of the substrates 81 at 65 ~ gave predominantly the 2,3disubstituted indoles 82. On the other hand, when the same reactions were conducted a t - 2 0 ~ the corresponding 2,3-dihydroindole-2,3-diols 83 could be isolated as the major products <03T1917>.

Ph. OH X~~AIH., r 83

Sml2, THF -20 *C, 5 min 70-75%

X

O ~ ILL/.~ Ph v NH

H

81

Sml2, THF 65 *c, 30 min,. 84-88%

jP h

X ~

O ~ Ar

A

r 82

H

Reaction of o-iodoaniline 84 with carbanions under irradiation produced several 2substituted indoles 85, or various fused indolic systems in moderate yields. The events leading to this outcome featured a C-C bond formation via the SRN1 mechanism <03JOC2807>.

'N H2

RCOCH2 DMSO,hv

.

R

84

85

H

Base-induced (KH or t-BuOK) cyclizations of o-alkynylanilines were utilized to prepare 2-substituted indoles and poly-substituted indoles. For example, treatment of alkynes 86 with KH gave the corresponding indoles 87 <03T1571 >. Similar base-mediated cyclizations and related indole syntheses were utilized to prepare indole inhibitors of 5'-inosine monophosphate dehydrogenase <03BMCL1273>. Moreover, base-induced cyclizations of arylacetonitriles with oxalic acid bis(imidoyl)chlorides provide a route to 2-alkylidene-3iminoindoles <03CEJ3951 >. R K.

l-,equiv,

NMP,rt 86

=

R 87

H

Processes based on metallation are also useful for the synthesis of indoles. For example, a series of substituted indoles and carbazoles has been synthesized from 2-fluorophenyl imines. Thus for instance, treatment of the imine 88 with LDA in refluxing THF gave the thienoindole 89. Based on labelling experiments, it was suggested that the reaction is probably proceeding via the benzyne intermediate 90 <03S 1661 >.

13 9

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

LDATHF

reflux 42%

H 88

89 90

In an approach based on addition of organolithium reagents, for example t-BuLi to the ovinylanilines 91, several trisubstituted indoles 92 were obtained. The events leading to this outcome comprise an addition of the organolithium to the vinyl group to generate the intermediates 93, an ensuing addition to a nitrile, and subsequent cyclization under acidic conditions <03JA4054>. It has also been demonstrated that N'-(2-bromophenyl)-N,Ndimethylurea derivatives undergo double lithiation, followed by carbonylation to provide access to isatins (indole-2,3-diones) <03S2047>.

BocHN

Li~ N.B~

R~

-~

93

1. R2CN,-25 ~ R1 2. 12M HCI, EtOAc,rt 40-67%

/

/~t-Bu

R2 92

H

Transition-metal catalyzed reactions are now common and attractive routes to exotic indoles with substitution patterns which are otherwise difficult to realize. Using an intramolecular Heck reaction, the precursors 94 were converted to a number of 3-aryl-3alkenyl oxindoles 95 in good yield and with good ee. The requisite compounds 94 are available in three steps from N-benzylbenzoxazolin-2-one using palladium-based chemistry <03JA6261>.

~OTf

r/OMe

[ L . x ~ N...~ 94

Bn Ar

Pd(OAc)2(5-40 m o l % ) A (R)-BINAP (10-80 mol%) 1,2,2,6,6-pentamethylpiperidine THF, 80 ~ ~

~

OMe

"~

95

, Bn

Taking advantage of a palladium-catalyzed C-H bond activation, the t~-chloroacetanilides 96 were transformed to the oxindoles 97. The reaction conditions applied tolerate a wide variety of functional groups <03JA12084>.

RI_~ 96

O N.~J.C I ~2

Pd(OAc)2(1-3 mol%) 2-(di-t-butylphosphino)biphenyl (2-6 mol%)=. Et3N, PhMe, A R1 76_990/0

O 97

~2

140

I". Janosik, J. Bergman and E. T. Pelkey

Relying on a tandem hydroformylation/Fischer indole synthesis, a number of indoles possessing various substituents at C-3 and/or C-5 were prepared in moderate yields. Thus for example, the tryptamines 98 were produced from hydrazines 99 and the methallylic phthalimide 100 <03OL3213>.

R..[~

II

1. ~

100

tRh(cod)~cl(I]~molO/o) " ~ N

NHNH 2

99

NHPht

CO (50 bar), H2 (10 bar) p-TsOH, 100 ~ 3 d 2. TsCl, NaOH, PhMe, rt 48-60%

R

NHPth

,. 98

Ts

The use of metal-mediated cyclizations involving alkynes is another common strategy for preparing indoles. A route to 2-aryl- or 2-heteroaryl indoles 101 utilizing a domino couplingcyclization of o-iodotrifluoroacetanilide 102 with alkynes has been devised. Similar results were obtained for the catalytic system CuI/PPh3 <03OL3843>. Employing a IPy2BF4 promoted intramolecular cyclization of o-(alkynyl)anilines, direct access to 3-iodoindoles was gained <03AG(E)2406>. Moreover, 2,3-diphenylindole has been prepared from 2bromoaniline and 1,2-diphenylacetylene in a TiC14-catalyzed intermolecular hydroamination reaction <03OM4367>. 'N

+ ~

Ar

[Cu(phen)(PPh3)2]NO3 K3PO4, PhMe, reflux =

Ar

HCOCF3

H

102

101

A synthesis of a series of 2-aminoindoles, an interesting and often synthetically challenging class of heterocycles, has been devised. Thus for example, the alkynylanilide 103 took part in a palladium-catalyzed process with the amine 104 to give the indole 105 after final desilylation <03AG(E)4257>. Boc

MeO 103

t i Ts

s

SiMe3

N +

THF, K2CO3, A

2. TBAF, wet THF N H 104 89% from 103

m B Oc

b

MeOA~/~q 105

X___/ Ts

A series of l-alkoxycarbonylindoles has been prepared by a process catalyzed by a bimetallic catalyst. For instance, treatment of isocyanate 106 with allyl carbonate in the presence of Pd(0) and CuC1 gave the indole 107 <03JOC4764>. Pr

~OCO2Me Pd(PPh3)4, CuCl THF

[ ~ ~ ~ N pr

81% 106

107

CO2Me

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

141

The substituted tryptophan 108, an amino acid residue present in the naturally occurring octapeptide celogentin C, was prepared in high enantiomeric purity employing a palladiumcatalyzed heteroannulation from the reaction partners 109 and 110, for which efficient syntheses were also developed <03OL3611>. In a similar approach, N-Boc-2-iodo-3methoxyaniline was converted to psilocin in a three-step process, involving a palladiumcatalyzed cyclization with an appropriate TMS-alkyne as the key feature <03OL921>. Moreover, tryptophan analogues possessing chains of various lengths at C-2 instead of C-3 have been accessed via palladium-catalyzed cyclization of suitable o-alkynylanilines <03OL1717>. NHCbz

t-BuO2C. LiCI, Na2CO3,DMF, 90 ~c

+

TBSO TES

H2

58%

.....

110

109

CO2t_Bu

T B S O . . . J ~ I/L...~/~-~TES H

108

A palladium-catalyzed amination of triflate 111 with 2-bromoaniline 112, followed by an intramolecular Heck-reaction gave the [3-carbolinone 113 <03OL4195>. 1. Pd2(dba)3 2. Pd(PPh3)4, Cs2CO3

..,-

NH2

TfO

112

D.

o

H

0

113

111

Other metal-mediated processes leading to indoles include a regioselective synthesis of 2substituted indoles by ruthenium-catalyzed ring-opening of epoxides with anilines <03TL2975>, preparation of highly substituted indoles via thermal decomposition of N-(2alkenylphenyl)amino substituted Fischer carbene complexes <03T8775>, and the construction of thienocarbazoles via a two-step procedure employing a palladium-catalyzed amination/cyclization strategy <03 T3 737>. Triggered by the development of transition-metal catalyzed amination reactions of aryl halides, numerous extensions to intramolecular processes leading to the synthesis of nitrogen heterocycles have been reported. Nickel-mediated intramolecular amination of aryl chlorides 114 has been used as a tool for the synthesis of indolines 115 employing 2,2'-bipyridine or N,N'-bis(2,6-diisopropylphenyl)dihydroimidazol-2-ylidene (SIPr) as ligands. The procedure was also found to be useful for the formation of six- or seven-membered tings <03OL2311>. Moreover, indolines have been obtained by intramolecular palladium-catalyzed amination of a variety of differentially substituted amine precursors similar to 114 <03EJO2888>. Hydroamination of (o-chloroaryl)alkynes with primary amines catalyzed by CpzTiMe2, followed by palladium-catalyzed intramolecular amination provides a route to indoles with some exotic substitution patterns <03AG(E)3042>. Ni(0), ligand ~ ~ C I

NHR

t-BuONa THF or dioxane, A I= I

114

115

R

142

I:. Janosik, J. Bergman and E. T. Pelkey

Employing a new double N-arylation protocol, a series of carbazoles was prepared. Thus for example, aniline participated in a palladium-catalyzed reaction with the biphenyl 116 to give the carbazole 117 <03AG(E)2051 >. I

I

F3C

CF 3

C6H5NH2, Pd2(dba)3 (5 mol%) t-Bu3P (20 mol%), t-BuONa PhMe, A

116

F3C

CF 3

73%

117

I

Ph

Reductive intramolecular cyclizations constitute a powerful tool for the synthesis of various indoles. The tricyclic indole derivative 118, a key intermediate in a previous synthesis of the alkaloid d/-physostigmine, was prepared by reductive cyclization of the precursor 119, for which an interesting synthetic route was developed <03JOC6133>. OMe

119

118

Ullmann cross-coupling of the o-halonitroarenes 120 with a-haloenones 121 mediated by palladium has provided a route to various carbazoles 122 after cyclization of the intermediates 123. Other fused indoles could also be obtained depending on the chosen combination of a-haloenone and o-halonitroarene. In all cases, a by-product arising from homo-coupling of 120 was observed <03OL2497>. A number of substituted derivatives of the system 123 have also been used for the synthesis of a variety of 1,2-dihydro-4(3H)carbazolones by a palladium-catalyzed reductive annulation <03T6323>. Reductive cyclization strategy has also been employed for the synthesis of sterically hindered 3-amino2-oxindoles <03SL2135>. Cu, DMSO, 70 ~

+

R

H 2,

Pd/C

NO 2

1 2 0 X = I or Br

R 121 X = I or

H

Br 123

122

In a similar approach, a series of [3-carbolines was prepared. Thus for example, the natural product 124 was obtained after reductive cyclization of the precursor 125 <03T5507>. MeO

~

Pd(dba)2, dppp

N NO2

-Me 125

1,10-phenanthroline

CO (4 atm.), DMF 80%

MeO

~

N ~

Me ~N H

124

143

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

All available practical methods for the preparation of 2,2'-biindoles, important starting materials for the synthesis of indolo[2,3-a]carbazole natural products, do not tolerate sensitive functional groups, and pose severe difficulties whenever non-symmetrical products are required. Therefore, a new route to substituted 2,2'-biindoles 126, involving cyclization of the intermediate nitrostyrenes 127, is a valuable development. The substrates 127 were obtained by reaction of the nitrobenzenes 128 with indole-2-carboxaldehydes 129, followed by dehydration of the intermediate alcohols 130 in one pot. Suitable 2,2'-biindoles were further manipulated to the natural products tjipanazoles B, D, E, and I. The use of indole-3carboxaldehydes in this procedure enables synthesis of 2,3'-biindoles <03OL3721>. Likewise, a variation of this strategy, involving quinoline-3-aldehydes or pyridine-3aldehydes also proved to be useful for the synthesis of indol-2-yl-lH-quinolin-2-ones and indol-2-yl-2-pyridones <03OL3975>. Cyclization of o-nitrostilbenes leading to indoles has also been effected by treatment with phenylmagnesium chloride <03CEJ5323>.

X~TM Sr 128 -NO2 =. y

Y~ ~ C H O SO2Ph

'--

O2N

~

1.TFAA 2. DBU

TBAF(cat.)

129

y

02N

S02Ph 127

130

SO2P

P(OEt)3, or Y . ~ ~ . ~ ~ ~ Pd(OAc)2,PPh3_-.. X

' PhO2S

H 126

The development of a new synthesis of 1-hydroxyindoles 131, via a lead-promoted intramolecular reductive cyclization of the o-nitrobenzyl ketones (or aldehydes) 132 in the presence of tetraethylammonium formate (TEAF), offers a new useful route to this interesting class of compounds <03JOC9865>.

O-~ R3 I~R2 "-R1-77

R2 Pb,TEAF,ieOH, 55~

t~.~NO 2

RI_I~~"~

R3

66-96%

132

131

bH

A series of 1-methoxyindoles has been prepared by an interesting transformation. Thus for example, treatment of the precursor 133 (available in two steps from 2fluoronitrobenzene) with NaC1 in DMSO gave the 1-methoxyindole 134 <03TL7065>.

M

~ ,,,

I'lu2 133

NaCI,DMSO,155~ 60%

~ C O 2Me ~L'~jL~d \hl---~ 134

OMe

144

T. Janosik, J. Bergman and E. T. Pelkey

The isatogen 135 was synthesized under mild conditions from the acetylene 136 employing TBAF in THF, a transformation that normally requires heating in pyridine, or UVirradiation <03T2497>. NO 2

Ph

~

Ph.~~

TBAF,THF,rl: SAc = 73%

O

~~~~-SAc

136

O

135

Several solid-phase approaches towards indoles have been reported, such as the synthesis of 2-substituted indoles from titanium benzylidene reagents and resin-bound esters <03JOC387>, preparation of a variety of indoles using the Bartoli indole synthesis from nitrobenzoic acids immobilized on Merrifield resin <03OL2829>, synthesis of a 1,2dialkoxyindole library on SynPhase lanterns involving nucleophilic displacement of fuorine in immobilized o-fluoronitrobenzenes with dimethylmalonate anion, followed by cyclization with SnC12 and subsequent sequential alkylations <03OL2935>, formation of indoles via microwave assisted Cu(II)- or Pd(II)-mediated cyclization of 2-alkynylanilines <03OL2919>, synthesis of poly-substituted indoles by a rhodium carbenoid N-H insertion from anilines and polymer-bound Gt-diazo-~-ketoesters <03JCC188>, S-oxidation of 0t-sulfanyl N-aryl acetamides followed by Pummerer cyclization to oxindoles <03CC2380>, and preparation of indole-2-carboxylates by intramolecular palladium catalyzed amination of immobilized dehydrohalophenylalanines <03JOC6011>. Recently, several examples of solid-phase Fischer indole synthesis have appeared, leading to tetrahydrocarbazoles <03CC1822>, and naltrindole derivatives <03OLl159>. A solid-phase synthesis of indolines based on intramolecular palladium-catalyzed amination has also been reported <03TL2569>. 5.2.5

REACTIONS OF INDOLES

As a n-excessive heterocycle, indole readily undergoes reaction with electrophiles preferentially at C-3. Treatment of indole-3-carboxylate 137 with in situ generated sulfenyl chloride 138 provided 2-phenylthioindole 139 presumably via a rearrangement of the initally formed adduct 140. Compound 139 was then cyclized to the novel ring system, benzothiopyano[2,3-b]indol-ll-one 141, by treatment with PPA <03T9649>. The chemoselective oxidation of indolylmalonates at the indole C-2 using bromine was examined in detail <03JOC305>.

~ N

CO2MephscI138 ~ S P h CHCI3 =

H 137

69%

~"~-/~" N+ 140

1 J

=

@ N

CO2Me PPA, A= SPh" 73"/o

OON{~~

H 139

H

141

Addition of Grignard reagents to 2-aryl-3H-indol-3-ones such as 142 takes place at C-3 to give the alcohols 143, which in turn readily undergo rearrangement to give good overall yields of the disubstituted indoxyls 144 <03JOC2618>. This methodology was also utilized

145

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

to generate a key intermediate in the synthesis of a desbromo-derivative of the pentacyclic indole alkaloid hinckdentine A <03JA4240>. o

o RMgX, THF

HCO2H, PhMe

59-96%

51-96%

142

143

Br

R

In a detailed investigation of the mechanism and scope of palladium catalyzed amination of five-membered heterocycles, the 1-methyl-3-bromoindole 145 was aminated with secondary amines to the 3-aminoindoles 146. Similar results were obtained for 1-methyl-2bromoindole <03JOC2861>. Rhodium-catalyzed cyclopropanation reactions involving 1methyl-3-diazooxindole and exocyclic alkenes provided novel dispirocyclic cyclopropanes <03SL1599>. New applications of palladium-mediated cross-coupling reactions have been utilized to prepare a variety of functionalized indoles. Suzuki-Miyaura coupling reactions of indole-3-boronates <03H(59)473> and indole-5-boronates <03H(60)865> were utilized to prepare inhibitors of lipid peroxidation and melatonin analogues, respectively.

~ ~ N

Br

NRPh

PhNHR

Pd(dba)2(2 mol%), t-Bu3P t-BuONa, PhMe _---

Me

Me 146a R = Me (70%) 146b R = Ph (71%)

145

Directed metallation techniques have for a long time been useful tools for the regiospecific functionalization of heterocycles. In an approach leading to a series of useful 7substituted indoles 147, the indole 148 was sequentially deprotonated at C-2 and C-7, followed by treatment of the resulting lithio-derivatives with electrophiles. In an alternative approach, indoles possessing the directing group -P(O)(t-Bu)2 at the nitrogen were directly metallated at C-7 and converted to several 7-substituted indoles in moderate to good yields after quenching with suitable electrophiles <03OL1899>. Lithiation of indoles at C-2, followed by reaction with 1,2-anhydro-mannose was used as a key step in the total syntheses of mannosyl tryptophan and derivatives thereof <03CEJ1435>. Furthermore, polystyrenebound 1-ethoxymethyl indoles have been lithiated at C-2 and underwent subsequent reaction with benzonitrile <03S2236>. 1. t-BuLi, THF, TMSCI,-78 ~ 2. s-BuLl, TMEDA, THF, -78 ~

"~"" ~

3. E+ CONEt2 148

33-82%

T

MS E

CONEt2 147

Selective lithium-bromine exchange in 1-alkyl-5,7-dibromoindoles 149 offers a route to the corresponding indoles 150 or 151 in one pot. The initial, highly selective metalation at C7 is the key feature of this approach <03TL689>. Moreover, indole-5-carboxylates attached to a resin via an amide linkage, which also acts as a directing group, have been shown to

146

T. Janosik, J. Bergman and E. T. Pelkey

preferentially undergo lithiation at C-4, along with some C-6 metalation <03TL2093>. Directed ortho-metalation chemistry has also been utilized to prepare further substituted indoles. The directed ortho metalation of 2-(N,N-dimethylhydrazinecarbonyl)-l-methylindole gave 2,3-disubstituted indoles which were converted into indole-fused lactones <03SL173>. R3 Br~

R3 1. t-BuLi, Et20, -78 *C 2. E 1+

R2

Br

R3 1. t-BuLi, Et20,-78 *C R 2 2. E2+ ,2-8

149

%

R2

om

150

151

Regioselective lithiations have also been utilized to prepare other benzene-ring fimctionalized indoles. For example, the selective halogen-metal exchange of 4,7dibromoindole 152 led to the formation of 7-1ithioindole intermediate 153, which in turn gave indole-7-carboxaldehyde 154 upon treatment with DMF <03TL5987>.

Br

Br

Br SEM

t-BuLi ~

Br

= 9

152

D ~M8F2=%~ N CHO SEM

153

154

A number of reports describing Michael additions of indoles to enones have appeared. Catalyst systems that have been employed to promote this reaction include iodine <03SL2377>, cerium trichloride <03JOC4594>, and cerium ammonium nitrate (CAN) <03SL2074>. A synthesis of 1,3-bisindole compounds has been developed which utilized an indium-catalyzed Michael addition reaction <03S397>. An intramolecular Michael addition of 155 catalyzed by indium tribromide in water/THF gave 13-carboline 156 <03JOC7126>. In addition, several enantioselective Michael additions of indoles to various substrates, such as unsaturated phosphonates <03JA10780>, a,13-unsaturated ketones <03TL5843>, and aziridines <03TA3503> have been developed.

Boc,,

,nB omo,oo,

PhOC~

N-Boc

H 2 0 / T H F (9:1) ,

Boc155

COPh

7O%

~

~N

Boc

156

In a new simple synthesis of pyrazino[1,2-a]indole derivatives, 3-methylindole 157 was N-alkylated to 158, followed by treatment with formaldehyde and benzotriazole to produce the system 159. Displacement of the benzotriazolyl moiety with various nucleophiles gave the final products 160 <03JOC4938>.

147

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

Me CICH2CH2NH2,NaOH

Me BtH, HCHO

Bu'NH O 'OH ON

ls7

85%

H

Me

MeOH, H2O 96%

\

lsa

__jR

/

\ NH2

Nu78-95%

Bt 160 R = Nu

-159 R =

The Pictet-Spengler reaction involving indole substrates, an acid-catalyzed cyclization of tryptamine/tryptophan derivatives with aldehydes, is one of the most well utilized methods for the preparation of tetrahydro-~,-carbolines (for example: <03JMC4525, 03JMC4533>). A study of Lewis acids for the Pictet-Spengler reaction revealed ytterbium triflate as a highly effective catalyst under microwave irradiation <03CC916>. A solid-phase Pictet-Spengler reaction provided ~-carboline derivatives <03TL2211>. Treatment of a tryptophan derivative with ninhydrin gave the yohimbanone ring system by a novel rearrangement <03T6933>. An asymmetric variant has been reported which utilized an 8-phenylmenthyl group as a chiral auxiliary. Condensation of 161 with isobutyraldehyde in the presence of trimethylsilyl chloride preferentially gave ~-carboline 162 <03TA177>. Moreover, an asymmetric PictetSpengler reaction was the key step in the total syntheses of sarpagine alkaloids <03TL543>.

H

O~O'"' H

161

O

TMSCl, CH2Cl2,-30 ~

89%, 80% de

Ph

o

/

= 162

Ph

Diels-Alder (DA) cycloaddition reactions involving indoles (2,3-~ bond dienophile) or 2vinylsubstituted indoles (diene) provide a powerful strategy for the preparation of fused indoles. For example, a regioselective DA cycloaddition of vinylogous 2-(phenylthio)indole 163 with methyl propiolate led to carbazole 164 after elimination of thiophenol. The regiospecificity can be reversed by utilizing the corresponding sulfones <03JOC3299>. A DA cycloaddition of 2-(2-indenyl)indoles with maleimides provided entry to the indenopyrrolocarbazole ring system <03JHC135>. Novel indole-based heptacycles were prepared by a DA cycloaddition of 3-indolylquinones <03T2821>. A high pressure DA cycloaddition of indole-3-carbonyl compounds led chemoselectively to the corresponding 2,3-fused indole cycloadducts (as opposed to the products resulting from a hetero-DA reaction) <03JOC7990>. Finally, an inverse-electron demand DA of triazine-tethered indoles provided fused ~-carboline alkaloids <03TL4495>.

CO2Me Me~'~'~~~ 163

~N (;bz

-SPh

CO2Me . M e ' ~ " i ~ ' / ~ AICI3' CH2CI2 57%

N 164 Cbz

148

T. Janosik, J. Bergman and E. T. Pelkey

In a remarkable transformation, electrolysis of 1-methyl-5-nitroindole 165 in the presence of cyclopentadiene gave the cycloadduct 166. This outcome was attributed to a cycloaddition between a diiminoquinoid intermediate and cyclopentadiene <03CJC 1108>.

O 2 N ~ ~ ~N

+

~

4e, 4H*_2H20 = H2N

Me

165

31%

~

~'N 166

Me

Numerous fused indoles have been prepared utilizing palladium chemistry. A palladiummediated annulation reaction provided a synthetic route to naphth[3,2,1-cd]indoles (3,4-fused indoles) <03H(60)2095>. The regioselectivity of a Heck cyclization reaction of indole-2carboxamides containing allyl side chains was studied. Depending on the reaction conditions employed, either [3-carbolines or pyrazino[1,2-a]indoles could be prepared <03JOC7625, 03TL1919>. A range of cyclopent[b]indoles 167 has been accessed via an oxidative palladium-catalyzed cyclization of compounds such as 168. The interesting feature of this process is the catalytic C-H bond functionalization at the indole C-2 <03JA9578>.

Pd(OAc)2(10 mol%) ethylnicotinate(40mol%)

N•• 168

/~

0 2 (1 atm), 80 ~

R

t-amyl alcohol / AcOH (4:1)

Me

167 kle

An intramolecular iminoannulation reaction of alkyne-tethered indole 169 gave ~,carboline 170. Employing this methodology, a wide variety of 1,-carbolines and related fused systems were obtained <03JOC5132>.

~~_N

"•

Pd(OAc)2(5 mol%) PPh3 (10 mol%) Na2CO3, DMF,A = 93%

N

Br 169

Ph

.__~

Ph

170

A new route to a series of carbazoles 171 based on palladium-catalyzed annulation of the indole 172 with various alkynes has been described. The use of unsymmetrically substituted alkynes possessing electron-withdrawing groups gave higher yields, although in this case, mixtures of isomers were produced <03JOC7342>. I

Me

Ph

172

R ~ R

Pd(OAc)2(5 mol%) PPh3, Et3N,DMF 33-56%

R

R

Me

149

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

Synthesis of the seco-analogues 173 of ergot alkaloids was achieved employing an intramolecular Heck-reaction on the precursor 174, followed by full deprotection of the intermediate 175. The same ring system was also created by a ring-closing metathesis approach <03OL3519>. _

t-BuPh2SiO'~~

J

Pd(OAc)2 (35 mol%) P(o-Tol)3 (105 mol%) DBU, xylenes, reflux

m

t-BuPh2SiO'~~, / "N--Me

HO'~'NN..M HCl, MeOH reflux. . . . 41% from 174

3N

Boc

L

N~,N~

(N,

H

Boc

174

e

I

173

175

A few synthetic applications of isatins (indole-2,3-diones) merit attention. Thus for example, a one-pot synthesis of the spirolactones 176 in good yields has been achieved by treatment of isatins with vinyl triphenylphosphonium salts generated from acetylenes and PPh3 <03Tl169>. A thorough and detailed study on the reactions of isatins with 2aminobenzylamine has been performed, showing that the indolo[3,2-b]quinolin-6-ones 177 are obtained by heating the reactants in acetic acid. This outcome was attributed to a rearrangement of the initially formed isolable intermediates 178 <03T1033>. In a one-pot procedure, isatins can be transformed into 3-alkyl oxindoles in overall yields of 71-97%, via initial hydrogenation in the presence of Raney-nickel, and a subsequent alkylation at C-3 with alcohols, also catalyzed by Raney-nickel <03EJO3991>. Finally, spiroheterocycles derived from 1,3-dipolar cycloadditions of isatin with derivatives of L-proline have been the subject of a theoretical and synthetic study <03HC36>.

O0•g

OR2

NH

O2R2

~

--N

176

~1

/~ HN ~

177

R

~N

178

R

Several other procedures for the functionalization of indole derivatives have been developed. Thus for example, efficient N-methylation of indoles has been achieved using dimethyl carbonate in the presence of 10 mol% DABCO <03JOC1954>. Iodination of ethyl indole-2-carboxylate with periodic acid formed in situ (I2/NaOIa/H2SO4) gave selectively ethyl 3,5-diiodoindole-2-carboxylate, which in turn underwent selective zinc-mediated dehalogenation at C-3 <03SC2423>. A protocol for the reductive alkylation of indoles with aldehydes in the presence of Et3SiH has been developed <03TL4589>. In an interesting reduction of indole with cesium in liquid ammonia, the 5,8-dihydroindolide anion was produced as the ammoniate CsCsHsN'3NH3, the structure of which was studied by X-ray crystallography <03ZN(B)990>. Employing an oxidation reaction involving concomitant alkylation, 1-substituted 6-nitroindoles have been prepared from indolines <03M1037>. Treatment of 2-(trimethylstannyl)indoles with tetranitromethane under various conditions has

150

T. Janosik, J. Bergman and E. T. Pelkey

been shown to lead to 2-nitroindoles in modest yields, providing a new synthetic approach to this class of indoles <03EJO1711>. In a series of transformations starting from the indolo[3,2-b]carbazole 179, a selective mono-deprotection to 180 set the stage for an alkylation to furnish 181, followed by cleavage of the remaining Boc-group to give 182. This procedure provides a useful tool for mono-N-alkylation of indolo[3,2-b]carbazoles, which is otherwise a process marred by co-formation of dialkylated products <03T1265>. R2 i

Boc 180R I=H, R2=Boc 179 R 1 = R 2 =

181 R 1 = C H 2 C H 2 N M e 2, R 2 = B o c

182 R 1 =

C H 2 C H 2 N M e 2, R 2 = H

Finally, some miscellaneous approaches towards various indole-containing systems should be mentioned. Gramine has been shown to undergo cyclotrimerization to the potent estrogen agonist hexahydrocyclonona[1,2-b:4,5-b':7,8-b"]triindole 183 with co-formation of a cyclotetramer upon treatment with dimethyl sulfate and sodium metal in ethanol, providing a simple synthesis of this interesting compound <03JOC167>. Dimerization of 2-[2-(ptoluenesulfonyl)ethyl]indole led to the formation of the azocino[1,2-a:6,5-b']indole ring system 184 <03TL7183>. A key step in the total synthesis of the calothrixins A 185 and B utilized an Friedel-Crafts acylation reaction followed by an intramolecular orthometalation/cyclization reaction <03JOC8906>. The indolo[2,3-a]carbazole staurosporinone has been prepared using a new approach in a high overall yield from 2,2'-biindole by a photocyclization as the final annulation step <03TL2577>. A thorough study of radical-based annulation leading to various fused indoles has been reported <03TL1795>. Zirconocenes based on cyclopent[b]indoles have been prepared and studied as catalysts in liquid propylene polymerization <03OM2711>. The indolic diterpene 186 has been prepared using an enzymatic cyclization by the oxidosqualene synthase LUP1, a lupeol synthase from Arabidopsis thaliana <03JA9002>. Likewise, the mechanism of a biomimetic-type cyclization leading to indole-diterpene mycotoxins was investigated <03CC1546>. A samarium-promoted intramolecular cyclization of some ketoindoles led to benzannulated pyrrolizidines and indolizidines <03OL4305>. A series of bis(indol-3-yl)methanes 187, possessing aryl, alkyl, or alkenyl substituents, has been prepared under mild conditions by treatment of indoles with aldehydes or ketones in the presence of iodine, thus avoiding the use of acid catalysis <03TL1959>. A combination of heterogenous catalysts, silica supported hydrogen sulfate and Amberlyst-15, were utilized in an efficient synthesis of bis(indol-3yl)methanes and tris(indol-3-yl)methanes from indoles and indole-3-carboxaldehydes <03ASC557>. Additional catalysts have been utilized for the preparation of bis(indol-3yl)methanes, including those employing zeolites <03SC3687>, CAN in CH3CN <03JCR(S)72>, and indium triflate (in ionic liquids) <03SL2077>. N-Acetylated tris(indol-3yl)methanes were prepared and evaluated as cytotoxic agents <03H(60)1307>.

151

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

0

NH

H

H

185

184

183

._N

~___~~_ NH

HO H H

H

187

H

186

5.2.6

REFERENCES

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03BMCL1939 03CC916 03CC1546 03CC1822 03CC2316 03CC2380 03CC2454 03CEJ449 03CEJ1435 03CEJ3951 03CEJ5323 03CHE3 03CHE405 03CHE1521 03CJC988 03CJC 1108

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Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

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153

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154 03S1753 03S1959 03S2047 03S2236 03SC 1031 03SC2423 03SC2527 03SC3687 03SL75 03SL173 03SL417 03SL711 03SL1599 03SL1619 03SL1993 03SL2013 03SL2074 03SL2077 03SL2135 02SL2258 03SL2265 03SL2377 03T1033 03Tl169 03T1265 03T1557 03T1571 03T1917 03T2125 03T2497 03T2821 03T3737 03T5265 03T5395 03T5507 03T6323 03T6933 03T8775

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Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

03TL2211 03TL2569 03TL2577 03TL2865 03TL2943 03TL2975 03TL3501 03TL3701 03TL3923 03TL3971 03TL4175 03TL4257 03TL4495 03TL4589 03TL5163 03TL5843 03TL5987 03TL6853 03TL7065 03TL7183 03TL7269 03TL7337 03TL8229 03TL8417 03ZN(B)990

15 5

G. Klein, J. M. Ostresh, A. Nefzi, Tetrahedron Lett. 2003, 44, 2211. Y. Yu, J. M. Ostresh, R. A. Houghten, Tetrahedron Lett. 2003, 44, 2569. S. P. Gaud~ncio, M. M. M. Santos, A. M. Lobo, S. Prabhakar, Tetrahedron Lett. 2003, 44, 2577. B. C. Ranu, S. S. Dey, Tetrahedron Lett. 2003, 44, 2865. E. Paredes, M. Kneeteman, M. Gonzalez-Sierra, P. M. E. Mancini, Tetrahedron Lett. 2003, 44, 2943. C. S. Cho, J. H. Kim, H.-J. Choi, T.-J. Kim, S. C. Shim, Tetrahedron Lett. 2003, 44, 2975. B. A. Trofimov, A. P. Demenev, L. N. Sobenina, A. I. Mikhaleva, O. A. Tarasova, Tetrahedron Lett. 2003, 44, 3501. S. R. Cheruku, M. P. Padmanilayam, J. L. Vennerstrom, Tetrahedron Lett. 2003, 44, 3701. M. Curini, F. Montanari, O. Rosati, E. Lioy, R. Margarita, Tetrahedron Lett. 2003, 44, 3923. A. J. F. N. Sobral, N. G. C. L. Rebanda, M. da Silva, S. H. Lampreia, M. R. Silva, A. M. Beja, J. A. Paix~o, A. M. d'A. Rocha Gonsalves, Tetrahedron Lett. 2003, 44, 3971. H. Nakano, T. Ishibashi, T. Sawada, Tetrahedron Lett. 2003, 44, 4175. K. L. Milkiewicz, D. J. Parks, T. Lu, Tetrahedron Lett. 2003, 44, 4257. C. W. Lindsley, D. D. Wisnoski, Y. Wang, W. H. Leister, Z. Zhao, Tetrahedron Lett. 2003, 44, 4495. A. Mahadevan, H. Sard, M. Gonzalez, J. C. McKew, Tetrahedron Lett. 2003, 44, 4589. H. Uno, T. Ishikawa, T. Hoshi, N. Ono, Tetrahedron Lett. 2003, 44, 5163. M. Bandini, M. Fagioli, P. Melchiorre, A. Melloni, A. Umani-Ronchi, Tetrahedron Lett. 2003, 44, 5843. L. Li and A. Martins, Tetrahedron Lett. 2003, 44, 5987. J. H. Byers, M. P. Duff, G. W. Woo, Tetrahedron Lett. 2003, 44, 6853. N. Selvakumar, B. Y. Reddy, A. M. Azhagan, M. K. Khera, J. M. Babu, J. Iqbal, Tetrahedron Lett. 2003, 44, 7065. K. Sripha, D. P. Zlotos, S. Buller, K. Mohr, Tetrahedron Lett. 2003, 44, 7183. K. Nakao, Y. Murata, H. Koike, C. Uchida, K. Kawamura, S. Mihara, S. Hayashi, R. W. Stevens, Tetrahedron Lett. 2003, 44, 7269. N. Bazari6, Z. Marini6, M. Sindler-Kulyk, Tetrahedron Lett. 2003, 44, 7337. P. Haldar, J. K. Ray, Tetrahedron Lett. 2003, 44, 8229. G. Bashiardes, I. Safir, F. Barbot, J. Laduranty, Tetrahedron Lett. 2003, 44, 8417. C. Suchentrunk, N. Korber, Z. Naturforsch. 2003, 58b, 990.

156

Chapter 5.3 Five-Membered Ring Systems 9Furans and Benzofurans Xue-Long Hou

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

Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry, Peking University, Beijing 100871, China. zyan g @chem.pku.edu.cn Kap-Sun Yeung Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, P.O.Box 5100, Wallingford, Connecticut 06492, USA. kapsun, yeun g @bms.com Henry N.C. Wong Department of Chemistry, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, t The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. hncwon g @cuhk.edu.hk and Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China. hncw ong @mail.sioc.ac.cn t An Area of Excellence of the University Grants Committee (Hong Kong).

5.3.1 INTRODUCTION We have aimed to review articles that were published in 2003 on the applications and syntheses of furans, benzofurans and their derivatives. An account summarizing transition metal-catalyzed enantioselective ring-opening reactions of 2,5-dihydrofurans has appeared in 2003 <03ACR48>. The absolute stereochemistry of a diterpene isolated from Ballota aucheri was confirmed by a semi-synthetic transformation of hispanolone <03P(63)409>. Overman and Pennington published an excellent review concerning the use of pinacol-terminated Prins cyclizations in the synthesis of tetrahydrofuran-containing molecules <03JOC7143>. Like previous years, many new naturally occurring molecules containing tetrahydrofuran and dihydrofuran rings were identified in 2003. In these families, the compounds whose biological activities have not been assessed are: lycopanerols I-L from a strain of the green microalga Botryococcus braunii (L race) <03JNP772>; (+)-6,11-epoxyisodaucane from the essential oil of the liverwort Tritomaria polita <03P(64)637>; 4-demethoxyniranthin,

Five-MemberedRing Systems : Furansand Benzofurans

157

urinatetralin, dextrobursehernin and urinaligran from the aerial and the root parts of Phyllanthus urinaria L. <03P(63)825>; [(2S,3R,4R)-4-(3,4-dimethoxybenzyl)-2-(3,4dimethoxyphenyl)tetrahydrofuran-3-yl]methyl (2E)-2-methylbut-2-enoate from the roots of Leontopodium alpinum <03HCA733>; cararosin A from the aerial part of Caragana rosea Turcz. <03CJO873>; (+)-syringaresinol 4-O-~-D-glucopyranosyl-(1---6)-f~-D-glucopyranoside from the rhizomes of Smilax glabra <03H(60)1633>; argelosides A and B from Solenostemma argel fruits <03TL8553>; moponeols A and B from Colophospermum mopane <03JNP30>; vernoguinoside, its 3-oxo derivative and two sucrose esters from the stem bark of Vernonia guineensis <03P(63)841>; neoglabrescins A and B from the stem bark of Neoboutonia glabrescens Prain (Euphorbiaceae) <03P(64)575>; chagosensine from the Red Sea sponge Leucetta chagosensis <03EJO4073>; orientalol E from the rhizome of Alisma orientalis (SAM) JUZEP <03P(63)877>; amphidinolide X from a marine dinoflagellate Amphidinium sp. (strain Y-42) <03JOC5339>; aldingenin. A from red algae Laurencia aldingensis <03TL2637>; micrandilactone A from Schisandra micrantha <03OL1023>; pseudolarolide P from the seeds of Pseudolarix kaempferi Grod. (Pinaceae) <03HCA787>; lowdenic acid from nonsporulating cultures of a new fungicolous Verticillium sp. (MYC-406 = NRRL 29280) <03JNP1259>; reissantins A-E from Reissantia buchananii <03JNP1416>, and xanthanolides called lf~,4~epoxy-513-hydroxy-10c~H-xantha-1 l(13)-en-12,8f~-olide and lf~,4~,4a,5~3-diepoxy-10a,1 lc~Hxantha-12,8f~-olide from the aerial parts of Carpesium longifolium <03JNP1554>. Those naturally occurring compounds containing tetrahydrofuran or dihydrofuran skeletons, whose biological activities were assessed are (biological activities shown in parentheses): simplakidine A from the Caribbean sponge Plakortis simplex (weakly cytotoxic against RAW 264-7 with 30% growth inhibition at 60 ~tg/mL) <03OL673>; epimeric mixtures of annomolons A and B (substantially cytotoxic against the human pancreatic tumor cell line MIA PaCa-2 with EDs0 = 3.12 x 1 0 -3 - 7.48 x 1 0 -3 ~ t g / m L ) <03JNP(66)1369>; rel(7R,8R,7'R,8'R)-3 ',4'-methylenedioxy-3,4,5,5'-tetramethoxy-7,7'-epoxylignan and rel(7R,8R,7'R,8'R)-3,4,3 ',4'-dimethylenedioxy-5,5'-dimethoxy-7,7'-epoxylignan from Piper solmsianun (active against the trypomastigote form of Trypanossoma cruzi with IC50 = 17.6 and 3.47 ~tg/mL, respectively) <03P(64)667>; saucerneol D and saucerneol E from the roots of Saururus chinensis (active against NF-nB dependent reporter gene expression with IC50 = 6.1 and 12.7 ~M, respectively) <03P(64)765>; jaspines A and B from the sponge Jaspis sp. Gaspine B hydrochloride was cytotoxic against the A549 lung tumor cell line with IC50 = 3.4 x 10-' M) <03TL225>; four new antitumor sesquiterpenene polyol esters from the seed oil of Euonynys nanoides <03HCA3320>; five new dihydro-~-agarofuran sesquiterpenes from the leaves of Maytenus chiapensis (one of them showed weak activity against a multidrug-resistant Leishmania tropica line) <03JNP572>; briarellins J-P and polyanthellin A from the gorgonian Briareum polyanthes (antimalarial tests indicated that some of them were active against Plasmodium falciparum) <03JNP357>; ajugasalicigenin and ajugasaliciosides F-H from the aerial parts of Ajuga salicifolia (ajugasalicigenin was cytotoxic against KB and Jurkat T cancer cells with IC50 = 1 ~tg/mL, while the other three were less active or inactive) <03JNP461>; rubianoside I from the roots of Rubia yunnanensis (inhibitory effect of rubianoside I on NO production in LPS-activated mouse peritoneal macrophages was 5.1 _ 2.9% at 1 rtM) <03JNP638>; 3,5,17-O-triacetyl-7-O-benzoyl- 15-hydroxycheiradone, 3,5,15,17-O-tetraacetyl-7O-benzoylcheiradone and 3,5,15,17-O-tetraacetyl-7-O-nicotinoylcheiradone from Euphorbia decipiens (3,5,15,17-O-tetraacetyl-7-O-benzoylcheiradone showed a positive response to DNA--damaging activity with IC12 = 750 ~g/mL against RS322Y (rad 52) and 1090 ~tg/mL against wild-type LF 15 (Rad +)) <03JNP 1221 >, four insecticidal pyrido[ 1,2-a]azepine alkaloids protostemonine, dehydroprotostemonine, oxyprotostemonine and stemocochinin from four Stemona species <03P(63)803>; two dammarane triterpenes called 3-acetyl-24-epi-polacandrin and 1,3-diacetyl-24-epi-polacandrin from the aerial parts of Ibicella lutea (they showed weak cytotoxicities against human colon carcinoma A-549, H-116 and HT-29) <03JNP1586>, and tricholomalide A from the fruiting body of Trichloloma sp. (significantly induced neurite outgrowth in rat pheochromocytoma cells PC-12 at concentration of 100 ~tM) <03JNP1578>. Those furan-containing compounds whose biological activities were not mentioned are: swietenialides A, B, C, D and E from the stem bark of Swietenia mahogany <03T8027>; methyl

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

15,16-epoxy-12R-acetoxy-8(17),13(16),14-ent-labdatrien-19-oate and 15,16-epoxy-12Racetoxy-8(17), 13(16), 14-ent-labdatrien- 19-oic acid <03P(64) 1309>; salvigresin from the aerial parts of Salvia greggii <03P(63)859>; 12(S)- 15,16-epoxy- 19-hydroxy-neo-cleroda- 13(16),14dien-18,6a:20,12-diolide from the aerial parts of Teucrium chamaedrys <03P(63)977>; leandreanins A, B and C from the stem bark of Madagascan Meliaceae Neobeguea leandreana <03JNP735>; salvinorins D-F from the leaves of Salvia divinorum <03JNP703>; 5~-hydroxycis-dehydrocrotonin and (12R)-12-hydroxycascarillone from the aerial part of Croton schiedeanus <03P(62)551>; norcaesalpinins A and B from the seed kernels of Caesalpinia crista <03TL6879>, 7-epitsugicoline H from the fungus Clavicorona divaricata <03T5033> and sandrapins A, B and C from the leaves of Sandoricum koetjape <03P(64)1345>. Those naturally occurring compounds containing furan skeletons, whose biological activities have been assessed are (biological activities shown in parentheses): ten new neoclerodane diterpenes cornutins C-L from the leaves of Cornutia grandifolia var. intermedia (cornutins C-F were shown to exhibit only marginal in vitro antiplasmodial activity) <03P(64)797>; halisulfates from the sponge Darwinella australensis (inhibited cell division of the fertilized eggs of the sea urchin Strongylocentrotus intermedius at IC50 50 and 35 ~g/mL, respectively) <03JNP 1010>; teuctosin from Teucrium tomentosum (effective antifeedant activity_ of 71.5 + 2.0% and 77.4 + 2.1% against Plutella xylostella and Spodoptera litura at 10 ~tg/cm2 of leaf area, respectively) <03P(64)1119>; 1 l[~,12a-diacetoxyneotecleanin, 1 lf~,12~-diacetoxy14~, 15~-epoxyneotecleanin, 7a, 12a-diacetoxy- 14[~,15~-epoxy- 11 ~-hydroxyneotecleanin, 7a, 12a-diacetoxy- 11 ~-hydroxyneotecleanin and 11 ~, 12a-diacetoxy- 1-deoxo- 14[3,15~-epoxy-3~hydroxy-2-oxo-neotecleanin from the root bark of Turraea wakefieldii (the first, second and fourth compounds showed dose--dependent larvicidal activity against larvae of Anopheles gambiae s.s.) <03P(64)817>. Cynatrosides A, B and C from the roots of Cynanchum atratum (Asclepiadaceae) (inhibitory activity against AchE with IC50 = 6.4, 3.6 and 52.3 ~tM, respectively) <03HCA474>; 5-oxo-cystofuranoquinone and 5-oxo-isocystofuranoquinone from the brown alga Cystoseira crinita Duby (antioxidative activity on TBARS Assay with 82% inhibition at 7.6 and 11.1 ~tM, respectively) <03JNP968>; 12-O-deacetylscalarafuran from a marine sponge of the genus Spongia (cytotoxic against HeLa cells with IC50 = 19.5 ~tg/mL) <03JNP438>; massarinin B from the freshwater aquatic fungus Massarina tunicata (active against Staphylococcus aureus (ATCC 29213) with a zone of inhibition of 12 mm) <03JNP73>; providencin from the Caribbean gorgonian octocoral Pseudopterogorgia kallos (modestly in vitro cytotoxic against MCF7 breast cancer, NCI-H460 nonsmall cell lung cancer and SF-268 CNS cancer) <03OL2551>, and a new furanoeudesmane (ichthyotoxic at 10 ppm in the feeding deterrence test) <03JNP 1517>. Those benzo[b]furan- or dihydrobenzo[b]furan--containing compounds whose biological activities were not mentioned are: 2-(l'-methylethenyl)-5-hydroxynaphtho[2,3b]furan-4,9-dione, 2-(1 '-methylethenyl)-7-hydroxynaphtho[2,3-b]furan-4,9-dione and 2-(l'methylethenyl)-6-hydroxybenzo[b]furan <03P(64)583>; afzelone A from the stem bark of Ochna afzelii <03P(64)661>; lawsonicin from the aerial parts of Lawsonia alba <03HCA2164>; (+)-viniferol D from the stem of Vitis vinifera 'Kyohou' <03H(60)1433>; cribrarione A from a myxomycete Cribraria purpurea <03T3433>; 1-{(2R*,3S*)-3-(~-Dglucopyranosyloxy)-2,3-dihydro-2- [ 1-(hydroxymethyl)vinyl]- 1-benzofuran-5-yl }ethanone from the roots of Leontopodium alpinum <03HCA733>; pervilline and pervillinine from the root bark of Millettia pervilleana (<03P(63)471>; erypoegins F-J from the roots of Erythrina poeppigiana <03P(63)597>; murrayanine from Murraya koenigii (<03JNP416>; cis- and trans-diptoindonesin B from the tree bark of Dryobalanops oblongifolia (Dipterocarpaceae) <03P(63)913>; shorealactone from the stem bark of Shorea hemsleyana <03HCA3394>; gnetofurans A-C from the stems of Gnetum klossii <03JNP558>; 5-(3"-benzoyloxypropyl)-7methoxy-2-(3' ,4'-methylenedioxyphenyl)-benzofuran and 4- [3"- ( 1cmethylbutanoyloxy)propyl]-2-methoxy-(3 ',4'-methylenedioxyphenyl)- 1a,5bdihydrobenzo[3,4]cyclobutaoxirene from the seeds of Styrax officinalis <03P(63)939>; flavumones A and B from the stem bark of Ouratea flava <03P(63)427>; citreobenzofurans A, B and C from the mycelium of the hybrid strain KO 0031 <03T5055>; isotecleoxine and methylnkolbisine from the aerial parts of Teclea nobilis <03P(64)1405>, and pestacin from the fungus Pestalotiopsis microspora <03T2471>. Those naturally occurring compounds containing benzo[b]furan, dihydrobenzo[b]furan or dihydrobenzo[c]furan skeletons, whose biological activities have been assessed are

Five-Membered Ring Systems : Furans and Benzofurans

159

(biological activities shown in parentheses): eryvarins J, K and L from the roots of Erythrina variegata (eryvarin L exhibited weak anti-MRSA activity, as well as inhibited the growth of 5 strains of vanocomycin-resistant enterococci at 50 ~tg/mL) <03H(60)2767>; hierochins A, B and C from the whole plants of Anastatica hierochuntica (inhibitory effects on NO production and induction of inducible NO synthesis) <03H(60)1787>; 9-(1-methylpropyl)-4-hydroxy-5(4-hydroxy-3-methylbutyryl)-2-(1-hydroxy-1-methylethyl)-2,3-dihydrofuro [2,3-f] chromen-7one from the stem bark of Kielmeyera albopunctata (not cytotoxic at 20 ~tg/mL) <03JNP634>; acronyculatin E from the stem and root bark of Acronychia pedunculata (inactive as an antioxidant at 500 ~tM with inhibition percentage 2.9%) <03JNP990>; uncinanones B and C from the root exudates of the legume Desmodium uncinatum (Jacq.) DC (uncinanone B induced germination of seeds from the parasitic weed Striga hermonthica (Del.) Benth. and uncinanone C moderately inhibited radical growth) <03P(64)265>; bismorphine B from wounded capsules of Papaver somniferum (treatment of the cell wall polysaccharide pectins with bismorphine B showed 86% inhibition of hydrolysis of pectins by pectinases) <03JNP987>; cyclorocaglamide from the tropical plant Aglaia oligophylla (inactive against neonate larvae of Spodoptera littoralis up to 100 ppm) <03JNP80>; gnemonols K, L, M and gnemonoside K from the root of Gnetum gnemon (Gnetaceae) (gnemonols K and L showed effective scavenging activity for lipid peroxide inhibition with IC50 = 19 and 7 ~tM, respectively) <03P(62)601>; (+)-a-viniferin and kobophenol A from the aerial part of Caragana rosea Turcz. (no promising in vitro anti-HIV activity) <03CJO873>; machaeriol D and machaeridiol C from the stem bark of Machaerium multiflorum (antimicrobial activities against S. aureus with ICs0 = 25 and 3.0 ~tg/mL, respectively) <03JNP804>; 5-methoxymaculine, 5,8dimethoxymaculine and 4,5,6,7,8-pentamethoxyfuroquinoline from the wood of Vepris punctata (weakly cytotoxic against A2780 human ovarian cancer cell line) <03JNP532>; two new benzo[b]furan compounds from the stems of Dalbergia cochinchinensis (inhibitory activity against testosterone 5~-reductase) <03JNP1128>; artoindonesianins X and Y from the roots and tree bark of Artocarpus fretessi (moderately active against the brine shrimp Artemia salina) <03P(64)831> and dehydrooxoperezinone from the stems of Aristolochia manshuriensis (inhibitory activity against the replication of HIV with an ECs0 of 17.5 ~g/mL) <03JNP996>. 5.3.2 R E A C T I O N S 5.3.2.1 Furans

Many publications in 2003 illustrated the use of furans as versatile n-nucleophiles for ring formation. To exemplify, an intramolecular Mannich-type cyclization of a functionalized furan to a cyclic iminium cation was the key step in the construction of the strained ABCD ring system of nakadomarin A <03JA7487>. An efficient intramolecular Friedel-Crafts alkylation of a furan was employed to assemble the unusual bicyclo[6.1.0]nonane skeleton of the crenulide diterpenoids in high yield <03JOC9487>. Another interesting example is the anodic cyclization reaction of a furan derivative to form the tricyclic core of alliacol A. As shown below, the furancontaining key intermediate was oxidized electrochemically, resulting in an overall Umpolung-type reaction <03JA36>.

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

1. RVC anode carbon cathode 0.4 M LiCIO4

1.12 PPh3 imidazole

H o -

2,6-1ulidine, r.t. I 15-20 mA, 2.2 F/mo tBuMe2SiO,

2. TsOH r.t.

O~, '~T

H -

88%

85 ~ 87% 2. AgNO3 ' THF-MeOH (2:1) r.t., 3.5 hr 92%

O" /~

Chiral Fischer-type (menthyloxy)(3-furyl)carbene complexes underwent nucleophilic 1,4-addition with lithium reagents in a regioselective and diastereoselective manner. In particular, a reaction with (Z)-2-phenylethenyllithium provided the (Z)-alkene product shown below in excellent %ee <03CEJ5725>.

(CO)5Cr

~

+pLi3

1. Et20 R*O -80 ~ 2. MeOTf (CO)nCr -80 ~ to r.t.

3 steps

n=5 / n=4 65 / 35 62%

HO

90% yield 98% ee

An intramolecular thermocyclization from furan C3 carbon to azide provided furo[3,2b]pyrrole, which was used as a diversity template for library generation <03TLA257>. The addition of Grignard reagents to 2-nitrofuran, and subsequent treatment of the intermediates with F3BoOEt 2, induced a self-condensation reaction to form 4-formyl-2-hydroxy-3substituted 2,3-dihydrofuran derivatives <03TL3167>. Furan analogs were used as a useful precursor of v-hydroxybutenolides in several examples. The oxidation of furan to ~hydroxybutenolide was used to prepare an A-ring precursor of vitamin D 3 analogs <03TL1161 > and the furopyran core of dysiherbaine <03OBC772>. The photosensitized singlet oxygen oxidation of a furan was applied in the final steps of the total synthesis of the marine sesterterpene called cacospongionolide F <03OL991>, cladocorans A and B <03JOC3476>, and in the synthesis of oxepane rings <03TI_A467>. A related and notable example is the chemoselective photo-oxidation of 2-geranylfuran as depicted below, using methylene blue (MB) as the photosensitizer. The intermediate hydroperoxide was converted to a 19:1 mixture of litseaverticillols A and C in 2 steps <03AG(E)5465>.

O

~

0 2, hv

MB ~_MeO - % ~ - -OOH oH

MeOH 0oc / 3 0 sec 9 ~k 97~

1. Me2S CHCI3 25~

/~d.. ) 6'

2. i-P r2NEt, 4 hr 55o/ A:c \

/

\

OH

/

litseaverticillolA (or-OH)\

litseaverticillolC (13-OH)

The 2,4-dinitrobenzoic acid (DNBA) salt of the chiral amine shown below catalyzed an enantioselective vinylogous Mukaiyama-Michael addition of 2-silyloxyfurans to a,~unsaturated aldehydes, producing v-butenolides with a high level of syn-selectivity and enantiomeric excess <03JAl192>. A vinylogous Mukaiyama aldol reaction between 2silyloxyfuran and D-glyceraldehyde acetonide produced the desired 6-hydroxy-,t-butenolide in a highly diastereoselective manner. Such a boron trifluoride etherate-promoted reaction was the key step in the synthesis of 4a-carbafuranoses <03TA1665>. A similar approach was also applied to the synthesis of septanose from L-threose <03JOC5881>.

Five-Membered Ring Systems : Furans and Benzofurans

Catalyst Me3SiO~

+

O ~--O ,,,

161

O / Catalyst~ - - N

CH2CI2-H20"- ~ O -70 ~ 11 hr 81% syn: anti=22 : 1 92% ee

ph~N'~

The asymmetric addition of 2-silyloxyfuran to achiral aldehydes, catalyzed by a BINAP-containing second generation Cr(salen) complex, to produce 6-hydroxy-,t-butenolides was also reported. Although the anti : syn diastereoselectivity of this reaction was low to moderate, high enantiomeric excess up to 99% could be achieved by the addition of water <03CL584> or an alcohol <03OL974>. As illustrated in the scheme below, the catalytic asymmetric cyclopropanation of methyl furan-2-carboxylate with diazoacetate could be achieved by the use of the Cu(I)-bisoxazoline catalyst to provide an 2-oxa[3.0.1]bicyclohexene, which was elaborated to the v-butyrolactone via a 3-step sequence <03CEJ260>. The same authors also reported the use of a new amino acid-containing Cu(I)-bisoxazoline complex to produce the e x o adduct in up to 91% ee <03TA765>. This strategy was applied to the asymmetric synthesis of paraconic acids <03CEJ260>, and the fused cyclic ring systems of xanthanolides, guaianolides and eudesmanolides <03OL941>.

N2CHCO2Et 2 mol% Cu(OTf)2 2.5 mol% (S,S)-tBu-box H 2 mol% PhNHNH2 EtO2C, , , , , ~ ~ ~CO2Me

CH2C12 91% ee recrystallizaUon> 99% ee

CHO

3 steps ~

H,~O,2a"~CO2Me

-O~o/

,,,~"~

A sequence of acid-catalyzed dehydration-spiroketalization on furfuryl alcohol derivatives was used for the synthesis of lactam-containing analogs of antifeedant tonghaosu. The reaction provided a high level of diastereoselectivity at the quaternary carbon atom when a chiral amide was used as a substrate <03S1995>. Rearrangement of furfuryl alcohol to vhydroxycyclopentenone in aqueous medium is a mechanistically related reaction that was the key step in the synthesis of E type I phytoprostanes <03TL7411> and prelactone B <03SL2092>. Mo(CO)6-catalyzed oxidation of 2,5-dialkylfurans by cumyl hydroperoxide provided the corresponding (E)-enediones selectively. In the presence of Na2CO 3, the corresponding (Z)-isomers were obtained <03TL835>. Oxidation of furan derivatives by a methanolic solution of bromine was used in the synthesis of crocetin dimethyl ester <03JOC9126>, and a C 1-C9 segment of tylonolide <03T 10181 >. Oxidation of the substituted furan shown below with magnesium monoperoxyphthalate (MMPP) to the a,6-unsaturated 1,4dicarbonyl compound was followed by a reductive amination to complete the synthesis of the indolizidine alkaloid (+)-monomorine <03JOC5395>.

u

MMPP EtOH-H20 (1 "1) r.t., 3 hr 61%

H2

u 10% Pd-C

H

MeOH r.t., 5 hr 45%

Oxidative ring cleavage of furan moieties to carboxylic acids under Sharpless conditions provided the paclitaxel side chain <03OL3987>, and amino acid derivatives <03HCA91>. An intramolecular ring opening of a furan derivative by an alkenyl radical was attempted as an

162

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

approach to construct 5,6-fused ring systems <03EJO1729>. The oxidative ring expansion of furan is very useful in the synthesis of 6-membered rings. Examples reported in 2003 included the construction of trans-fused ether ring subunits of polycyclic ether natural products <03TL8227>, and dihydropyridone intermediates for the synthesis of imino-sugars <03EJO 1104>. As shown in the following scheme, oxidative ring expansion of the bis-furfuryl alcohol provided the C2-symmetric dipyranone, which was used as a template for the synthesis of C-linked disaccharides <03OBC338>. OH O

VO(acac)2 t-BuOOH

OH -

O

O

.._

~

CH2CI2-PhMe r.t., 6 hr 95%

.._ C-linked - disaccharides

OH

Inter- and intramolecular Diels-Alder cycloadditions between furan derivatives and dienophiles remains a powerful reaction for the construction of 6-membered and polycyclic ring systems. Intermolecular Diels-Alder reaction was used for the synthesis of eleutherobin aglycone <03OL1805>, oryzoxymycin <03OL239>, cyclohexyl-g-amino acids <03SL736> and haloconduritols <03T3643>. The a-stereogenic center of a chiral furfuryl alcohol controlled the facial selectivity of the Diels-Alder reaction of masked o-benzoquinone, as illustrated below <03OL1637>. Recent experimental evidence supported a stepwise double Michael addition as the mechanism of this type of reaction <03JOC7193>.

Meoc

e +

OH OH

DAIB MeOH r.t., 1 hr 77% yield

98% de

~ I

MeOO'~1"~.

2,3-Dimethylfuran reacted with an isobenzopyrylium salt generated from a 2-alkynyl benzaldehyde in the presence of 3 mol% of AuC13 and H20 to give the interesting bis-acetal cage compound depicted below <03AG(E)4399>.

Ph ~")AuCI3

H20 MeCN 80~ 3 hr

Ph

2-Methoxyfuran reacted with cyclobutane-fused benzyne to give a 4:1 mixture of 1- and 4-methoxynaphthalene. Theoretical calculations showed that the regioselectivity was derived from the directing effect of the strained cyclobutane ring <03OL351>. A glycosyl furan tethered to a benzyne precursor via a silicon linker was used as a substrate for benzyne-furan cycloaddition in the regioselective synthesis of unsymmetrical C-aryl glycosides <03JA12994>. Intramolecular Diels-Alder reaction of furan derivatives was employed in a diversity-orientated synthesis <03OL4125>, in the synthesis of a library of 10-oxa-3-aza-tricyclo[5.2.1.01'5]dec-8en-4-ones <03TL7341>, to prepare 5,5-dimethyl-11-oxoisoindolo[2,1-a]quinoline-10carboxylic acid <03TL3641>, to construct the D-E rings of noryohimban ring system <03TL5137> and sulfur-containing polycyclic heterocycles <03OL2619>. The presence of a halogen substituent at the 5-position of 2-furanyl amides markedly enhanced the rate of

163

Five-Membered Ring Systems : Furans and Benzofurans

intramolecular Diels-Alder reaction <03OL3337>. The stereochemical outcome of an intramolecular Diels-Alder reaction of furan-substituted chiral ethanol amides was shown to be dependent on the C3 substituent, regardless of its configuration <03OBC3592>. The transannular Diels-Alder reaction of a furanophane was used in an approach towards the total synthesis of chatancin. As shown below, cycloaddition of the macrocycle produced the penultimate tricyclic intermediate with high diastereoselectivity <03JOC6847>. i,,"

2Me

"q

DMSO-H20 (2:1) 115 ~ 3 days 70% conversion

"~'"

(5 H CO2Me

An AuC13-catalyzed intramolecular reaction between 2-methylfuran and a terminal alkyne to produce a phenol was the key step in the synthesis of jungianol and epi-jungianol <03CEJ4339>. This reaction could also be catalyzed by PtC12. Based on density functional theory calculations and on the trapping of certain intermediates; the mechanism was proposed to involve the cyclopropyl platinacarbene complex shown below as a key intermediate <03JA5757>.

LICI

2

R

CI2

R

OH

A number of different furan-based approaches to the synthesis of 7-membered ring systems were reported in 2003. In the novel example shown below, the furan participated in an intramolecular [4+3] cycloaddition with nitrogen-stabilized chiral oxyallyl cation to form polycyclic structures <03JA12694>. Attempts to construct the [4.4.1] bicyclic BC ring system of ingenol via a type-II intramolecular [4+3] cycloaddition between furan and an oxyallyl cation produced the desired product but only in 14% yield <03JOC7899>.

'-N ~ ' - - ON..~ ,,~

dimethyl dioxirane

O~..~N

CH2CI2 -45 ~ 75%

The chiral amine catalyst shown below was used to promote the asymmetric [4+3] cycloaddition between 2,5-disubstituted furans and trialkylsilyloxypentadienals to generate 7-membered carbocycles with endo-selectivity and in a promising 89% ee <03JA2058>. Computational studies of the AIC13-catalyzed [4+3] cycloaddition between 2(trimethylsilyloxy)acrolein and furan at the B3LYP/6-31G* level showed that the reaction was a three-step process <03OL4117>.

OSiMe3

O

Catalyst . . . ~ ~ H 2 C CH2CI2 -78 ~ 96 hr

H2OH Catalyst ph~~ N/

164

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

The rhodium-catalyzed reaction between diazocarbonyl compounds and furan derivatives led to the formation of 2,4-diene-l,6-dicarbonyl systems. An intramolecular version of this method was exploited in the construction of the 6,7-fused ring system of the guanacastepenes as illustrated below <03OL4113>. O ",,.

CO2Et

2

,

O -

Rh2(OAc) 4 0H2012 r.t -.._

%

O2Et tBuPh2SiO

/~,,,~.O

50% SiOr ( ~ ~ , - , u,,-, tBuPh2 UHO

5.3.2.2 Di- and Tetrahydrofurans Interesting dihydrofuran coupling reactions continued to be explored in 2003. 2,3Dihydrofuran produced furotetrahydroquinoline derivatives in the presence of cerium ammonium nitrate <03CL222>, 1-butyl-3-methylimidazolium tetrafluoroborate <03T159>, 10 mol% of tris(4-bromophenyl)aminium hexachloroantimonate <03SL1707> and an aqueous HC1 solution of In. As shown below, 2,3-dihydrofuran underwent an InC13-catalyzed reaction with 1,2-dimethylindole to produce a cis-fused perhydrofuro[2,3-b]oxepine ring selectively incorporated at the 3-position of the indole <03TL2221>.

+ \

O

InCI3

2.5 equiv,

CH2CI2 r.t., 3 hr

83%

\

Ring opening of oxabicyclic alkenes by organometallic reagents to highly substituted cyclohexenols remained a very active area of research in 2003. The effects of halide on the rhodium-catalyzed asymmetric ring opening of oxabenzonorbornadienes were described <03JA14884>. Pd-BINAP and Ni-BINAP complexes catalyzed the asymmetric reductive ring opening of oxabenzonorbornadienes by zinc powder in up to 90% ee <03OL1621>. The FeC13-catalyzed ring opening of oxabicyclic alkenes by Grignard reagents provided the all syn-substituted cyclohexenols regio- and stereoselectively <03OL1373>. The first example of the corresponding highly ant/-selective reaction shown below was accomplished by using CuC1/PPh 3 as a catalyst system <03OL 1333>. A rM gB r (1.5 equiv. ) 10 mol% CuCI 10 mol% PPh3

OH

F

PhMe r.t., 1.5 hr 94%

The Ni(dppe)Br2-catalyzed condensation of oxabenzonorbomadienes with either ~iodo-(Z)-propenoates or o-iodobenzoate provided a new synthesis of annulated coumarins. As shown below, this reaction was also found to be regioselective <03OLA903>. The same group also reported the reductive coupling of oxabenzonorbornadienes and 7-oxanorbornenes with various propiolates under similar Ni-catalyzed conditions at room temperature <03CEJ3165>.

165

Five-Membered Ring Systems 9Furans and Benzofurans

O §

T

"CO2Me

O

5 mol% Ni(dppe)Br2

I

80 MeCN ~ 12 hr 68%

O

Zn

A BC13-mediated ring opening of a chiral b i s - 2 , 5 - d i h y d r o f u r a n derivative furnished a pivotal intermediate in the synthesis of long chain 1,3-polyols <03EJO2959>. Ring opening metathesis polymerization of a dihydrofuran moiety was utilized in a capture-release strategy for the Mitsunobu reaction <03TL7187>. Addition of primary or secondary amines to 3trichloroacetyl-4,5-dihydrofuran gave the E-isomer of 3-aminomethylenedihydrofuran-2-ones as the predominant products <03TL961>. As illustrated below, ring opening of 2-amino-4,5dihydrofuran-3-carbonitriles by acetyl chloride to the 2-acetyl-4-chloro-2-cyanobutanoyl amide was followed by basic treatment to give the 1-cyanocyclopropancarboxamides in a one-pot sequence <03EJO2383>.

CN

CN

AcC,

MeCN r.t., 4 hr

CN

.

CI

EtOH r.t., 2 hr 80%

Hetero-l,l-dimetallo-l-alkenes and hetero-l,l-dihalo-l-alkenes could be obtained in a stereoselective manner from 2-1ithio-2,3-dihydrofuran via a dyotropic-type rearrangement of the derived cuprate. An example is depicted below <03SL955> <03S2530>.

1. (Bu3Sn)2CuNLi2 THF-Et20 _-Li

2. NIS 75%

SnBu3

~

NBS

,.._ "HO!

HO

/~

Br I

An intermolecular Pauson-Khand reaction of a dihydrofuran intermediate was used to prepare a benz[y]indenone, allowing for the first synthesis of a zirconocene benz[f]indene complex <03OL3153>. A stereoselective intermolecular Pauson-Khand reaction of 3-(R)methyldihydrofuran was used to construct the desired diastereoisomer of oxabicyclo[3.3.0]octanone ring shown below in the total synthesis of the sesterterpene terpestacin <03JA11514>. Me3Si +

H

NMO ,F'---'Co(00)3

C H2CI2 51%,> 95" 5d.r. > 9 5% regioselectivity

~SiMe3 " H

A Heck-type coupling of 2,3-dihydrofuran with a secondary chloroacetamide produced the two double bond isomers in about 2:1 ratio <03TL5751>. A palladium-catalyzed Heck-type coupling between the heterocyclic iodide shown below and 2,3-dihydrofuran was used as the key step in the synthesis of C-nucleosides. Conditions were optimized to include Ag2CO 3 to prevent double migration and thereby obtain a good yield of the desired 2,5-dihydrofuran products <03JMC1449>.

166

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

Pd(OAc)2 AsPh3

~,'Y-CI

Ag2CO3 Et3N-DMF 45~ 48 hr 81%

Excellent enantioselectivity and double-bond regioselectivity can be achieved in an asymmetric Heck reaction between 2,3-dihydrofuran and aryl triflates by using a combination of chiral diphosphine-oxazoline ferrocenyl ligand and Pd catalyst <03CEJ3073>, as shown below. Chiral diphosphine-containing (arene)tricarbonylchromium(0) complexes were also used as ligands for this reaction to obtain the 2,3-isomer, however, both the yield and enantioselectivity were modest <03TA1455>.

~

Pd(OAc)2 (1.5 mol%) Pd(dba)2-dba Ligand Ugand ", ~+PhOTf - ~ "Ph/.Pr2NEt_PhMe (CH2CI)2 Ph 60 ~ 36 hr 68% conversion 67% conversion 92%ee

Ligand O..../ ~ ...J Fe'PPh2N ",t.Bu ,~;~~PAr 2 Ar = p-MeOCsH4

Magnetic isotopic effects on the endo/exo diastereoselectivity were observed in the Patern6-Biichi photocycloaddition between 2,3-dihydrofuran and an aldehyde <03JA9016>. 2,3-Dihydrofuran was used to trap the acyloxyketene that was generated from the unstable mesoionic 1,3-dioxolylium-4-olate to form the bicyclic cyclobutanone product <03TL7945>. The acid-catalyzed addition of soft nucleophiles to the dienyl acetal system of tonghaosu analogs produced 1,6-adducts exclusively <03EJO4016>. 2,5-Dihydrofuran was transformed to a C 14-C20 segment for the total synthesis of marine macrolide peloruside A <03AG(E)1648>. TMSOTf-promoted condensation of trans-3-hydroxymethyl-2-phenyl-2,3-dihydrofuran with anisaldehyde dimethyl acetal was used in the synthesis of exo-endo and exo-exo isomers of furofuran skeleton of lignan natural products <03JOC9159>. Regioselective oxidation at C3 (versus C7) of the tetrahydrofuran ring in buergerinin F under Sharpless conditions provided buergerinin G <03JOC4117>. An unusual oxidation of hexahydro-benzofuran-3a-ol using a catalytic amount of RuO 4 provided a medium sized keto-lactone. The usual regioselectivity was reversed in this example where the tertiary C7a-H was oxidized selectively over the secondary C2-H <03OL1337>. The chemoselective addition of tetrahydrofuran radical to an aldehyde or an aldimine was dependent on the radical initiators used. As shown in the scheme below, dimethylzinc-air promoted the addition to C=N bond, while triethylborane-air conditions favored the addition to C=O bond <03OL 1797>.

OMe

Conditions

"-

Me2Zn, air, r.t., 21 hr ~ Et3B, air, r.t., 16 hr

/1~ 74% 10%

OMe +

H 75%

Triethylborane / tert-butyl hydroperoxide was found to efficiently generate the tetrahydrofuran radical for addition to aldehydes, providing the threo-alcohol products with moderate to high selectivity and in good yields <03JOC625>. This method was applied to the synthesis of cytotoxic (+)-muricatacin <03JOC7548>. Allyl 2-tetrahydrofuryl ether was transformed into diol under Pd(OAc)z-catalyzed, EtzZn-promoted allylation conditions <03AG(E)3392>. Nucleophilic zinc species derived from tetrahydrofuran added to various aldehydes to provide C-glycals of the furanose type <03TL8433>. The tetrahydrofuran-

167

Five-Membered Ring Systems : Furans and Benzofurans

containing spiroketal moiety found in some steroid derivatives could be ring-opened to give a dihydrofuran ring in high yield under mild conditions using trifluoroacetyl trifluoromethanesulfonate <03OL3619>. An F3B ,OEt2-promoted ring expansion reaction of spiro tetrahydrofuran to dihydrobenzopyran was a key step in the synthesis of the sesquiterpene heliannuol E <03SL411>. A 2-(iodomethyl)tetrahydrofuran derivative underwent a stereoselective ring expansion when treated with p-iodotoluene difluoride to give a fluoropyran as shown below <03TL4117>.

H1105'~O'~, , , ~ I k__/

p-Tol-IF2 Et3N-5HF C H2CI2 r.t., 1 hr 70%

5.3.2.3 Benzo[b]furans and Related Compounds Treatment of 5-trimethylsilylthebaine with L-selectride gave 10-trimethylbractazonine. In this reaction, a rearrangement of a phenyl group took place, and the generated compound was desilylated to give (+)-bractazonine. A mechanistic interpretation for this reductive rearrangement was provided <03JOC1929>. Me

Me I

N-Me

L-Selectride ~ M

Me3Si

THF - )~k ~ Me reflux MeO" bH 92%

TFA bMe

CH2CI2= 96% M

Me

A catalytically enantioselective synthesis of benzofuranones bearing quaternary stereocenters at the C-3 position was achieved using a chiral catalyst as shown below <03AG(E)3921>. Another catalytic process of Sharpless asymmetric dihydroxylation was applied to determine the absolute configuration of some natural products (such as remirol, remiridiol, angenomalin, and isoangenomalin), which have an isopropenyldihydrobenzofuran skeleton <03JOC6274>.

O Ph O

Catalyst ,- ~ ~ ~ = O CH2C12 35~ 81% (97% ee)

~ OCMe2(CCI3)

Catalyst ~l~~~,,Ph ph--- ~IF- 7-.h Ph

A highly regio- and stereoselective Diels-Alder reaction was achieved by the AuC13 catalyzed reaction between benzofurans and phenylacetylenes with carbonyl groups at ortho positions <03AG(E)4399>.

168

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

+

OH

" Ph

61%

OH

O'/"Ph

Anodic fluorination of ethyl (3-benzofuranyl)acetate was applied to the syntheses of 2,3difluoro-2,3-dihydrobenzofuran derivatives, together with 2-fluoro-3-hydroxy derivatives as minor products <03SL 1631>. F ~'~,,""'~302Et

Et4NF'4HF- ~~~.O.~F ,

MeCN-H20 1.8 V, 4F/mol

HO ~-~CO2Et

-I-~~~'O~

40%

5.3.3 SYNTHESIS 5.3.3.1 Furans

(_)-Dihydrospiniferin-1, with the skeleton of a 1,6-methano[10]annulene and a 2,3disubstituted furan, was synthesized and the furan ring was formed via cyclization of a 1,4dicarbonyl precursor <03CC838>. Suzuki-Miyaura coupling of furan-3-boronic ester with a vinyl triflate derivative was adopted to introduce the furan unit in the total synthesis of nakadomarin A <03JA7484>. A Stille coupling reaction was used in the synthesis of metabolites of the prodrug 2,5-bis(4-o-methoxyamidinophenyl)furan <03H(60)1133>, a DNA minor groove dimer binding model <03H(60)1367>, and antimicrobial active compounds <03JMC4761>. 3Lithiofuran derived from bromine-lithium exchange of 3-bromofuran was used in natural product synthesis <03JNP1623>. C-N Cross-coupling of a bromo-substituted furan with various amides, carbamates, and lactams catalyzed by CuI furnished 2- and 3-substituted amidofurans in 45-95% yields <03JOC2609>. Arylboronic acids were used as aryl sources in the synthesis of 2-arylfurans under Mn(II) acetate-promoted radical reaction conditions. Although the yields were not high, they were better than in the phase-transfer Gomberg-Bachmann synthesis using arenediazonium ions <03JOC578>. Reaction of furan and N-tosyl imines produced in situ from TsN=S=O and aldehydes in the presence of ZnC12 gave no Diels-Alder reaction products. Instead, furyl sulfonamides were separated in high yields <03T4939>. This procedure provides an efficient synthesis of 2-substituted furans and is general with respect to the aldehydes. Additionally, it is possible to synthesize 2,3-disubstituted furans by an intramolecular aromatic substitution of N-tosyl imines at the 3-position of furans. A regioselective arylation of a 3-furoate using Pd(PPh3) 4 as catalyst in toluene was developed <03OL301>. Interestingly, 5-aryl products were generated predominantly when Pd/C was used as catalyst and NMP as solvent.

d~

gr

CO2Et

CO2Et

Pd(PPh3)4, PhMe, KOAc: 73% (,6, : B = 50 : 1 ) Pd/C, NMP, KOAc 55% ( A : B = 1 : 3)

As illustrated below, the reaction of cyclic carbinol amides with triflic anhydride provided et-trifluoromethyl-sulfonamidofurans in high yields. <03OL189>, <03JOC2609>, <03JOC5139>. A wide range of lactams was used and the reaction proceeded under mild conditions. ~,-Keto amides were also suitable substrates in these reactions.

169

Five-Membered Ring Systems : Furans and Benzofurans

O

C5H5N 83%

~O20 F3

2-Butene-l,4-diones and 2-butyne-l,4-diones were converted into 2,5-diaryl- and 2,3,5triarylfurans in high yields in the presence of HCOOH and a catalytic amount of Pd on carbon under microwave-irradiation conditions <03JOC5392>. This procedure provides a new approach to the starting material used in the Paal-Knorr furan synthesis, as unsaturated diones are reduced to saturated diones in situ by formic acid and palladium. The solid-phase synthesis of 2,3,5-trisubstituted furans from 1,4-diketones was also reported <03SL711>.

HCO2H, 5% Pd/C conc. H2SO4 (cat.)

O p h ~ P h

PEG-200 microwave 95%

..

~ ' ~ Ph

h

..

HCO2H, 5% Pd/C conc. H2SO4 (cat) PEG-200 microwave 93%

O ~\ Ph/r

Ph / ~O

Double aldol reaction followed by a series of tandem reactions of a Co-complex of bisacetal of acetylenedicarbaldehyde afforded furyl-a-pyrone. The quantity of Lewis acid was shown to affect the result greatly. As shown below, a quantitative amount of furan product was provided when 6 equivalents of F3BoOEt 2 were used. However, a mixture of alkylation products as well as furan was provided if 2 equivalents of BF 3 ~ 2 were used <03EJO 1652>.

OTMS EtO H

(oet OEt

',

H

co2(CO)6

Ph

~ Ph

6 BF3"OEt2 CH2CI2 quantitalive

h

A simple one-pot method for the synthesis of 2,5-diformylfuran was developed from fructose via dehydration followed by catalytic air-oxidation. This procedure used air, the most economical oxidant, in a second step and obviated the costly isolation of 5(hydroxymethyl)furfural and thus would be practical <03OL2003>. The most expanded annulene system known so far was synthesized from a 1,6-bisfuryltriene and an aldehyde using Ca(NO3) 2 as an inducing reagent albeit the yield was low and a number of linear oligomers were also formed <03HCA760>. Acid-catalyzed cyclization of a 5-oxo-akyne provided the furan-containing intermediate in the total synthesis of (+)-citreofuran, and TsOH turned out to be optimal in terms of yield and reaction rate <03JOC1521>.

O MeO

~o

p-TsOH 85%

-'-

,,o OMe

170

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

Chiral furfuryl alcohols were prepared via high-pressure Friedel-Crafts reaction of 2methylfuran and alkyl glyoxylates using (salen)Co(lI) complex as a catalyst, although the enanfioselectivity was not very high (up to 76% ee) <03TA3643>.

Ca,a, s, ( ) Catalyst (5 mol~

+.J%O2Bu

._~~_

"NO~ ~

PhMe, 10 kbar

~

B

CO2Bu

47%

~H

But

u

(R)-, 76% ee

\tBu

tBu/

Symmetrical and unsymmetrical 2,5-bis-acetylenic furan derivatives were produced in high yield using Pd-catalyzed cross-coupling reaction of 2,5-bis(butyltelluro)furan, which was prepared from furan through lithiation-transmetallation and alkylation <03TL1387>.

/._ / uH

1. n-BuLi, TMEDA hexane

2. Te (2.5 eq.)

3. BuBr (3 eq.) 90%

400 mol%

BuTe

eBu

,,,/~ ~,,=

PdCI2(20 tool%) MeOH, Et3N 82%

a-Acetyl or ct-acetonyl radicals, generated by reaction of dilauroyl peroxide (DLP) on xanthates, added to 2-acetylfuran in a conjugate addition manner to produce the corresponding 2,5-disubstituted furans <03CC2316>. The furan ring subunit of a natural product was synthesized from a dihydrofuran using a dehydrogenation procedure. The formation of tanshinone IIA is shown below <03TL2073>. The dihydrofuran was obtained by reduction of the corresponding lactone <03JA5642>. o

DDQ 1.

benzene, rt 95%

The first example of nucleophilic aromatic substitution of 2-methoxyfurans with Grignard reagents was reported <03TL5781>. In this reaction, the Grignard reagents derived from allylic and benzylic halides gave lower yields and the presence of an ester group at the 3position was important. If the group was an acetyl, or an ester at the 5- or 4-position, the reaction provided the alcohol exclusively or as a main product derived from the addition of Grignard reagent to these groups. Conjugated ene-yne-carbonyl compounds were employed again as 2-furylcarbene precursors that were allowed to react with allyl sulfides to form S-ylides followed by [2,3]sigmatropic rearrangement to provide the corresponding tetrasubstituted furans in high yields <03OL2619>.

H+CH O

z

CH2C,-"

2.5 mol%

reflux 98%

Rh]

Five-Membered Ring Systems : Furans and Benzofurans

171

Reaction of diacetyl ketones in the presence of F3B.OEt 2 and water afforded bisfuryl methanes in good yields. When the reaction was carried out in dry THF and in the presence of 2,4-pentanedione, tri- and tetrasubstituted furans were delivered <03T755>. As depicted in the following scheme, 2,3,4-trisubstituted furans were provided with high regioselectivity and high yields through Pd-catalyzed isomerization of alkylidene cyclopropyl ketones <03AG(E)184>. The reaction is quite general and shows a dramatic salt effect. The reaction provided furans in the presence of sodium iodide, or 4H-pyrans in the absence of NaI.

PdCl2(CH3CN)2 (5 mol%)

PdCl2(CH3CN)2 5 ~ 0 2 Et_.. (5acetonemOl%1507 )H ~ C O 2 E t _ _ C7H1 e O/~'-Me r.t. 80%

acetoneNalC7H15~ 2 ~ t reflux 74%

Ma and coworkers reported an elegant regioselective synthesis of 2,3,4-trisubstituted furans using a Cu--catalyzed ring-opening cycloisomerization reaction of cyclopropenyl ketones <03JA12386>. It is noteworthy that the regioselectivity of this reaction can be tuned using different catalysts. 2,3,5-Trisubstituted furans can be produced from the same starting material using a Pd catalyst with excellent regiocontrol.

2C•

EtO P h "

conditions

~ Ph

A

.CO2Et Ph ~ e

CO2Et Cul (5 mol%), CH3CN,reflux: A : B = 1 : 99, 89% e PdCI2(CH3CN)2(5 mol%),CHCI3, reflux 9

%% B

A

9

B =99"1,73%

Full details for the synthesis of 2,3,5-trisubstituted furans via an oxypalladation-reductive elimination domino reaction were given <03T4661>. Under an atmosphere of CO, the reaction afforded furan derivatives with incorporation of a carbonyl group.

O EtO

Pd(PPh3)4 (0.5 mol%)

+

~

K2003, DMF 60 ~ 55%

Radical cyclization of divinyl ethers prepared from the reaction of 1,3-dicarbonyl compounds and ethyl propynoate gave rise to trisubstituted furans as shown in the following example <03TL2125>.

~CO2Et

Bu3SnH ~ AIBN 63%

CO2Et

Regioselective synthesis of substituted furans utilizing allene derivatives is still a focus of attention this year. An efficient procedure for the synthesis of 3-thio-substituted furans was developed using thioallenyl ketones via 1,2-migration of the thio group from an sp 2 carbon atom in allenyl sulfides <03AG(E)98>. Propargyl sulfides gave similar results. If thiopropargyl

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

aldehydes were used as starting materials, 2,3-disubstituted furans were generated. This protocol therefore provides a simple means for the preparation of di- and trisubstituted furans.

BUs~:=:(c~2)3 Ph MOMO

Cul (5mo1%), P h ~ O

r.t. 36 h 82%

Bu

CH2)3OMOM

Another example of the regioselective synthesis of substituted furans using Pd-catalyzed coupling cyclization reactions of allenyl ketones with organic halides was reported <03CEJ2447>. This methodology shows high substituent-loading capacity and functional group tolerance, as well as generality and versatility. If one of the substituents of the allenyl ketone is H, 2,3,4- and 2,3,5-trisubstituted furans were also formed.

HllC5

Bu

Phi (2 equiv) Pd(PPh3)4(5 mol %) K2CO3 (2 equiv) TBAB(0.2 equiv) DMA, 100 ~ 72%

Ph Bu ) ~ , H11C

Isomerization of an a-allenylcyclopentenone, obtained from a propargyl ether and a mopholino a,13-unsaturated amide, in the presence of Hg-catalyst to a furanyl cyclopentenone provided another example of the conversion of allenyl ketones to furans <03OL 1171>.

Me HO

Ph O

Ph

Hg(O2CCF3) 2

~ v t-Bu 0H2CI2 71%

M~~t_Bu

Another approach to tetrasubstituted furans via allenes also appeared <03TL3263>. In this reaction, cumulenes were produced as an intermediate from alkynyl epoxides and SmI 2 and the allyl group was incorporated regioselectively.

OAc /Bu ipr

1. Sml2,THF 2. , ~ B r Pd(PPh)4(10 mol%) 2,2-dimethyloxirane K2003

. i

B

u

~

~r

Me Me

70%

Tri- and tetrasubstituted furans were provided via Ru- and Pt-catalyzed sequential reactions of propargylic alcohols and ketones <03AG(E)2681>. In this synthesis, two different kinds of catalysts sequentially promoted each catalytic cycle in the same medium and gave the products with high regioselectivity and good yields.

Cp*RuCl(~t2-SMe)2RuCp*CI (10 mol%) PtCl2 (20 mol%) NH4BF4 (20 mol%) reflux, 36 hr (Cp*= TI5-C5Me5) 75%

Five-Membered Ring Systems 9Furans and Benzofurans

173

Substituted furo[2,3-b]pyridones were assembled by a Pd-mediated sequential crosscoupling Sonogashira reaction-Wacker-type heteroannulation and deprotection reactions of pyridones, alkynes and organic halides in an one-pot operation <03OL2441>. The coupling products of pyridones and alkynes could be separated and a single palladium catalyst intervened in three different transformations.

~~O2Me OBn

OBn

CO2Me PdC12(PPh3)2 (4 mol%)

+

.,,,t~ .,~ I

Cul (4 mol%) MeCN-Et3N 60~ 24 hr 63%

I

Me

O

-"-

O2Me Me

Furo[3,2-b]pyrroles were synthesized from commercially available 5-bromofuran-2carbaldehyde via a 4-step transformation <03TL4257>. These procedures show the divergence and allow for the potential for the construction of compound libraries. 5.3.3.2 Di- and Tetrahydrofurans

Extensive efforts have been given to the synthesis of di- and tetrahydrofurans in 2003. Like before, Williamson cycloetherization continues to be one of the most popular and practical methods. In the total synthesis of muconin, Takahashi converted the tosylate as shown below into the tetrahydrofuran <03T1627>. Marshall <03JOC1771>, Fleet <03TL5847> <03TL5853>, Lewis <03OBC2307> and Paquette <03OL177> also synthesized tetrahydrofuran rings in their respective works employing the same strategy <03JOC1771>.

O H25012

1.

~

-

OH

5Ts

6H

13"(x = 93" 7

H

NaOMe MeOH r.t. to 50 ~

H25012 " 2. (MeO)2CMe2 HO CSA CH2CI2 78%

In addition to a "real" leaving group like a tosylate, treatment of 1-iodomethyl-l,5-bisepoxides with zinc also afforded substituted tetrahydrofurans. An example is illustrated below <03OL 1931 >. o Me

"

I~

O

H

"~

Zn EtOH reflux 95%

Me~,,O ........

dr = 90" 10

H LOH

On the other hand, treatment of the benzenesulfonate depicted below with 3 equivalents of LDA gave an intermediate propargyl alkoxide through a double elimination. Then a concomitant intramolecular nucleophilic substitution led to the formation of the tetrahydrofuran ring <03TA1363>.

174

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

OBs =

F . ~

O

0~~'"

x3;~

LDA

~ c l

THF -40~ 1 hr 600/0

F

Another way in which a tetrahydrofuran ring can be constructed is via the opening of an epoxide <03TL3175>. Xu studied the synthesis of methyl isosartortuoate employing an epoxide opening route , and Yadav also prepared both enantiomers of altholactone and isoaltholactone utilizing a similar approach <03TL583 l>. In the total synthesis of malayamycin A, a diol cyclization step was used to construct the tetrahydrofuran skeleton <03OI..4277>. Ambeflyst has also been reported to induce diol cyclization <03CC2696>. Highly enantioselecfive mercuriocyclizafion of ,t-hydroxy-cis-alkenes was reported by Kang who generated optically active 2-monosubstituted tetrahydrofurans in up to 95% ee <03JA4684>. Kang later reported a catalytic enantioselecfive iodocyclizafion of y-hydroxy-cis-alkenes, but the ee% was not as good as those obtained from the mercufiocyclization route <03JA15748>. An efficient preparation of a trisubstituted tetrahydrofuran in >90% de was reported by Snider en route towards his synthesis of ent-haterumalide NA methyl ester, and this key reaction is shown below <03OLA385>. Several similar applications of iodoethefizafion approach were also recorded in 2003 <03TL8365> <03OL4109> and <03CEJ390>.

OH OH

OSiMe2t-Bu

OSiMe2t-Bu

12

NaHCO3 Et20 0 ~ 4 hr 81%

|"H HO

As can be seen in the following scheme, bromoetherization <03JA2374> <03SL51> was also employed to form tetrahydrofurans with a 3:1 diastereoselectivity. Selenoetherization of (E)- and (Z)-2-ene-l,5-diols, on the other hand, reportedly produced a mixture of tetrahydrofurans and oxetanes <03T7365>.

HO~Me2t-Bu

OH

NBS 0 - 23 ~ 91%

J

,

~

Me2t'Bu

NO

Prins-pinacol condensation of a (Z)-a,13-unsaturated aldehdye and an (S)-carvonederived alkynyl dienyl diol as illustrated below provided the formyl tetrahydroisobenzofuran as a single diastereomer in 84% yield in two steps <03JA6650>.

.CHO ipr3SiO HO tBuPh2SiOi Me3S

~

1. p-TsOH.H20 MgSO4 CH2CI2 ,OH -78~ -20~ 2. SnCI4 (0.1 equiv) CH2CI2 -78~ ---, r.t. 84% (2 steps)

ipr3SiO

~

tBuPh2SiO

O

SiMe3

Other syntheses of tetrahydrofurans involving cationic mechanisms were also recorded in 2003 <03OL1107> <03JOC9159>. Michael addition was also extensively studied in tetrahydrofuran ring formation. As an example, the unsaturated ester shown below was converted into a tetrahydrofuran by treatment with TBAF in THF through Michael addition.

Five-Membered Ring Systems : Furans and Benzofurans

175

After reduction and protection steps, a mixture of diastereomers was obtained in a ratio of 1:1 <03T1613>.

-r~ '-' H

B n O " ~

CO2Et

/

1. n-Bu4NF THF r.t., 1 hr

2.DIBAL-H

BnO~~.-,-~.~

OSiMe2t Bu

CH2CI2 -78 ~ 1 hr 3. t-BuMe2SiCI imidazole, DMF r.t., 3.5 hr 43% Construction of tetrahydrofuran frameworks by Michael addition was also employed in the synthesis of 15-epi-haterumalide NA methyl ester <03OL957>, pentacyclic derivatives <03OL2425>, diquinanes <03JA3682> and other functionalized tetrahydrofurans <03TL2795> <03JOC4239>. A structural analog of podophyllotoxin was prepared utilizing a strategy in which a phenylsulfonyl group was used to promote the dearomatizing Michael-type cyclization of tethered organolithiums onto aromatic tings <03OL831 >. A novel cycloaldol approach to the isobenzofuran core common to many eunicellin diterpenes was reported <03OL1039>. An unusual reaction route leading to the formation of a 2,2,5,5-tetrasubsfituted is shown below <03T1483>. In this procedure, a bicyclic aziridine was proposed to be an intermediate.

HO ~ " H

HO N a O M e O ~ Ph -OMs MeOH r.t O

3,5-(CF3)2C6H3COCI Ph

Et3N CH2CI2

CO2Me I,~CO2Me

C

F3 \ \ "F CO2Me ~,__7 - ~ 3 Y F3C' Radical versions of the bromo- and iodoetherization reactions of bis(homoallyl alcohols were reported by Hartung in 2003 <03EJO4033>. Other radical procedures that led eventually to tetrahydrofurans were also reported <03AG(E)3687> <03AG(E)3943> <03TLA331> <03JO1633> <03T77>. Two examples in which alkoxy radical cyclizations <03CC422> and gallium-or indium-promoted radical cyclizations were involved <03T6627> are illustrated in the following schemes. I1

~lJ~Br

n-Bu3SnH Ac

C6H6 reflux 40%

O

HInCI2 THF r.t., 30 min 92%

A cobalt(II)-catalyzed oxidative cyclization converted a secondary alcohol to the trans2,5-disubstituted tetrahydrofuran <03JA14702>. Oxidants such as vanadium(V) complex <03EJO2388>, ruthenium tetroxide <03TL5499> and osmium tetroxide <03AG(E)948> were all employed to convert either homoallyl alcohol or polyenes to molecules that contain

176

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

tetrahydrofuran structural units. Other transformations from which tetrahydrofurans can be obtained are by starting from tetrahydrofuran-containing precursors like tetrahydrofuran <03CEJ2123> <03OBC318>, lactols <03OIA983> <03CC2062> <03AG(E) 1387> <03OL625> <03H(59)101> and lactol acetates <03JA14149> <03T2423>. The following example depicts a pathway showing the preparation of a substituted tetrahydrofuran from a spiroketal <03EJO4003>.

~~_

,,hiI~

H

Et20 590/0

HO

Iq

HO

Stereoselective synthesis of tetrahydrofuro[3,2-c]benzothiopyrans was achieved by an intramolecular [4+2] cycloaddition of o-thiobenzoquinone methides that were generated from bis(2-formylphenyl)disulfide and alkenols in the presence of iodine <03TL6513>. In Chiu's approach towards the total synthesis of pseudolaric acids, a tandem rhodium carbene cyclization--cycloaddition was employed to afford pivotal intermediates containing tetrahydrofuran rings <03JOC4195>. Five catalyst precursors and thirteen phosphorus ligands were screened to lead to the favorable combination. In this manner, the palladium-catalyzed cyclization of bisdienyl ethers shown below proceeded smoothly to give essentially a single diastereomer <03OL3595>.

Bn f-~/~~"""~'~'nC5H11 ~N~"~,.,~

Pd2(dba)3 (2,4-di-t-butylphenyl)phosphite Bn ... N-hydroxyphthalirnide . O ~ THF-MeCN ( 1 " 1 ) 25 ~ 3 hr 67%

ONPht ' ' ' ' ' ~ nC5H11

k,,.~..,,~

The cyclization of the dianions of some 1,3-dicarbonyl compounds with l-bromo-2chloroethane led to the generation of a number of 2-alkylidenetetrahydrofurans with good regioand E/Z-diastereoselectivity. An example is shown in the following scheme <03JOC9742>. O

O

1. LDA (2.3 equiv) 2. CICH2C H2BrTHF --78 ~ --, 20 ~ 14 hr 68 ~ 2hr E: Z>98:2 58%

High chemo- and regioselectivity were observed for the metal complex-catalyzed cycloisomerization of readily available 4-propargyl-cyclohexanediones, leading to the formation of fused oxabicycles. As can be seen in the reactions below, a proper choice of metal catalyst can provide the 2-alkylidenetetrahydrofuran almost exclusively <03OL1975>.

R ,MjoV LvLv

~

THF" ~ r.t.

. A

Ro +

R B

177

Five-Membered Ring Systems : Furans and Benzofurans R

[M] (mol%)

Time

Product

H Pd(OAc)2(5) 2 min H W(CO)5-THF (10) 0.5 hr Me Pd(OAc)2(5) 8 hr Me PdCI2 (5) 9 hr

Yield

A A A : B= 8 : 1 A : B= 1 : 14

85% 85% 75% 91%

A novel chemo-, regio-, and stereoselective cascade featuring an isoxazole benzoisoxazole rearrangement was uncovered by Suzuki. The reaction below illustrates the preparation of a polycyclic molecule having an embedded 2-alkylidenetetrahydrofuran moiety from readily available fused isoxazoles <03OL395>. Br

Br

,,~ 9

",,~ CO2Et

LD A

CO2Et ,

55 ~ hr 38%

As shown below, a simple way to construct 3-alkylidenetetrahydrofurans was the Lewis acid promoted reaction between alkylidenecyclopropanes and diethyl ketomalonate <03TL3839>. Wittig reaction of a 3-ketotetrahydrofuran expectedly led to the formation of a 3vinyltetrahydrofuran <03JOC 1150>.

P Ph+

O

EtO2C'~O2Et

Ph Yb(OTf)3 (5 mol%) .. ~ Ph C ICH2CH2CI 40~ 24 hr 84%

Et

t

Mikami reported a procedure as shown below which concerned a highly effective Cl-symmetric N,P-ligand for the enantioselective palladium(II)-catalyzed carbocyclization of allyl propargyl ethers, affording a variety of 3-alkylidene-4-alkenyltetrahydrofurans <03EJO2552>. Zhang also reported his approach towards similar products in >99% ee by employing [Rh(COD)C1] 2 and (S)-BINAP <03JA11472>. A subsequent Suzuki reaction of the intermediate during the palladium(0)-catalyzed cyclization of allyl propargyl ethers was also possible, furnishing more diversified products <03OL3645>. CO2Me ~~1

Ligand ._ / ~ ~ _ _ ~ 0 0 2 I [(MeCN)4Pd](BF4)2 (5 mol%) .... ~) HCO2H (0.2 equiv) DMSO 88 % e e 80 ~ 24 hr (S)-(+) 8 7%

Me

~ ~ N " ~ . Ligand

"

--~ "" ~ ~ P h 2 ~

(10 mol~

On the other hand, hydroxylative cyclization of allyl propargyl ethers was catalyzed effectively by Hg(OTf) 2 to generate 3-methylenetetrahydrofurans in good yields <03OL1609>. Structurally more elaborate bicyclic alkylidenetetrahydrofurans could be realized via Pauson-Khand-type reactions. Thus, Chung reported the rhodium-BINAP complex catalyzed enantioselective Pauson-Khand reaction under phase-transfer conditions with sodium dodecylsulfate (SDS) <03S2169>. Chung also used an entrapped Rh complex prepared by a

178

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

sol-gel process <03TL2827>, as well as immobilized heterobimetallic Rh/Co nanoparticles <03CC1898> in similar Pauson-Khand processes. Vaska's complex [IrCI(CO)(PPh3)z] was shown to efficiently catalyze the intramolecular Pauson-Khand reaction of ethers tethered with an allyl group and a propargyl group <03SL573>. In the presence of a catalytic amount of [Rh(COD)C1] 2, the allenene illustrated below underwent cycloisomerization to form the 3methylenetetrahydrofuran in a meager yield and 84% purity <03TL6335>.

[Rh(COD)CI]2 P(O-o-Tol)3

/-,..,~"

O

dioxane 110 ~ 24 hr 32%

For precursors containing a methylenecyclopropane, palladium-catalyzed reactions led to cycloadducts with an exocyclic double bond, and an example is shown in the following scheme <03JA9282>.

Pd2(dba)3 P(O/-Pr)3 O~.~-~" CH2OSii'BuMe2

dioxane 100 ~ 0.5 hr 67%

O ~ II

CH2OSii.BuMe 2

A palladium(II)-catalyzed three component coupling reaction was established by Lu, who performed the intermolecular carbopalladation involving propargyl alcohols and alkenes, and this was followed consecutively by allylic chloride insertion to the C-Pd bond and its quenching by 13-heteroatom elimination in the presence of an excess of chloride ions. An example is shown below <03TIA67>.

Me c, Me

II

I%

H

1. n-BuLl 2. Pd(OAc)2

oc,

, , MeO2C / r - - / _ M eO2C~ ~ '

CH2=CHCH2CIrt.(5 equiv) 47%

Phil)/

A simple way to form 2,3-dihydrofurans is by utilizing an organoselenium approach <03JOC4422>. Elimination of water from a ~,-lactol is also a viable route towards 2,3dihydrofurans <03OL3619>. Intriguing transformations of 2-nitro-3-substituted-2,3dihydrofurans in the presence of F3BoOEt 2 led to the formation of 3-formyl-5-hydroxy-2,3dihydrofurans <03TL3167>. It was shown by Karade that a variety of alkenes react with 1,3dicarbonyl compounds in the presence of diacetoxyiodobenzene to provide polysubstituted 2,3dihydrofurans as displayed in the following scheme <03TL6729>. Similar conversions were reported using other oxidants such as ceric ammonium nitrate (CAN) <03SC213> <03H(60)939> <03S 1977>, ceric tetra-n-butylammonium nitrate <03OL2363>, Mn(OAc)3o2H20 <03EJO1410> <03S1977>. Miiller, on the other hand, investigated the enantioselective rhodium-catalyzed reactions between 2-diazocyclohexane-l,3-diones and alkenes, which led to products with similar structures <03HCA3164>. Palladium-mediated coupling of alkenes and a 1,3-dicarbonyl derivative was utilized in the total synthesis of (+)brevione B <03TL5235>.

179

Five-Membered Ring Systems : Furans and Benzofurans

o

. . ~

+

PhI(OAc)2

ph,,~,,,"~Ac

MeCN

0~ lhr 77% Nacci, whose procedure involved the use of the ionic solvent n-butylpyridinium tetrafluoroborate, reported a stereoselective synthesis of 2,3-dihydrofurans <03JOC4406>. O +

O

Me(CH2)12CHO

bpy+BF4-

P'n-~"~'O~\//Ph

K2003 50 ~ 38 hr 82%

Me(OH2)12'S~ S ~ ~ E: Z> 99 : 1

]

A ruthenium complex catalyzed an oxidative cyclization reaction as depicted below to give 2,3-dihydrofurans with PPh 3 as ligand, and in the presence of allyl acetate and CO <03CL24>.

Me Ph H O ~

+ 77"',,f OAc

Ru3(CO)12 PPh3 K2CO3 CO (5 atm) PhMe 160 ~ 20 hr 99%

"

Meh...a/~/.,,O f~" Me P

The most obvious method for synthesizing 2,5-dihydrofurans is by employing ring-closing metathesis reactions. Along this line, Wallace reported the first example of a quadruple ring-closing metathesis reaction. Thus, the polyene shown below underwent a ruthenium complex catalyzed reaction to afford a mixture of two cyclic compounds <03TL2145>. Trost <03CEJ4442>, Liu <03JOC7889> and North <03TL8157> also made use of similar metathesis approaches to synthesize 2,5-dihydrofurans.

--~o

o--~

CI. PCY3 "Ru CI" i~Cy3:~ph CH2C12 r.t., 24 hr

,"

-I65%

xxT 12%

A manganese carbyne complex was found to catalyze the cyclization of dipropargyl ether in the presence of i-Pr2NEt and catalytic amounts of CuBr and LiI to give the manganese enediyne complex. Upon air oxidation, the free enediyne was generated in excellent yield <03OM3915>. Dipropargyl ether also reacted with 1,3-butadiene in the presence of 10% [CpRu(MeCN)3PF 6] and 10% EtaNC1 to furnish a 2,5-dihydrofuran fused with an 1,3,5cyclooctatriene <03OL2841>. In Pattenden's synthetic study towards the total synthesis of phomactin A, deprotection of the MOM ether group of the precursor shown below using camphorsulfonic acid was accompanied by cyclization to give a 2,5-dihydrofuran <03OBC3917>.

180

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

LO

HO

o.MOM CSA

0 ~..,,"~,,.

OSiMe2t-Bu

CH2CI2 0oc

OSiMe2t-Bu

As can be seen in the scheme below, a mixture of allenylcarbinols was found by Burger to undergo a cyclization reaction catalyzed by AgNO 3 to lead to a mixture of 2,5-dihydrofurans in good yield <03T1389>. Hoppe also reported similar cyclizations employing an iodoetherization procedure <03SL 1969>. H

. , ~ -/ . ~ ~,-,.,,., CF3~2Me H,f, OH n-Pr

H

oJ~ C FCO#Me 3 AgNO3 ,, "n,,.]~ +H,,f OlH acetone_H20n.Prr n-Pr 90% 1:12

\,., C"r 3

H,,./~ \,,,GU21VI .... e n.p r4~',O/'~C F3

+

1:12

Wills investigated the intramolecular cyclizations of alkylidene carbenes and showed that the ketone depicted below was converted to a 3.6:1 mixture of two 2,5-dihydrofurans utilizing the Shiori protocol <03T4739>.

0SiMe2t-Bul~~

Me3SiC(Li)N2 DME-C6H14 -78 ~ --* r.t. 64%

OSiMe2t'Bu

H HO

= t. BuMe2SiO/ ' " y

+ t.BuMe2SiO / ,,.

....

OSiMe2t-Bu

OSiMe2t-Bu

3.6:1

Nair described a reaction in which the 1:1 zwitterionic intermediate generated in situ from dimethyl acetylenedicarboxylate and cyclohexyl isocyanide reacted with a quinone to furnish the spiro-iminolactone as illustrated in the following scheme <03T10279>.

Cy ~N O

CIO2Me + II I

I

O2Me

+

Cy-N=C"

06H6 80 ~ 4 hr 92%

CO2Me O2Me

J-

O

5.3.3.3 Benzo[b]furans and Related Compounds The palladium-catalyzed Sonogashira reaction of aryl bromide and aryl acetylene gave non-symmetrical diarylethynes, which can spontaneously cyclize to give 2-arylbenzo[b]furans in a modest yield as shown below <03T7509>. Other types of 2-alkyl/aryl substituted benzo[b]furans were also obtained by the palladium--catalyzed coupling reaction of oiodophenols (even o-iodophenols with a base-labile nitro group) with a variety of alkynes in the presence of prolinol as base in water. This environmental friendly procedure does not need a phase transfer catalyst or water-soluble phosphine ligands and is free from the use of any organic co-solvent <03TL8221>. A similar process was also reported with an amphiphilic polystyrene-polyethylether (PS-PEG) resin-supported palladium-phosphine complex as a catalyst in water to give the corresponding aryl-substituted alkynes in high yields under copper-free conditions <03H(59)71>. In the total synthesis of pterulinic acid, the core 2-

Five-Membered Ring Systems : Furans and Benzofurans

181

substituted benzofuran structure was generated by the palladium-catalyzed heteroannulation of an o-iodophenol derivative with methyl 3-butynoate <03T1277>.

A c O " ~ ~ ,-OAc Br" v -t-

~~

Me

v

AcO.~,l~T,,OAc Pd(OAc)2 ~ Cul "-

~

Me(3

KOH HO.,~lf~.-O \

DIPA 50~ 95"/o

O --../

62%

In the total synthesis of (_+)-linderol A, the 6,5,5-tricyclic cyclopenta[b]benzofuran was made by a tandem reaction of a 3-ethoxycarbonylcoumarin derivative with dimethyl sulfoxonium methylide <03JOC 1216>.

OMe

H2C=S(O)Me2NaH ~ DMF 76%

~ O O E t MeO"- ~

-"u N

H

A variety of biologically interesting dihydrofurocoumarins were synthesized in high yields by a palladium-catalyzed annulation of 1,3-dienes with o-iodoacetoxycoumarins. This is a general, regio-and stereoselective reaction, and a wide variety of terminal, cyclic, and internal 1,3-dienes can be selected as substrates. A syn-zc-allyl palladium intermediate was proposed in this synthetic transformation <03OL797>. To establish the absolute configuration of some naturally occurring furocoumarins, 4-methyl-8-(2-E-phenylethenyl)-8,9-dihydro-2H-furo[2,3h]-l-benzopyran-2-one was synthesized as shown below, resolved, and its absolute configuration investigated <03OBC186>. Other similar work was also described <03JOC6314>.

Pd(dba)2(5 mol%) dppe Ag2CO3 ph/ I

dioxane-H20 (5:1) 24 hr

O

~

p

h

N-Acyltetrahydro-l-aza-9-oxafluorenes were synthesized by cycloaddition of 3-acyl1,4-dihydropyridines with p-benzoquinone under acid catalysis, the generated N-acyltetrahydro1-aza-9-oxafluorenes can undergo further oxidation to give 1-aza-9-oxafluorenes, a novel type of cyclin-dependent kinase inhibitor <03JMC876>. The synthesis of optically active 2,3dihydrobenzofurans was also achieved through a combined strategy by ferric ion-catalyzed cycloaddition of styrene with quinone, followed by lipase-catalyzed enantioselective acylation <03TIA081>. A similar process for the synthesis of some interesting dihydrobenzofuran derivatives was developed by nucleophilic addition of stilbene to 1,4-benzoquinone, followed by an intramolecular cyclization. A biomimetic approach was proposed to account for the stereochemistry of the generated molecules <03T1501>. InC13-catalyzed [3+2] cycloaddition was also applied to the synthesis of 2,3-dihydrobenzofurans employing a similar concept <03S 1100>.

182

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

HO

Ph O

.%

Me+

HO ~

Ph O~e

doi xaneHCIO ,.4 o

~

Pb(OAC)4THF ---~N

70%

,,-L-,o

~

"~T ''Me

0.r

84%

A tandem cyclization approach was applied to the synthesis of mescaline analogs via a direct C-H activation followed by an olefin insertion <03OL 1301>.

nN

H

[RhCl(coe)2]2 FcPCy2 PhMe 150~ 75%

s

OMe

Titanium benzylidenes based arylboronates were generated from thioacetals with low valent titanium species, CP2Ti[P(OEt)3] 2, which reacted with Merrifield resin-bound esters to give enol ethers. The remaining boronate then underwent further Suzuki cross-coupling to give diversified 2,5-disubstituted benzofurans, which eventually were released from the solid support by 1% TFA <03OL4389>. The same concept was applied to generate a 2-substituted benzofuran library with Wang resin-bound esters as starting materials <03JOC387>.

1-.o

T,c,

,. oro..r., o

PG

._

2. Arl, Pd(0) 3. TFA-CH2CI2 4.10%HCI-MeOH

8-Nitro-2-dimethylamino-l,2,3,4-tetrahydro-2-dibenzofuran was prepared by an acid--catalyzed [3,3]sigmatropic rearrangement of an O-aryloxime as a key step as depicted below <03JOC770>. A similar pathway was also presented for the synthesis of other dihydrobenzofurans <03OBC254>. N Me2

O2N

HCI-HOAc

O2N~

5

/ NMe2

ip

90-110 ~ 7.5hr 95% In the total synthesis of (-)-ephedradine A, the key intermediate, transdihydrobenzofuran, was prepared by Davies catalyst catalyzed C-H insertion with high diastereoselectivity <03JA8112>. In another total synthesis of (+)-epi-conocarpan, the key intermediate 5-bromo-cis-2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzofuran was also made by ruthenium-porphyrin--catalyzed intramolecular C-H insertion using an aryl tosylhydrazone salt as a carbene source <03TL1445>. o-Alkenylphenols were oxidized with VO(acac)2/TBHP to the corresponding o-hydroxybenzyl ketones under mild reaction conditions, which eventually led to 2-substituted benzo[b]furans by a series of reactions <03JOC3691>. 3-Aryl substituted benzo[b[furans were generated from the aryl ketones shown below. In this reaction, the

183

Five-Membered Ring Systems : Furans and Benzofurans

substrate was treated with MeLi for a halogen-metal exchange process, and the resulting aryllithium underwent an intramolecular nucleophilic addition to the ketone. Elimination of water then gave 3-aryl substituted benzo[b]furans, being the key intermediate for the total synthesis of natural products malibatol A and balanocarpol <03OL1191>. OMe MeO

~CHO/

OM e OMel

OMe

OMe

' , 2 p-TsOH 75%

OMe OMe

The palladium-catalyzed three-component reaction depicted below was reported for the creation of polysubstituted bicyclic molecules (including dihydrobenzofurans) in good yields from readily available substrates. A mechanistic interpretation was also presented <03OL4827>.

{~

O-~'~

1

+

Pd(OAc)2 PPh3

~

0S2003

.,,,CO2t-Bu I1 + n-Bul

norbornene DME 80 ~ 85%

I

n

-gU \

CO2t-Bu

2-Hydroxy-l,2,2-triphenylethanone based carboxylic esters upon irradiation with a medium pressure mercury lamp resulted in a rapid and quantitative photolysis to afford the carboxylic acid and benzo[b]phenanthro[9,10-d]furan. No yield was reported for this synthetic transformation <03TL3151 >.

.-~O'2CR Ph , , ~ P h Ph" J] u

hv

,. -RCO2H

r[~y~

Ph

ll-"~'~

hv [O]

_--

SmI2-H20-amine mediated diastereoselective intramolecular couplings were reported for the synthesis of dihydrobenzofuran, and a radical mechanism was proposed to account for this reaction <03OBC2423>. A similar approach for the synthesis of pyridine-fused polycyclic amines was also developed by use of AIBN/Bu3SnH as a reducing system <03TL2995>. Me

Me

H

H20-amine 72%

Dibenzofurans were synthesized from 6-substituted-3-alkoxycarbonylhex-3-en-5-ynoic acids. An interesting mechanistic interpretation was given <03SL2005>.

184

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

O2H

NaOAc hydroquinone "~

Ac20 reflux 77%

CO2Et

Oxygen-bridged phenyl morphans were synthesized by an intramolecular phenolic hydroxyl based SN2 displacement of bromine as shown below <03T4603>. Two other phenylmorphans were also synthesized by almost identical conditions <03HCA484>. Closely related benzo[b]furan based oxaspirocyclic molecules were made by a similar approach <03TL2971>.

1. NaBH4 H O

N~-CH3

~Bt

H

~ r

MeOH

"r (\ ~ N-CH3 ~" ~,~..,,,,,L__/ MeOH-H20 " O ~" 11%

2. KOH

The Sonogashira coupling reaction was applied to the synthesis of phenyl acetylenes, which were used as substrates in the synthesis of spirodihydrobenzofurans, a central motif of some natural occurring antibiotics <03OLA425>.

OMOM /

OMe [~,OMOM /II%~,,~jCHO

1. n-BuLi THF 2. H2, Pd/C K2CO3 EtOAc

OMe

3. TPAP NMO 4. Me3SiBr CH2Cl2 83%

3-Nitrocoumarins underwent intermolecular Diels-Alder reaction with substituted dienes, followed by sequential hydrolysis / decarboxylation / Nef reaction / cyclodehydration to afford dihydrodibenzo[b,d]furans. All these reactions were carried out in an aqueous medium <03JOC9263>.

I ..

1. NaOH neat

heaUng

c,

2. H2S04

0~

As depicted below, Swem oxidation and acid-catalyzed ring closure reactions were employed to construct fully functionalized benzo[b]furan, a key intermediate for the total synthesis of natural product kendomycin <03OL4657>.

185

Five-Membered Ring Systems : Furans and Benzofurans

Me 9

Me

E,N

OMOM

:

1. (COCI)2

Me

Me

-78 ~ to r.t. e

2. TfOH, 4,/x,MS PhMe-EtOH 60 ~ 81%

9

Me

M

e

~k tBuPh2S i O - - j

Cycloalkanonaphthofurans were obtained by acid catalyzed cyclization of naphthols with cycloalkadienes <03S1043>. In a similar ring formation pathway, a variety of substituted 2,3dihydro-5-benzofuranols was realized <03JMC3083>. Amberlyst-15 was utilized to induce intramolecular cyclization to afford polycyclic benzo[b]furans, which were key intermediates in the total synthesis of Stachybotrys spirolactams <03JOC7422> <03OL1785>. The palladium-catalyzed intramolecular Heck reaction was applied to functionalized heterocyclic molecules, e.g. methyl 4-(6-chloro-2-iodopyridin-3-yloxy)butenoates as shown below <03TL725>. The same reaction was also employed in the synthesis of tetracyclic benzo[b]furans with Pd2(dba)3/HP(t-Bu)3BF4 as a catalyst under mild conditions <03OL3679>. The 3,3-disubstituted-2,3-dihydrobenzofuran scaffold was made from iodophenol and methyl bromoacrylate by an intermolecular Heck coupling <03TL8657>. CI

N

Pd(OAc)2 HCO2Na Na2CO3

_1 R

CI ~

O

2

Me

n-Bu4NCI DMF 80~

The palladium-catalyzed carbonylative annulation of o-hydroxyphenylacetylene was employed to generate methyl benzo[b]furan-3-carboxylate, a key intermediate for the total synthesis of the natural product wedelolactone <03JOC8500>.

d n__ OBn

MeO

Pdl2~ rea CBr4

HO OB n

B

OBn

CO MeOH-THF 50 ~ 87%

OBn ..... M eO ~

~

o_ .OBn

~)~,%\ ~

BnO

~ ~ C02Me

"OBn

In the total synthesis of furaquinocins A, B, and E, the key intermediate dihydrobenzofurans were synthesized by the reductive Heck cyclization with sterically hindered pentamethylpiperidine (PMP) as a base <03JA13155>.

~ I

O

HCO2H PMP, DMF 5O ~ 2. Ac20 Et3N-DMAP CH2CI2 81%

"

N

~ "OAc 87% ee

186

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

A radical cyclization approach was developed to synthesize dihydrobenzofurans, which were converted to benzofurans by dehydrogenation (aromatization) <03CC526>.

OH

0

phl(OAc)2

0

0

HoaX

OH 56%

OMe

oM

Mc~' 1 ~

An intramolecular Wittig reaction was employed to synthesize furotocopheryl derivatives <03T3231 >. +

PPha Br-

R2COCI Et3N

H

+

R

PPha Br-

u~j~,f~

PhMe reflux 62% A one-pot procedure to construct the key intermediate of natural product egonol was developed using carbene-alkyne coupling and oxidative aromatization as key steps <03T5609>. Novel tetracyclic psoralen derivatives were synthesized from commercially available 2methoxyresorcinol through a series of synthetic transformations <03JMC3800>.

(OC)3CFj~.OMe 0~~

+

~

iMe3

12

470

An improved procedure for the rapid synthesis of aryl dihydrobenzofurans with a boron tribromide-mediated cyclization was discussed and is shown below <03HCA343>. In the second total synthesis of diazonamide A, the late key step accounting for the dihydrobenzofuran formation was a DIBAL-H mediated lactam reduction and cyclization <03AG(E)1753>. R

OH MeO2C~R MeO..~ v

~OMe "CHO

OH BBr3 .

..~0

0H2CI2 0 ~ 2 hr OHC

C02Me

5.3.3.4 Benzo[c]furans and Related Compounds 1-Oxaspiro[4.5]deca-6,9-dien-8-one showed strong n-facial stereoselectivity in its Diels-Alder cycloaddition with in situ generated benzo[c]furan, leading to the formation of the bridge ether in 63% yield as shown below, together with minor amounts of other isomers. The

187

Five-Membered Ring Systems : Furans and Benzofurans

relatively high stereoselectivity was attributed to an efficient electrostatic control by the tetrahydrofuran ring <03OL2639>.

diglyme heat

Structurally intriguing furanophane derivatives were obtained by employing an [8+2] cycloaddition of dienylisobenzofurans and dimethyl acetylenedicarboxylate (DMAD). The pivotal dienylisobenzofurans were in turn obtained through reactions between alkynylbenzophenones and alkenyl chromium carbene complexes. An example is shown in the following scheme <03JA12720>.

"~[~

Bu +

Cr(CO)5 .,% MeO

Ph

OMe

Bu

Bu

OMe

DMAD

,,. dioxane 85 ~

.._ dioxane 85 ~ 1-2 hr 76~176

Ph

Me

CO2Me

A one-pot synthesis of isoquinolines through coupling of 2-alkynylbenzaldehyde derivatives with chromium cyanocarbene complexes was reported. The reaction involved formation of an isobenzofuran first, which then underwent intramolecular Diels-Alder cycloaddition with the nitrile. One important feature of this process was the deoxygenation of the initial adduct to give the isoquinoline ring <03OIA261>.

I(CO)3Cr H [ ~

+ Me2N HO NC"4M H

Me2N H

Me2N ,,

-I

Bu 100 ~_-PhMe 59%

The generation of azuleno[5,6-c]furan, 4-chloroazuleno[4,5-c]furan <03OBC2383> and naphtho[1,2-c:5,6-c]difuran <03JOC8373>, as well as their cycloaddition reactions were reported. These molecules were shown to be relatively stable compounds, whose spectroscopic data could be recorded.

o,

kVq

Sarkar and coworkers reported a route from which heterocyclic analogs of 1arylnaphthalene lignans were synthesized via a sequential Pummerer-Diels-Alder pathway, featuring furo[3,4-c]pyridines as intermediates. An example is depicted below <03JOC6919>.

188

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

Cl ~ O P h

p-TsOH.

~

CI

C

l

~

C F,CO) O

PhMe

C6H4-p-OMe reflux, 1 hr

SPh dimethyl maleate .CI~ 40%

CI

C6H4"P'OMe

SPh

~"~ Y CI

,CO2Me "CO2Me

C6H4-P-OMe

A simple synthesis of dihydrobenzo[c]furans was recently reported by Yus by starting from the lithiation reactions of 4-heterosubstituted dibenzothiins <03T2083>. Another way in which dihydrobenzo[c]furans can be prepared was recorded by Cheng who made use of a CoI2(PPh3)JZn catalyzed [2+2+2] ene-diyne cycloaddition of 1,6-heptadiynes with allenes as illustrated below. It was shown that these conversions were highly regio- and chemoselective. <03CC718>.

/

ON,

~

Ph

+

= O CI(CH2)2CI 80~ 8hr 71%

+ 94 : 6

Rhodium--catalyzed [2+2+2] cyclotrimerization of alkynes in an aqueous-organic diphasic system was also employed in the formation of dihydrobenzo[c]furans as depicted in the scheme below. Medium- and large-sized rings could be obtained by utilizing this approach <03JA7784>.

[RhCl(cod)]2 tppts

= H20-Et20 24 hr

+ 50%: 11%

Cobalt-cycloheptyne complexes tethered with propargylic ethers were found to undergo also intermolecular as well as intramolecular [2+2+2] reactions to provide polycyclic benzocycloheptanes <03CC2936>.

toluene reflux, 3 hr 60~ Acknowledgements: HNCW wishes to thank the Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, China (Project No. AoE/P-10/01) for financial support. XLH acknowledges with thanks support from the National Natural Science Foundation of China, National Outstanding Youth Fund, the Chinese Academy of Sciences, and Shanghai Committee of Science and Technology. KSY thanks Dr. Nicholas A. Meanwell for support. 5.3.4 REFERENCES 03ACR48 03AG(E)98 03AG(E)184 03AG(E)948 03AG(E)1387

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Five-Membered Ring Systems 9Furans and Benzofurans

03AG(E)1648 03AG(E)1753 03AG(E)2681 03AG(E)3392 03AG(E)3687 03AG(E)3921 03AG(E)3943 03AG(E)4399 03AG(E)5465 03CC422 03CC526 03CC718 03CC838 03CC 1898 03CC2062 03CC2316 03CC2696 03CC2936 03CEJ260 03CEJ390 03CEJ2123 03CEJ2447 03CEJ3073 03CEJ3165 03CEJ4339 03CEJ4442 03CEJ5725 03CJC811 03CJO873 03CL24 03CL222 03CL584 03CL974 03EJOl104 03EJO1410 03EJO1652 03EJO1729 03EJO2383 03EJO2388 03EJO2552 03EJO2959 03EJO4003 03EJO4016 03EJO4033 03EJO4073 03H(59)71 03H(59)101

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190

03H(60)939 03H(60)1133 03H(60)1367 03H(60)1433 03H(60) 1633 03H(60) 1787 03H)60)2767 03HCA91 03HCA343 03HCA474 03HCA484 03HCA733 03HCA760 03HCA787 03HCA2164 03HCA3164 03HCA3320 03HCA3394 03JA36 03JAl192 03JA2058 03JA2374 03JA3682 03JA4684 03JA5642 03JA5757 03JA6650 03JA7484 03JA7784 03JA8112 03JA9016 03JA9282 03JAl1472 03JAl1514 03JA12386 03JA12694 03JA12720 03JA12994 03JA13155 03JA14149 03JA14702 03JA14884 03JA15748 03JMC1449 03JMC4761 03JNP30

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

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

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194

03OL4389 03OL4425 03OL4657 03OL4827 03OL4903 03OL4983 03OM3915 03P(62)551 03P(62)601 03P(63)409 03P(63)427 03P(63)471 03P(63)597 03P(63)803 03P(63)825 03P(63)841 03P(63)859 03P(63)877 03P(63)913 03P(63)939 03P(63)977 03P(64)265 03P(64)575 03P(64)583 03P(64)637 03P(64)661 03P(64)667 03P(64)765 03P(64)797 03P(64)817 03P(64)831 03P(64)1119 03P(64)1309 03P(64)1345 03P(64)1405 03S1043 03S 1100 03S1977 03S1995

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

G.J. Mckieman, R.C. Hartley, Org. Lett. 2003, 5, 4389. K.Y. Tsang, M.A. Brimble, J.B. Bremner, Org Lett. 2003, 5, 4425. S. Pichlmair, M.M.B. Marques, M.P. Green, H.J. Martin, J. Mulzer, Org. Lett. 2003, 5, 4657. S. Pache, M. Lautens, Org. Lett. 2003, 5, 4827. D.K. Rayabarapu, P. Shukla, C.-H. Cheng, Org. Lett. 2003, 5, 4903. J.D. White, G.-Q. Wang, L. Quaranta, Org. Lett. 2003, 5, 4983. C.P. Casey, T.L. Dzwiniel, S. Kraft, I.A. Guzei, Organometallics 2003, 22, 3915. P. Puebla, J.L. L6pez, M. Guerrero, R. Carr6n, M.L. Martin, L.S. Rom~in, A. San Feliciano, Phytochemistry 2003, 62, 551. I. Iliya, Z. Ali, T. Tanaka, M. Iinuma, M. Furusawa, K.-i. Nakaya, J. Murata, D. Damaedi, N. Matsuura, M. Ubukata, Phytochemistry 2003, 62,601. C.A. Gray, D.E.A. Rivett, M.T. Davies-Coleman, Phytochemistry 2003, 63, 409. J.N. Mbing, D.E. Pegnyemb, R.G. Tih, B.L. Sondengam, A. Blond, B. Bodo, Phytochemistry 2003, 63, 427. G. Palazzino, P. Rasoanaivo, E. Federici, M. Nicoletti, C. Galeffi, Phytochemistry 2003, 63, 471. H. Tanaka, T. Oh-Uchi, H. Etoh, M. Sako, M. Sato, T. Fukai, Y. Tateishi, Phytochemistry 2003, 63, 597. E. Kaltenegger, B. Brem, K. Mereiter, H. Kalchhauser, H. K~ihlig, O. Hofer, S. Vajrodaya, H. Greger, Phytochemistry 2003, 63, 803. C.-C. Chang, Y.-C. Lien, K. C. S. Chen Liu, S.-S. Lee, Phytochemistry 2003, 63, 825. A.T. Tchinda, P. Tane, J.F. Ayafor, J.D. Connolly, Phytochemistry 2003, 63, 841. N. Kawahara, M. lnoue, K.-i. Kawai, S. Sekita, M. Satake, Y. Goda, Phytochemistry 2003, 63, 859. G.-P. Peng, G. Tian, X.-F. Huang, F.-C. Lou, Phytochemistry 2003, 63, 877. Y.M. Syah, N.S. Aminah, E.H. Hakim, N. Aimi, M. Kitajima, H. Takayama, S.A. Achmad, Phytochemistry 2003, 63, 913. Y.Y. Akgul, H. Anil, Phytochemistry 2003, 63, 939. E. Bedir, R. Manyam, I.A. Khan, Phytochemistry 2003, 63, 977. M.K. Tsanuo, A. Hassanali, A.M. Hooper, Z. Khan, F. Kaberia, J.A. Pickett, L.J. Wadhams, Phytochemistry 2003, 64, 265. A.T. Tchinda, A. Tsopmo, M. Tene, P. Kamnaing, D. Ngnokam, P. Tane, J.F. Ayafor, J. D. Connolly, L. J. Farrugia, Phytochemistry 2003, 64, 575. R. Gormann, M. Kaloga, X.-C. Li, D. Ferreira, D. Bergenthal, H. Kolodziej, Phytochemistry 2003, 64, 583. A.M. Adio, C. Paul, W.A. K6nig, H. Muhle, Phytochemistry 2003, 64, 637. D.E. Pegnyemb, R.G. Tih, B.L. Sondengam, A. Blond, B. Bodo, Phytochemistry 2003, 64, 661. R.C.C. Martins, J.H.G. Lago, S. Albuquerque, M.J. Kato, Phytochemistry 2003, 64, 667. B.Y. Hwang, J.-H. Lee, J.B. Nam, Y.-S. Hong, J.J. Lee, Phytochemistry 2003, 64, 765. K. Jenett-Siems, I. K6hloer, C. Kraft, K. Siems, P.N. Solis, M.P. Gupta, U. Bienzle, Phytochemistry 2003, 64, 797. M. Ndung'u, A. Hassanali, A.M. Hooper, S. Chhabra, T.A. Miller, R.L. Paul, B. Torto, Phytochemistry 2003, 64, 817. N.H. Soekamto, S.A. Achmad, E.L. Ghisalberti, E.H. Hakim, Y.M. Syah, Phytochemistry 2003, 64, 831. G.N.K. Kumari, S. Aravind, J. Balachandran, M.R. Ganesh, S.S. Devi, S.S. Rajan, R. Malathi, K. Ravikumar, Phytochemistry 2003, 64, 1119. P. Waridel, J.-L. Wolfender, J.-B. Lachavanne, K. Hostettmann, Phytochemistry 2003, 64, 1309. I.S. Ismail, H. Ito, T. Hatano, S. Taniguchi, T. Yoshida, Phytochemistry 2003, 64, 1345. A.J. AI-Rehaily, M.S. Ahmad, I. Muhannad, A.A. AI-Thukair, H.P. Perzanowski, Phytochemistry 2003, 64, 1405. O. Orovecz, P. Kov~ics, P. Kolonits, Z. Kaleta, L. P~k~inyi, 1~. Szab6, L. Nov~ik, Synthesis 2003, 1043. J.S. Yadav, B.V.S. Reddy, G. Kondaji, Synthesis 2003, 1100. Y.R. Lee, K.Y. Kang, G.J. Lee, W.K. Lee, Synthesis 2003, 1977. B.-L. Yin, Z.-M. Yang, T.-S. Hu, Y.-L. Wu, Synthesis 2003, 1995.

Five-Membered Ring Systems 9Furans and Benzofurans

03S2169 03S2530 03SC213 03SL51 03SL411 03SL573 03SL711 03SL732 03SL735 03SL955 03SL1631 03SL1707 03SL1969 03SL2005 03SL2092 03T77 03T755 03T1277 03T1389 03T1483 03T1501 03T1599 03T1613 03T1627 03T2083 03T2423 03T2471 03T3231 03T3433 03T3643 03T4603 03T4661 03T4739 03T4939 03T5033 03T5055 03T5609 03T6627 03T7365 03T7509 03T8027 03T10181 03T10279 03TA765 03TA1363 03TA1455 03TA1665

195

W.H. Suh, M. Choi, S.I. Lee, Y.K. Chung, Synthesis 2003, 2169. P. Le M6nez, J.D. Brion, N. Lensen, E. Chelain, A. Pancrazi, J. Ardisson, Synthesis 2003, 2530. G. Bar, F. Bini, A.F. Parsons, Synth. Commun. 2003, 33, 213. J. Hartung, P. Kunz, S. Laug, P. Schmidt, Synlett 2003, 51. F. Doi, T. Ogamino, T. Sugai, S. Nishiyama, Synlett 2003, 411. T. Shibata, S. Kadowaki, M. Hirase, K. Takagi, Synlett 2003, 573. S. Raghavan, K. Anuradha, Synlett 2003, 711. L. Chen, Z. Li, C.-J. Li, Synlett 2003, 732. I.B. Masesane, P.G. Steel, Synlett 2003, 735. P. Le M6nez, J.D. Brion, J.-F. Betzer, A. Pancrazi, J. Ardisson, Synlett 2003, 955. K. M. Dawood, T. Fuchigami, Synlett 2003, 1631. X. Jia, H. Lin, C. Huo, W. Zhang, J. Lu, L. Yang, G. Zhao, Z.-L. Liu, Synlett 2003, 1707. C. Schultz-Fademrecht, M. Zimmermann, R. Fr6hlich, D. Hoppe, Synlett 2003, 1969. S. Serra, C. Fuganti, Synlett 2003, 2005. A.G. Cs~ikS?, M. Mba, J. Plumet, Synlett 2003, 2092. H. Nambu, G. Anilkumar, M. Matsugi, Y. Kita, Tetrahedron 2003, 59, 77. S. Onitska, H. Nishino, Tetrahedron 2003, 59, 755. Y.-L. Lin, H.-S. Kuo, Y.-W. Wang, S.-T. Huang Tetrahedron 2003, 59, 1277 A.S. Golubev, N.N. Sergeeva, L. Hennig, A.F. Kolomiets, K. Burger, Tetrahedron 2003, 59, 1389. X.-J. Wu, S. Toppet, F. Compernolle, G.J. Hoornaert, Tetrahedron 2003, 59, 1483. X.-C. Li, D. Ferreira Tetrahedron, 2003, 59, 1501. J.S. Yadav, B.V.S. Reddy, J.S.S. Reddy, R.S. Rao, Tetrahedron 2003, 59, 1599. T. Kubota, M. Tsuda, J. Kobayashi, Tetrahedron 2003, 59, 1613. S. Takahashi, A. Kubota, T. Nakata, Tetrahedron 2003, 59, 1627. M. Yus, F. Foubelo, J.V. Ferr~indez, Tetrahedron 2003, 59, 2083. R.M. van Well, M.E.A. Meijer, H.S. Overkleeft, J.H. van Boom, G.A. van der Marel, M. Overhand, Tetrahedron 2003, 59, 2423. J.K. Harper, A.M. Arif, E.J. Ford, G.A. Strobel, J.A. Porco, Jr., D.P. Tomer, K.L. Oneill, E.M. Heider, D.M. Grant, Tetrahedron 2003, 59, 2471. C. Adelw6hrer, T. Rosenau, W.H. Binder, P. Kosma, Tetrahedron 2003, 59, 3231. A. Naoe, M. Ishibashi, Y. Yamamoto, Tetrahedron 2003, 59, 3433. A. Baran, C. Kazaz, H Seqcen, Y. Stitbeyaz, Tetrahedron 2003, 59, 3643. D. Tadic, J.T.M. Linders, J.L. Flippen-Anderson, A.E. Jacobson, K.C. Rice, Tetrahedron 2003, 59, 4603. A. Arcadi, S. Cacchi, G. Fabrizi, F. Marinelli, L.M. Parisi, Tetrahedron 2003, 59, 4661. G. Hobley, K. Stuttle, M. Wills, Tetrahedron 2003, 59, 4739. A. Pdwas, A. Zanka, M.P. Cassidy, J.M. Harris, Tetrahedron 2003, 59, 4939. A. Arnone, G. Candiani, G. Nasini, R. Sinisi, Tetrahedron 2003, 59, 5033. S. Kosemura, Tetrahedron 2003, 59, 5055. J. Zhang, Y. Zhang, Y. Zhang, J.W. Herndon, Tetrahedron 2003, 59, 5609. K. Takami, S. Mikami, H. Yorimitsu, H. Shinokubo, K. Oshima, Tetrahedron 2003, 59, 6627. P. Van de Weghe, S. Bourg, J. Eustache, Tetrahedron 2003, 59, 7365. Z. Nov~ik, G. Time'-i, A. Kotschy, Tetrahedron 2003, 59, 7509. M.M.G. Saad, T. Iwagawa, M. Doe, M. Nakatani, Tetrahedron 2003, 59, 8027. J. Raczko, Tetrahedron 2003, 59, 10181. V. Nair, A.U. Vinod, N. Abhilash, R.S. Menon, V. Santhi, R.L. Varma, S. Viji, S. Mathew, R. Srinivas, Tetrahedron 2003, 59, 10279. M. Schinnerl, C. B6hm, M. Seitz, O. Reiser, Tetrahedron: Asymmetry 2003, 14, 765. M.K. Gurjar, A.M.S. Murugaiah, P. Radhakrishna, C.V. Ramana, M.S. Chorghade, Tetrahedron: Asymmetry 2003, 14, 1363. S.E. Gibson, H. Ibrahim, C. Pasquier, V.M. Swamy, Tetrahedron: Asymmetry 2003, 14, 1455. G. Rassu, L. Auzzas, V. Zambrano, P. Burreddu, L. Battistini, C. Curti, Tetrahedron: Asymmetry 2003, 14, 1665.

196

03TA3643 03TL225 03TL467 03TL725 03TL835 03TL961 03TL1161 03TL1387 03TL1445 03TL2073 03TL2125 03TL2145 03TL2221 03TL2637 03TL2795 03TL2827 03TL2971 03TL2995 03TL3151 03TL3167 03TL3175 03TL3263 03TL3641 03TL3839 03TL4081 03TL4117 03TL4257 03TL4351 03TL4467 03TL5137 03TL5235 03TL5499 03TL5751 03TL5781 03TL5831 03TL5847 03TL5853 03TL6335 03TL6513 03TL6729 03TL6879 03TL7187 03TL7341 03TL7411

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

P. Kwiatkowski, E. Wojaczynska, J. Jurczak, Tetrahedron: Asymmetry 2003, 14, 3643. V. Ledroit, C. Debitus, C. Lavaud, G. Massiot, Tetrahedron Lett. 2003, 44, 225. G.-S. Liu, X.-Y. Lu, Tetrahedron Lett. 2003, 44, 467. B.M. Mathes, S.A. Filla, Tetrahedron Lett. 2003, 44, 725. A. Massa, M.R. Acocella, M. De Rosa, A. Soriente, R. Villano, A. Scettri, Tetrahedron Lett. 2003, 44, 835. N. Zanatta, R. Barichello, M.M. Pauletto, H.G. Bonacorso, M.A.P. Martins, Tetrahedron Lett. 2003, 44, 961. W.H. Miles, K.B. Connell, Tetrahedron Lett. 2003, 44, 1161. G. Zeni, C.W. Nogueira, D.O. Silva, P.H. Menezes, A.L. Braga, H.A. Stefani, J.B.T. Rocha, Tetrahedron Lett. 2003, 44, 1387. S.-L. Zheng, W.-Y. Yu, M.-X. Xu, C.-M. Che, Tetrahedron Lett. 2003, 44, 1445. Y.Y. Jiang, Q. Li, W. Lu, J. C. Cai, Tetrahedron Lett. 2003, 44, 2073. J. Tae, K.O. Kim, Tetrahedron Lett. 2003, 44, 2125. D.J. Wallace, Tetrahedron Lett. 2003, 44, 2145. J.S. Yadav, B.V.S. Reddy, G. Satheesh, A. Prabhakar, A.C. Kunwar, Tetrahedron Lett. 2003, 44, 2221. L.R. de Carvalho, M.T. Fujii, N.F. Roque, M.J. Kato, J.H.G. Lago, Tetrahedron Lett. 2003, 44, 2637. R. Ballini, D. Fiorini, M.V. Gil, A. Palmieri, E. Rom~in, J.A. Serrano, Tetrahedron Lett. 2003, 44, 2795. K.H. Park, S.U. Son, Y.K. Chung, Tetrahedron Lett. 2003, 44, 2827. H. Abe, Y. Arai, S. Aoyagi, C. Kibayashi, Tetrahedron Lett. 2003, 44, 2971. S. Richard Baker, M. Cases, M. Keenan, R.A. Lewis, P. Tan, Tetrahedron Left. 21103, 44, 2995. M.A. Ashraf, M.A. Jones, N.E. Kelly, A. Mullaney, J.S. Snaith, I. Williams, Tetrahedron Lett. 2003, 44, 3153. J.R. Hwu, T. Sambaiah, S.K. Chakraborty, Tetrahedron Lett. 2003, 44, 3167. T. Saitoh, T. Suzuki, M. Sugimoto, H. Hagiwara, T. Hoshi, Tetrahedron Lett. 2003, 44, 3175. J.M. Aurrecoechea, E. P6rez, Tetrahedron Lett. 2003, 44, 3263. A.V. Varlamov, F.I. Zubkov, E.V. Boltukhina, N.V. Sidorenko, R.S. Borisov, Tetrahedron Lett. 2003, 44, 3641. M. Shi, B. Xu, Tetrahedron Lett. 2003, 44, 3839. T. Itoh, K. Kawai, S. Hayase, H. Ohara, Tetrahedron Lett. 21103, 44, 4081. T. lnagaki, Y. Nakamura, M. Sawaguchi, N. Yoneda, S. Ayuba, S. Hara, Tetrahedron Lett. 2003, 44, 4117. K.L. Milkiewicz, D.J. Parks, T. Lu, Tetrahedron Lett. 2003, 44, 4257. M. Sasaki, C. Tsukano, K. Tachibana, Tetrahedron Lett. 2003, 44, 4351. Y. Fall, B. Vidal, D. Alonso, G. G6mez, Tetrahedron Lett. 2003, 44, 4467. D. Fokas, J.E. Patterson, G. Slobodkin, C.M. Baldino, Tetrahedron Lett. 2003, 44, 5137. H. Takikawa, M. Hirooka, M. Sasaki, Tetrahedron Lett. 2003, 44, 5235. G. Bifulco, T. Caserta, L. Gomez-Paloma, V. Piccialli, Tetrahedron Lett. 2003, 44, 5499. F. Glorius, Tetrahedron Lett. 2003, 44, 5751. M.R. Iesce, M.L. Graziano, F. Cermola, S. Montella, L.D. Gioia, Tetrahedron Lett. 2003, 44, 5781. J.S. Yadav, G. Rajaiah, A.K. Raju, Tetrahedron Lett. 2003, 44, 5831. G.J. Sanjayan, A. Stewart, S. Hachisu, R. Gonzalez, M.P. Watterson, G.W.J. Fleet, Tetrahedron Lett. 2003, 44, 5847. M.P. Watterson, A.A. Edwards, J.A. Leach, M.D. Smith, O. Ichihara, G.W.J. Fleet, Tetrahedron Lett. 2003, 44, 5853. T. Makino, K. Itoh, Tetrahedron Lett. 2003, 44, 6335. T. Saito, T. Horikoshi, T. Otani, Y. Matsuda, T. Karakasa, Tetrahedron Lett. 2003, 44, 6513. N.N. Karade, S.G. Shirodkar, M.N. Patil, R.A. Potrekar, H.N. Karade, Tetrahedron Lett. 2003, 44, 6729. A.H. Banskota, F. Attamimi, T. Usia, T.Z. Linn, Y. Tezuka, S.K. Kalauni, S. Kadota, Tetrahedron Lett. 2003, 44, 6879. S. Mukherjee, K.W.C. Poon, D.L. Flynn, P.R. Hanson, Tetrahedron Lett. 2003, 44, 7187. K.L. Milkiewicz, I.B. Neagu, D.J. Parks, T. Lu, Tetrahedron Lett. 2003, 44, 7341. A.R. Rodriguez, B.W. Spur, Tetrahedron Lett. 2003, 44, 7411.

Five-Membered Ring Systems 9Furans and Benzofurans

03TL7945 03TL8157 03TL8221 03TL8227 03TL8365 03TL8433 03TL8553 03TL8657

197

M. Hamaguchi, N. Tomida, E. Mochizuki, T. Oshima, Tetrahedron Lett. 2003, 44, 7945. D. Banti, M. North, Tetrahedron Lett. 2003, 44, 8157. M. Pal, V. Subramanian, K.R. Yeleswarapu, Tetrahedron Lett. 2003, 4, 8221. U.M. Krishna, G.S.C. Srikanth, G.K. Trivedi, Tetrahedron Lett. 2003, 44, 8227. D. Dabideen, D.R. Mootoo, Tetrahedron Lett. 2003, 44, 8365. A.M. G6mez, A. Barrio, A. Pedregosa, S. Valverde, J.C. L6pez, Tetrahedron Lett. 2003, 44, 8433. A. Plaza, G. Bifulco, A.I. Hamed, C. Pizza, S. Piacente, Tetrahedron Lett. 2003, 44, 8553. M. Szlosek-Pinaud, P. Diaz, J. Martinez, F. Lamaty, Tetrahedron Lett. 2003, 44, 8657.

198

Chapter 5.4

Five Membered Ring Systems" With More than One N Atom Larry Yet Albany Molecular Research, Inc., Albany, N Y USA larryy@al b mo le cular, co m

5.4.1

INTRODUCTION

The synthesis and chemistry of pyrazoles, imidazoles, 1,2,3-triazoles, and 1,2,4-triazoles continue to be actively pursued in 2003. Publications relating to tetrazole chemistry were not particularly well represented this year. The solid-phase and combinatorial chemistry of these ring systems have not been heavily investigated as in past years. No attempt has been made to incorporate all the exciting chemistry or biological applications that have been published this year.

5.4.2

P Y R A Z O L E S AND R I N G - F U S E D D E R I V A T I V E S

A review on the synthetic utility of N-acylpyrazoles has been published <03H(60)437>. 1,3-Difunctional systems are good substrates to react with various hydrazines to prepare pyrazole derivatives. Tetrasubstituted pyrazoles 2 were synthesized regioselectively in good yields from the reaction of Baylis-Hiliman adducts 1 with various hydrazine hydrochlorides in 1,2-dichloroethane <03TL6737>. 3-Aminophenylpyrazoles 4 were prepared from c~-oxoketene O,N-acetals 3 using montmorillonite K-10 under sonication conditions <03S 1160>. The one-pot three-component reaction of polyethylene glycol-supported acrylate 7 with aldehydes 5 and hydrazines 6 in the presence of chloramine-T followed by methanolysis afforded pyrazolines 8 in good yields and in high purities <03SL1467>. Cyclocondensation of alkenones 9 with phenylhydrazine under microwave irradiation furnished 5-trichloromethyl substituted pyrazoles 10 in excellent yields <03TL6669>. Reactions of ot,13-unsaturated ketones 11 with hydrazinediium dithiocyanate gave in one-pot 1-thiocarbamoyl-2-pyrazolines 12 or 1-formyl-2pyrazolines 13, in different ratios depending on the structure of the ketone <03T2811 >.

199

Five Membered Ring Systems: With More than One N Atom

/ R1

OH ~

R3NHNH2.HCl

O

ClCH2CH2Cl 50-60 ~

R2

NHR

R1

O

R2~ ' ~ " R 3 11

R1

hydrazine, ultrasound

Ph""L]""~OEt ,3

)'

R2

R1 = Ph, C5Hll R2= Me, Et, cycloalkenone R3 = Ph, t-Bu

1

O

R3 'N-N Me 2

H N-N

_-.

montmorillonite K-10, 25 ~

NHR

PIi 4

R = H, Me, Ph, Bn, allyl, CH(Me)Ph

[H3N-NH3] 2+ 2SCNQ

,DMF, reflux R1 = Me, i-Pr, Ph, Ar

H2N'.~S

R1R2 ~ -N./ N

+

~ R2

R3

R 2= H, Me

R3 = Me, Ph, Ar

I CliO .N. N

R1

12

/ R3

13

Pyrazolidine derivatives 16 were obtained from the intermolecular [3+2] cycloaddition between hydrazones 14 and olefins 15 <03TL3351>. A convenient method for the synthesis of 1H-pyrazole-4-carboxylic acid esters 18 from 13-ketaminoesters 17 has been reported using

200

L. Yet

conventional and microwave assisted Vilsmeier reactions <03SC1483>. N-Alkyl-substituted phthalimides 19 were easily converted to di-, tri-, and tetrasubstituted pyrazoles 20 via a one-pot addition-decyclization-cyclocondensation process <03H(60)2499>. Regioselective synthesis of several ethyl pyrazolecarboxylates could be prepared from different precursors <03JHC487>. Cyclocondensation of diacetylenic ketones 21 with hydrazines afforded alkynyl-substituted pyrazoles 22 <03T2197>. Treatment of nitropyrimidine derivatives 23 with various hydrazines under very mild conditions gave 4-nitro-3,5-diaminopyrazoles 24 for new efficient and insensitive explosives synthesis <03TL5943>. A practical approach of continuous processing was utilized in the nitration of substituted pyrazole-5-carboxylic acids <03S2827>.

N

NHBz

S

R4 '~

R~]~.

R3 R2

14

15

Bz = .N R4

BF3oOEt2 0H2012,0 ~

"

R H I ~ R R3 16

R1 = PhCH2CH2, Ph, CO2Et R2, R3, R4 = cyclopentadiene, dienes, eneyne

NO2

O2N

DMF, POCI3 reflux or microwave ,. R1 = Me, Ar

o

RI~.~OR

3

R2 = H, NO2 R3 = Me, Et

R2~ N-N // _\ R1 CO2R3

17

18

R2

i

O ~ N - R O 19

1

1. (Me)H~CMgBr THF, 0 ~ ,. 2. H20 3. R2NHNH2, EtOH

Me L~ /.L H (Me) ~ ~CONHR 1

R1 = Me, Et,/-Pr, t-Bu R2 = H, Ph, Ar

20

R2

O R2NHNH2.H2O R I ~ C O 2 E t 21

EtOH, 80 ~

N-N"

R I ~ C O 2 E t

R1 = Ph, Pr, Bu, CO2Et R2= H, Ph

22

201

Five Membered Ring Systems: With More than One N Atom

R1 O2N~N

NH2 R3NHNH2

R2.-L.~N~J

O2N~,

MeOH, 25 ~

H2N- -NRN

R I = R 2 = CI, NR2, OMe R3 = H, Me, Bn, SO2Ph

23

24

Diazonium intermediates have also been employed in the synthesis of pyrazoles. A convenient one-pot procedure for the preparation of 3-phenyl- or 3-pyridylpyrazoles 27 from the 1,3-dipolar cycloadditions of phenylacetylene or 3-(pyridyl)acetylene with diazo compounds 26 generated in situ from aldehydes 25 has been reported <03JOC5381>. Cyclization of ortho(arylethynyl)benzene diazonium salts 28 having substituents at the para-position of the aryl ring furnished indazoles 29 <03TL5453>.

O R..JL.H 25

1. TsNHNH2,CH3CN,25 ~

2.5M NaOH R = Ph, Ar, 3-pyridyl

=

I~

X = CH, N

R"J~H

50 ~ 48 h

26

Ar

Ar NaNO2, HCl acetone/H20 " -10 ~

N-NH R _~//~..~/'~X/,~X - "~" -'~/~/

"

27

~ N A r ,.

Q Q 28

29

H

Many pyrazole-type compounds have been elaborated further. Zirconium(IV) nitrate was found to be a versatile oxidizing agent for the aromatization of 1,3,5-trisubstituted pyrazolines 30 to the corresponding pyrazoles 31 in acetic acid at ambient temperature <03S1267>. 4Iodopyrazole derivatives 33 were efficiently synthesized in high yields from 32 at room temperature by the combined reagents iodobenzene diacetate (or polymer-supported (PS) iodobenzene diacetate) with iodine <03SC2671>. 4-Iodopyrazole 34 was protected with ethyl vinyl ether to pyrazole 35, which underwent palladium-catalyzed cross-couplings with substituted alkynes and deprotection to afford 4-alkynyl-substituted pyrazoles 36 <03H(60)879>. Efficient and regioselective syntheses of 2-methyl- and 2-ethyl-2H-indazoles were accomplished with trimethyloxonium tetrafluoroborate or with triethyloxonium hexafluorophosphate, respectively, as alkylating agents in ethyl acetate at room temperature <03JOC4093>. Ruthenium-catalyzed reaction of 1-arylpyrazoles 37 with carbon monoxide and ethylene resulted in the regioselective carbonylation at the ortho C-H bonds to 38 via the directing role of the pyrazole group <03JOC7538>.

202

L. Yet

R I - - - . ~ ~ R2 N-N 3O

R2

Ph

Zr(N03)4 HOAc 25 ~

RI"'~~ N-N

"

R1 = Ph, 4-CIC6H4 R2= Ar, 2-thienyl

Phl(OAc)2 or PS-PhI(OAc)2

R2 Ph

31

R2

I

12, CH2CI2, 25 *C RI= H, Ar R2 = Me, Ph R3 = Me, Ph

32

I

N.N ~1 H

ethyl vinyl ether

Phil, HCI (1 drop)

34

Me.."L',.OEt 35

33

1. R~C-CH, Phil, 80 *C PdCI2(PPh3)2, Cul or Pd(OAc)2, Cul 2. HCI, H20, CHCI3 R = Ph, Ar, CMe2OH

Ru3(00)12 CO, CH2=CH2 N,N-dimethylacetamide 20atm, 160oC R =Me, OMe, CF 3, CO2Me D

R 37

Oi

R

H 36

~'.~/~

L.,_.L L

R~ V

~-Me O

38

5-Aminopyrazoles 39 were readily converted to 4,5-diaminopyrazoles 40, which were selectively condensed with isocyanates to yield 5-amino-4-pyrazolyl ureas 41 <03TL3009>. 3Aminopyrazoles 42 could be selectively protected at the N-2 position to Boc-protected pyrazoles 43, which reacted with various acyl chlorides followed by Boc removal to provide 3-acylated pyrazoles 44 <03TL4491>. Other protecting groups such as Cbz, Bn and SEM could be introduced at the N-2 position with biphasic conditions using potassium hydroxide as the base. A parallel synthesis route to 3-acylaminopyrazolinones from 3-aminopyrazolinones was accomplished using a sequence of functionalized polymers, both as stoichiometric and purification reagents to allow for the clean formation of the desired target compounds <03TL3843>. The synthesis and chemistry of 3-tert-butyl-l,5-diaminopyrazole has been discussed <03OBC4268>.

203

Five Membered Ring Systems: With More than One N Atom

R2

NaNO2, HCl; SnCI2"2H20 = H20, 0 ~

NH 2 i~1 39

N"N ~.~~

R3NCO EtOH 25 ~

R2, ~ N H - - ~ O

r_

40

NH2

N~'~ .Boc HMDS, Me3SiCl .. Me\ , i . ~~.'N Boc20,MeCN i )--f \ 130, C ~NH2

42

NHR 3

N- N-2"" N H2 I~1 41

R 1 = R2 = R 3 = alkyl, Ar

H

Mex

R2 NH 2 N.N~ NH2 I~1

H

1" RC(O)CI, i-Pr2NEt, CH2CI2, 25 ~ 2.4N HCI, dioxane

Mex. i N~..~ - N

43

44

.-. .u N"JJ~" H R

Reaction of 2-bromoacetophenone 45 with dimethylformamide dimethylacetal (DMF-DMA) to the intermediate enaminoketones followed by reaction with various arylhydrazines afforded diarylpyrazoles 46, which underwent Mizoroki-Heck palladium-catalyzed intramolecular couplings to give pyrazolo[ 1,5-fl]phenanthridines 47 <03OL1095>. o

~ B r

45

Me

. NHNH 1. DMF-DMA 2. R1

_-.

- - ~

Pd(OAc)2, K2CO3, LiCI TBAF, DM F, 110 ~

_

R2

R1 = R2 =R3 = OMe, H, Me

R3 46

"N R3 47

Nucleophilic substitution reactions of 5-chloropyrazoles 48 with amines and thiols under mild conditions provided 5-alkyl amino and thioether pyrazoles 49 as selective COX-2 inhibitors <03TL7629>. 4-Chloromethylpyrazoles 50 reacted readily with amides, carbamates, urea, azoles, alcohols, and thiols under neutral conditions to give substituted benzylic products 51 in moderate yields <03H(60) 167>. SO2Me

.SO2Me or

Et3N (1.2-2.0 eq), CH2CI2,40 ~ N~ F3C

48

~CI R

or8CICH2CH2CI 0= ~NR2R 3, SR ( 2 R = H,

CHO

N q ~ ~ R1 F3C

49

R

204

L. Yet

Me.

/~CI

N.N. ~

M e x / _ ~ ~ Nuc nucleophile=_ DMF, 80 ~

I

Ph

N'N'~ I

Ph

50

51

Pyrazolidinediones 52 were oxidized with manganese(III) acetate in the presence of alkenes 53 at elevated temperatures to produce 4,4-bis(alkenyl)pyrazolidinediones 54 in good yields <03T8383>. Photolysis of chiral trisubstituted pyrazolines 55 afforded cyclopropanes 56, in which the mechanism and stereospecificity were studied in detail <03JOC4906>.

O"~'~ ~O

+

R3 ===~

,N-N.R 2 R1

R4

52

53

0•0

N,! R 2N"/" N" 55

R3

Mn(OAc)3 HOAc, reflux.

R4

R1 = R2 = Et, Me, Ph, Bn R 3 = R4

Me, Et, Ph, Ar

=

hv

- N2 ,.

R3 R4

R

='_~'~-N.R2 54

0"~0

~.,1~1

acetone or

CH2CI2

R1 = R2 = Me, NO2, CO2Me,NHCbz

/R 2 56

Biarylphosphine ligands 57 were found to have fairly broad substrate applications in the palladium-catalyzed amination reactions of aryl halides <03S 1727>. Chiral bis(pyrazolyl)methanes were employed as catalysts in the asymmetric Diels-Alder reactions of 1acryloyl-3,5-dimethylpyrazole with cyclopentadiene in the presence of magnesium perchlorate <03JHC68 l>.

PR2 Ph 57 R =/-Pr, t-Bu

Amino polystyrene pyrazolone linker resin 58 provided various amide products 59 with a high conversion rate and good purity under mild conditions; the resin linker was stable under the reaction conditions, resistant to hydrolysis, and reused repeatedly without loss of activity <03TL8063>. The preparation of pyrazoline derivatives 61 was accomplished with traceless solid-phase sulfone linker 60 with phenylhydrazine <03OL1067>. Aniline cellulose-bound enaminones 62 reacted with phenylhydrazine under microwave irradiation to produce pyrazo|ocarboxylic acid derivatives 63 in high yields <03JCO465>.

Five Membered Ring Systems: With More than One N Atom

205

Several reports on syntheses of unique fused-pyrazole heterocyclic systems have been published in 2003. Pyrazolinyl derivatives of protoporphyrin IX and chlorins related to chlorophyll a have been reported <03T499>. N-Aroyldihydrocyclopenta-pyrazolidinols underwent unusual reactions with ketenes to give 1,3,4-oxadiazoles <03T4591>. The synthesis and dopamine receptor binding of some pyrazolo[3',4':6,7]azepino[5,4,3-cd]indoles has been reported <03H(60)1339>. Desulfurization of 3,4-dimethyl-4H-1,3,4-thiadiazines under acidic thermal conditions provided entry to 5-imino-l,2-dimethylpyrazoles by valence isomerization into thia-6-homopyrazoles <03SL2392>. Several synthetic approaches to a new class of 7amino-3-pyrimidinyl-pyrazolo[1,5-a]pyridine scaffolds has been published <03T9001>. Two different synthetic approaches led to the synthesis of a novel class of 1-(thiazol-2-yl)-lHpyrazolo[3,4-b]quinoxalines <03T6311 >. Reaction of hydrazines with dimethyl 2-pyrrolidino-4oxo-2-pentenedioate 64 in the presence of acid provided N-substituted pyrazole-3,5dicarboxylates 65, which could be further elaborated to bicyclic pyrazoles 66 if R is an alkyl amine or alcohol side-chain <03TL5867>. 1-Phenyl-5-arylcarboxamidopyrazoles 67 reacted with phosphorus halides to give 5-(aminopyrazol-4-yl)-phosphonic acid derivatives 68 <03S906>. Reaction of N-aziridinylimino carboxamides 69 with triphenylphosphine in carbon

206

L. Yet

tetrachloride provided access to pyrazole-fused heterocycle 71 via thermal rearrangement of Naziridinylimino ketenimines 70 <03JHC363>. 4-Benzoyl-3-chloropyrazoles 72 were converted to the intermediate oximes followed by intramolecular base-promoted cyclizations to give 3phenyl-6H-pyrazolo[4,3-d]isoxazoles 73 <03JHC303>. 5-Hydroxypyrazoles 74 were acylated at the C-4 position followed by acid-catalyzed cyclizations to afford 5,6-dihydropyrano[2,3c]pyrazol-4-ones 75 <03H(60)2323>.

O

O

MeOH

RNHNH2,

MeO2C-'~-~CO2Mev 64

2N HCl, 25 ~

N ~ N

PI~

N

Me/'J~~

O

NHR

69

Ph

72

5.4.3

N-J~.Ar H

1. NH2OHM = 21 Nail, F R1 = Me, Ph R2 = H, Me

-"

65

N'N'~--O I~1 73

"~)"n "N

CO2Me

X = NH, O 66

R

PBr3~ ~I~0 pyridine, 25 ~ = NN I~N/_.J....Ar R = Br (from PBr3) Pl~ R = Ph (from PhPBr2) 68

PPh3, CCl4 Et3N, CH2Cl2 .. reflux R = Me, Ph, Ar

Ph

N.N.~"--CI i~1

R

Me

0

67

CO2Me

,N-N

R = H, Me, Bn, Ph, 2-pyridyl, (CH2)nNH2, (CH2)nOH Me

N"

MeO2C~

"

Ph-.,.~__7 ~N"N R] Jl c<.N. Me

R2

70

Ph ; N'N ~ -N--R \ /~ M 71

"--

O ~..~

1. (E)-PhCH=CHCOCI, R2

N.Nk~ /

R1 74

Ca(OH)2,dioxane OH 2. H2SO4 R1 = Me, eh, Bn R2= H, Me

Ph

ID !

R1 75

IMIDAZOLES AND RING-FUSED DERIVATIVES

A detailed review on the chemistry of the pyrrole-imidazole alkaloids from marine sponges has been published <03S 1753>.

207

Five Membered Ring Systems: With More than One N Atom

Many published papers on the syntheses of imidazoles appeared in 2003. A one-pot preparation of 2,4,5-triarylimidazolines 77 from aromatic aldehydes 76 was accomplished by heating with hexamethyldisilazane under solvent-free conditions <03S 1236>. The same authors also reported the synthesis of cis- and trans-2,4,5-triarylimidazolines from aromatic aldehydes via microwave irradiation in the presence of alumina <03SL 1117>. The rhodium-catalyzed N-H insertion of ureas with t~-diazo-~-ketoesters 78 gave insertion intermediate 79, which underwent acid-catalyzed cyclodehydration to yield imidazolones 80 <03OL511>. Amidinyl radicals generated from amidoxime benzoates 81 were useful intermediates for the synthesis of imidazolines 82 <03CC 1870>. Carbodiimides 83 reacted with various aliphatic amines or with sodium sulfide followed by alkylations to give 2-dialkylamino-4H-imidazolin-4-ones 84 <03SC1651> and 2-alkylthio-4H-imidazolin-4-ones 85 <03SC1267>, respectively. Fatty chain amides 86 were cyclized efficiently to give 2-alkyl-l-(2-hydroxyethyl)-2-imidazolines 87 under microwave conditions with calcium oxide as the support <03SL1847>. A three-step transformation of various ot-aminonitriles into protected 4-substituted 5-aminoimidazoles via intermediate amidines has been reported <03JOC50>. A practical synthesis of 2ethoxycarbonylimidazole-4-phosphonate and diethyl imidazole-2,4-dicarboxylate has been published <03JHC 159>.

2

Ar--CHO

(Me3Si)2NH(1.1 eq) =_ H N ~ N 120 ~ Ar / ~ A r

76

77

O O

O

EtO/J~R1 N2 78

R2HN/J'L--NH2 Rh2(oct)4 (2 mol%) PhMe/CICH2CH2Cl (1:1) 80 ~

o

HN~o

RII~N ~j

R2

I COPh

81

q /

NHR2I_I

Bu3SnH AIBN PhMe reflux

-"

o

H

25 ~ ="

79

R1 = Me, Ph R2= Ph, Me, Bn PhCO2.N R 2 . ~

o

~2 80

R2 N~ N R2 RI"~

I

COPh

R1 = alkyl aryl, furanyl, thienyl R2 = cycloalkyl; Me; H, Bn

82

208

L. Yet

O / ~ N " Ph

Ar

N_~NR1 84

= R2

1. Na2S, HOAc, I I O MeCN, 25 ~ /~...j~...Ar 2. RX, K2003, P MeCN, 60 ~ SR 85 Ar = Ph, 3-CIC6H4 R = Me, Et, Pr,/-Pr, Bu, CH2FG FG = functional group

,CO2Et

R1R2NH

CH2CI2,25 oc ph./-~N=C=NAr

4-MeC6H4, 4-CIC6H4 83 R 1 = R2= Et, Pr, C5Hll, morpholino, piperidinyl

Ar =

O

"

H o ~ N ~ N

H

R R

86

CaO

N N~OH k__/ R = fatty acids 87 microwave

=

L

The reaction of amines with 1,2-diketo substrates led to a variety of substituted imidazole derivatives. Treatment of various substituted anilines 88 with glyoxals 89 gave the imine intermediate 90, which was then cyclized to the 1-arylimidazoles 91 with paraformaldehyde and ammonium chloride under acidic conditions <03S2661>. A one-pot, three-component condensation of benzil 92, benzonitrile derivatives and primary amines on the surface of silica gel under solvent-free conditions and microwave irradiation provided tetrasubstituted imidazoles 93 <03TL 1709>. a2 ~ R 2 R2 R2 NH2 N ~ L~ R2"~O MeOH ~ O 37%(CH20,n = ~ N . , , ~ N R1 88

+

R2..."~O 89

25 ~

=-

NH4CI, 85% H3PO4

R1 90

R1 91

R1 = Me,/-Pr, OMe, acetyl, CO2Me R2 = H, Me Ph O Ar-CN,R-NH2 Ph N "~ silica gel "~>Ar Ph" ~O microwave(850 VV) Ph/ N R 92 Ar = Ph, 4-MeC6H4, 3.BrC6H4 93 R = Me, Et, Ph,/-Bu Electrophilic diamination of alkenes has been employed in the syntheses of functionalized imidazoles. N-Chlorosaccharin 95 has been shown to undergo electrophilic Ritter-type reactions with various terminal, disubstituted, and trisubstituted alkenes 94 in acetonitrile to give the intermediate [3-chlorosulfonylamidines, which can be ring-opened to imidazolines 96 in the presence of potassium ethoxide <03OL3313>. A direct electrophilic diamination reaction of ct,13-unsaturated ketones to give imidazolines has been established using acetonitrile as the

209

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

nucleophilic nitrogen source and N,N-dichloro-p-toluenesulfonamide electrophilic nitrogen source <03JOC5742>.

(TsNCI2) as the

O 1.

R"~

~s'N-CI 02

Me

CH3CN, -40 ~

94

02

CO2Et

95

R

2. KOEt, EtOH,-40 ~

96

Several multicomponent reactions have been reported to give various substituted imidazoles in good yields. A variety of fused 3-aminoimidazoles 98 have been synthesized in good yields by microwave assisted Ugi three-component coupling reaction of aminopyridines 97, isocyanides, and aldehydes catalyzed by scandium triflate in methanol <03TL4369>. The threecomponent condensation between isocyanides 99, amines, and aldehydes efficiently provided substituted 2-imidazolines 100 in a one-pot reaction under mild conditions <03OL3759>. A silicon mediated 1,3-dipolar cycloaddition of the in s i t u generated mtinchnone with the intermediate imine resulted in the diastereoselective formation of highly substituted imidazolines 102 from oxazolones 101 in good yields <03S 1433>.

R2

R2NC, R3CHO

T/NH2

~

R'LT~" N 97

c oT0 , eOH

R1

micr~ 160 ~ R R1 = Me, Br, fused Ph R2 = Bn, CH2CO2Et R3 = 2-naphthyl, 2-pyridyl

CN'~CO2Me 99

98

R3-CHO R4-NH2 TMSCI 101

R2

CH2CI2 40 ~

I

R2NH2, R 3 C H O

R3%N/~

Na2SO4,CH2Cl2"

MeO2 CR'~I N

25 ~

R1 = H, Ph R2 = Ph, PMB, CHPh2, i-Pr R3 = i-Pr, Ar, 2-furanyl, 2-pyridyl

100

R4 R1

i

N

R3

~N _~CH202 H

R 1 = Ph, Bn; R2 = Me, Ph R3 = Ph, CO2Et, 4-pyridyl R4 = Bn, Ar, alkyl esters

~2

102

Several different methods of synthesis of benzimidazoles have been reported. Intramolecular aryl guanidinylation of aryl bromides 103 with copper- and palladium-catalyzed methods led to

210

L. ret

efficient syntheses of 2-aminobenzimidazoles 104 <03OL133>. 2-Aryl benzimidazoles were synthesized conveniently by treatment of trifluoromethyl aryl ketones with o r t h o - d i a m i n e s in polar solvents <03SC79>. A series of benzimidazoles 106 containing aryl and heteroaryl substituents were efficiently and quickly synthesized by condensation of 1,2-phenylenediamine 105 with carboxylic acids in the presence of polyphophoric acid (PPA) under microwave irradiation <03H(60)1457>. Similarly, substituted 1,2-phenylenediamines 107 were employed in the preparation of 2-substituted benzimidazoles 108 with aldehydes in the presence of oxone under mild conditions <03S1683>. Condensation of 1,2-phenylenediamine 105 with aldehydes by silica gel supported thionyl chloride provided 2-substituted benzimidazoles 106 <03TL5935>. A mild and efficient synthesis of 2-aminobenzimidazoles 110 was developed from 109 and di(imidazole-l-yl)methanimine <03JHC191>. New, improved conditions for the synthesis of benzimidazoles 112 by intramolecular palladium-catalyzed aryl-amination chemistry of aryl amidines 111 under microwave irradiation has been published <03JOC6814>. Solid-phase synthesis of benzimidazole libraries <03TL2807> and solid-phase synthesis of benzimidazole Noxides <03TL2293> have also been investigated. R4 HN" R1 N~L,,.

~

N..R 2

Br

r3 103

Pd(PPh3)4 (10 mol%) or Cul (5 mol%), 1,10-phen (10 mol%) ~ Cs2CO3 (2 equiv), DME, 80 ~ R1 = Ph, Bn, 4-OMeBn

R4 R1 r.,\. I-~~N,~',,,,.~I~ R2 ~L'~"~N"

'R3

104

R 2 = R 3 = isoquinolinyl, piperazinyl

R4 = H, 4-Me, 4-CI, 5-CF3

NH2

RCO2H,PPA

[ ~

= ~.- -NH2 microwave(200 W) 105 210-270 ~ 106 R = aryl, pyridinyl, Bn, pyrimidinyl

H ~/~.__ R

~ 107

NH2

R2CHO,Oxone =_ [ ~

N~___R2

NHR1 DMF/H20(30:1)

N 108

R1 = Ph, t-Bu, c-C6H11 R2 = aryl, alkyl, pyridyl, quinolinyl, thiophenyl NH

[ ~ 105

NH2

RCHO,CH2Cl2

H

NH2 SOCl2-SiO2,25~ [~~/~R R = Et, Pr, Ph, Ar, 106 2-pyridyl, 2-furanyl

N.J]'~N

109

THF, reflux R=H, Ph

N 110 R

211

Five Membered Ring Systems: With More than One N Atom

B ~ . HR2

~'i~

RI""~ - N 111

R

Pd2(dba)3 (1 mol%) PPh3 (2 equiv, NaOH (2 equiv), 160 ~ H20, DME, microwave

,.

R2 ~/>_.R 3

/ ~ R1

112

R1 = H, Me, OMe, NO 2

R2 = Me, i-Pr, Ph R3 = Me, Ph

Benzimidazoles have been used as precursors to give other compounds. Microwave irradiation strongly accelerated the rhodium-catalyzed intramolecular coupling of benzimidazoles 113 C-H bond to pendant alkenes to afford tricyclic compounds 114, which are currently difficult to access by alternative methods <03OL2131 >. Reaction of 2-aminoimidazole 115 with isatoic anhydride gave benzamide 116, which then reacted with orthoesters to provide benzimidazolyl quinazolinones 117 under microwave irradiation <03T4757>. R3 R2~R

1

(7)o

RhCI(PPh3)3 (10 mol%) o-dichlorobenzene, acetone 250 ~ microwave

113

n=1,2 RI=H, Me R2 = R3 = H R2=R 3=Ph,H,Et

satoicao,,~176 NH2 H 115

m=crowave(300 VV) ~ N,N-dimethylacetamide

y

N//'~R3R2 114

icrowave,000 -"N H

H2N 116

N,N-dimethylacetamide" R1 = H, Me, Et, Pr, Bu R2 = Me, Et

R 117

4,5-Dihalo- and 4-vinyl imidazoles have been useful precursors in several reactions. 4,5Diiodoimidazole 118 underwent selective efficient Grignard-type coupling to give imidazoles 119, whose subsequent Sonogashira or Heck-type cross-couplings gave diverse imidazoles 120 as part of a MAP kinase inhibitors study <03TL7115>. The same diiodo imidazole 118 was converted to the bis(allyl) imidazole 121, which underwent ring-closing metathesis reactions to give fused bicyclic imidazoles 122 <03TL1379>. Novel bicyclic imidazole 123, an effective imidazoline anion equivalent, underwent regioselective halogen-metal exchange followed by reaction with various electrophiles to give bicyclic imidazoles 124 <03S659>. 4,5-

212

L. Yet

Dibromoimidazoles were employed as precursors to syntheses of 6-substituted imidazol[4,5d]pyridazin-7-ones <03H(60)1329>. 4-Vinyl imidazoles participated in intermolecular DielsAlder reactions with N-phenylmaleimide <03H(60)1> and in intramolecular Diels-Alder reactions <03OL3623>. I.~N> i / -"N SO2NMe2 118

1. EtMgBr, THF,-20 *C

I-~N>

2. CuCN.2LiCI 3. electrophile

E"

"

N

R

Heck Couplings

Br

N~~O

Br

N

SO2NMe2 120

Grubbs catalyst CH2CI2, 25 ~ 121

N 122 SO2NMe2

SO2NMe2 R = H, Me

Me 1. n-BuLi, THF

"~N>

E/ -'N

SO2NMe2 119

1. EtMgBr, THF,-20 *C 2. CuCN~ , I N 3. allyl bromide 118 SO2NMe2 4. repeat steps 1-3

123

Sonogashira and

Me

=

-78 ~

2. electrophile

E~N/" ~ Br

E = H, CHO, CO2Me, Ph2COH

N 124

5-Hydroxymethyl imidazoline 125, prepared from 2,3-diaminepropionic acid in four steps, underwent Mitsunobu reaction with a series of phenols to give imidazolines 126; phthalimide and N-benzyl trifluoroacetamide also reacted under these reaction conditions <03TL9111>. 4Cyanoimidazole 128 was prepared from commercially available 4-imidazolecarboxaldehyde 127, which readily reacted with various alkylmagnesium bromides followed by acidic conditions to give acyl imidazoles 129 without need for N-protecting groups <03S677>. ROH or R N H 2

___(--OH

DIAD,PPh3

BoctN,,~N

THF, 20 ~

125

OHC.II~ NN>1. NH2OH.HCI, H 127

pyridine, 25 ~

2. Ac20, 80 ~

X =

O, NH

,__.~XR

/

\

--- Bocl N,,~ N 126

O 1. RMgBr, THF, 10 ~ 2. H2SO4

11,

128

R = alkyl

N

129

H

Five Membered Ring Systems: With More than One N Atom

213

The concept-guided development of selective new C-arylation methods for imidazoles via CH bond functionalization has been reported <03JA5274, 03JA10580>. By judicious choice of the proper catalyst, 2-phenylimidazole 130 can be selectively arylated at the 4-position to imidazoles 131 (palladium catalyst in presence of magnesium oxide and triphenylphosphine) or at the 2'-position to produce imidazoles 132 (ruthenium catalyst in the presence of cesium carbonate). R

Pd(OAc)2 (5 mol%)

~

I~__~--'k R

PPh3 (20 mol%) MgO (1.2 eq) dioxane, 150 ~

(1.8 eq)

CpRu(PPh3)2CI (5 mol%) Cs2CO3 (1.2 eq), DMF, 130 ~ 130

131

132

An efficient synthesis of tertiary amides 134 from carbamoylimidazolium salts 133 and carboxylic acids has been published <03TL7485>. Highly enantioselective catalytic asymmetric epoxidation of ot,13-unsaturated carboxylic acid imidazolides in the presence of lanthanideBINOL complexes have been developed <03T10485>. Chiral 1,2-diamines were prepared by lithiation, subsititution, and hydrolysis of Boc-substituted imidazolidines in the presence of chiral ligand (-)-sparteine <03OBC1532>. Ytterbium triflate was found to effectively catalyze the reactions of various epoxides with substituted imidazole in high yields <03SC2989>. Tartaric acid was transformed into imidazole-4,5-dicarboxylic acid, followed by esterification, hydrazinolysis, and condensation with aromatic aldehydes to furnish imidazole-4,5diacylhydrazones <03SC2429>. O

RI.N~L.~ ~(~) IC) 1~2

'~L.~jN-Me -'~ 133

R3CO2H, Et3N ,. MeCN, 25 ~

0

RIN-~R3 i~2

R1 = R2 = morpholinyl; Bn, Me; 134 piperdinyl R3 = various alkyls, amino acids, Bn

The reactivity of 6-haloimidazol[1,2-a]pyridine 135 towards different azoles can be modulated to give ipso product 136 in the presence of copper(I) catalyst or to yield cine product 137 in the absence of copper catalyst <03JOC5614>. Imidazo[1,2-a]pyrimidine 138 can be arylated at the 3-position with aryl bromides in the presence of cesium carbonate with catalytic palladium(II) acetate to give 139 <03OL4835>.

214

L. Yet

azole (1 equiv) Cul (5 mol%)

~"~'N

~~NN~~ F

K3PO4(2equiv) "PhMe,110~ 24h

c,,~NHMe L J,,. (15 mol~ V",NHMe X=l

136

azole

F

X 135

(1 equiv)

Cs2CO3 (2 equiv)

DMF, 110 ~ 24 h X= Br cine Substitution

F

~/N.~

137

ipso Substitution

9

~

HBr

ArBr, Pd(OAc)2 PPh3, Cs2CO3 (2 equiv) dioxane, 100 ~

N....// 138

----~FN"r~% N~ ' Ar 139

Imidazole-containing compounds have been utilized as ligands and catalysts in some reactions. Chiral 2-(hydroxyalkyl)imidazolines 140 were employed in the study of the ligand electronic effects in enantioselective diethylzinc additions to aldehydes <03SL102>. Peptidebased catalysts of the type 141 were evaluated for their potential regioselective acylation of carbohydrate monomers <03T8869> and enantioselective Baylis-Hillman reactions <03OL3741>. Palladium(lI) bisimidazole ligand 142 was proven to be an effective catalyst for the Heck reaction under phosphine-free conditions using ionic liquids as solvents <03OL3209>. lmidazolium salts 143 were utilized in the palladium-catalyzed borylation process with aryldiazonium ions <03OL4635> and in the carbonylative amidation with boronic acids, aryl diazonium ions, and ammonia <03S2886>. Imidazolium salt 144 was employed in the palladium-catalyzed Sonogashira coupling of aryl halides <03OL3317>. R2

O BocHN-v~peptid e : N - ~N ~ ",,R1

140 R1 = Bn,/-Pr, t-Bu R2 = CF3, Me, OMe

9

Me

141

MeaN zlN. ~ d'CI J/ Me"N N Me 142

x|

/-q|

R~N,,,~N-R 143 R = Ar, X = CI 144 R = naphthyl, X = PF6

5-Thioxo(or oxo)-6H-imidazol[ 1,2-c]quinazolines 147 were prepared from reactions of 2isothio(or oxo)cyanatobenzonitrile 145 with various ct-aminoketones 146 <03TL5965>.

Five Membered Ring Systems: With More than One N Atom

1. Na2CO 3, H20, CN N~.C.. X 145

R2 +

H2 N 146

CH2CI 2, 20 ~ R1

O

2. reflux ,. R 1 = Me, t-Bu, Ar R 2 = H, Ph X=O,S

215

R1

/ .,~,...j./~-~ v

-N~-"X H 147

Solid-supported u-bromoketone 148 was condensed with various 2-aminopyridines or 2aminopyrimidine derivatives to give imidazo[1,2-a]pyridines or imidazo[1,2-a]pyrimidine derivatives 149 after cleavage with acid <03TL6265>. An abnormal aza-Wittig reaction on solid-phase parallel synthesis of 3-aryl-2,4-dioxo-l,3,5-triazino[1,2-a]benzimidazoles was observed <03TL3705>. New spiroimidazolidinone derivatives 151 were prepared from SynPhase lanterns from dipeptides anchored on the solid-supports 150 <03JCO356>.

5.4.4

1,2,3-TRIAZOLES AND RING-FUSED DERIVATIVES

A review on the 1,2,3-triazole formation via 1,3-dipolar cycloaddition of acetylenes with azides under mild conditions has been published <03H(60)1225>. The synthesis of a benzotriazole azo dye phosphoramidite and the subsequent use in solid phase synthesis of oligonucleotides has been reported <03TL 1339>. The chemical reactivity of [ 1,2,3]triazolo[ 1,5a]- and [1,5-c]-pyrimidinium salts has been published <03T4297>. A review on the use of benzotriazole as an ideal synthetic auxiliary has been disclosed <03CEJ4586>. 1,2,3-Triazole derivatives could be synthesized from different starting substrates. Various triazoles 155 were synthesized from nonactivated terminal alkynes 152, allyl methyl carbonate 153 and trimethylsilyl azide 154 in a [3 + 2] cycloaddition with the use of the Pd(0)-Cu(I) bimetallic catalyst <03JA7786>. The allyl group of 155 was efficiently deprotected by ruthenium-catalyzed isomerization followed by ozonolysis to give 4-substituted triazoles 156. tz-Aminoacetophenones 157 were reacted with hydrazines in acetic acid to give an efficient

L. Yet

216

preparation of 2,4-disubstituted-l,2,3-triazoles 158 <03SC3513>. N-(Uracil-6-yl)-S,Sdiphenylsulfilimine 159 reacted with aryldiazonium salts to give arylsulfilimines 160, which were thermolyzed to the 1,2,3-triazolopyrimidine diones 161 in good yields <03H(60)2677>. A domino sequence of reactions of 2-azidoindole led to the syntheses of indolo[3,2e][ 1,2,3]triazolo[ 1,5-a]pyrimidines <03H(60)2669>.

R m

H

+

~OCO2Me

152

R

Pd2(dba)3-CHCI3 (25 mol%) CuCI(PPh3)2 (10 mol%) + TMSN 3 P(OPh)3 (20 mol%) 154 EtOAc, 100 ~

153

R 1. HRuCI(CO)(PPh3)2

N'N'N 2.03; Me2S 155 ~1

R = t-Bu, Ph, At, C6H13, BnOCH2, 1-naphthyl

156 i

0 R2NHNH2

157

reflux, 2 h

-

R 1 = CI, Br, OMe, F R 2 = Me, Ph

R1

o

158

o

N2C

Me-N NN

O L. .:Sp. H OO F Me 159

R2

N---N +

Me.N

N.~.N

L

THF, 5 ~

I~le 160

P.Mere,ux

Me-N N

; O LN NN

R = H, Me, OMe, CI, NO 2

Me

161

(z,13-Unsaturated systems are good substrates for azide additions to prepare 1,2,3-triazole derivatives. A series of 5-fluoroalkylated IH-1,2,3-triazoles 163 were prepared in good yield by the regiospecific 1,3-dipolar cycloaddition reaction of (~-ethyl 3-fluoroalkyl-3pyrrolidinoacrylates 162 with awl azides <03SL 187, 03T4395>. Benzyl azides also participated in these reactions but sodium carbonate was required to provide good yields of the triazoles. 4Acyl-lH-1,2,3-triazoles 165 were formed from diethylaluminum azide and ct,13-unsaturated ketones 164 by [3+2] cycloaddition of azide, followed by 1,5-hydride transfer to the 13carbon of the triazoline side chain and fragmentation of the tertiary amino group <03TL9095>. Rf ArN 3, 80 ~ = Rf/.~./.CO2Et

162

CO2Et /

~

ArIN'N'~N

163 Rf = CICF 2, BrCF2, CF3, CI(CF2)2CF2 Ar = Ph, 4-OMeC6H4, 4-NO2C6H4

217

Five Membered Ring Systems: With More than One N Atom

R1 B n 2 N ~ R

Et2AIN3 2

O 164

PhMe 25 ~

N=N

.

R I ~ ' N H O

R1 = i-Pr, Bn R2 = Me, Bn, i-Pr

R2 165

Many benzotriazole-based methodologies were utilized in the synthesis of variety types of compounds. N-Acylbenzotriazoles 166 were efficiently acylated with primary and secondary cyanides 167 to give the corresponding t~-substituted f3-ketonitriles 168 in good to excellent yields <03JOC4932>. N-Acylbenzotriazoles 170 reacted with pyrrole or N-methylpyrrole 169 in the presence of titanium(IV) chloride to yield 2-acyl pyrroles 171 <03JOC5720>. Similarly, indoles were acylated at the C-3 position using these conditions. N-Acylbenzotriazoles 166 and acyclic sulfones 172 were utilized in the synthesis of ]3-ketosulfones 173 <03JOC1443>. NAcylbenzotriazoles, when treated with samarium diiodide in tetrahydrofuran, underwent a selfcoupling reaction to afford 1,2-diketones; however, reactions in acetonitrile underwent ringopening reaction to afford 1-acylamido-2-alkyl(or aryl)benzimidazoles <03T4201>. NAcylbenzotriazoles were also intermediates in the efficient conversions of carboxylic acids into O-alkyl, N-alkyl, and O,N-dialkylhydroxamic acids <03S2777>.

[~

N CN n-BuLi,THF, -78 ~ 'IN + t1... or N RI~------.O R2 R3 KOt-Bu, DMSO, 25 ~ 166

167

~2~R 1 CN R 3

R1= alkyl, Ar, 2-thienyl, 2-furyl R2=H, Me R3 = H, Ph, Bn, Ar

[~

N N

R1 166

02 R2.S~R3 172

168

N

+ RI (Me) 169

R/~----O 170

TiCl 4 CH2CI2 25 ~

R (Me) IR

O 171

R = Ar, 2-furyl, 2-pyridyl, 2-indolyl

n-BuLi, THF

02 R2.S..

R3

-78 ~

R 1= alkyl, Ar, 2-thienyl, 2-furyl R2= Ph, Me, Et R3 = H, Ph, Me, vinyl

173

Reformatsky reaction of ethyl bromodifluoroacetate with N,N-(dibenzyl)-lH-benzotriazolyl1-methylamine 174 gave the fully protected t~,~-difluoro-13-alanine 175 <03TL2375>. Hydrogenolysis and hydrolysis furnished t~,t~-difluoro-13-alanine 176. This methodology was also applied to the synthesis of N-protected 3,3-difluoroazetidin-2-ones <03S2483>.

218

L. Yet

"N N' ~'NBn2 174

Zn, TMSCI, THF " 25 ~ 3 h

Bn2N

F

F 175

OEt

0.5N HCI, 25 ~ 2. Dowex, NH4OH

=

H2N

F

F

OH

176

Benzotriazole-based methodologies were also used to convert 3-substituted pyrroles to indoles <03SJOC5728>, to give facile N-derivatization of t~-amino esters and amides via benzotriazolylmethyl derivatives <03JOC9088>, and to provide substituted 2H-azirines from benzotriazolylmethyl ketones <03JOC9105>. Benzotriazole-based methodologies have been utilized in the syntheses of various ring-fused heterocycles, such as 1,2,3,4tetrahydropyrazino[l,2-a]indoles <03JOC4938>, imidazo[1,2-a]pyridines and pyrimidines <03JOC4935>, and other complex systems <03JOC5713>. There have been two published reports on the use of polymer-supported azide reagents in the 1,3-dipolar cycloadditions of alkynes. Various alkyl bromides reacted with Merrifield resin supported ammonium azide 177 to give various alkyl azides 178, which were reacted with methyl propiolate to give 1,2,3-triazoles 179 in excellent yields <03TL2153>. The monomethylether of poly(ethylene glycol)- or MeOPEG-bound azide 180 was utilized in the 1,3dipolar cycloadditions with various alkynes to afford regioisomeric mixtures of 181 and 182 <03TL1133>. The 1,2,3-triazoles could be cleaved with formic acid in dioxane in one example (R = COEMe).

Merrifield 1,2,3-triazole resins 183 and 184 were prepared and utilized in the BAL (Backbone Amide Linker) strategy to synthesize amides 185 via sequential reductive aminations, amide couplings, and traceless resin cleavage with trifluoroacetic acid <03OL1753>.

219

Five Membered Ring Systems: With More than One N Atom

5.4.5

1,2,4- TRIAZOLES AND RING-FUSED DERIVATIVES

Several synthetic routes to 1,2,4-triazole derivatives have been reported in 2003. A novel one-pot synthesis of 1,2,4-triazole-3,5-diamine derivatives 189 and 190 from isothiocyanates 188 and monosubstituted hydrazines has been published; derivatives 190 were obtained with higher regioselectivity when aromatic and sterically bulky hydrazines were used <03TL1409>. Cyclocondensation of C-acetyl-N-arylnitrilimines 191 with various benzoylhydrazones 192 furnished 1,2,4-triazoles 193 <03SC243>. Three-component condensation of acid hydrazides 194 in the presence of S-methyl isothioamide hydroiodide 195, silica gel and ammonium acetate under microwave irradiation afforded 1,2,4-triazoles 196 in good yields <03SC113>. Unusual hydrazinolysis of 5-perfluoroalkyl-l,2,4-oxadiazoles 197 provided an expedient route to 5perfluoroalkyl-l,2,4-triazoles 198 <03JOC605>. N-Tosylamidrazones 199 can react either with acid chlorides or with ethyl chloroformate to give tosylated 1,2,4-triazoles 200 or 1,2,4-triazole3-ones 201, respectively <03SC3861>. R2

R1NCS 188

1. NaNHCN, DMF, 25 ~ R 1HN.~.~N.N..R2 2. R2NHNH2, EDC, Et3N = - YN - ~ 60 ~ R 1 = Ph, CH3CH2CH 2 R 2 = t-Bu, Ph, C6H 11, Ar

i

R 1HN.~/N, , +

NH 2 189

NH2 190

220

L. Yet

COPh

|174

'

N'N"H

CH3COC---N-N-Ar

RI-J~R2

191

192

|

O 194

RI

197

RI~,N,~ O H 201

u

Ar R2 -- Me, Ph

R

91

Z!

>

R~ =H, Me

R2 = Me, Et R1 = R2 = cycloalkyl

R 1 = Me,

NH2NH2 MeOH 25 ~

~,JN

CHC'3,0 ~

NNHTs 199

"N

R2

HN..cOPh

193

N-N RI-ff~.N ~.~--R2 H 196

198

R2COCI, pyridine CHCl 3, 0 ~

RJ~'NH2

R1 = Ph, Bn, i-Pr, 4-MeC6H4

,-,1

R ,/N-~'~ RI'Iq'N" N H

Rf = OF3, 03H7, 07H15 R = Ph, C11H23

CICO2Et, pyridine

Ar

iexv.j ~ ~.K

,|

195

iTs

THF, 25 ~

NH2 silica gel, NH4OAc R2"JJ"SMe Et3N, microwave (900 VV)

RI"J~'NHNH2

N-N

N-N'

R1 = Ph, Bn,/-Pr, 4-MeC6H4 R2 = Me, Bn,/-Pr

N-N

/ms

200

Urazoles 202 were easily converted to their corresponding triazolinediones 203 with silica sulfuric acid and sodium nitrite <03SC833>. 3-Phenylthio-l,2,4-triazoles 204 were alkylated to their triazolium salts 205, which under aqueous basic conditions provided 2,4-disubstituted1,2,4-triazol-3-ones 206 <03H(60)351 >. HN-NH O.~ N/~ O R 202

silica/sulfuricacid

NaNO2 CH2Cl2, 25 ~

R = alkyl, Ar

N=N O~X. N / ~ O R 203

221

Five Membered Ring Systems: With More than One N Atom

N--~ P h S ' ~ N -N

R2X EtOAcor = CHCl 3 or neat

R2 ~ X Q /N--~ PhS-14~,N.N

K2CO3 = water

R2 IN--~ O'"~N" N

80 oc

204

R 1 = Me, Et, Bn R2 = Me, Bn, allyl, Bu

205

206

[1,2,4]Triazoline-3,5-dione 207 was an effective fluorous dienophile in scavenging excess diene after the Diels-Alder reactions have been completed <03OL3293>. 0

N~N---~--C8F17 II

O

207

There have been two published reports on the syntheses of stable 1,2,4-triazolyl carbenes. Thermal decomposition in v a c u o of 5-methoxytriazoline 208 provided in quantitative yield 1,2,4-triazol-5-ylidene 209, a stable carbene in the absence of oxygen and moisture <03S1292>. This nucleophilic carbene 209 could react with a variety of alcohols, thiols, amines, oxygen, sulfur, selenium, isocyanantes, and metal carbonyls to form a myriad of addition products. Reactions of 1,2,4-triazolyl perchlorate salts 210 with base afforded stable nucleophilic 1,2,4triazol-5-ylidenes 211, which could react with acetonitrile and elemental sulfur and selenium to yield addition products <03JOC5762>.

,Ph

N-.N

, ~ >--OMe Ph N Ph 208

90 ~ 0.01 m b a r neat

Ph

N--N

ph/JL.N~> 9 Ph 209

CI04Q Q , Ad

KOt-Bu, Phil or

/~~\>---H Nail (60%), CH3CN R1 R1 = Ph, 4-BrC6H4 ~2 R2 = Ph, 4-BrC6H4 210 Ad = 1-adamantyl

Ad R 1N Z : > ~2 211

Reaction of resin bound S-methyl-N-acylisothioureas 212 with hydrazines followed by acidic cleavage yielded 3-amino-l,2,4-triazoles 213 under mild conditions <03TL7841>. 3,4,5Trisubstituted 1,2,4-triazoles 215 were synthesized on solid-phase from various thioamides 214 and hydrazides leading to peptidomimetic scaffolds <03OL4465>.

9

222

L. Yet

Several unique heterocyclic fused-l,2,4-triazole structures have been published. Pyridine amination of 216 with O-mesitylenesulfonylhydroxylamine followed by condensation with various aryl and heterocyclic aldehydes and subsequent cyclization and oxidation gave triazolopyridines 217 <03TL 1675>. Triazolopyridines 217 were utilized in the direct conversion to the triazolopyridine amides 218 with methylaluminoxane premixed with amines in a combinatorial library synthesis. A convenient synthesis of novel 4-(l,2,4-triazol-l-yl)-2pyrazolines and their derivatives has been reported <03SC1449>. A novel triheterocyclic ring system, thieno[2,3-f] [ 1,2,4]triazolo[ 1,5-a]azepines, has been published <03S 1231>.

,.O-

MeO...~O

es,t,,enesu,,on,,-

25hydr~176

dioxane, ,.

2. R1CHO, 100 ~ H2N -N- NH 2 3. KOH, MeOH, 0 2 216

methylaluminoxaneR2R3NH, dioxane 90 H2N N ~-N

I~1"~-"<

217

R1

oC

"

H2N- N "N ILI-~ 218

R1 = aryl, pyridyl, furanyl, thiophenyl R2 = R3 = H, primary, secondary amines

R

223

Five Membered Ring Systems: With More than One N Atom

5.4.6

TETRAZOLES AND RING-FUSED DERIVATIVES

Density functional theory calculations using the hybrid functional B3LYP have been performed to study tetrazole formation by intramolecular [2+3] dipolar cycloaddition of organic azides and nitriles <03JOC9076>. Very few syntheses of tetrazoles were reported in 2003. Various tz-dialkylated [3-keto esters 219 underwent Schmidt rearrangement with trimethylsilyl azide to give tetrazole 220, which could be elaborated further to azido acid 221, precursors to tx-dialkylated ix-amino acids <03TL3179>. Di(benzotriazolyl)methanimine 222 reacted with various secondary amines to generate 223, which when treated with sodium azide in the presence of acetic acid yielded N,Ndisubstituted 5-aminotetrazoles 224 in moderate to good yields <03JOC4941 >.

O

O

TMSN 3 (2.5 eq)

M e M e ~ ~ R OEt

ZnBr2(leq) 60 ~ 18 h

N-N "~ " Me N" N _L...-C~ Et Me~R

"

R = Et, Bn, Ph, i-Bu

219

1. Mel 2KOH'80~ 3. HCI

Me

R2NH CH2CI2 ,25 ~

Bt"~Bt 222

Bt

~

NH NR2

..OH O

220

NH

R~

221

H ----.d'.N. N R2N \\ ,, N-N

NAN3' CHCI3 .. HOAc,25 ~

223

224

Vinylsilanes 227 in various E / Z ratios are formed in high yields in the reactions of acyl(trialkyl)silanes 225 with anions generated from tetrazolyl sulfones 226 <03OL2789>. The synthesis and chemistry of tetrazolylacroleins has been reported <03T7485>. Fused tetrazole derivatives were obtained from intramolecular iodocyclization of tetrazolyl olefins <03T6759>.

O R1..EL ~SiR2 225

+

N-N ".,. R 3 ~ S02 ~ N . , '~~ Ph I/

226

LiHMDS THF or .. PhMe -78 ~

SiR2 . . ~ R3 R1

RI= Ph(CH2)n, C12H25 R2 = Me, Et R3 = Ph(CH2)n, CllH23

227

L. Yet

224

5.4.7

REFERENCES

03CC1870 03CEJ4587 03H(60)1 03H(60)437 03H(60)167 03H(60)351 03H(60)879 03H(60)1225 03H(60)1329 03H(60)1339 03H(60)1457 03H(60)2323 03H(60)2499 03H(60)2669 03H(60)2677 03JA5274 03JA7786 03JA10580 03JCO356 03JCO465 03JCO826 03JHC 159 03JHC191 03JHC303 03JHC363 03JHC487 03JHC681 03JOC50 03JOC605 03JOC1443 03JOC4093 03JOC4906 03JOC4932 03JOC4935 03JOC4938 03JOC4941 03JOC5381 03JOC5614 03JOC5713 03JOC5720 03JOC5728 03JOC5742 03JOC5762 03JOC6814 03JOC7538 03JOC9076

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Five Membered Ring Systems: With More than One NAtom

03JOC9088 03JOC9105 03OBC1532 03OBC4268 03OL133 03OL511 03OL1067 03OL1095 03OL1753 03 OL2131 03OL2789 03OL3209 03OL3293 03OL3313 03OL3317 03OL3623 03OL3741 03OL3759 03OL4465 03OL4635 03OL4835 03S659 03S677 03S906 03Sl160 03S1231 03S1236 03S1267 03S1292 03S1433 03S1683 03S1727 03S1753 03S2483 03S2661 03S2777 03S2827 03S2886 03SC79 03SCl13 03SC243 03SC833 03SC1267 03SC1449 03SC1483 03SC1651 03SC2429 03SC2671 03SC2989 03SC3513 03SC3861 03SL102

225

A.R. Katritzky, N. Kirichenko, B.V. Rogovoy, H.-Y. He, J. Org. Chem. 2003, 68, 9088. A.R. Katritzky, M. Wang, C.R. Wilkerson, H. Yang, J. Org. Chem. 2003, 68, 9105. N.J. Ashweek, I. Coldham, T.F.N. Haxell, S. Howard, Org. Biomol. Chem. 2003, 1, 1532. A.J. Blake, D. Clarke, R.W. Mares, H. McNab, Org. Biomol. Chem. 2003, 1, 4268. G. Evindar, R.A. Batey, Org. Lett. 2003, 5, 133. S.-H. Lee, B. Clapham, G. Koch, J. Zimmermann, K.D. Janda, Org. Lett. 2003, 5, 511. Y. Chen, Y. Lam, Y.-H. Lai, Org. Lett. 2003, 5, 1067. S. Hernandez, R. SanMartin, I. Tellitu, E. Dominguez, Org. Lett. 2003, 5, 1095. S. L6ber, P. Rodriguez-Loaiza, P. Gmeiner, Org. Lett. 2003, 5, 1753. K.L. Tan, A. Vasudevan, R.G. Bergman, J.A. Ellman, A.J. Souers, Org. Lett. 2003, 5, 2131. P. Jankowski, K. Plesniak, J. Wicha, Org. Lett. 2003, 5, 2789. S.B. Park, H. Alper, Org. Lett. 2003, 5, 3209. S. Werner, D.P. Curran, Org. Lett. 2003, 5, 3293. K.I. Booker-Milburn, D.J. Guly, B. Cox, P.A. Procopiou, Org. Lett. 2003, 5, 3313. Y. Ma, C. Song, W. Jiang, Q. Wu, Y. Wang, X. Liu, M.B. Andrus, Org. Lett. 2003, 5, 3317. Y. He, Y. Chen, H. Wu, C.J. Lovely, Org. Lett. 2003, 5, 3623. J.E. Imbriglio, M.M. Vasbinder, S.J. Miller, Org. Lett. 2003, 5, 3741. R.S. Bon, C. Hong, M.J. Bouma, R.F. Schmitz, F.J.J. de Kanter, M. Lutz, A.L. Spek, R.V.A. Orru, Org. Lett. 2003, 5, 3759. D. Boeglin, S. Cantel, A. Heitz, J. Martinez, J.-A. Fehrentz, Org. Lett. 2003, 5, 4465. Y. Ma, C. Song, W. Jiang, G. Xue, J.F. Cannon, X. Wang, M.B. Andrus, Org. Lett. 2003, 5, 4635. W. Li, D.P. Nelson, M.S. Jensen, R.S. Hoerner, G.J. Javadi, D. Cai, R.D. Larsen, Org. Lett. 2003, 5, 4835. G.A. Kraus, P.K. Choudhury, Synthesis 2003, 659. J.-i. Kwakami, K. Kimura, M. Yamaoka, Synthesis 2003, 677. D.M. Volochnyuk, A.O. Pushechnikov, D.G. Krotko, G.N. Koydan, A.P. Marchenko, A.N. Chernega, A.M. Pinchuk, A.A. Tolmachev, Synthesis 2003, 906. M.E.F. Braibante, H.T.S. Braibante, J.K. da Roza, D.M. Henriques, L. de Carvalho Tavares, Synthesis 2003, 1160. Q. Wang, Z. Li, H. Yang, F. Li, Z. Ding, F. Tao, Synthesis 2003, 1231. H. Uchida, T. Shimizu, P.Y. Reddy, S. Nakamura, T. Toru, Synthesis 2003, 1236. G. Sabitha, G.S.K.K. Reddy, C.S. Reddy, N. Fatima, J.S. Yadav, Synthesis 2003, 1267. D. Enders, K. Breuer, U. Kallfass, T. Balensiefer, Synthesis 2003, 1292. S. Peddibhotla, J.J. Tepe, Synthesis 2003, 1433. P.L. Beaulieu, H. Hache, E. von Moos, Synthesis 2003, 1683. R.A. Singer, S. Caron, R.E. McDermott, R. Arpin, N.M. Do, Synthesis 2003, 1727. H. Hoffmann, T. Lindel, Synthesis 2003, 1753. S. Lacroix, A. Cheguillaume, S. Gerard, J. Marchand-Brynaert, Synthesis 2003, 2483. J. Liu, J. Chen, J. Zhao, Y. Zhao, L. Li, H. Zhang, Synthesis 2003, 2661. A.R. Katritzky, N. Kirichenko, B.V. Rogovoy, Synthesis 2003, 2777. G. Panke, T. Schwalbe, W. Stirner, S. Taghavi-Moghadam, G. Wille, Synthesis 2003, 2827. Y. Ma, C. Song, Q. Chai, C. Ma, M.B. Andrus, Synthesis 2003, 2886. J.Y. Hao, Z.Y. Ge, S.Y. Yang, Synth. Commun. 2003, 33, 79. S. Rostamizadeh, H. Tajik, S. Yazdanfarahi, Synth. Commun. 2003, 33, 113. A.-R.S. Ferwanah, Synth. Commun. 2003, 33, 243. M.A. Zolfigol, G. Chehardoli, S.E. Mallakpour, Synth. Commun. 2003, 33, 833. M.-W. Ding, Y. Sun, Z.-J. Liu, Synth. Commun. 2003, 33, 1267. S. Wang, B. Shi, Y. Li, Q. Wang, R. Huang, Synth. Commun. 2003, 33, 1449. R. Sridhar, P.T. Perumal, Synth. Commun. 2003, 33, 1483. M.-W. Ding, Y. Sun, S.-J. Yang, X.-P. Liu, Z.-J. Liu, Synth. Commun. 2003, 33, 1651. G. Su, J. Qin, Q. Ni, H. Mu, Synth. Commun. 2003, 33, 2429. D.-P. Cheng, Z.-C. Chen, Q.-C. Zheng, Synth. Commun. 2003, 33, 2671. S. Luo, B. Zhang, P.G. Wang, J.-P. Cheng, Synth. Commun. 2003, 33, 2989. Y. Luo, Y. Hu, Synth. Commun. 2003, 33, 3513. H. Chouaieb, M.B. Mosbah, M. Kossentini, M. Salem, Synth. Commun. 2003, 33, 3861. M. Casey, M.P. Smyth, Synlett 2003, 102.

226

03SL187 03SLl117 03SL1467 03SL1847 03SL2392 03T499 03T2197 03T2811 03T4201 03T4297 03T4395 03T4591 03T4757 03T6311 03T6759 03T7485 03T8383 03T8869 03 T9001 03T10485 03TL1133 03TL1339 03TL1379 03TL1409 03TL1675 03TL1709 03TL2153 03TL2293 03TL2375 03TL2807 03TL3009 03TL3179 03TL3351 03TL3705 03TL3843 03TL4369 03TL4491 03TL5453 03TL5867 03TL5935 03TL5943 03TL5965 03TL6265 03TL6669 03TL6737

L. Yet

W. Peng, S. Zhu, Synlett 2003, 187. H. Uchida, H. Tanikoshi, S. Nakamura, P.Y. Reddy, T. Toru, Synlett 2003, 1117. Y.-G. Wang, J. Zhang, X.-F. Lin, H.-F. Ding, Synlett 2003, 1467. R. Martinez-Palou, G. de Paz, J. Marin-Cruz, L.G. Zepeda, Synlett 2003, 1847. W.-D. Pfeiffer, E. Dilk, H. RoBberg, P. Langer, Synlett 2003, 2392. A.N. Kozyrev, J.L. Alderfer, B.C. Robinson, Tetrahedron 2003, 59, 499. M.F.A. Adamo, R.M. Adlington, J.E. Baldwin, G.J. Pritchard, R.E. Rathmell, Tetrahedron 2003, 59, 2197. W. Seebacher, G. Michl, F. Belaj, R. Brun, R. Saf, R. Weis, Tetrahedron 2003, 59, 2811. X. Wang, Y. Zhang, Tetrahedron 2003, 59, 4201. S. Batori, E. Gacs-Baitz, S. Bokotey, A. Messmer, Tetrahedron 2003, 59, 4297. W. Peng, S. Zhu, Tetrahedron 2003, 59, 4395. C.A. Tsoleridis, J. Stephanidou-Stephanatou, P. Gounaridis, H. Zika, M. Pozarentzi, Tetrahedron 2003, 59, 4591. H. Hazarkhani, B. Karimi, Tetrahedron 2003, 59, 4757. G. Sarodnick, M. Heydenreich, T. Linker, E. Kleinpeter, Tetrahedron 2003, 59, 6311. F. Ek, L.-G. Wistrand, T. Frejd, Tetrahedron 2003, 59, 6759. I. Nagy, D. K6nya, Z. Riedl, A. Kotschy, G. Tim~iri, A. Messmer, G. Haj6s, Tetrahedron 2003, 59, 7485. M.T. Rahman, H. Nishino, Tetrahedron 2003, 59, 8383. K.S. Griswold, S.J. Miller, Tetrahedron 2003, 59, 8869. B.A. Johns, K.S. Gudmundsson, E.M. Turner, S.H. Allen, D.K. Jung, C.J. Sexton, F.L. Boyd, Jr., M.R. Peel, Tetrahedron 2003, 59, 9001. T. Ohshima, T. Nemoto, S.-y. Tosaki, H. Kakei, V. Gnanadesikan, M. Shibasaki, Tetrahedron 2003, 59, 10485. L. Garanti, G. Molteni, Tetrahedron Lett. 2003, 44, 1133. R. Brown, W.E. Smith, D. Graham, Tetrahedron Lett. 2003, 44, 1339. Y. Chen, H.V.R. Dias, C.J. Lovely, Tetrahedron Lett. 2003, 44, 1379. C. Liu, E.J. lwanowicz, Tetrahedron Lett. 2003, 44, 1409. B. Brodbeck, B. Pullmann, S. Schmitt, M. Nettekofen Tetrahedron Lett. 2003, 44, 1675. S. Balalaie, M.M. Hashemi, M. Akhbari, Tetrahedron Lett. 2003, 44, 1709. B.E. Blass, K.R. Coburn, A.L. Faulkner, W.L. Seibel, A. Srivastava, Tetrahedron Lett. 2003, 44, 2153. Z. Wu, N.J. Ede, M.N. Mathieu, Tetrahedron Lett. 2003, 44, 2293. A. Cheguillaume, S. Lacoix, J. Marchand-Brynaert, Tetrahedron Lett. 2003, 44, 2375. D. Vourloumis, M. Takahashi, K.B. Simonsen, B.K. Ayida, S. Barluenga, G.C. Winters, T. Hermann, Tetrahedron Lett. 2003, 44, 2807. B.E. Blass, A. Srivastava, K.R. Coburn, A.L. Faulkner, W.L. Seibel, Tetrahedron Lett. 2003, 44, 3009. H.-J. Cristau, X. Marat, J.-P. Vors, J.-L. Pirat, Tetrahedron Lett. 2003, 44, 3179. S. Kobayashi, R. Hirabayashi, H. Shimizu, H. lshitani, Y. Yamashita, Tetrahedron Left. 2003, 44, 3351. C.E. Hoesl, A. Nefzi, R.A. Houghten, Tetrahedron Lett. 2003, 44, 3705. J. Fu, S.J. Shuttleworth, Tetrahedron Lett. 2003, 44, 3843. S.M. Ireland, H. Tye, M. Whittaker, Tetrahedron Lett. 2003, 44, 4369. W. Seelen, M. Sch~ifer, A. Ernst, Tetrahedron Lett. 2003, 44, 4491. L.G. Fedenok, N.A. Zolnikova, Tetrahedron Lett. 2003, 44, 5453. R.J. Cvetovich, B. Pipik, F.W. Hartner, E.J.J. Grabowski, Tetrahedron Lett. 2003, 44, 5867. A.B. Alloum, K. Bougrin, M. Soufiaoui, Tetrahedron Lett. 2003, 44, 5935. J. Guillard, F. Goujon, P. Badol, D. Poullain, Tetrahedron Left. 2003, 44, 5943. P. Langer, A. Bodtke, Tetrahedron Lett. 2003, 44, 5965. S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet, Tetrahedron Lett. 2003, 44, 6265. M. A. P. Martins, C. M. P. Pereira, P. Beck, P. Machado, S. Moura, M. V. M. Teixeira, H.G. Bonacorso, N. Zanatta, Tetrahedron Lett. 2003, 44, 6669. K.Y. Lee, J.M. Kim, J.N. Kim, Tetrahedron Lett. 2003, 44, 6737.

Five Membered Ring Systems: With More than One N Atom

03TL7115 03TL7485 03TL7629 03TL7841 03TL8063 03TL9095 03TL9111

M.R. Dobler, Tetrahedron Lett. 2003, 44, 7115. J.A. Grzyb, R.A. Batey, Tetrahedron Lett. 2003, 44, 7485. S.M. Sakya, B. Rast, Tetrahedron Lett. 2003, 44, 7629. Y. Yu, J.M. Ostresh, R.A. Houghten, Tetrahedron Lett. 2003, 44, 7841. J.-W. Byun, D.-H. Lee, Y.-S Lee, Tetrahedron Lett. 2003, 44, 8063. I. Adamo, F. Benedetti, F. Berti, G. Nardin, S. Norbedo, Tetrahedron Lett. 2003, 44, 9095. N. Defacqz, V. Tran-Trieu, A. Cordi, J. Marchand-Brynaert, Tetrahedron Lett. 2003, 44, 9111.

227

228

M.G. Saulnier, U. Velaparthiand K. Zimmermann

Chapter 5.5 Five-Membered Ring Systems" With N and S (Se) Atoms Mark G. Saulnier, Upender Velaparthi and Kurt Zimmermann Bristol Myers Squibb Company, 5 Research Parkway, Walling)Cord, CT 06492-7660, USA mark.saulnier@bms, com, upender, velaparthi@bms, corn and kurt.zimmermann@bms, com

5.5.1

INTRODUCTION

The syntheses and reactions of 5-membered heterocyclic ring systems containing nitrogen and sulfur (or selenium) that have been reported during 2003 are the topic of this review. The importance of these pi-rich heterocycles in medicinal chemistry and natural products is also covered. Thioamides represent a common intermediate for the synthesis of these heterocycles and this topic has been reviewed during the past year <03CRV197>. A review on the chemistry of isothiazoles has also appeared <03T7445>. The reaction of thiazoles with alkylidenecyclopropanes has been reviewed <03CRV1213>. The use of ebselen (2-phenyl1,2-benzoisoselenazol-3(2H)-one), a glutathione peroxidase mimic, has also been covered in a review <03EJO4329>. 5.5.2

THIAZOLES

5.5.2.1

Synthesis of Thiazoles and Fused Derivatives

The use of thioamides and ct-halocarbonyl compounds (Hantzsch reaction) is a well known method for the synthesis of thiazoles and many new examples have been reported during the past year. This approach has been used to synthesize a potent and selective anxiolytic mGlu5 receptor antagonist 2 from propargyl ketone 1 and thioacetamide <03JMC204>. The cognition enhancing agent 4 is obtained from thioamide 3 (derived from the corresponding nitrile and H2S) and chloroacetaldehyde, followed by sulfide exchange (oxidation of thiomethyl and then RSH treatment) <03JMC2227>. Several other thioamidederived thiazole syntheses have also been reported <03T1317, 03T2679, 03HAC132, 03JCR(S)225, 03H(60)321, 03JHC435, 03H(60)2417, 03BMC1493>. Generation of the c~halocarbonyl component and condensation with thioamide in one pot has been described <03IJC695>. An interesting variant on this theme is the oxidative ot-tosylation of alcohols with iodosylbenzene to give a-tosyloxyketones, which condense readily with thioamides to give thiazoles (e.g. 5 to 6) <03JOC6424>. 2,2'-Bithiazoles, obtained from dithiooxamide and 1,3-dichloroacetone, can be mono or dilithiated (e.g. 7) and this chemistry is used to synthesize bithiazole oligomers, n-stacked molecules which have been extensively characterized <03JA5040>. 2-Aminothiazoles, which display a diverse array of biological activities (see section 5.5.2.5), are similarly prepared using thioureas in lieu of thioamides <03AP551, 03IJHC307, 03IJC931, 03SCl109>. For example, 8 derives from the

229

Five-Membered Ring Systems: With N and S (Se) Atoms

corresponding 1-(4-aminofurazan-3-yt)bromomethyl ketone and the mono-R-substituted thiourea <03H(60)2417>. 2-Aminobenzothiazoles are obtained from di(imidazole-1yl)methanimine and 2-aminothiophenol <03JHC191>, from phenylthioureas by oxidative

S

TMS

~.J~..~

O

s ~

~

2. Pd(0)/ Cul 3-Br-pyr

Ar

SMe

_-_s

2 (Ar = 3-pyridyl)

NH2

S(CH2)2OH

O

~.c,..~.

2. m-CPBA 3. HS(CH2)2OH

S PhlO> T s O ~ p-TsOH Ph

h 2O.

Ph/J~ NH2~

5

RO

N

6

OR

N

Li/ ~S

~.~N~~ Ph Ph

S~ \Li

NH2 8

cyclization (Hugerschoff reaction) <03JFC207, 03IJC621, 03JOC8693 >, and by palladiumcatalyzed intramolecular cyclization of o-bromophenylthioureas <03TL6073>. 2,4-Disubstituted thiazoles 10 are obtained from thioamides or thioureas and (Z)-(2acetoxy-l-alkenyl)phenyl-X3-iodanes 9 in good yields <03JOC7887>, probably through the intermediacy of highly reactive c~-X3-iodanyl ketones (leaving group ca 106> triflate). An intramolecular cyclization of thioamide 11 with Burgess reagent gave thiazole 12 after MnO2 oxidation of the intermediate thiazoline <03OL4421>. Similar oxidation of thiazoline 14 with bromotrichloromethane provides a route to thiazole 15, an intermediate in the synthesis of the recently isolated 2,4'-bithiazole antibiotic (+)-cystothiazole A. A key step in this synthesis is electrophilic activation of amide 13 with triflic anhydride followed by cyclization with L-

E HO"v~ NH 1. Burgess AcO FBF3 RI-J~-NH2 R'~"- i-"Ph R'~ ~\/k__ _/~ ~ reagent >~ O FBF3~ RI\\ N'; .~ ~Z 2. MnO2 Et3N/ MeOH / ~ O ~ 117E lO ( = " E ozM e ) E ~_~CO2Et F~CO2Et o 1.Tf20 BrCCi3 S"~~ MeHN.~/ 2. L-Cysteine % N DBU > SAN

S I

9

"

O'"

1

"

12 (E = CO2Me)

HO

NC-~OMe 16

13

14

D-Cysteine

15

HO

,...._

17

230

M.G. Saulnier, U. Velaparthi and K. Zimmermann

cysteine <03OL4163>. Intramolecular nucleophilic attack of sulfur follows electrophilic activation of amide with bis-(triphenyl)oxodiphosphonium trifluoromethanesufonate (Tf20 + Ph3PO) <03AG(E)83, 03JOC9506> or TIC14 <03H(60)1219> and provides a "biomimetic" synthesis of thiazolines from which the corresponding thiazoles are obtained by MnO2 oxidation. Condensation of nitrile 16 with D-cysteine at pH 6 generates thiazoline 17, an iron chelating agent <03JMC1470>. Aldehydes react with [3-aminothiols to give thiazolidines which are oxidized to thiazoles with MnO2 <03T6579>. 1,3-Thiazolidinones arise from 2-mercaptoacetic acid cyclization onto imines <03IJC927> and an interesting spiroannulation <03SC563> strategy exploits this chemistry under microwave-irradiation (e.g. 18 to 19) <03OPP401>. When nitriles 20 are substituted for imines, reaction with 2-mercaptoacetic acid esters 21 produces 4-oxothiazolines 22 <03T7803, 03SC535>. Three component reactions of 2-mercaptoacetic acid, ArNH2, and Ar'CHO give 2,3-diaryl-l,3-thiazolidin-4-ones 23 as anti-HIV agents <03IF115>. Multicomponent synthesis of 4-carboxy-2-acylaminomethylthiazoles 25 on solid support utilize a precondensation of aldehyde (RICHO) and the Rink amide resin followed by thiocarboxylic acid (RZCOSH) and 3-(N,N-dimethylamino)-2-isocyanoacrylate 24 <03TL3679>. Related multicomponent syntheses of 2,4-disubstituted thiazoles have been described <03SL2410, 03TL8947>. Katritzky has described a solid phase synthesis of 2amino-4,5-substituted thiazoles 26 using thiourea resins, linked to the support via the phenol of 26 before TFA-induced cleavage <03JCO392>. Solid phase synthesis of benzothiazoles has also been reported <03T4851 >. R

NAt

__{ll~ SH s/~O O EtO2C--~ X H O R-'j'CO2H._._X--t~ ~ ~ N N~rO R/~.CN + )--HSCO2Et 18

19 H

R

N

o..N.~R 2 O

RICHO MeO2c'~--/NMe2 + 24 -~ ~NH 2 O R2"J~sH

s '~ -~A r

22

23

TFA

=

21

NC

O~_N"Ar

COR

EtO2

20

~-

S"~ RI~N~CO2Me HN-,,~ R2 o 25

.o

N / ~ T R3 ~1

26

Other methods for the synthesis of thiazoles than those discussed above have been reported during the past year. The 2-bromo-N-methylthiazolium bromide (BMTB) 29 is synthesized by cyclization of thiocyanate 27 with HBr to give 2-bromothiazole 28 in quantitative yield <03TL4393>. Methylation of 28 provides BMTB which serves as a thiazolium peptide coupling reagent that works more efficiently than HATU for the coupling of two sterically hindered N-methylated amino acids. 1,4-Bis(cyanothioformamido)benzene 30 is cyclized with 2-aminothiophenol to bis-benzothiazole 31 <03JCR(S)162>. Bis-

231

Five-Membered Ring Systems: With N and S (Se) Atoms

benzothiazoles also arise from 2-aminothiophenol and bis-aromatic acid chlorides, but with 2,6-pyridinedicarboxylic acid chloride, the resulting bis-amide (bearing free thiol groups) fails to further cyclize <03SC1943>. Flash vacuum pyrolysis of 1,2,4-benzotriazine 32 generates a low-yielding mixture of benzothiazole 33 and isobenzothiazole 34 <03T851>. 4Vinyl-l,3-thiazolidin-2-one 36 is the major product of the rearrangement of the Salkyloxazoline 35 in refluxing acetonitrile <03H(60)523>. The synthesis and nitration of 2chloromethylbenzothiazole has been described <03SUL67> and a rebuttal of a previously published benzothiazole synthesis (from ArSH and Ar'CN) also appeared <03OL543>.

O HBr __~N~I NCS..,.,~ "~ 27

CN S'~NH CH3Br ~"S/~Br ~~" 29

28

O

SH ~ N / ~

NH

NH2

HN...~S

,___ N.,.~NH

30 N(~

/~_~S

31

_

N~N F.V.P.750~ [~N/~SCH3 I

[~

33 +

Sv_.

32

O

S

c H3oN

reflux

Ph

36

34 5.5.2.2

Reactions of Thiazoles and Fused Derivatives

Substitution at the C-2 position of 2-bromothiazole 37 and 2-chlorobenzothiazole via palladium-catalyzed amination (e.g. 37 to 38) has been reported by Hartwig <03JOC2861> and Padwa has disclosed the copper(I)-catalyzed amidation of 37 to give 39 <03JOC2609>. While the former reaction does not proceed without palladium catalyst, amination of ethyl 2bromo-l,3-thiazole-5-carboxylate occurs directly (e.g. 40) <03JHC353>. Alkoxide nucleophiles react readily with 2-chlorobenzothiazole, allowing access to the 2benzothiazolyloxy products <03CPB697>. Suzuki coupling of 2-bromobenzothiazole with aryl boronic acids gives 2-arylbenzothiazoles <03TL8535> and related chemistry with 2chlorothiazoles and N-tosyl-3-indolylboronic acid yields a 2-thiazoyl-substituted indolyl library <03JCO754>. An interesting palladium-catalyzed annulation to similar 2-thiazolylsubstituted indoles has been reported by Cacchi (e.g. 41 to 42) <03S728>. Direct C-H bond functionalization of thiazoles and benzothiazoles has received considerable attention during the past year. For example, the t-Bu-P4 phosphazine base, t-Bu-P4 (pK = 42.7) induces the C-2-H deprotonative functionalization of benzothiazole 33, in the presence of benzophenone, to generate alcohol 43 in quantitative yield: This reaction has been extended to the direct C-4H functionalization of 3-bromopyridine in the presence of both aldehydes and ketones, but only succeeds with zinc iodide present as an additive <03JA8082>. The combination of polymethylhydrosiloxane (PMHS) and CsF facilitates the direct palladium/copper-catalyzed C-2-H cross-coupling of 33 with aryl halides to 2-arylbenzothiazoles <03JOC6775>. 2(Trimethylsilyl)-thiazole directly reacts with aldehydes to yield 2-thiazolyl alcohols related to

232

M.G. Saulnier, U. Velaparthi and K. Zimmermann

43 <03EJO821 >. An elegant cobalt-catalyzed [Co(OAc)2] method for the direct arylation of thiazole 44 with iodobenzene in the presence of the ligand, 1,3-bis-mesitylimidazolylcarbene (IMes), has tuneable regioselectivity: The exclusive C-5 arylation product 45 switches to the sole C-2 aryl analog 46 simply by the addition of CuI to the reaction mixture <03OL3607>. Similar palladium-catalyzed tandem thiazole C-H substitution chemistry has also appeared <03JA1700, 03T5685>. Direct substitution at C-4-H of the thiazole ring occurs if C-2 and C5 hydrogen atoms are not present. Br S

HNMePh ._ N

37

Pd(O2CCF3)2 (t_Bu)3P

~NMePh ~ ' ~ NH S ~

NaOt-Bu

N 38

O

Ph 45

Cul/K3PO 4 1,2-diamine

S

33

,...-

41

~

ligand

37

Pd(0) NHCOCF3 Cs2CO3

._

37

HN-"'%Ph

~

O EtO2C\~~/~)~ N

N O N_.__/

39

40

PhCOPh > t-Bu-P4 base

Ph ~

~S 43

42

Co(OAc)2 / IMes Cs2CO3 / DMF

Ph

44

Co(OAc)2 /IMes / Cul Cs2CO3 / dioxane

Ph 46

Simultaneous disclosures by Liebeskind <03OL801> and Guillaumet <03OL803> describe the palladium(0)-catalyzed cross-coupling of 2-(methylthio)benzothiazole 47 with heteroarylstannanes (e.g. 47 to 48) in the presence of copper(I) salts (CuMeSal complex in the case of Liebeskind). A palladium(II) / copper(I) catalyst system allows for a tandem onepot aminovinylation of 5-bromo-2-nitrothiazole 49 with acetylenes in the presence of secondary amines to give, for example, the 5-(aminovinyl)thiazole 50 in moderate yield <03JOC1503>. Base-induced intramolecular aminovinylation of C-2 acetylene-substituted thiazoles 51 accomplishes a particularly creative route to 2-(1,3-thiazol-2-yl)-lH-indole 52 <03T1571>. Lithiation of 2-(methylthio)thiazole 53 with n-butyllithium occurs at C-5 and subsequent quenching with aromatic nitriles yields 5-thiazolyl ketones (e.g. 54) <03T6363>. C-5 lithiation of N-Boc-2-aminothiazoles with LDA provides access to C-5-1ithio-2aminothiazole 55, an intermediate en route to C-5-ct-(2-aminothiazolyl)-C-nucleosides <03TL2199>. A novel radical-mediated route to benzothiazole sulfonyl ethyl C-glycosides <03JCHC423> and the synthesis of 2-(mercapto)benzothiazole S-nucleosides <03NNN2061> have also been disclosed during the past year. New sulfonyl-substituted 2benzylthiazoles are reported via the well established C-2 lithiation of benzothiazole <03S1112>. Alpha-lithiation of 2-(chloromethyl)thiazoles 56 with n-butyllithium at -78~ followed by quenching with imines (or ketones) provides aziridines (or oxiranes) 57 with moderate to good diastereoselectivity <03T1381>. Samarium diiodide mediated Barbier-type reaction of related 2-(chloromethyl)-benzothiazoles 58 with ketones or aldehydes yields the 2-(13-hydroxyalkyl)-benzothiazoles 59 <03SC3551 >.

Five-Membered Ring Systems: With N and S (Se) Atoms

.__•\• ~

MeS

Pd(Ph3P)4 2.2 CuMeSal

47

H2N~

N

Me\

S

CI

N

~ ~SMe

pyrrolidine

50

1. n-BuLi M e S a s

=

|1 iX/~

53

Ar

Boc

%)

54

S~

j

Li

55

Y

1. n-BuLi Me -~ 2. R1R2C=X X = O, NPh

Ph

HccPh_

49

52 ~ j

R 56

HN ,~

Bsr/~ ~ N

48

KH

51 ~

ONe( ~ S

233

N 57

R1

S, /, N 58

CI

"Sml2/ THF ~

S. /, N

Y = H, Cl

5

R1

Olefination of carbon substituted thiazoles with carbonyl substrates has been achieved via standard Wittig chemistry, as exemplified by the use of 60 with a homochiral ketone in the context of epothilone A synthesis <03TL3745>, by Horner-Emmons reaction with a phosphonate such as 61 <03BMCL4201>, or by Knoevenagel-type condensation between 2methylthiazole 62 and aldehyde 63 to give olefin 64 <03BMCL4201>. Base-induced condensation of 2-methylbenzothiazole with aromatic aldehydes is also a useful olefination protocol <03S371>. Various condensation reactions of aldehydes with ring methylene nucleophiles alpha to carbonyls in thiazolidinones <03SUL127>, 4-thioxo-thiazolidin-2-ones <03SUL17>, and thiazolidine-2,4-diones (e.g. 65 to 66 ) <03JCR(S)330> have been reported during the past year. Such 5-benzylidinethiazolidine-2,4-diones as 66 represent key intermediates for the synthesis of peroxisome proliferator-activated receptor ~, (PPARv) antagonists such as rosiglitazone, an important antidiabetic drug (see section 5.5.2.5 for more details). An interesting report of an asymmetric tandem Michael-aldol reaction of homochiral 1,3-thiazolidine-2-thione 67 with 4-chlorobenzaldehyde gives 68 (and its C8 epimer) as confirmed by X-ray analysis <03AG(E)2889>. N-Acylations of N-unsubstituted thiazolidinethiones with carboxylic acids and DCC / 4-DMAP give products related to 67 <03SL2351>. Rearrangement of 2-alkylidene-4-oxothiazolidine 69 by reaction with Lawesson's reagent (LR) presumably proceeds via intermediacy of the dithione, followed by ring opening-closing to the 1,2-dithiole 70 <03TL7087>. A novel rearrangement of 5-(tertbutylamino)-3-N-methyl-2-phenylthio-4-phenylthiazolium chloride to imidazolium-4-thiolate 71 is initiated by thiophenol in the presence of triethylamine <03SL2167>.

234

M.G. Saulnier, U. Velaparthi and K. Zimmermann

H s

P"Bu~c,- ,.-.-Z,"ii

o..( ~'.-~L ~ Etd \OEt 7 "

6O

o,~ HN

S.

S-~

61

R1R2C= Opiperidine"HOAc

o

"S"~ s N~ . , . ~

s

O

H

69

Ph

ArCHO BF3 Et20 9

H

LR

,S,

to,uer,:

Ph

S--S

t-Bu,

R I ~ N~~.~ R2

A

70

S

H

67

O H

2.HCl "-H264N. -1'4

63

Ar

O

66

RL,r_-s

BocHN

62

H,H~N~2R1

65

1.Ac20 N .-,,. S

+

S"

/~~N +

H

71

68

I CHa

Ph

Asymmetric hydrogenation of a 5-benzoylthiazole using a homochiral RuC12 catalyst gives the corresponding alcohol 72 quantitatively and in 99.4% ee. Other 5-benzoylthiazoles are similarly processed to their alcohols in 92-99% ee <03OL5039>. 1,3-Dipolar cycloadditions of 2-dialkylaminothioisomunchnones 73 with aliphatic aldehydes proceed via the initial [3+2] cycloadduct 74, which fragments to 13-1actams 75 or thiiranes 76 depending on the electronic character of the aryl substituents on the nitrogen atom of 73 <03JOC6338>. An interesting thiophene synthesis proceeds from 2-(mercaptomethyl)benzothiazole 77, 4phenyl-3-butyn-2-one, and DBU to generate biheteroaryl 78 <03SC1433>. Symmetrical benzothiazole C-2-disulfides have been prepared using CsF-Celite as a solid base <03TL6789>. N-Benzyl-3-cyanopyridinium chloride reacts with 4-substituted-2aminothiazoles at the open C-5 position of the aminothiazole and the 4-position of the

F3C

Ph

F 3 C ~ OMOM

H3C..~

S-~-N

Bn

HO",

)"--O-H-'JJ'-.Ar2

F

~ Ph

Ar1 S N--Bn

Ar~ 74

75

CH3 Bn--N-,~ O

F2CHO k ~ ( 99.4% ee via ketone hydrogenation ) 72

?H 77

o

Ar2/J-- N,,ArI

73

O

H3C..N..Bn

CH3

Ph --

COCH3 [ ~ N

DBU / CH3CN

S~/ S J ~ ~] 78 H3C

Ph

AF 1. N,,,~O

S~'~Ph H" "A~

76

235

Five-Membered Ring Systems: With N and S (Se) Atoms

pyridinium to give 1,4-dihydropyridine addition products <03TL391>. Nonselective anodic fluorination of (4-arylthiazole-2-yl)acetonitriles generates 5-fluorinated products in addition to fluorination alpha to nitrile <03H(60)15>. 5.5.2.3

R i n g A n n u l a t i o n on T h i a z o l e s

The synthesis of thiazole[4,5-c]quinoline-4(5H)-ones 80 derives from palladium(0)catalyzed coupling of 5-chlorothiazole-4-carboxylate 79 with 2-aminophenyl boronic acid. The intermediate amino ester cyclizes under the reaction conditions <03OL2911>. Dibromoethane serves as a 2 carbon fragment to transform 5-amino-2,3-dihydro-lH-1,2,4triazole-3-thione 81 into intermediate 82. Base-induced cyclization of 82 gives 2-amino-5,6dihydrothiazolo[3,2-b][1,2,4]triazole 83, however heating 82 in the absence of base affords isomeric 3-amino-5,6-dihydrothiazolo[2,3-c][1,2,4]triazole 84 <03JHC821>. Annulation of 2-aminothiazole 85 with 2H-pyran-2-one 86 yields the thiazolo[3,2-a]pyrimidine 87 <03T7141>. Thiazolo[3,2-a]pyrimidines related to 87 are also prepared from thiourea via double annulation, wherein a dimethylformamidine derivative of a 2-aminothiazole serves as useful intermediate <03EJO421, 03JOC4912>. A related pyrimidine ring annulation onto 2aminothiazoles provides an entry to 6,7-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-ones under microwave irradiation and solvent free conditions <03T5411>. The same laboratory also has described a similar synthesis of thiazolo[3,2-a]triazine C-nucleosides 88 <03TL8951> and pyran-annulated thiazoles 89 <03S2395>. A synthesis of thiazolo[4,5-d]pyrimidine-7(6H)thiones, via annulation of an isothiocyanate onto a 2,4-diarninothiazole intermediate, was also reported <03HCA1949>. Br

N~ S

S..~ ~

1)" ArB(OH)2' Pd(Ph3P)4

O~' 2). 2-NH2C6H4B(OH)2"OEt CI

~

H

79

NH2

+

SMe

..~CN Ar

85

~

80

Br(CH2)2.S

S

HN~ BrCH2CH2Br N~, HI~I-~N Hl~l'~N NaOMe ~ NH2 NH2 82 81 heats ,

NC~,,L~S -~ - cO2 Ar N A

O 86

~2

87

84

N'N/'~NH2 83

Ar1

NvNH 88 (R -

D-arabinobub/I, D-ribobutyl)

O//'\O / -'N Ar 89

Rapid entry to the imidazo[2,1-b]thiazole ring system 90 has been described using thiourea as starting material <03JOC4912 >. This same ring system is also fashioned via an Ugi three-component coupling of 2-aminothiazole 85, benzylisocyanide, and 2naphthaldehyde catalyzed by scandium triflate <03TL4369>. The isomeric imidazo[5,1b]thiazole ring system is derived by annulation of the 2-(aminomethyl)thiazole (e.g. 91 to 92) <03BMC3475>. Pyrrolo[2,1-b]thiazoles 94 are obtained by Vilsmeyer-type formylation of

236

M.G. Saulnier, U. Velaparthi and K. Zimmermann

thiazolones 93 <03S2632>. Bergman has reported an intramolecular SNAr reaction of a thiourea anion which serves as an interesting annulation procedure for the synthesis of the thiazole[4,5-b]pyridine ring system, even when the site of ring halogen substitution is not particularly activated (e.g. 95 to 96) <03JHC261>. Condensation of the aldehyde moiety of D-arabinuronolactone 97 with L-cysteine methyl ester precedes intramolecular attack of nitrogen on the lactone carbonyl, resulting in ring expansion to the bicyclic thiazolidinelactam 98 <03EJO878>. S

R2

CO2Et

90

91 NC

NC

O

L~

92

Ar

O

Br

S\ ~jNMe2

DMF / POCI3

Br NaOMe

0

93

,CO2Et

Ar" " O

o

HN

CI NMP / 120 ~

94

~==S PhCOHN 95

N.,.,S 96 NHCOPh

OH NH3+CI- .~ 97

Ho~,N 98 O

CO2Me

The benzylidene derivative of 4-thiazolidinone 99 (formed by condensation of the parent thiazolidinone with benzaldehyde and sodium methoxide) undergoes initial 1,4-Michael addition with the Wittig reagent, methoxycarbonylmethylenetriphenylphosphorane, to give an intermediate which cyclizes to the furo[2,3-d]thiazolidine 100 via intramolecular displacement of triphenylphosphine by the thiazolidinone oxygen <03JHC721>. A Russian group has reported a novel synthesis of various annulated sulfur heterocycles (e.g. 102) via activation of aromatic and heteroaromatic substrates bearing pendant methylthioalkyl side chains (e.g. 101) with triflic anhydride. The presumed electrophilic intermediate trifluoromethane-sulfonylsulfonium salt cyclizes to an isolable methyl sulfonium salt which is readily demethylated to the fused sulfur heterocycle (e.g. 102) by triethylamine <03Sl191>. The thiazole o-quinodimethane 104 is generated from tribromide 103 and undergoes Diels-Alder addition to indoloquinone 105 to give a 52:48 unseparable mixture of regioisomeric tetracyclic quinone adducts of which only the major isomer 106 is shown <03BMC3407>. The pyrazolo[3,4-d]-l,3-thiazolino[2,3-f]pyrimidine 108 results via annulation of intermediate 107 with triethyl orthoformate. Intermediate 107 is synthesized from malononitrile and cyanoacetophenone in two steps <03SUL35>. Dehydrogenative cyclization of thiazole 109 with chloranil leads to the novel thiazolo[2,3-c][1,2,4]triazole 110 <03HCMS281>. The synthesis of a new 3,5-dithia-l-aza-norbornane was also reported <03SL1731>.

237

Five-Membered Ring Systems." With N and S (Se) Atoms

R S,,~N.-Ar Ph S-~/R ~ O " N,,Ar Ph3P=OHOO2Me ;h,~ O

tf, o

"-

101

100 CO2Me

99

o

CH2Br I-N CH2 -] N/fS~~ l_~ CHBr2 DMFNal / 60 ~> [/~.S~ CHBrj 103

NH

NHBoc

Ph CH(OEt)3

N.~

107

102

0

N.

0

oc

106

~.(Ar

N.~N~--~Ar \ SHN'~~~,/~, , N chlorani/ N I

H2N~N-N ~~/NH2 >-H2N~, ~ ~/ N N-N 5.5.2.4

N

104

/=( Ph

S L___.J

L,,,,/SMe 2. Et3N

108

1 0 ~

110

Thiazole Intermediates in Synthesis

Perhaps the most widely reported use of the thiazole ring system as a synthetic intermediate for the synthesis of non-thiazole containing molecules is the application of the 2-sulfonyl- 1,3benzothiazole moiety in the Julia olefination, and several reports on this topic have appeared during the past year. The use of the Julia olefination in the total synthesis of natural products includes its application in the syntheses of proteasome inhibitors <03OL197>, the antitumor macrolide Rhizoxin D <03JOC4215>, the 14-membered unsaturated macrolide cineromycin B <03TL9219>, enantiopure 19-norvitamin D3 analogues <03SLl175, 03JOC7407>, phorboxazole A <03AG(E)1255>, and (+)-cassiol <03TA717>. The Julia olefination protocol allows a convenient one-step synthesis of fluoroethylidene derivatives 112 using 2-(1fluoroethyl)sulfonyl- 1,3-benzothiazole 111 <03TL8127>, as well as an efficient synthesis of substituted vinyl ethers 114 from a-alkoxy sulfones 113 <03OL4851>. The 6-nitro-2benzothiozoate 115 serves as a highly efficient donor for 13-stereoselective glycosylation of acceptors bearing primary hydroxyl groups (e.g. 116). For example, Mukaiyama reports that ~-glycoside 117 results from activation of 115 with triflic acid in the presence of 116. The anomeric [~:ct ratio is 96:4 at -78 ~ and donor 115 gives [~-saccharides with better [3stereoselectivity than other typical glyosyl donors, such as imidates or fluoride, under the same conditions <03CL340>. Related S-benzoxazolyl (SBox) glycosides serve as versatile glycosyl donors for stereoselective 1,2-cis glycosylation and thus complement the Mukaiyama method <03OL455>. The influence of the benzothiazolyl moiety to enhance the

238

M.G. Saulnier, U. Velaparthi and K. Zimmermann

leaving group ability of sulfur and oxygen heteroatoms attached at the 2-position is further exemplified by Mukaiyama in the Friedel-Crafts phenethylation reaction. Herein, thiocarbonate 118 reacts with anisole catalyzed by scandium triflate to yield 119 as an equal mixture of ortho and p a r a isomers <03CL814>. The use of 2-thiobenzothiazolyl (2-SBtz) ethers as a leaving group for

[[.,~"'.,J I[ N~ - s - O( , ~S

F

R1COR2

O

>

O CH3 base/THF 111

Bn~.IoO---,, O Bn.. , _ . . - ~

BnO'~BnO ~

113

HO,,,--~_..-O

N-

I~~ NO2

Ph

o1(CH2)2 S Ph

118

CH3 112

BnO\_~.-,..T~

115 S

S/~N ~

F

PhOMe Sc(OTf)3

'OMe

119; 1:1 olp

OR

s__/ ~

BnO~Bns~)Me 116 ._ TfOH/ CH2CI;

,.._

R

RCOR' LiHMDS"-RO/~I"'R1 114

BnO--,,

BnO"~XI~O\ .O O

BnO-"~_ L~'~ ~..,~-~O ~nu ~nu \~.~...~ 117 BnO"~BnE)OMe

o. ~ "/cH3

H3C Ph,,,/~ ~

s/J~N _ PhCHO.._ I S " ~ O (~ Bu4NBr"- S/~N CH3

120

~

121

"R +'' generation and trapping in synthesis has also been described <03JOC 1641 >. The role of the 2-SBtz moiety as a leaving group in synthesis is further demonstrated by the conversion of 120 to 121. The 2-SBtz group is cleaved with ethylmagnesium bromide to yield the free vinyl SH group <03JOC4406>. Benzothiazole also serves as a formyl group equivalent via reductive processing of its C-2 ring carbon <03TL13>. The use of thiazolidinethiones in the asymmetric aldol addition reaction has seen two very elegant applications during the past year. Evans has reported an enantioselective, syn diastereoselective aldol reaction of N-propionylthiazolidinethione 122 using 10 mol % of [Ni((S,S)-t-BuBox)](OTf)2 to give syn aldol adduct 123 in 94% ee. While a 97% ee results from substituting TESOTf with TMSOTf in this reaction, the TES adducts (e.g. 123) are directly converted to Weinreb amides (e.g. 124) <03JA8706>. Liotta has described a diastereoselective addition of the chlorotitanium enolate of thiazolidinethione 125 with Omethyl oximes to give the anti azetine isomer 126 as the major product. The formation of the azetine presumably results via cyclization of the initially-formed bis-titanium intermediate 127. Treating azetinyl thiazolidine-2-thione 126 with benzoyl chloride provides the a,13disubstituted 13-amino carbonyl adduct 128 <03JA3690>. Thiazolidinethione 125 is similarly transformed into anti aldol adducts using titanium enolate chemistry with dibenzyl acetals in lieu of imines or aldehydes <03SL1109>. Remote functionalization of a non-activated C-H bond (e.g. 129 to 130) results from treating thiazolethione 129 with bromotrichloromethane and AIBN. Homolytic cleavage of the nitrogen-oxygen bond in 129 leads to 130 and 131 <03SL227>. Functionalization of the double bond of 2(3H)-thiazolone provides a new route to chiral synthons for 2-amino thiols <03H(59)323>.

239

Five-Membered Ring Systems: With N and S (Se) Atoms

S

[Ni((S,S)_t_Bu_Box)](OTf)2 ~

PhCHO/2,6-lutidine TESOTf

0

O

OTES

& ' ~

Ph Me(OMe)NH2Cl

[ ~

123

122

0

N..OMe

S

R/J~H S

CI3Ti ~

124

cla

m

Ti

oi"s

R.-". %

TiCI4 / CH2CI2 (-)-Sparteine

125

, ~ Ss PhCOCI~R

\" -

127

OTES

imid~uzole ~ M e O . N ~ ~ J . ~ p h

s

....

126

-

0 HN"~

128

Ar

H3C

129

5.5.2.5

I

f ,O -.[~

S

BrCCl3 .~ AIBN / Phil

4"

~/ S H3C

130

SCCI3

131

Biologically Important Thiazoles

The thiazole ring system is found in a wide variety of medicinally important compounds and many such examples have been reported in the 2003 literature. For example, thiazolidine2,4-diones (TZD's, glitazones) constitute an important class of antidiabetic drugs which control hyperglycemia by enhancing tissues' sensitivity to insulin. These agents, most notably represented by the approved drug rosiglitazone 132, are known as PPAR 7 agonists as they target the nuclear receptor known as the peroxisome proliferator-activated receptor ), (PPAR?). Several reports in the TZD/PPAR domain have appeared during the past year <03BMCL2795, 03BMC4059, 03BMCL1801, 03BMCL1517, 03JOC9116, 03IF79, 03JMC1306, 03CPB276, 03CPB807, 03CPB138, 03BBR406, 03BBR793, 03PNA6712>. Thiazolidinones possess anti-inflanmlatory activity <03CPB1351 > and also show inhibition of the synthesis of dTDP-rhamnose which is an essential component of the M y c o b a c t e r i u m tuberculosis cell wall <03BMCL3227>. Ureas of 2-aminothiazole inhibit growth of grampositive bacteria <03BMCL4463>. The aminothiazole class itself is highly prevalent in several important areas of medicinal chemistry <03JMC2631>, particularly as kinase inhibitors, including the Src-family kinase p56 lck (Lck) <03BMCL2145, 03BMCL2587, 03BMCL4007>. For example, 2-aminobenzothiazole 133 (BMS-35075 l) is an exceptionally potent, non-cytotoxic inhibitor of Lck (ICs0 = 0.5 nM) <03BMCL2587>. 4-Acylamino-l,3thiazoles are described as selective inhibitors of CDK5, a serine/threonine kinase that is required for normal neuronal development, and thus are potential agents for the treatment of Alzheimer's disease <03BMCL3491>. 2-Arylaminothiazoles are corticotrophin-releasing factor-1 receptor (CRF1R) antagonists (e.g. 134; Ki = 8.6 nM) and display anxiolytic activity in a mouse canopy model <03BMCL3997>. Orally active, dual ErbB-2/EGFR tyrosine

240

M.G. Saulnier, U. Velaparthi and K. Zimmermann

kinase inhibitors of the 6-(2-(aminomethyl)thiazolyl)quinazoline class (e.g. 135) show significant antitumor activity against both erbB-2 and EGFR over-expressing human tumor cell lines in mouse xenografl models <03BMCL637>. Thiazole 136, a 0.71 nM inhibitor of farnesyltransferase, potentially useful as an antitumor agent, has also been reported <03BMCL1359>. Furthermore, thiazole-containing molecules are reported to have in vitro and/or in vivo antitumor activity <03BMC5179, 03BMCL471, 03EJO4842, 03JMC532>, anti-HIV activity <03 BMC4769, 03IF259>, antifungal activity <03 BMCL 191 >, antibacterial activity by inhibition of peptide deformylase (PDF) <03BMCL3273>, and inflammatory activity useful for the treatment of asthma via inhibition of phosphodiesterase-4 (PDE4) <03JMC2413> or inhibition of mast cell leukotriene release <03BMCL485>. Benzothiazoles also are reported as selective inhibitors of cyclooxygenase-2 (COX-2), an enzyme which is induced and expressed during the inflammatory process <03BMCL657>. Two other important targets, both useful for the development of antithrombotic agents, which are inhibited by thiazole-containing molecules are factor VIIa <03JMC4043, 03JMC4050> and factor Xa <03BMCL723, 03BMCL729, 03BMCL2255>. Some of the factor Xa analogs are not only active against factor Xa, but selective over thrombin <03BMCL723>. The argthiazole analog 137 is one of the most potent factor Xa inhibitors, with IC50of 0.9 nM.

O

H ~ 0

9H3

O ~ N N ~~

132 Rosiglitazone PPAR7 agonist

/

H CI S/~T~N--~ ---~F3~C~NC l ~ C I

H3C

HN HO~N~ H

133

N H

BMS-350751 Lck ICs0 = 0.5 nM

~N<~ N~/~ N O /.._NH~S~J Hl~l~

134 CRF1 R antagonist I~ = 8.6 nM

135 ErbB-2 = 14 nM EGFR = 10 nM

SON3

O O

HN'~NH2 136 FT ICso = 0.71 nM

5.5.2.6

137 Factor Xa ICso = 0.9 nM

Novel Thiazole Catalysts and Transition Metal Complexes

The thiazolium-catalyzed addition reactions of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) and the benzoin condensation (most often between two aldehydes) are well-known synthetic tools leading to the synthesis of highly funtionalized

241

Five-Membered Ring Systems." With N and S (Se) Atoms

products. Suzuki has reported <03JA8432> a catalytic intramolecular crossed aldehydeketone benzoin reaction using the commercially available thiazolium salt catalyst 138. This reaction proceeds with excellent diastereoselectivity using substrates with stereogenic centers. For example, chiral keto-aldehyde 139 affords tertiary alcohol 140 in 90% yield and in a >20:1 ratio of stereoisomers. The enantiomerically pure, C2 symmetric bisthiazolium salt 141 catalyzes the dimerization of benzaldehyde to benzoin in 15% ee <03TA3827>. Reaction of palladium carbene catalyst 142 with tetrabutylammonium acetate dissolved in the ionic liquid, tetrabutylammonium bromide, leads to formation of palladium nanoparticles which catalyze the stereospecific reaction of cinnamate 143 with 4bromotoluene to give Heck adduct 144 in > 99:1 E / Z ratio <03JOC2929>. Thiazolium-based carbene catalysts are reported for ring-opening polymerization (ROP) <03JA3046>. A palladium-catalyzed three component reaction of aromatic iodide 145, allene, and benzylamine gives heterocycle 146 using 10 mol% of palladacycle 147 <03TL7445>.

H3C,,,~i~Et Br-

0~1~ H3c~OM

138

,.. .,L

..

OH 2 Br-

v 141

0 141 2 PhCHO > Ph'~

Ph OH 15% ee

/CO2Et

Pd~ N~ ' J ~ H3C

142

140

_jOH

OH3

O~N OMe ~ I ~

2 0 % 1 3 8..~ 70% DBU t-BuOH H3C

e

139

~ ~IH3C~

CliO

~

~

t

4-MePhBrH3C--,.~ 143

..~ 144 F

P.o.2NH2

145

I

146

AcO 147

2

The reaction of benzothiazoline 148 with RhCI(PPh3)3 gives rhodium(III) complex 149 as determined by X-ray diffraction <03CL 1058>. The nickel(II) Schiffbase complex 150 is also synthesized from the corresponding benzothiazoline <03BCJ 127>.

M. G. Saulnier, U. Velaparthi and K. Zimmermann

242

.PPh3 H3C~.~ H3 H MeO

[RhCI(PPh3)3]

s, I ,ct

toluene MeO 148

5.5.2.7

149

150

3

-

CH3

Synthesis and/or Isolation of Thiazole and Isothiazole Natural Products

During the past year there have been several reports on the isolation and structure determination of various macrocyclic peptides containing the thiazole ring system, including marine-based cyclic hexapeptides <03JNP247, 03JNP575, 03JNP719>, and myriastramides A-C, new cyclic octapeptides from the Philippines marine sponge Myriastra clavosa, <03T10231>. Pattenden has reported the synthesis of novel thiazole based cyclic hexa- and octapeptides <03T6637, 03T6979>, the total synthesis of the reverse prenyl substituted cyclic peptide mollamide <03T2701> and the total synthesis of trunkamide A, a novel thiazolinebased prenylated cyclopeptide metabolite of marine origin <03T2713>. Forsyth has described the total synthesis of Apratoxin A 151, a cyclodepsipeptide with a [3-oxy thiazoline moiety which is constructed via a one-pot Staudinger reductionintramolecular aza-Wittig sequence on an azido thiolester <03JA8734>. The first total synthesis of the marine cyclic heptapeptide Leucamide A 152 has been described using a sequence which includes a DAST-mediated cyclization of a ~-hydroxy amide to give the oxazole portion of the 4-(oxazol-2-yl)-thiazole heterocycle <03JOC1636>. The synthesis of derivatives of the macrocyclic thiazole peptide antibiotic GE2270 that retain potent antimicrobial activity against many gram-positive pathogens, including methicillin resistant Staphylococcus aureus (MRSA), but possess greatly enhanced aqueous solubility, has been described <03BMCL3409>. The isolation, characterization, and structure determination of a new group of complex thiazolyl peptide antibiotics, the nocathiacins (e.g. 153, nocathiacin I), has been reported by Leet <03JAN232>. These nocathiacins exhibit potent in vitro activity (ng/mL) against a wide spectrum of gram-positive bacteria, including multiple drug resistant pathogens such as MRSA, and also show excellent in vivo efficacy in a systemic Staphylococcus aureus infection mouse model <03JAN226>. Other novel thiazole and pyridine containing macrocyclic antibiotics, isolated from a marine sponge, are also reported <03JAN129>. The novel cytotoxic macrolactones, archazolid A and B, have been isolated from the myxobacteria Archangium gephyra. These archazolids consist of a 24-membered macrocyclic lactone bearing a thiazole side chain and show exceptional cytotoxicity against mammalian cells with ICs0 values ranging from 0.1 to 1 ng/mL <03JAN520>.

243

Five-Membered Ring Systems: With N and S (Se) Atoms

o

MeO z-~.~,,,,

N

~

.~o,-'-To o

N/"

~

~ N.v.~

../-"O-

H

~

,,~o

_L .:

152

151 S---~

S

, H

.V._~N

~

s-.e

0

N

I

o

o~....oa,

...'--o /o

H

0

,o.

~ ,,.'N \N"h

.

H ---~ O=~O

~o

.og 9

153

\

Synthetic activity in the area of the epothilones continued to expand during the past year <03SL2033, 03T9979, 03EJO1042, 03JA26, 03JA3428>. Most notable is a report by Danishefsky <03JA2899> of a ring-closing metathesis (RCM) reaction, wherein an acyclic precursor leads to the first (E)-9,10-dehydro-12,13-desoxyepothilone B analog (e.g. 154) that possesses substantially improved cytotoxicity relative to that of 12,13-desoxyepothilone B. Analog 154 is a member of a new family of epothilones and displays better plasma stability than 12,13-desoxyepothilone B and excellent in vivo efficacy in nude mice bearing the human tumor xenografl, HCT-116. The corresponding 12-trifluoromethyl analog 155 was also synthesized and evaluated.

s

\

o~

155; R = CF3 R" ~ - ~

O

pH

,/'~OH

244

M. G. Saulnier, U. Velaparthi and K. Zimmermann

Syntheses of new cytotoxic tiazofurin nucleoside analogs have been reported <03NNN2039> including the novel fluoro sugar 156 <03BMCL3167>. The total synthesis of the [2,4]-bis(thiazole) antifungal agent, (+)-cystothiazole A 157 is described using electrophilic activation of amide (vide supra section 5.5.2.1, 13 to 15) as a key step to assemble the [2,4]-bis(thiazole) moiety <03OL4163>. Ring-closing metathesis (RCM) chemistry generates the macrocyclic thiazole ring system in the synthesis of muscothiazoles A and B (e.g. 158, 159) <03OL2785>. The success of RCM chemistry using substrates containing the thiazole ring system contrasts with the special conditions required for those containing the imidazole ring system, which serves as a ligand for deactivating the Grubbs' ruthenium catalyst <03TL1379>. Other syntheses of thiazole-containing natural products reported during the past year include dimethyl sulfomycinamate 160, the oxazole-thiazolepyridine methanolysis product of the thiopeptide antibiotic sulfomycin I <03OL4421> and mycothiazole, a polyketide thiazole from marine sponges <03T6579>. A synthesis of (+)biotin is accomplished from 4-functionalized 2-thiazolidinone derivatives <03TL8905> and an enzymatic synthesis of thiamine pyrophosphate 161 using overexpressed thiazole kinase OH

MeO

OH

OMe

O

R2 157

156

158 R1 = CH3, R 2 _- H 159 R 1 = H, R 2 = C H 3

CO2Me

0

N

CO2Me

160

161

has also been described <03BMCL4139>. Finally, the isolation and structure determination of 15-norlyngbyapeptin A and lyngbyabellin D has been reported <03JNP595> and Hecht has disclosed the construction of a 108-member deglycobleomycin library <03JA8218>.

5.5.2.8

Miscellaneous Thiazole Chemistry

Two intramolecular C - H X (X = O, S) hydrogen bond interactions in (S)-N-acyl-4isopropyl-l,3-thiazolidine-2-thiones 162 are confirmed via crystallographic and spectroscopic data and high level theoretical calculations <03OL2809>. Crystal structures of benzothiazolines 163 and 164 reveal 1,5-type O 'S and S S interactions of 2.691 A ( S O close contact) and 3.001 A (S S close contact), respectively. Density functional B3LYP/6311G** calculations for all conformers and tautomers of 163 and 164 explain the preference for S O and S S close contact structures and agree with the observed crystallographic structures only when solvent effects are included via a continuum model <03T10187>. Hoogsteen hydrogen bonds in 2-aminothiazole containing triple helix forming oligonucleotides have been described <03NNN 1281 >. A novel class of DNA cleavage agents bearing a benzothiazole moiety are reported that derive activity from amino acids tethered to a photoactive intercalator <03CC1956>. Related benzothiazole containing structures that are

245

Five-Membered Ring Systems: With N and S (Se) Atoms

part of merocyanine dyes are reported as powerful tools for studying protein conformational changes, ligand binding, or posttranslational modifications in living cells <03JA4132>. The structures, electronic states, and electroluminescent properties of a zinc(II) 2-(2hydroxyphenyl)benzothiazolate complex 165, one of the best white electroluminescent materials used in organic light-emitting diodes, have been reported <03JA14816>. Novel thiazolidine reagent 166 serves as an efficient electrophilic cyanating agent for activated methylene compounds <03H(59)161>.

..•

~

H--.O

S~S

""

2.20 A

.HX

OMe

EtO~NH

H

I~].,.C i EtO 2.46A

162

2.691 A-'~ "O

CF3

3.oo~ A J "

163

~

S" \OF 3

164

SyN'-cN ,N NC" 165

5.5.3

166

ISOTHIAZOLES

The chemistry of isothiazoles has been reviewed during 2003 <03T7445>.

Synthesis of Isothiazoles by Ring Formation

5.5.3.1

Most isothiazole syntheses (or those of its partially or completely saturated analogs) published in 2003 include synthesis of an open chain that already contains the sulfur and nitrogen atom and all 3 carbons, followed by ring formation. The most widely used retrosynthetic disconnection is formation of the S-N bond as the ring-closing step, by either nucleophilic attack of an amine on an oxidized sulfur atom or attack of a sulfide nucleophile onto an oxidized nitrogen species. Isothiazole 170 is formed upon treatment of aldehyde dithionite 169 with ammonia, and is further lithiated at C-5 and quenched with DMF to give aldehyde 171. Aldehyde 171 is converted to the phosphonium salt 174 by standard methodology. The same sequence of steps can be used to convert but-3-in-2-ol into 3-methylisothiazole, which undergoes radical bromination at the methyl group <03BMCL463>.

CrO3

/ 167

OHC

_

//10 Na2S203 168

S 171

NaBH4 > HO N 172

S-"SO3Na 169

>

NH3

S 170

n-BuLi DMF

Br N PPh3 N > BrPh3+p. 173

174

246

M.G. Saulnier, U. Velaparthi and K. Zimmermann

2-Alkyl-(or aryl)-isothiazol-3-ones 178 are formed by oxidative cyclization of dithiopropionic amides 177 with SO2C12. These can be further rearranged into 3-alkyl(or aryl)-aminoisothiazoles 181 and then oxidized to the corresponding 1,1-dioxides 184. Harsher treatment of 177 with SO2C12 leads to 5-chloro- and 4,5-dichloro derivatives 179 and 180, which are transformed by the same series of steps to give chlorinated compounds 185 and 186. Bromination of the isothiazole dioxide 184 (Rl=R2=H) gives (via an addition / elimination sequence) the 4-bromo-derivative 187 <03T9399>.

(SCH2CH2COOH)2

SOCl2 (SCH2CH2COCI)2 RNH2> (SCH2CH2CONHR)2 SO2Cl2

175

RI~~ R R2

176

~2) 1)NH3 POC'3

S

NHR RI~, N

177

rn--CPBA ~

R2~S

178 RI=R2=H 179 RI=H, R2=CI 180 RI=R2=Cl

R~~HR ,,/~ ,.,,' R" (~/~\x0

181 RI=R2=H 182 R1=H, R2=Cl 183 RI=R2=CI

1, Br2=

NHR Br~ # ~ N O

2) NEt3 or heat

O

184 RI=R2=H 185 RI=H, R2=Cl 186 RI=R2=CI

187

In a very similar sequence, fluorobenzophenone 188 reacts with potassium benzylthiolate, followed by S-chlorination and cleavage of the benzyl group with SO2C12 to give the corresponding sulfenyl chloride. Quenching with ammonia yields benzo[d]isothiazole 189. The isolated benzo[d]isothiazoles are oxidized to the corresponding S,S-dioxides with potassium permanganate <03JMC3354>. A more environmentally friendly and processchemistry appropriate procedure uses hydrogen peroxide to facilitate ring closure between an imid-nitrogen and an oxidized sulfur atom to give 1,2-benzoisothiazolin-3-one. The published experimental procedure, "one-pot" from 2,2'-dithiodibenzoic acid methyl ester, synthesizes eighteen kg 1,2-benzoisothiazolin-3-one <03SL1967>. Chloramine-T and hydroxylamine-Osulfonic acid were used for S-amination of thiosalicyl amides, followed by cyclization to give N-substituted benzoisothiazole-3-ones <03H(60)1855>. 2-Alkylthio-3-acyl-4-quinolinones

R1

R1 O

O

O

_

2) SO2012 3) NH3

S

R2 188 0/

R2 189

0

O~NH MeO ~---Br ~---/~ 192

H 190

191

0 MeNH2MeOOC~'~ NH >

MeH

193

MeOOC MeOOC'~ O.,,L./ Na2S II "NH Br ~ MeHN ~ ( / ~ ~ NaS 194

H202 or12>

M e~N . ~,'" N ~;--~

195

247

Five-Membered Ring Systems: With N and S (Se) Atoms

190 (and the related quinolines) can be cyclized to the corresponding annelated isothiazols 191 by treatment with O-mesitylenesulfonylhydroxylamine (MSH) <03SL166>. 1HPyrrolo[3,2-c]isothiazole-5(4H)-ones 195 are formed via oxidative cyclization of pyrrolidinones 194 with hydrogen peroxide or iodine. Further stepwise oxidation by H202 in AcOH affords first the corresponding sulfinamides and then the sulfonamides, depending on reaction time. These sulfinamides are shown to insert Pt into the S-N bond <03HCA2471>. Two examples of ring-closure by formation of the C3-N bond have been published in 2003. Spirocyclic isothiazolidine 196 is formed via N-oxidation of N-methoxy-2-(pmethoxyphenyl)-ethanesulfonamide 197 (n=2) with hypervalent iodine reagents via an ipsocyclization. Examples without the strong electron donating group on the aromatic ring give ortho-cyclization in good yields, leading to cyclic sulfonamides of general structure 198 <03OBC1342>. Oxidation of benzene-sulfonamides 199 bearing a 2-vinyl or 2-allyl function in the presence of chiral rhodium catalysts results in nitrene formation and aziridination of the carbon-carbon double bond in 55-76% e.e. and up to 75% yield of 200 <03TL5917>.

O•.•

O~ N /(3 ~S-,~ O

196

PhI(OH)OTs R I . ~ ~ ] -" -" ~, ~ R' =OCH3 n=2

H N .O 802 197

n

PhI(OH)OTs R I ~ "~ "R'=H,F,Cl,OH 3 n= 1 or2

198

SO 2

n

Cyclization via formation of the C3-C4 bond has also been described. Indium mediated alkyl radical addition-cyclization-trap reactions of N-allyl-vinyl-sulfonamides 201a proceed smoothly in aqueous media. The electrophilic vinyl sulfonamide group of 201 reacts with nucleophilic alkyl-carbon radicals, generating electrophilic sulfonamide-stabilized radicals, which show excellent reactivity towards the vinyl group to give cyclic sulfonamides 202a, in low cis-trans selectivity. The analog radical addition-cyclization reaction of vinylsulfonamide-hydrazone 201b gives the 4-hydrazino-functionalized cyclic products 202b <03OL3835>.

~T/SO2NH2 ~ ' ~ R 199

[Rh2(L*)4] ~-oxidant

O~ R 200

~ O2S. N/ R' 201

RI, In a) X=CH2, Y=CH21 b) X=NNPh2, Y=NHNPh2

I~' 202

Cyclization by formation of the C4-C5-bond is demonstrated by intramolecular alkylation of the dianion of methylsulfonamide 203 to give sultam 204. This method has been applied towards the synthesis of chiral sultams, which are valuable auxiliaries <03OL4175>. The required [3-chloroalkanesulfonamides 203 are easily accessible from ~-aminoalcohols via bismesylation and displacement of the O-mesyl group by chloride.

248

M.G. Saulnier, U. Velaparthi and K. Zimmermann

02

HN--S\

~

H ..N.~SO 2

LDA

S

NH2 CH3SO2NSO

X

Cl

203

N"S~s+ Cl,~ Cl 209 .-----Cl

O Xy~

207 X=Br

O

O NC

s

y

~N~

O"~N ~ ~

Nu

X~~~d

NH2

X = 208(y

206 X=H

205

204

I

O'~ 210 ./'~'~

211

O

R. H

CN _

O

212

I

NC.

S

N-S /

S

NC , O" 215 216 213 214 Only few examples of ring formation by combination of 2 fragments (= formation of 2 bonds in 1 reaction) were published in 2003. N-sulfinylmethane sulfonamide (CHaSO2NSO) reacts with 2,4-dimethylaniline 205 to form 2,1-benzoisothiazole 206, which is further brominated at the methyl group (using NBS) or at C5 (using BuLi, Br2) to give 207. These intermediates can be further transformed into nucleoside transport inhibitors <03BMC899>. Keto-enamines 208, e.g. 6-amino-l,3-dimethyluracil, react with Appel's salt (4,5-dichloro1,2,3-dithiazolium chloride, 209) to form 5-cyanoisothiazoles 210. The uracil-based cyanoisothiazoles undergo substitutive replacement of the cyano group with various nucleophiles to give 211, whereas pyrone-isothiazoles 210 undergo ring-opening of the pyrone-ring to form monocyclic isothiazole derivatives 212 when treated with primary amines <03OL507>. Another example of an isothiazole formation by combination of multiple fragments in one reaction is the treatment of 213, a 13-bromo-ot,13-unsaturated aldehyde, with 2 equivalents of NH4SCN, which gives isothiazole 214, without interference from the free nitroxyl radical <03S 1361>. Treatment of thien-2-yl-methylene-malonitrile 215 with $2C12 gives 3-chloro-4-cyano-5-(2-thienyl)isothiazole 216 <03OBC2900>. The 3thienyl regioisomer undergoes the same reaction. ~).

5.5.3.2

Reactions of Isothiazoles

3,5-Dichloro-isothiazole-4-carbonitrile 217 undergoes a regiospecific Suzuki coupling replacing only the C-5 chloride when reacted with aryl- or methyl-boronic acid to form 3chloro-5-(aryl or methyl)-isothiazole-4-carbonitrile 218 <03OBC2900>. Commercially available ethyl-5-amino-3-methyl-isothiazole-4-carboxylate 219 can be converted to 4aminomethyl-3,5-dimethyl-isothiazole 220 via diazotization and conversion to the iodide, palladium (II) catalyzed methylation with Sn(CH3)4, reduction of the ester with LAH, conversion of the alcohol to azide and reduction to the amine <03BMCL 1821>. Isothiazolemalonate 222 can undergo debenzoylation to give 223 when treated with NaOH in a water/benzene two-phasic system, and both of these compounds (222 and 223) can undergo

249

Five-Membered Ring Systems: With N and S (Se) Atoms

ring expansion to 1,3-thiazin-4-one 224 and 225, respectively, upon treatment with triethylamine in chloroform <03SC4339>. N-S

N-S

217

218

N-S

N-S

219

220

Ph SOCl 2,~ O

HN)__E E

NaOH,.~

E

221

Et3N~

O

E/I,.. E E 222

MeOOC S ,,~ MeO0 O 224 R=H 225 R=PhCO (from 222)

223

Isothiazolium salts 226, which are prepared from 13-thiocyanatovinyl aldehydes and anilines, can be oxidized with magnesium monoperoxyphthalate (MMPP) in water or alcohols to give 2-aryl-3-hydroxy-sultames 227 <03S2265>. This publication also reviews, in its introduction, a variety of other methods to form highly oxidized isothiazoles and their biological properties.

~S

N+._~__R1

MMPP ROH

226

RO

/.s.- o

O

221

An interesting difference in regioselection in the reaction of an allyl-palladium complex 228 with either a sulfonamide 231 or an amide 232 is reported by Cook and coworkers <03JA5115>. The differential outcome is explained by the steric difference between the planar amide and tetrahedral sulfonamide nucleophile.

250

M.G. Saulnier, U. Velaparthi and K. Zimmermann

Ph Ph

Ph

Ph

O ' ~ N-H

: L/

O " ~ NH

-I-

-

7

Nu

,k

Nu

229

228

230

O II O~S-NH Nu =

~

Nu =

231

0

"

100

232

88

"

12

Sharp and coworkers report two decomposition reactions of ziprasidone 234, an antipsychotic drug. The benzoisothiazole portion of this molecule can be photoisomerized to the corresponding benzothiazole 233. This reaction does not involve the oxindole part of the molecule, as was shown by the similar conversion of 3-(piperazin-l-yl)benzo[d]isothiazole to the corresponding benzothiazole <03TL1559>. The same group showed further that ziprasidone and other benzoisothiazoles can undergo reductive ring opening to form 235 or its isobaric isomer dihydrobenzoisothiazole 236. This transformation can be accomplished synthetically by treatment with benzyl mercaptan but it was also observed in the dithiothreitol-dithioerithritol matrix that is commonly used for FAB-mass spec analysis. FAB-mass spectra of several benzoisothiazoles show only the reduction product (2 units heavier) when this reducing matrix is used <03TL2117>.

N N

hu

~'~

Cl

0 233

N

BnSH

/Cl

0

N

or

Cl

DMSO, 100~

0 234

Cl

0 235

236

251

Five-Membered Ring Systems: With N and S (Se) Atoms

The anion generated by deprotonation of 1-methyl-3-chloro-l,3-dihydro-2,1benzoisothiazole-2,2-dioxide reacts in a vicarious nucleophilic substitution reaction with nitrobenzenes 239 to give compounds 240. It is advantageous to use an equimolar mixture of non-chlorinated 237 and dichlorinated 238, which form the mono-chloro-compound in situ, rather than to attempt selective mono-chlorination of 237 <03S 1503>. Prikryl and coworkers report the formation of triazenes rather than the expected diazo-dyes when reacting 5-nitro2,1-benzoisothiazole-3-diazonium salts 241 with N-alkyl-anilines 242 or diphenylamine. Anilines are ambivalent nucleophiles, which can be attacked at nitrogen, but for nonbenzoisothiazole based diazonium salts this is a reversible reaction (under acidic conditions), which ultimately leads to reaction between the diazonium component and the C4-carbon of the aniline. Triazene 243 is protonated at the isothiazole-nitrogen rather than the anilinenitrogen, making the kinetically favoured attack of the diazonium ion on nitrogen irreversible <03EJO4413>. /

/

/ +

R" ~

\

+

--,,7"" H

R" x~

237

7""Cl Cl

238

NaOH

x

_

Y

NO2

DMSO

R"

Q = N or CH

239

X 240

Y

NO2

~ K N,s

O2N

~ 241

5.5.3.3

-~ N2+

H

4-

N-R

O 2 N ~

s N= N

/,~

%

N-- R 242

243

~

R=CsH5 or alkyl

Isothiazoles as Auxiliaries and Reagents in Organic Syntheses

Oppolzer's camphor sultam is a well known chiral auxiliary and several interesting examples of its use have been published in 2003 <03OBC381, 03TA239, 03SL1500, 03TL8153, 03TL5355, 03T5475, 03TL3915>. (S,E)-2-Methylhex-4-enal 245 reacts with high anti-selectivity with the silyl enol ether 244 to form, after hydrolysis, acid 246 <03JA3849>.

252

M.G. Saulnier, U. Velaparthi and K. Zimmermann

~

O

O

O

Z>N OTBS §

> H 245

244

y

o o

S~ N" I~--~NII

247

x

O

249

N'~Br

Q

~ 246

\7 ~ o ~ .IS"; R - \

RI Zn

X = OBn or NPh2

Ar,N000 02

OH

250> 251

248

NHX

O

jar

H eO' A t

H,"~N'''H ~lpp

NH2 252

Paintner et al. prepare a chiral glycine analog based on the camphor sultam by deprotonation with n-BuLi and alkylation (98% d.e.) in the context of their synthetic approach to biphenomycin antibiotics <03SL522>. Sultam based glyoxylic oxime ether and hydrazones 247, when treated with alkyl iodide and zinc in aqueous media, undergo alkyl radical addition to form chiral ot-aminoacid derivates 248 in good enantiomeric excess <03TA2857, 03JOC6745>. Asymmetric aza-Darzens reactions of bromoacylated champhor sultam 249 with N-diphenylphosphinyl-arylaldimines 250 give substituted aziridines 251 with high level of enantiomeric purity <03SL1898>. Cleavage of the N-P bond with BF3etherate, followed by hydrogenolytic opening of the aziridine and hydrolysis of the amide converts these intermediates into "unnatural" aminoacids 252 without loss of stereochemical integrity.

253

Five-Membered Ring Systems: With N and S (Se) Atoms

N-Chlorosaccharin 254 has been shown to undergo electrophilic Ritter-type reactions with alkenes (e.g. 253) in acetonitrile. The resulting labile [3-chloro sulfonylamidines can be ringopened and cyclized to imidazolines 255. Overall this provides a one pot method for the electrophilic diamination of alkenes. Competing aziridine formation as well as allylic chlorination are also observed depending on the nature of the alkene used <03OL3313>. Norbornene-based sultam 256 can be used as a starting material for ring opening metathesis (ROM) mediated phase trafficking purification. The polymer formed via ROM is soluble in dichloromethane and allows most reactions to be performed in homogenous solution, but can be precipitated by addition of methanol to separate from excess reagents and byproducts <03OL15>. 0

>

253

5.5.3.4

2) KOEt

pfi

255

256

Pharmaceutically Interesting Isothiazoles

Isothiazoles and their saturated and/or oxygenated analogs play an important role in pharmaceutical research. Isothiazoloethenyl side chains were incorporated into carbapenems <03BMCL463>, isothiazolidine-l,l-dioxide into HIV integrase inhibitors <03JMC453>, isothiazoles into HIV protease inhibitors <03BMCL1821> and 1,2-benzoisothiazol-3-one1,1-dioxide into repinotan (BAYx3702 257), a potent 5-hydroxytryptamine antagonist <03TL8563>. Benzo[d]isothiazoles e.g. 258 show promising inhibition of human 2,3oxidosqualene cyclase and efficacy in lowering plasma cholesterol levels <03JMC3354>. Indolyl-glyoxylamides of 3-methyl-5-aminoisothiazole 259 are active (in vitro) against several cancer cell lines and show in vivo activity against P388 murine leucemia <03JMC1706>. Condensation of 2-ethylisothiazolidine-l,l-dioxide 261 with substituted benzaldehydes 260 is used in the synthesis of S-2474 262 (R=H), an anti-arthritic drug candidate and its metabolites <03JOC1128>. One of the two major pathways of metabolic degradation of this compound is N-deethylation of the isothiazolidine-dioxide <03BMC2415>, the other one being oxidation of the t-butyl group (262 R=H to 263 R=OH). This publication also describes the synthesis of sulfonimide 264 and its reduction product 265.

254

M.G. Saulnier, U. Velaparthi and K. Zimmermann

257

H 02 ..../N~/~/~N.S Repinotan O ~

R--k N ~

s--N

~

N~O'--.T;../~ I

R

L ~ ~ CHO

H

258

02

~S~N--~ ~J

,.,_

261

R=HorOTHP

259

N

. o ON

'264

5.5.4

THIADIAZOLES

5.5.4.1

1,2,3-Thia diazoles

~

B

O

R

~

HO" "~

/

HO" ~

r

2

N-~

262 S-2474R=H 263 R=OH

2651CHO

The Hurd and Mori reaction is undoubtedly the most popular method for the construction of 1,2,3-thiadiazoles, and many applications of this reaction have been reported during the past year <03JHC427, 03JOC1947, 03JHC925, 03IF63, 03JHC149>. For example, the reaction of 266 and 267 with semicarbazide affords the corresponding semicarbazones 268 and 269, which are transformed to 1,2,3-thiadiazoles 270 and 271 upon treatment with thionyl chloride. Interestingly, when there are no methyl groups on the cyclohexenone ring, oxidized fully aromatic tricyclic 1,2,3-thiadiazoles are obtained <03JHC427>. The 1,2,3thiadiazole 273 is also synthesized by the reaction of N-acylhydrazone 272 with thionyl chloride. A novel series of a-substituted phenoxy-N-methyl-1,2,3-thiadiazole acetamides 274 is obtained through the reaction of compound 273 with several phenols, and the resultant phenoxy derivatives were evaluated against heptatitis B virus (HBV) <03JHC925>.

255

Five-Membered Ring Systems: With N and S (Se) Atoms

O

O~. NH2

~ ~ ~ X ph NH2NHCONH2

266 X=O 267 X=S

SOCI2

N"NH

N~N "~ ~ X

268 X=O 269 X=S

270 X=O 271 X=S

0.,,%/NHMe N~ N O ,N~ N O O =S ~ ? EtO/jj'" N" N~-~Cl SO012 NHMe ArOH S ~ N H M H CI OAr 272

ph

273

e

274

Thiadiazole-naphthalimides are synthesized and evaluated in the context of a new family of photonucleases. For example, ortho-bromo nitrobenzene 275 is transformed into the 2thiobenzyl aniline 276, which is then diazotized to obtain 1,2,3-thiadiazole 277 <03BMCL3513>. These thiadiazoles intercalate into DNA efficiently and damage DNA at as low as 10 ~tM under photochemical conditions. Zeleska et al. have shown that thioanilide 278 is transformed into phenyl hydrazone 279 which subsequently undergoes oxidative heterocyclization with H202 to yield the 1,2,3-thiadiazole 280 <03S2559>.

a) BnSH, K2CO3 NO2 275 Br

NaNO2,HCI

b) SnCI2, HCI 276

NH2 S'Bn

Ph MeO NHPh S PhNHNH2 N"N. H MeOH - - . ~ ~ S O,,,H,N-.Ar reflux O,,H..N~Ar

~

278

279

86%

N 277 S-N /

Ph

H202 N "~N MeOH" ~ S O

N~Ar 280

Tumkevicius et al. report the formation of the novel benzimidazole[ 1,2-c][ 1,2,3]thiadiazole 283 by refluxing 281 with thionyl chloride. When the reaction is performed at room temperature, compound 282 is isolated instead. Refluxing the compound 282 with thionyl chloride also furnishes thiadiazole 283. The formation of 283 is explained by Hurd-Mori's mechanistic model, wherein the first step is presumably formation of the thiadiazole-S-oxide which undergoes a Pummerer-like rearrangement, initiated by the attack of thionyl chloride followed by subsequent elimination of HC1 to give 283. Following the addition of sodium bicarbonate, the fused chloro thiadiazole 284 is then obtained. These chloro thiadiazoles are suitable substrates for SNAr reaction with various amines, and for instance heating with morpholine yields 285 <03TL6635>.

256

M.G. Saulnier, U. Velaparthi and K. Zimmermann

SO012 =,, I~Nx~/CI 281

rt SOCl2

NH2

SOCI2 reflux

N .HCI

r~0 1 ~

Morpholine/J"

NaHCO3 ,. N

"N~S .HCl

283

5.5.4.2

N

~

/

~CI

85%

II

"~'~'~N~~/~"O N Nv" j

:282 ~IH2

/

N

EtOH,reflux

N= S 285

II

"N~-S

284

1,2,4-Thiadiazoles

Several methods are known to form 1,2,4-thiadiazoles via dimerization of thioureas. A novel method has been reported this year that involves oxidative azacyclization of 1monosubstituted thioureas. In this reaction, thiourea 286 reacts with [bis(acyloxy)iodo]arenes (BIA) to form 3,5-bis-phenylamino-l,2,4-thiadiazole 287. A reaction mechanism is proposed wherein the polyvalent iodo intermediate 288 undergoes elimination of iodobenzene to form 289. BIA-initiated oxidative azacyclization of 289 yields 1,2,4thiadiazole 287 <03T7521 >.

PhHNVNH2 II S 286

2 PhI(OAc)2 .- PhHN -20~ 30 min ~/I N 55% N'SX~--NHPh 287

H

H

2 PhHN~ NH2 -CH3Co2HPhI(OAc)2 PhHN~ S\I"Na " ~ NHPh S NH Ph S 286

PhI(OAc)2 -CH3CO2H

-PhI_s = PhHN..]I/N..~ NHPh NH S

288

PhHN..~NyNPh I~I/S |

289

-CH3CO2H,.PhHNN/~sX/~__ _N -Phi NHPh

Oxidative cyclization of dithiobiuret under basic conditions provides bis(5-amino-l,2,4thiadiazolyl)-3,3'-disulfide 293 via oxidative dimerization of intermediate 5-amino-3mercapto-l,2,4-thiadiazole 292. However, alkylation of 293 under basic conditions gives the thioalkyl- 1,2,4-thiadiazole 294 <03H(60) 1401 >.

SH H 291

N"2 2N NaOl~

/~--S H2N 292

.

NZ-

H2N~ s " N

SR RX N N N N,,S~ NH2 KOH ~ H2N

293

294

2-Amidinobenzothiazoles 298 are prepared in high yield by a thermally-promoted rearrangement of thiadiazolium salts 296 or thiadiazolines 297. Addition of base to the rearrangement of the thiadiazolium salts 296 can improve the yield by the prior conversion of

Five-Membered Ring Systems: With N and S (Se) Atoms

257

the diazolium salts to the corresponding thiadiazoline free bases 297. The authors speculate that thiadiazolines 297 may go through an electrophilic aromatic substitution or free radical pathway to furnish 2-amidinobenzothiazoles 298 <03SC2053>.

[~

S "-y=' NHR2 NBS

o---N+ R2

295

296

~

~

,

F~2

s-.

2971

'

~--N

+

,p='

A R2HN

EtOH,reflux

I 298

Morel et al. report the preparation of 5-chloro-l,2,4-thiadiazol-2-ium chlorides 301 by treatment of formimidoyl isothiocyanates 299 with a twofold excess of methanesulfenyl chloride. These salts show interesting chemical behavior toward several nitrogen and carbon nucleophiles. The nature of the N-substituent determines the stability of the salt 301, and especially when the substitutent on nitrogen is t-butyl, the salt 301 decomposes in solution into 5-chloro- 1,2,4-thiadiazole 302 <03 HAC95>.

RIs~

--N

N"C+s

299

FR'S . ~ ]

MeSC,/.~~ / esc' / 'C-S /-Me2S; L C" L..SMeJ 300

RIs + ~

Y-' c,--t-BuC'

NyS C, 301

"

R'S

'~N NyS C, 302

2-Hydroxylamino-4,5-dihydroimidazolium-O-sulfonate 303 is prepared by reacting 2chloro-4,5-dihydroimidazole with hydroxylamine-O-sulfonic acid. Reaction of 303 with carbon disulfide in the presence of triethylamine presumably proceeds via intermediate 304 to yield the 6,7-dihydro-5H-imidazo[2,1-c][1,2,4]thiadiazole-3-thione 305 by a tandem nucleophilic addition-electrophilic amination reaction <03JOC4791>. In an interesting photochemical reaction, irradiation of 5-phenyl-1,2,4-thiadiazole 306 results in the formation ofbenzonitrile 307 <03JOC4855>. s

-

s

O'N-H CS2/DMF ~ ' N ~ - / HN~NH+ Et3N H ~ L_J 303

304

-]

-SO4-2

H

N ~" ~; S

305

N~ N ~--~ 306

hv 307

Several biological applications of 1,2,4-thiadiazoles have been reported during the past year <03BMCL5529, 03BMC591, 03IF1073, 03BMC185>. For instance, a novel class of cathepsin B inhibitors has been developed with a 1,2,4-thiadiazole heterocycle as the thiol trapping pharmacophore. Within this series, compound 310 is the most potent inhibitor. The requisite 1,2,4-thiadiazole moiety 309 is assembled by treating amidine 308 with perchloromethyl mercaptan <03BMCL5529>. The 1,2,4-thiadiazole moiety has been incorporated in 13-1actam antibacterials to modulate pharmacokinetic properties. The 1,2,4thiadiazolo cephem 313 displays the best balance of serum stability and in vitro activity. The 1,2,4-thiadiazole intermediate 312 is synthesized from 3-aminoisoxazole 311 by a sequence of reactions <03BMC591>. In addition, 2,3-diaryl-5-anilino[1,2,4]thiadiazoles are found to

258

M.G. Saulnier, U. Velaparthi and K. Zimmermann

be potent and selective melanocortin-4-receptor (MC4) agonists for potential use for nerve regeneration and drug addiction <03BMC185>.

NH cc,3sc,.NaO MeO .,

H2N"J~OMe

CH2Cl2,H20-

308

O

Me . N

CI

309

N-OTr

I=

311

5.5.4.3

OH

310

a) KSCN, MeOCOCI

b) MeOH, 60~ NH2 c) CH3CO3H d) MeOH, SOCI2

,oro

N

L~N- ~ O MeO" " O

OMe

H2N-"~/Ns._N

312

O 313

% + S R O

O/~__OH

1,2,5-Thiadiazoles

Alkyl and aryl N-substituted 1,2,5-thiadiazolidine-1,1-dioxides 316 are synthesized in good yield from the reaction of sulfuryl chloride with 2-chloroethylamine. 2-Chloroethylamine hydrochloride is heated at 80~ with sulfuryl chloride in acetonitrile, and corresponding mono(chloroalkyl)sulfamyl chloride 314 is then extracted with diethyl ether to separate from unreacted amine hydrochloride. This ether solution is added to a solution of primary amine, and the resultant N-aryl (chloroalkyl)sulfamide 315 is treated with potassium carbonate in DMSO to afford N-substituted 1,2,5-thiadiazolidine- 1,1-dioxides 316 <03TL5483>. o

CI~/~

NH2

SO2012= CH3CN 75-80~

.

~Cl Ns. H / ci 314

Et3N -7~176

=

,S..N" H

R,Nrj

K2CO3 O~ ,,/O = R.. N.S~N.. H

DMso

cI 315

316

Caram et al. report that 3,4-diphenyl-l,2,5-thiadiazole-l,l-dioxide 317 serves as a Michael acceptor and addition of amides, ureas and aromatic amines to the carbon-nitrogen double bond proceeds in aprotic solvents such as DMF. For example, 3a,6a-diphenyl-tetrahydro-lHimidazo[4,5-c][1,2,5]-thiadiazol-5-one-2,2-dioxide 318 is readily formed upon treatment of urea with 317 in DMF at room temperature <03JPO220>. Interestingly, compound 319, which is prepared from corresponding Ar-N=S=O on treatment with Li(SiMe3)2, undergoes smooth SNAr type intra-molecular ring closure to furnish 4,5-difluoro-2,1,3-benzothiadiazole 320 <03EJI77>.

259

Five-Membered Ring Systems: With N and S (Se) Atoms

Ph H2NNH2 HNHN NHNH O

Ph N.s..N O" "O .,.

O

DMF,RT

~..

" Ph > ( Ph

317

CsF

F

(~/S\xO

" -ae3SiF N=S=NSiMe3

318

319

S 320

In the study of novel fluoroionophores as receptors for transition metal cations, 1,2,5thiadiazole-l,l-dioxide 322 is used as an intermediate to produce the 4,5-dicyano analog 323. Upon treatment of compound 321 wth sulfamide and HC1 in anhydrous ethanol, 1,2,5thiadiazole-l,l-dioxide 322 is obtained. Vacuum pyrolysis of compound 322 yields 1-nitro4,5-dicyanonaphthalene 323 <03TL2087>.

N'S"N Sulfamide= HCl, EtOH 321

NO2

CN CN I I

vacuum ~ 220~ 322

NO 2

NO2

323

1,2,5-Thiadiazoles have also been used in pharmaceuticals, especially as M1 (muscarinic) selective agonists for the treatment of Alzheimer's disease. The synthesis of a series of alkylsulfanyl bioisosteric congeners of xanomeline is described by Jung et al. <03AP230>. The cyanohydrin 324 is converted to aminonitrile 325, which upon treatment with sulfur monochloride in DMF furnishes 1,2,5-thiadiazole 326. The 1,2,5-thiadiazole 326 is further transformed into compounds such as 327 as bioisosters of xanomeline <03AP230>. Merschaert et al. have reported palladium-catalyzed cross coupling reactions of commercially available 3,4-dichloro-1,2,5-thiadiazole under Stille and Suzuki conditions <03H(60)29>.

HO.. ..CN N~/N 324

5.5.4.4

NH4CI NH4OH

H2~~i]CN N~/N 325

S2CI2 DMF

~\

S CI

N~/N 326

- ~SN - N

SR

HN.~ N~ 327

iS-N . O(CH2)5CH3 ~

N~

Xanomeline

1,3,4-Thiadiazoles

The reaction of substituted thiosemicarbazides 328 with aldehydes yields the corresponding thiosemicarbazones 329, which upon oxidative cyclization with iron(III) chloride furnish substituted 1,3,4-thiadiazoles 330 in good yields <03TL7825>. A solid phase synthesis is also developed to produce several 1,3,4-thiadiazoles <03TL7825>. In addition, a solid phase synthesis of 2-alkylthio-l,3,4-thiadiazoles is also devised. Accordingly, treatment of di-(2-pyridyl)thionocarbonate with thiosemicarbazide 331 affords the immobilised 1,3,4thiadiazole-2-thione 332, which was selectively mono-S-alkylated to yield resin-bound 2alkylthio-l,3,4-thiadiazoles 333. Acidic cleavage of the resin with TFA yielded 2-alkylthio1,3,4-thiadiazoles in good yields 334 <03TL7825>.

260

M.G. Saulnier, U. Velaparthi and K. Zimmermann

S

RL N ~J~N ~NH2 H

328

H

H

H

R2CHO

R~

-H20

S

S

N H

~J~ 329

N" H

DPT, DOM=

N" ~ N" NH2

N~/R 2

H R1.N%S/~ R2 N-N

FeCi3 EtOH

330

ONH S O/~HN._._~S.. ~

R2X Dioxane

N..-NH

O

332

331

H

IP

N-N

TFA, DCM

33:3

H2N",,.,,-f~ J/N-N\L

R2

334

A new cyclizing reagent is used for the synthesis of 5-unsubstituted 1,3,4-thiadiazoles 336 in an efficient manner. The reaction of oxamic thiohydrazide 335 with Vilsmeier reagent (POC13/DMF) produced 5-unsubstituted carbamoyl-l,3,4-thiadiazole 336 in rather low yield. However, yields are significantly improved by using diethyl chlorophosphate in DMF as a one carbon source effecting cyclization to afford 5-unsubstituted 1,3,4-thiadiazoles 336 <04S17>. Reaction of phenyl isothiocyanate with various hydrazides gives thiosemicarbazides 337, which further react with phosphorus oxychloride to provide 1,3,4thiadiazoles 338 <03HAC 114>. The 1,3,4-thiadiazolidine-2-thiones 339 are readily obtained on exposure of tributylphosphine and carbon disulfide adduct to dialkyl azodicarboxylates and aromatic aldehydes <03S 195>.

O S CI--P-OEt ~R ,,i __ R/JL NHNH2 OEt S N DMF ,~1~1 335

NHPh / N HNH2 PhNCS S - ~ NH O::~ i " O.~NH R

H 336

Bu3P+

CS 2

POOl3 =

R 337

S Bu3§

PhHN

-

N SN/~N R 338

RO2C_N=N-CO2 R RO2C. ~CO2R = N-N ArCHO Ar-~s/~S 339

A novel series of 2-substituted-l,3,4-thiadiazoles 342 were synthesized and evaluated against NCI cancer cell-lines. The 1-(4-chlorophenyl)-4-hydroxy-lH-pyrazole-3-carboxylic acid hydrazide 340 is treated with various isothiocyanates, and the resultant semicarbazides 341 are exposed to cold sulphuric acid to afford 1,3,4-thiadiazoles 342 <03EJM959>. Chauviere et al. report the synthesis and biological activity of analogs of Megazol (344) as anti-infective agents against protozoal parasites. The synthesis of Megazol involves oxidative cyclization of thiosemicarbazone 345 with ferric sulfate, and Megazol is also obtained by condensation of carbonitrile 343 with thiosemicarbazide in TFA <03JMC427>.

261

Five-Membered Ring Systems: With N and S (Se) Atoms

O\ NH2 HO~/_~HN" <"N"N

0 NHR HObN,~N ~H~'~S RNCS

N"N ~ NHR HOx~S H2SO4

CI 340

CI

341

q"N"N

CI

342

SX~-NH2 N-NH

~_.~ NH2NHCSNH 2 O2N N CN

,/~N~>~S I~NH2 Fe§ I1~ N /"L"N N N 'N ~ O2 N O2N \ \

I

343

344 Megazol

345

The 1,3,4-thiadiazole ring system is an important structural motif in medicinal chemistry <03BMCL4193, 03IF1023, 03CPB838, 03BMCL1005, 03BMCL2867, 03EJM781, 03S2851>. For instance, Thomasco et al. used the 1,3,4-thiadiazole substituent as a bioisoster for morpholine in the Linezolid type of oxazolidinone antibacterials. The thiobenzhydrazide 346 is treated with acid chlorides to furnish 1,3,4-thiadiazole 347 <03BMCL4193>. The 1,3,4-thiadiazole is also found in fluoroquinolone antibiotics such as 348 <03IF1023>. Similarly, the 1,3,4-thiadiazoles 351 have been synthesized and evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis strain. The synthesis of 351 involves oxidative cyclization of thiosemicarbazone 349 to furnish 2-amino-l,3,4thiadiazole 350 <03IF 1073>.

R ~N,

Ar....T.>N"

0

H 346

~8 O2N

H

O'~

347

1NH, S ,.•

N"

NH2

349

R-

O"~

348

N..N~__NH2 Fe(NH4)(SO4)2=~ S ~'s H20 350

O

CO2H

I~-N,~-SCH2CO R

J J

O2N

__

O2N

351

262

M.G. Saulnier, U. Velaparthi and K. Zimmermann

SELENAZOLES AND SELENADIAZOLES

5.5.5

A number of selenium heterocycles are prepared utilizing carbon-selenium double bonds as 2n dienophilic intermediates for [4+2] cycloadditions. However, Koketsu et al. reported a novel hetero Diels-Alder reaction wherein selenoazadienes 353 serve as 4n components. Accordingly, compound 353 reacts with dimethyl acetylenedicarboxylate to yield 4selenazolone 354. The proposed mechanism involves the formation of hetero Diels-Alder adduct 355, which is converted into 4-selenazolone 354 following purification on silica gel. Protonation of cycloadduct 355 presumably affords the selenoamidine 356, which is converted into 357 by nucleophilic recyclization <03H(60)1211>. R2N

Se Me2NCH(OMe)2 Se H MeO2C ~ R2N.,~ NH2 " R2N.~ N~'~ NMe2 rt 352

CO2Me "

353

N.~ 4-II = )N"~CO2Me NMe2 CO2Me H+ ~-" ( i~lMe2

3s3

355

354

~Se N~__.~CO2Me 0 CHO

=_ -MeOH N ] HI ~ C O 2 M e l O

/

3s. J

I,~N+/

35 1

Reaction of 1,4-dicyanobenzene 358 with potassium selenocarboxylate 359 affords the corresponding cyanoselenoamides 360 and diselenoamides 361. The obtained cyanoselenoamides (e.g. 360) are reacted with potassium selenocarboxylate 359 again to afford the corresponding diselenoamides 361 in higher yields. When cyanoselenoamide 360 is reacted with chloroacetyl chloride, malonyl chloride, and phenacyl bromide 362, the corresponding selenazol-4-one, selenazin-4-one and selenazole 363 are respectively formed <03HAC 106>. In a separate publication, Geisler et al. report that 2-benzoyl-l,3-selenazoles 366 are obtained by cyclization of 2-bromoketones 362 with selenophenylacetic amide 364 that can be fragmented to fumish 2-unsubstituted 1,3-selenazoles 367 <03SL1195>. These same authors also report the synthesis of 4-chloromethyl-l,3-selenazole 371, which is subjected to nucleophilic displacement reactions to obtain double-functionalized, ionic and multivalent 1,3-selenazoles <03S 1215>. The cyclization of cx,ct'-dichloroacetone 369 with phenylselenourea 368 affords semi-aminal 370, which upon treatment with acetic anhydride fumish the 1,3-selenazole 371 <03S 1215>. Selenium compounds are also used in the class of porphyrazines, and for instance selenadiazole in the presence of 9,10-phenanthrenequinone or 2,3-butanedione results in the formation of pyrazines <03JOC1665>.

263

Five-Membered Ring Systems." With N and S (Se) Atoms

NC 358

Se

4"

H2

360

364

NC

359

NC

p

BF3Et20,0~

CN 4- R . ~ S e K

362, EtOH

H2

reflux

Se

p

365

H2 360(36%)

H2N

x~/ NH2 361(24%)

Ph

362

363

SeO2 Ph

Se

O

dioxane p

acetone C,~seN~ reflux

369

370

NaOH S/.e~ Ph

366

OH

H2N"~NHPh-I-CI~CI

S e n S e

Br

,~.(Sel-]

O

368

O

••e

+

EtOH

~NJL'- Ph 367

Ac20. C,'~N/~_..N(Ac)Ph Se

NHPh

371

There are few reports on the synthesis of 1,2,3-selenadiazoles from the corresponding semicarbazones during 2003 <03JHC427, 03JOC1947, 03JHC925, 03IF63>. For example, Attanasi et al. report the synthesis of 1,2,3-selenadiazole 374 by treatment of hydrazone 373 with selenium dioxide in acetic acid. However, under mild conditions (selenium oxychloride in dichloromethane), the aromatization process does not occur, and only the 2,3-dihydro compound 372 is observed <03JOC1947>. Sterically congested 1,3,4-selendiazolines 376 are obtained upon treatment of tetramethylindanone hydrazone 375 with diseleniumdibromide <03H(60)299>.

MeO2C

.CO2Me

~SS 372

MeO2C

4H...~ .,SeOC'2 OtBu CH2CI2

//~_

0

CO2Me NN__~O O 373

,NH2 375

Et3N

MeO2C, SeO2" AcOH

~u

CO2Me

/~/.N

374

~e

S 376

5.5.6

REFERENCES

03AG(E)83 03AG(E)1255 03AG(E)2889

S.-L. You, H. Razavi, J.W. Kelly, Angew. Chem. Int. Ed. 2003, 42, 83. M.A. Gonzalez, G. Pattenden, Angew. Chem. Int. Ed. 2003, 42, 1255. T. Kataoka, H. Kinoshita, S. Kinoshita, T. Osamura, S. Watanabe, T. Iwamura, O. Muraoka, G. Tanabe, Angew. Chem. Int. Ed. 2003, 42, 2889. M.H. Jung, J.G. Park, W.K. Park, Arch. Pharm. Pharm. Med. Chem. 2003, 336, 230. M.N.A. Nasr, S.A. Said, Arch. Pharm. Pharm. Med. Chem. 2003, 336, 551. K. Kotarsky, N.E. Nilsson, E. Flodgren, C. Owman, B. Olde, Biochem. Biophys. Res. Commun. 2003, 301,406.

03AP230 03AP551 03BBR406

264

03BBR793 03BCJ127 03BMC185 03BMC591 03BMC899 03BMC1493 03BMC2415 03BMC3407 03BMC3475 03BMC4059 03BMC4769

03BMC5179 03BMC5529 03BMCL191

03BMCL463 03 BMCL471 03BMCL485 03BMCL637

03BMCL657 03BMCL723 03BMCL729 03BMCL1005 03BMCL1359

03BMCL1517

03BMCL 1801

03BMCL1821

03BMCL2145

M.G. Saulnier, U. Velaparthi and K. Zimmermann

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Five-Membered Ring Systems: With N and S (Se) Atoms

03BMCL2255

03BMCL2587 03BMCL2795

03BMCL2867 03BMCL3167 03BMCL3227 03BMCL3273 03BMCL3409 03BMCL3491 03BMCL3513 03BMCL3997

03BMCL4007

03BMCL4139 03BMCL4193

03BMCL4201 03BMCL4463 03BMCL5529 03CC1956 03CL340 03CL814 03CL1058 03CPB138 03CPB276 03CPB697 03CPB807 03CPB838 03CPB1351 03CRV197 03CRV1213 03EJI77

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03EJO421 03EJO821 03EJO878 03EJO1042 03EJO4329 03EJO4413 03EJO4842 03H(59)161 03H(59)323 03H(60)15 03H(60)29 03H(60)299 03H(60)321 03H(60)523 03H(60)1211 03H(60)1219 03H(60)1401 03H(60)1855 03H(60)2417 03HAC95 03HAC106 03HAC114 03HAC132 03HCA1949 03HCA2471 03HCMS281 03IF63 03IF79 031Fl15 03IF259 03IF1023 03IF1073 03 IJC621 03IJC695 03IJC927 03IJC931 03IJHC307 03JA26 03JA1700 03JA2899 03JA3046 03JA3428 03JA3690 03JA3849

03JA4132 03JA5040 03JA5115

M.G. Saulnier, U. Velaparthi and K. Zimmermann

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Five-Membered Ring Systems: With N and S (Se) Atoms

03JA8082 03JA8218 03JA8432 03JA8706 03JA8734 03JA14816 03JAN129 03JAN226 03JAN232 03JAN520 03JCHC423 03JCO392 03JCO754 03JCR(S)162 03JCR(S)225 03JCR(S)330 03JFC207 03JHC149 03JHC 191 03JHC261 03JHC353 03JHC427 03JHC435 03JHC721 03JHC821 03JHC925 03JMC204

03JMC427 03JMC453

03JMC532 03JMC1306 03JMC1470 03JMC 1706

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03JMC2413

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M.G. Saulnier, U. Velaparthi and K. Zimmermann

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Five-Membered Ring Systems: With N and S (Se) Atoms

03OL2911 03OL3313 03OL3607 03OL3835 03OL4163 03OL4175 03OL4421 03OL4851 03OL5039 03OPP401 03 PNA6712 04S17 03S195 03S371 03S728 03S1079 03Sl112 03Sl191 03S1215 03S1361 03S1503 03S2265 03S2395 03S2559 03S2632 03S2851 03SC535 03SC563 03SCl109 03SC1433 03SC1943 03SC2053 03SC3551 03SC4339 03SL166 03SL227 03SL522 03SLl109 03SLl175 03SLl195 03SL1500 03SL1731 03SL1898 03SL1967 03SL2033 03SL2167 03SL2351 03SL2410 03SUL17

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M.G. Saulnier, U. Velaparthi and K. Zimmermann

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Five-Membered Ring Systems: With N and S (Se) Atoms

03TL6635 03TL6789 03TL7087 03TL7445 03TL7825 03TL8127 03TL8153 03TL8535 03TL8563 03TL8905 03TL8947 03TL8951 03TL9219

271

S. Tumkevicius, L.Labanausks, V. Bucinskaite, A. Brukstus, G. Urbelis, Tetrahedron Lett. 2003, 44, 6635. S.T.A. Shah, K.M. Khan, M. Fecker, W. Voelter, Tetrahedron Lett. 2003, 44, 6789. R. Markovic, M. Baranac, S. Jovetic, Tetrahedron Lett. 2003, 44, 7087. X. Gai, R. Grigg, I. Koppen, J. Marchbank, V. Sridharan, Tetrahedron Lett. 2003, 44, 7445. J.P. Kilbum, J. Lau, R.C.F. Jones, Tetrahedron Lett. 2003, 44, 7825. D. Chevrie, T. Lequeux, J.P. Demoute, S. Pazenok, Tetrahedron Lett. 2003, 44, 8127. J.E. Clare, C.L. Willis, J. Yuen, K.W.M. Lawrie, J.P.H. Charmant, A. Kantacha, Tetrahedron Lett. 2003, 44, 8153. V.J. Majo, J. Prabhakaran, J.J. Mann, J.S.D. Kumar, Tetrahedron Lett. 2003, 44, 8535. J.L. Gross, Tetrahedron Lett. 2003, 44, 8563. M. Seki, M. Kimura, M. Hatsuda, S. Yoshida, T. Shimizu, Tetrahedron Lett. 2003, 44, 8905. B. Henkel, B. Beck, B. Westner, B. Mejat, A. Doemling, Tetrahedron Lett. 2003, 44, 8947. L.D.S. Yadav, R. Kapoor, Tetrahedron Lett. 2003, 44, 8951. T. Takahashi, H. Watanabe, T. Kitahara, Tetrahedron Lett. 2003, 44, 9219.

272

Chapter 5.6 Five-Membered Ring Systems: With O & S (Se, Te) Atoms

R. Alan Aitken

University of St. Andrews, UK (e-mail: raa@st-and, ac. uk)

5.6.1

1,3-DIOXOLES AND DIOXOLANES

A comprehensive review chapter on 1,3-dioxolium salts has appeared <02MI13>. New catalysts for the reaction of carbonyl compounds with ethanediol to give 2,2disubstituted dioxolanes include sulfuric acid-derivatised polyaniline <03SL1793>, trimethylsilyl triflate in the presence of a trimethylsilyl ether <03JOC3413> and K]0 montmorillonite under solvent-free conditions <03MIl19>. A one-pot oxidation-Wittig reaction approach has been used to convert primary alcohols, RCH2OH into products 1 involving reaction with MnO2, the phosphonium salt 2 and the tricyclic guanidine base 3 <03CC2284>. Compound 3 is also an effective catalyst for reaction of epoxides with CO2 to give 1,3-dioxolan-2-ones <03TL2931> and other new catalysts investigated for this process include 8-hydroxyquinolinates of trivalent metals in the presence of Ph3PO <02BAU836>, (Ph3P)2NiC12/Ph3P/Zn/Bu4NBr <03CC2042> and a range of magnesium-containing heterogeneous catalysts <03GC71>. The process may also be carried out with supercritical CO2 in an ionic liquid <03CC896>.

0

+ 0

1 R3

O

~

5

2 R1

MeO"%--O~ CO2Me

rll

R2 O_.~al

Ph'~ O 0 9

R1 R ~ . , j O - ~ R2

6

Me Me O'~O

~_. 10

0

OH

[~,,.CO2Et

01~0~/ 11

R2

Me 3

4

O

R3Si'~OCH2Ph N2

'1

O~o PhCH 2

R1

273

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

Treatment of tx-hydroxyketones, R1CH(OH)COR 2 with triphosgene, (C13CO)2CO, gives the 1,3-dioxol-2-ones 4 in moderate yield <02IJC(B)1722> and palladium-catalysed reaction of propargylic acetates 5 with CO in methanol results in cyclisation to give the dioxolanes 6 <02TL6587>. Rhodium-catalysed reaction of the diazo esters 7 with carbonyl compounds, R1COR2, provides a new route to silyl dioxolanones 8 in a process involving an intermediate carbonyl ylide <02OL4631>. Reaction of mandelic acid with aldehydes and ketones to give 1,3-dioxolan-4-ones 9 is efficiently achieved by microwave irradiation with anhydrous CuSO4 under solvent-free conditions <03TL2573>. An improved synthesis of the key synthetic intermediate 10 from D-mannose in 23% overall yield has been described <03S 1087> and baker's yeast reduction of the corresponding ketone gives the chiral building block 11 <03T1773>. An enantioselective synthesis of the dioxolane-containing bicyclic amino acids 12 from erythrose has been reported <03T5251> and an asymmetric total synthesis of the marine natural product attenol B 13 has appeared <03SL2185>. The synthesis and unexpected stability of a range of 2-pyridyl-l,3-dioxolanes have been reported <03JHC277>.

0

R2N\ O%/~'"CO2H 12

Me

Ph 0.../R ph/~O]

Me 15 Me

16

Li 14 ~OH

~

Ph Ph R 17

The reactivity of lithiated benzodioxole 14 with a variety of electrophiles has been examined in detail <03EJO452>. Transformations of compounds 15 with the 6,8dioxabicyclo[3.2.1]octane skeleton have been reviewed <03SL1759>. Cleavage of 2,2disubstituted 1,3-dioxolanes to give carbonyl compounds can be achieved using T-picolinium chlorochromate <02RJO1671> and a study of ceric ammonium nitrate in the same process reveals that it is required only in a catalytic amount and acts as a Lewis acid rather than an oxidising agent <03T8989>. Rhodium-catalysed reductive cleavage of 2-substituted 1,3dioxolanes with PhSiH3 gives 2-hydroxyethyl ethers <03CC1192> while aerobic oxidation of the same starting materials catalysed by Co(OAc)2 and N-hydroxyphthalimide gives 2hydroxyethyl esters <03S2373>. A novel thermal isomerisation process occurs upon flowpyrolysis of 2-alkylidene-l,3-dioxolanes such as 16 to give the butyrolactone products 17 <03H(60)1673>. Reaction of chiral 1,3-dioxolan-4-ones with base and either nitroaryl fluorides <03SL2325> or acylsilanes <02TA1825> followed by deprotection has been used in asymmetric synthesis, and compound 18 is an effective chiral catalyst for the asymmetric epoxidation of alkenes with Oxone | <03T2159>. Samarium iodide-promoted conjugate addition of the chiral dioxolane nitrone 19 has been used in a formal asymmetric synthesis of (S)-vigabatrin <03SL1527>. Conjugate addition of organozinc compounds to chiral dioxolanones and dioxolanes such as 20 and 21 has been examined <03CEJ4179>, as has the hetero Diels-Alder reaction of methylenedioxolanes 22 to give products such as 23

274

R.A. Aitken

<03T341>. Inclusion complexes with TADDOLs such as 24 have been used to direct enantioselective Diels-Alder reactions in aqueous solution <03GC57>. Chiral cyclopentadienes such as 25 have been introduced for use as transition metal ligands <03OM1550>.

Me .0.,

M~.'

:o

Me

0

~O

Bu t

Me

N+-CH2Ph t

18

0

20

Me

O'~Ar R ~ "~O O Ar Me~O~ "~ ---~O"J'"Ar AoNH"'I"~O-_~ Me O"~ ~ 22

O...~Me RO2C~-~.~-../O

23

Ar

21

Ph Ph "---/ '0..--J.... OH

p./p,

25

24

The chiroptical properties of the benzodioxole 26 have been examined <03OBC391> and the photochromism of compound 27 has been studied <03ARK(xiii)147>. Anti-diabetic activity is claimed for compound 28 <03WOP2550> and the spiro indolone/dioxolanes 29 have monoamine oxidase inhibiting and psychostimulant properties <01RRC517>. 0

27

5.6.2

Me O

~

29

R1

1,3-DITHIOLES AND DITHIOLANES

A comprehensive review chapter on 1,3-dithiolium salts as well as selenium and tellurium and benzo annulated analogues has appeared <02MI 191 >. Reaction of 2-substituted 1,3-dioxolanes with ethanedithiol in an ionic liquid results in transthioacetalisation to afford the corresponding 2-substituted 1,3-dithiolanes <02JCS(P1)1520> and the combination of 2,4,6-trichloro-l,3,5-triazine and DMSO in CH2C12 results in cleavage of 2-substituted 1,3dithiolanes to give the corresponding carbonyl compounds in high yields <03S2547>. The asymmetric synthesis of various analogues of nucleosides in which the ribose is replaced by a 1,3-dithiolane has been reported <03EJO346>. In a rather remarkable process involving 3+2 cycloadditive dimerisation of a transient thiocarbonyl ylide, treatment of the oxidised trithiocarbonate 30 with Me3Si-CHN2 gives the product 31 whose structure was established by X-ray diffraction <03EJO813>. Reaction of phenylacetylene with sulfur and KOH in DMSO leads to direct formation of the dithiole 32 in low yield <03CHE128> while the salt 33 reacts with long chain alkyl iodides to give mainly the dithioles 34 <03TL4701>. Formation of the chiral dithiolane sulfoxides 35 by the action of a genetically-engineered yeast containing cyclohexanone monooxygenase, on the corresponding achiral dithiolanes, has been described <02ARK(xii)47>.

275

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

S ~~Cl PhSO2.~S 30

Me3Si~SiMe3 PhSO2 - ~+ S C,. ~ S ~ o 2Sh~S~ ' ~ ~ C '

Ph-,..,~s

U

Ph

32

31

O

II

K+K+-s~-sNo2R-I = RS...S ~ ~ ' s NO2 L-.. S/r~ S~C~ 33

= ~s/~'R%CO2Et

34

35

A convenient new synthesis of 1,3-diselenole-2-thione which avoids the use of CSe2 has been reported <03CC1940> and a new synthesis of the useful building block 36 has been described <02MI263>. A detailed mechanistic study of the reaction of compounds 37 with PzS5 or Lawesson's reagent to give 38 and 39 has appeared <03T8107>. A series of benzodithiole/ferrocene compounds 40 have been prepared <03T6353>, an iron complex of the ligand 41 has been examined as a spin crossover material <03CC2374> and further studies on compounds 42 related to molybdopterin have been described <03OBC129>. New dithiole-containing donor-spacer-acceptor compounds include the furan compound 43 <03OBC1447> and the heptacyclic spacer compound 44 <03T5719>. R

36

S

S/"~SCH2C(O)R

sO.~

37

38

S

39

s

Fe

Me "~--0 42

Me

S

I R s~

F3C

R

43

A great deal of work involving tetrathiafulvalenes has again appeared and there have been reviews of their application for molecular devices <03SM(133)309>, 2nd order nonlinear optical materials <01MI77> and advanced materials <02MI169>. An X-ray diffraction study of a complex between donor 45 and Re6Ses(CN)6 shows an unexpectedly complex structure of formula (45+')4 (45~ Re6Ses(CN)44- (CH2C12)2 (MeCN)2 <03CC1820> and isomer-dependent packing is observed for the E and Z isomers of TTF 46 <03CC906>. A range of polyfluorobenzyl TTFs have been described <03SM(133)329> and the TTF-based tetranitroxyl 47 has been prepared and its electrochemical and magnetic properties examined <03TL4415>. Other new TTF donors reported include 48 and 49 which show interesting patterns of hydrogen- and halogen-bonding in the solid state <03SM(133)317>. A range of new annulated tetraselenafulvalenes 50 and 51 have been prepared <03JOC5217> and

276

R.A. Aitken

superconductivity has been observed for the tetrafluoroborate salt of the dihydro-TTF 52 <03CC494>. s

s

S S~/sAr ArS'~ S~~SLsA r ArS/ -O~, Me ~, ~ //N :J/__Me Ar= ~~--"k~_~/~k.N..J%Me O' Hex

s

( S ~ S~~S~]jcOaaMe 018H3,..S~ 45

y CN

~S~s

48

46

S~

47

49

/S~ Se Se_ Se Se.~S\ (CH2)n (CH2!~;/~Se/~Se~ (CH2/,)~~]~ Se/~Se I-~S,, 50 n = 1,2,3

s .

52

51 n = 1,2,3

Electron transfer through the TTF bridge is observed in the radical anion of the diquinone 53 <03AG(E)2765> and 3rd order non-linear optical properties are observed for the compounds 54 <02MI609>. The new donor 55 has also been reported <03SM(133)333>. TTF-fused porphyrins have been used as anion sensors <03AG(E)187> and as fluorescence switches <03CC846> and a TTF/diquat cyclophane has shown donor/acceptor character <03TL2979>. Further examples of donor-acceptor diads are the nitrofluorene-based compound 56 <02CEJ4656> and the TCNQ-based compound 57 <03AG(E)4636>. The latter is remarkable in having the lowest gap between first oxidation and reduction potentials of any organic compound (0.17 eV) and it shows an ESR signal at RT due to thermal population of the charge-separated diradical state.

O o

ORv S 53

o

OR

NO2NO2 O2N

o

54

OR

55

CN O NC,,'L~v,'~v,"~~O~ S s~C5H11 "~[~~CN Me.~ S~)~SLOsH,,

CN

S..~..~ N~ S s~C5H11 .)Me/~ 02 PhCl.[12 I S~=~SL 05H11

57

56

Further studies on TTF-type systems linked in various ways to C60 <03SM(135)775, 03JOC779, 03OL557> and C60F18<03CC148> have appeared. A number of bis(TTF)s have been described with the two units linked either directly <02MI597>, by-SCH2CH2S<03JMAC1646>, by one or two-SCH2-2,6-pyridine-CH2S- units <03NJC560> or by a perylenediimide linker <03T4843>.

277

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

New extended TTFs include the anthraquinone type compound 58 <03OBC511>, a series of bridged link compounds 59 <02MCLC19> and compounds such as 60 <03SL1423> and 61 and 62 <03JMAC1324>.

MeS S HexS.

S

SMe

R

S

R

S

S

R

S

R

S

exs S

s 58

Ar

RO C" 2 - ~ S ~

,~

MeS

SMe

'~--/~~CO2R -\ CO2R

R

"rr" J/ S~ /~ - / /E ' " s/ R/ ~ S 61

S

Ar

~ R

R

62

A variety of other annulated TTF systems have been studied including 63 <02MCLC107>, 64 <03SM(133)321>, 65 and 66 <03SM(135)627>, 67 whose salts remain metallic down to 4K <03BCJ89> and 68 which despite lacking a TTF function gives a superconducting salt with GaC14- as counterion <03CC2230>.

O~

Sv

S

S-- ~ SeMe

~~~===~S.~ S ) = ~ S L SeMe 63

(i s

s_ se,

S~:~(S'~ S 65

Se

S e n S e lSe/~S

, S ~ . . . S[e ~

Sf ~S

sel~ SeMe

sere

S

s-J

S

S

S

SEt

67

Se'~SeMe

66 5.6.3

64

68

1,3-OXATHIOLES AND OXATHIOLANES

Comprehensive review chapters on 1,3-oxathiolium salts <02MI35> and 1,3oxaselenolium salts <02MI93> have appeared. Scandium triflate has been introduced as an efficient catalyst for reaction of aldehydes with mercaptoethanol to form 2-substitued 1,3oxathiolanes <03S2503>. Protection of c~-mercaptocarboxylic acids is readily achieved by

278

R.A. Aitken

reaction with hexafluoroacetone to give oxathiolanones 69 which are resistant to a variety of acidic and basic conditions but are readily hydrolysed back to the starting materials with water <03JHC435>. Reaction of substituted o-phthalimidosulfanylphenols with isocyanides directly affords the 2-iminobenzoxathioles 70 <03S662>. The phosphonate-substituted iminooxathiole 72 is formed by treatment of the ot-haloaldehydes 71 with a metal thiocyanate followed by heat or base <02RJO1216>. A variety of 1,3-oxathiolanes have been prepared and evaluated as flavouring agents <02MI614>.

O S~/.. CF 3

o

R'

F3c

69

~ ( P r"' O ) 2 P ~ o

X 71 X = CI, Br

70

pri_/S \

o

NR2 (P~O)21~L/CliO 1

R4

R2

S...~' 72 NH

R1

O-r-~O 73

R2k~/ " S j ' 74

R4

=" =H, Me

R3

75

h

Cleavage of 2-substituted 1,3-oxathiolanes to give the corresponding carbonyl compounds may be achieved using H202 in acetonitrile <02GC337> or NaNO2/AcC1 followed by water <03SL377>. Conversion of amino acid esters into the amides with mercaptoacetic acid can be carried out by treatment with the oxathiolanone 73 <03S19>. Titanium tetrachloride-mediated reaction of ct,13-unsaturated oxathiolanes 74 with styrene or ~-methylstyrene gives the dihydrothiapyrans 75 <03TL853>. 5.6.4

1,2-DITHIOLES AND DITHIOLANES

A comprehensive review chapter on 1,2-dithiolium salts has appeared <02MI107>. Synthesis of compound 76 which contains the core functionality of the antibiotic leinamycin has been reported <03PS(178)1163> and cycloaddition of the dithiolanethione 77 with DMAD results in generation of the thioacyl chloride function of 78 in an unusual way <03OL929>. The thiazolidinones 79 react with Lawesson's reagent to give 3-imino-l,2dithioles 80 <03TL7087>. The bis(1,2-dithiole) 81 has been prepared and is shown by X-ray diffraction not to have a significantly delocalised structure <03T10255> while a series of oxime-functionalised dithiolethiones 82 undergo S-methylation to give the nitroso products 83 <03JHC 155>.

279

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

s. Ss

0 HO(CH2)7

76

R

S O

0

77 S

/CO2Me

S

CI

0 S' S

S-S

S

I 78 S-S

81

80

79 5.6.5

~

MeO2C.,

1,2-OXATHIOLES AND OXATHIOLANES

Comprehensive review chapters covering 1,2-oxathiolium salts <02MI31>, 1,2oxaselenolium salts <02MI90> and 1,2-oxatelluronium salts <02MI97> have appeared. Full details of the asymmetric synthesis of chiral ~/-sultones 84 have been described <03S1856>. Reaction of the sultines 85 with bromine results in loss of SO2 to give 86 <03CHE113> and the 1,3-dipolar cycloaddition of nitrones to the sultone 87 has been reported <03S 1329>. OH S-S N ~ S R1

=

0N . . .@ . S-S II ~

R2

R1

82 Ar~,~ O-SO

Ar2

85

5.6.6

Br

86

O-O

SMe

R2

83

Br

NHz Oz

CO

84 R1-O

RZ

88 (Me3Si)2CH I 1 ~ i

02

87

89 n = 1 (Me3Si)2CH CH(SiMe3)2 90n=2 91X=S 9 2 X = Se

THREE HETEROATOMS

A wide range of di- and tri-spiro 1,2,4-trioxolanes have been evaluated as antimalarial agents and some such as 88 show good activity <02USP6486199>. New molybdenum and tungsten catalysts have been reported for the oxidation of the cyclic sulfites 89 to give sulfates 90 <03JAP238556> and the products 90 have also found use in synthesis <03SL675>. A review including coverage of benzotrithioles has appeared <02HAC419> and the first 1,2,3-trithia- and tri-selenagermolanes 91 and 92 have been prepared <03JOM(672)66>.

5.6.7

REFERENCES

01MI77 01RRC517 02ARK(xii)47

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

281

H. Kawanami, A. Sasaki, K. Matsui, Y. Ikushima, Chem. Commun. 2003, 896. E. Gomar-Nadal, M.M.S. Abdel-Mottaleb, S. De Feyter, J. Veciana, C. Rovira, D.B. Amabilino, F.C. De Schryver, Chem. Commun. 2003, 906. T. Ohta, T. Michibata, K. Yamada, R. Omori, I. Furukawa, Chem. Commun. 2003, 1192. 03CCl192 S. A. Baudron, P. Batail, C. Rovira, E. Canadell, R. Cl6rac, Chem. Commun. 2003, 1820. 03CC1820 T. Imakubo, T. Shirahata, Chem. Commun. 2003, 1940. 03CC1940 F. Li, C. Xia, L. Xu, W. Sun, G. Chen, Chem. Commun. 2003, 2042. 03CC2042 J. Yamada, T. Toita, H. Akutsu, S. Nakatsuji, H. Nishikawa, I. Ikemoto, K. Kikuchi, E.S. 03CC2230 Choi, D. Graf, J.S. Brooks, Chem. Commun. 2003, 2230. M. Reid, D.J. Rowe, R.J.K. Taylor, Chem. Commun. 2003, 2284. 03CC2284 K. Takahashi, T. Kawakami, Z. Gu, Y. Einaga, A. Fujishima, O. Sato, Chem. Commun. 2003, 03CC2374 2374. R.M. Su~rez, J.P. Sestelo, L.A. Sarandeses, Chem. Eur. J. 2003, 9, 4179. 03CEJ4179 E.V. Grigor'ev, L.G. Saginova, Chem. Heterocycl. Compd. (Engl. Transl.) 2003, 39, 113. 03CHE 113 N.K. Gusarova, N.A. Chemysheva, B.G. Sukhov, A.V. Afonin, S.V. Fedorov, G.A. Yakimova, 03CHE128 B.A. Trofimov, Chem. Heterocycl. Compd. (Engl. Transl.) 2003, 39, 128 [Chem. Abstr. 2003, 139,230656]. R. Caputo, A. Guaragna, G. Palumbo, S. Pedatella, Eur. J. Org. Chem. 2003, 346. 03EJO346 M. Schlosser, J. Gorecka, E. Castagnetti, Eur. J. Org. Chem. 2003, 452. 03EJO452 I. E1-Sayed, R.G. Hazell, J.O. Madsen, P.-O. Norrby, A. Senning, Eur. J. Org. Chem. 2003, 03EJO813 813. H. Miyamoto, T. Kimura, N. Daikawa, K. Tanaka, Green Chem. 2003, 5, 57. 03GC57 B.M. Bhanage, S. Fujita, Y. Ikushima, K. Torii, M. Arai, Green Chem. 2003, 5, 71. 03GC71 M. Oda, K. Morimoto, N.C. Thanh, R. Ohta, S. Kuroda, Heterocycles 2003, 60, 1673. 03H(60)1673 K. Nishikawa, N. Yamazaki, Jpn. Pat. 238,556 (2003) [Chem. Abstr. 2003, 139, 214494]. 03JAP238556 M. Chollet-Krugler, E. Finner, M.-O. Christen, J.-L. Burgot, J. Heterocycl. Chem. 2003, 40, 03JHC155 155. S.T. Hobson, J.D. Boecker, J.H. Gifford, T.L. Nohe, C.H. Wierks, J. Heterocycl. Chem. 2003, 03JHC277 40,277. K. Pumpor, E. Windeisen, K. Burger, Jr. Heterocycl. Chem. 2003, 40, 435. 03JHC435 P. Leriche, J.-M. Raimundo, M. Turbiez, V. Monroche, M. Allain, F.-X. Sauvage, J. Roncali, 03JMAC1324 P. Fr6re, P.J. Skabara, J. Mater. Chem. 2003, 13, 1324. L. Zou, W. Xu, C. Jia, D. Zhang, Q. Wang, D. Zhu, J. Mater. Chem. 2003, 13, 1646. 03JMAC1646 S. Gonz~lez, N. Martin, D.M. Guldi, J. Org. Chem. 2003, 68, 779. 03JOC779 M. Kurihara, W. Hakamata, J. Org. Chem. 2003, 68, 3413. 03JOC3413 K. Takimiya, Y. Kataoka, N. Niihara, Y. Aso, T. Otsubo, J. Org. Chem. 2003, 68, 5217. 03JOC5217 03JOM(672)66 N. Nakata, N. Takeda, N. Tokitoh, J. Organomet. Chem. 2003, 672, 66. 03MI119 S.K. Dewan, R. Singh, A. Kumar, Oriental J. Chem. 2003, 19, 119 [Chem. Abstr. 2003, 139, 164722]. 03NJC560 S. Bouguessa, K. Herv6, S. Golhen, L. Ouahab, J.-M. Fabre, New J. Chem. 2003, 27, 560. 03OBC129 B. Bradshaw, D. Collison, C.D. Garner, J.A. Joule, Org. Biomol. Chem. 2003, 1, 129. 03OBC391 E. Butkus, J. Malinauskien6, S. Stoncius, Org. Biomol. Chem. 2003, 1, 391. 03OBC511 C.A. Christensen, M.R. Bryce, A.S. Batsanov, J. Becher, Org. Biomol. Chem. 2003, 1, 511. 03OBC1447 P.R. Parry, M.R. Bryce, B. Tarbit, Org. Biomol. Chem. 2003, 1, 1447. 03OL557 S. Gonz~ilez, N. Martin, A. Swartz, D.M. Guldi, Org. Lett. 2003, 5, 557. 03OL929 M. Garcia-Valverde, R. Pascual, T. Torroba, Org. Lett. 2003, 5, 929. 03OM1550 A. Gutnov, B. Heller, H.-J. Drexler, A. Spannenberg, G. Oehme, Organometallics 2003, 22, 1550. 03PS(178)1163 A.H.F. Lee, J. Chen, A.S.C. Chan, T. Li, Phosphorus, Sulfur, Silicon, Relat. Elem. 2003, 178, 1163 [Chem. Abstr. 2003, 139, 197408]. G.A. Kraus, J. Bae, P.K. Choudhury, Synthesis 2003, 19. 03S19 V. Nair, B. Mathew, A.U. Vinod, J.S. Mathen, S. Ros, R.S. Menon, R.L. Varma, R. Srinivas, 03S662 Synthesis 2003, 662. D. Vonlanthen, C.J. Leurnann, Synthesis 2003, 1087. 03S1087 L. Tian, G.-Y. Xu, Y. Ye, L.-Z. Liu, Synthesis 2003, 1329. 03S1329 D. Enders, S. Wallert, J. Runsink, Synthesis 2003, 1856. 03S1856 B. Karimi, J. Rajabi, Synthesis 2003, 2373. 03S2373 B. Karimi, L. Ma'mani, Synthesis 2003, 2503. 03S2503 B. Karimi, H. Hazarkhani, Synthesis 2003, 2547. 03S2547 A.T. Khan, E. Mondal, P.R. Sahu, Synlett 2003, 377. 03SL377 J. O'Leary, C. Colli, J.D. Wallis, Synlett 2003, 675. 03SL675 03CC896 03CC906

282

03SL1423 03SL1527 03SL1759 03SL 1793 03SL2185 03SL2325 03SM(133)309 03SM(133)317 03SM(133)321 03SM(133)329 03SM(133)333 03SM(135)627 03SM(135)775 03T341 03T1773 03T2159 03T4843 03T5251 03T5719 03T6353 03T8107 03T8989 03T10255 03TL853 03TL2573 03TL2931 03TL2979 03TL4415 03TL4701 03TL7087 03WOP2550

R.A. Aitken M.B. Nielsen, Synlett 2003, 1423. G. Masson, W. Zeghida, P. Cividino, S. Py, Y. Vall6e, Synlett 2003, 1527. J.-G. Jun, Synlett 2003, 1759. S. Palaniappan, P. Narender, C. Saravanan, V.J. Rao, Synlett 2003, 1793. D. Enders, A. Lenzen, Synlett 2003, 2185. G. Blay, L. Cardona, I. Fernfindez, R. Michelena, J.R. Pedro, T. Ramirez, R. Ruiz-Garcia, Synlett 2003, 2325. J. Becher, J.O. Jeppesen, K. Nielsen, Synth. Met. 2003, 133-4, 309. M. Fourmigu6, O.J. Dautel, T. Devic, B. Domercq, Synth. Met. 2003, 133-4, 317. T. Shirahata, T. Mori, R. Kato, K. Takahashi, Synth. Met. 2003, 133-4, 321. G.G. Abashev, E.V. Shklyaeva, A.G. Tenishev, O.N. Kazheva, G.V. Shilov, O.A. Dyachenko, Synth. Met. 2003, 133-4, 329. T. Matsumoto, T. Kominami, K. Ueda, T. Sugimoto, H. Yoshino, K. Murata, E. Negishi, S. Endo, H. Matsui, N. Toyota, K. Takahashi, M. Shiro, Synth. Met. 2003, 133-4, 333. M. Ashizawa, H. Nii, T. Kawamoto, T. Mori, Y. Misaki, K. Tanaka, K. Takimiya, T. Otsubo, Synth. Met. 2003, 135-6, 627. S. Kojima, H. Nishikawa, T. Kodama, I. Ikemoto, K. Kikuchi, Synth. Met. 2003, 135-6, 775. P. Leeming, C.A. Ray, S.J. Simpson, T.W. Wallace, R.A. Ward, Tetrahedron 2003, 59, 341. T. Tachihara, T. Kitahara, Tetrahedron 2003, 59, 1773. T.K.M. Shing, Y.C. Leung, K.W. Yeung, Tetrahedron 2003, 59, 2159. X. Guo, D. Zhang, H. Zhang, Q. Fan, W. Xu, X. Ai, L. Fan, D. Zhu, Tetrahedron 2003, 59, 4843. A. Trabocchi, G. Menchi, M. Rolla, F. Machetti, I. Bucelli, A. Guarna, Tetrahedron 2003, 59, 5251. T.J. Chow, N.-R. Chiu, H.-C. Chen, C.-Y. Chen, W.-S. Yu, Y.-M. Cheng, C.-C. Cheng, C.-P. Chang, P.-T. Chou, Tetrahedron 2003, 59, 5719. A. Sarhan, Y. Nouchi, T. Izumi, Tetrahedron 2003, 59, 6353. F. Turksoy, J.D. Wallis, U. Tunca, T. Ozturk, Tetrahedron 2003, 59, 8107. A. Ates, A. Gautier, B. Leroy, J.-M. Plancher, Y. Quesnel, J.-C. Vanherck, I.E. Mark6, Tetrahedron 2003, 59, 8989. J.K. Bjernemose, E. Frandsen, F. Jensen, C.Th. Pedersen, Tetrahedron 2003, 59, 10255. S. Kerverdo, L. Lizzani-Cuvelier, E. Dufiach, Tetrahedron Lett. 2003, 44, 853. R.R. Ferrett, M.J. Hyde, K.A. Lahti, T.L. Friebe, Tetrahedron Lett. 2003, 44, 2573. A. Barbarini, R. Maggi, A. Mazzacani, G. Mori, G. Sartori, R. Sartorio, Tetrahedron Lett. 2003, 44, 2931. A. Ploug-Sorensen, M.B. Nielsen, J. Becher, Tetrahedron Lett. 2003, 44, 2979. G. Harada, T. Jin, A. Izuoka, M.M. Matsushita, T. Sugawara, Tetrahedron Lett. 2003, 44, 4415. H.S.P. Rao, L. Sakthikumar, S. Vanitha, S.S. Kumar, Tetrahedron Lett. 2003, 44, 4701. R. Markovic, M. Baranac, S. Jovetic, Tetrahedron Lett. 2003, 44, 7087. V. Akella, O.R. Gaddam, M.R. Siripragda, M. Gutta, N. Dussa, R.S. Mamillapalli, PCT Int. Appl. WO 2,550 (2003) [Chem. Abstr. 2003, 138, 73249].

283

Chapter 5.7

Five-Membered Ring Systems with 0 & N Atoms Stefano Cicchi, Franca M. Cordero, Donatella Giomi Universith di Firenze, Italy donatella, giomi@unifi, it

5.7.1

ISOXAZOLES

Interest in this class of heterocyclic compounds is well documented by many different applications, especially in the pharmacological domain. The development of new methodologies for facile isoxazole synthesis enhances even more the attractiveness of this system as a platform for the synthesis of complex molecules. Solid phase synthesis using the 'catch & release' approach allowed the efficient preparation of libraries of substituted isoxazoles. Starting from aniline-cellulose 1 as solid support, N-formylimidazole dimethyl acetal 2, and different [~-ketoesters or 13-ketoamides 3, the one-pot generation of cellulose-bound enaminones 4 was performed in quantitative yields. The following reaction with hydroxylamine hydrochloride afforded pure isoxazoles 5 in high yields directly in solution, restoring the starting resin <03CRC607>. Microwave-assisted synthesis was also reported <03JCO465>.

Cyclocondensation of malonyl derived O-acyl hydroxamic acid derivatives 6, in the presence of phosphazene super base P2-t-Bu 7, gave rise to isoxazolone carboxylic esters 8 <03TL7763>.

284

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

Lanost-8-en-3-one 9, as well as methyl oleanonate, afforded regioselectively the corresponding [2,3-d]isoxazole 10, and not the [3,2-c]fused systems previously reported. The first synthesis of a new lanostane triterpenoid 11 with a cyano enone moiety in ring A, interesting from the perspective of biological activity, was also achieved <03JOC4991>.

O••-=H .

1. HCO2Et,NaOMe Phil, 94% ,, 2. NH2OH.HCI aq. EtOH, 89%

9

j~_ H

10

1. NaOMe,MeOH Et20, 93% = 2. DOG, Phil 72%

11

A base-promoted cyclocondensation of cyclic 1,3-diketones 13 with C-chloro oximes, derived from oximes 12, gave rise to functionalised isoxazoles 14, under mild reaction conditions and with notable functional group tolerance <03OL391>. The above reactions were also performed with stable 2,6-disubstituted benzonitrile oxides, allowing the synthesis of more sterically-encumbered polycyclic isoxazoles in good yields. Mechanistic studies evidenced the necessity for a base, suggesting a key role for enolate species in the ratelimiting carbon-carbon bond forming step, either via nucleophilic addition to the nitrile oxide or 1,3-dipolar cycloaddition (1,3-DC) <03TL3555>. Anyway, molecular sieves (MS 4A) can even act as efficient promoters, broadening the scope of this simple approach <03SL1746>. Isoxazoles 14 can be directly converted to a variety of polyketide-derived polycyclic structures. Moreover, ester 14a gave rise, via dianion 15, to new chemo-, regio-, and stereoselective cascade reactions involving a novel base-induced isoxazole-benzisoxazole rearrangement, alkylation by dibromides 16, and SN2' cyclization with tetrahydrofuran ring closure. Compounds 17, obtained as single diastereomers, can be converted by different reducing agents to complex, structurally diverse polycyclic molecules <03OL395>.

R1 N"OH [ ~

+

O

O ~

12

R1 1. NCS,cat. py ',,R3 2. base

',,R 3

R 2 13

OH N~O [ ~ ~ 14a

_

O-

N~O

LDA (20 equiv) i ~ E Ii.

E

NmO

...... DME,-78~

E=CO2EtR,R'=H,Me

2

R

]

Br~ ...L~ ~

,l

, 78--~ 55 ~ 38-45%

......

15

RI=Br,OH,OMe polycyclic R2=H,CO2Et = polyketides R3=H,Me

16v

'r" - i ~ , Br

O~N

O

~

tessst

R

Reductive cleavage with TMSC1/NaI of fused systems such as pyrano- and furo[3,4c]isoxazole derivatives 18 gave predominantly polysubstituted isoxazoles 19, as key intermediates for further elaborations <03H1625>. Pyranoisoxazole derivatives 18a have been prepared by intramolecular 1,3-DC of nitrile oxides 21, obtained by treatment with n-

285

Five-Membered Ring Systems with 0 & N Atoms

BuLi and Ac20 of nitrooxaheptynes 20, generated in high yields from nitroalkenes and hydroxy alkynes <03H(59)685>. Domino [3+2] cycloaddition/annulation reactions of aminophenyl-ynones 23 with nitrile oxides, generated in situ from chloro oximes 22, allowed the synthesis of isoxazolo[4,5c]quinolines 24, in satisfactory yields <03EJO1423>. Bromine substituents on naphthoquinones activate and orient 1,3-DC with nitrile oxides. Compound 25 reacted with halo oximes 22 to give regioselectively only unsymmetrical naphthoquinones 26, as polyketide building blocks <03TL8901 >.

Ar

Ar

~ N

TMSCIINaI L ~ N ecm

R

18

80 ~ n=1,2

I R 19 26-87% O

A

Ar~ "N- ~

24 23-77%

~

Ar /'~~D ~ O

+ ~N-O 21

18a 37-46%

OMe O

r

~

.. 23 H 2 N ~

R

Ar ~ O

" ~ ' ~ ] I I"n-BuL. -18 ~ Ar ,. 2. Ac20 NO2 20

MeO~.Br

OMeO

R.,.~XN..

TEA

,,

OH

~II ~ I ~ N

TEA

OMe O

xyleneor toluene, A 22 X=CI,Br DCM, rt, 2-3 h

R

26 78-99%

[3+2] Cycloadditions of in situ generated nitrile oxides 28 with alkynols 27 provided isoxazolylalcohols 29 directly. Their catalytic hydrogenation under mild conditions, followed by acidic hydrolysis, afforded 3(2/-/)-furanones 30, through [3-aminoenone cyclization <03T5215>. Reductive ring opening by breaking of the N-O bond was also exploited for the synthesis of different pyrido-condensed heterocycles 33, containing from five to eight atoms in the fused ring. 4,6-Dichloroisoxazolo[4,5-c]pyridine 31 reacted regioselectively with nitrogen and sulfur bis-nucleophiles, affording 4-substituted derivatives 32, easily converted to 33 with Mo(CO)6 in refluxing methanol. The same ring opening/ring closure strategy was also applied to 4-chloro-3-methylisoxazolo[5,4-b]pyridine <03S2518>. a 1

R2

~>

40-74% -I-

HO

27

C'

N

"('~nNH2__ CI

31

/ ~N-O R3 28

R3 ~. N ~ o ~ ~ R 29

1 1. H2, Pd/C 10%=. R3 R2

Z'~n NH2

N

n=0,1,2,3

Z=NH,S

HO

O

Mo(CO)6,.

CI MeOH, A

32 54-85%

~

2. H +

63-88% N'~nZ

R1 "O" "R 2

30

RI

N CI

33 35-67%

R2

34 n=0,1,2

R3

286

s. CicchL F.M. Cordero, and D. Giomi

3,5-Diarylisoxazoles were easily halogenated at the C-4 position with N-halosuccinimides in acetic acid (37-97% yields) <03S1586>. The Dess-Martin periodinane oxidation of or-, 13-, and ~,-hydroxy isoxazoles into the corresponding ketones 34 was easily performed in good to excellent yields <03SL2213>. As previously reported for the corresponding 5-substituted compounds, 3-isoxazole carbaldehydes 35 gave rise to fast and efficient Baylis-Hillman (BH) reaction with a variety of activated alkenes 36 in the presence of DABCO and in the absence of any solvent, leading to adducts 37 in excellent yields. Analogous results were also obtained on solid phase <03S2325>. On the contrary, 4-isoxazole carbaldehydes were less reactive electrophiles in the same reaction and in general gave the desired adducts only in modest yelds, after longer reaction times <03S1347>. Acetates of BH adducts produced from 5-formylisoxazoles reacted with DABCO and phenol in aqueous media to give the corresponding 3-phenoxy prop-2-enoates 38 in good yields <03T663>. Isoxazolo[3,4-d]pyrimidine 39 when treated with cyanoolefins 40, in the presence of TEA as catalyst, gave biologically interesting pyrido[2,3-d]pyrimidine oxides 41 in excellent yields. Probably, a [4+2] cycloaddition of the azadiene moiety of 39 with keteneimine intermediates, derived from 40 and TEA, is involved in the process <03TL 1847>. Starting from 4- or 5-tributylstannanyl isoxazoles, prepared via 1,3-DC with chlorooximes and tributylethynyltin in the presence of base, a series of isoxazolyl tetrahydropyridinyl oxazolidinones 42 were synthesised and their in vitro antibacterial activity evaluated <03BMCL4117>.

O-N Ar~OHO 35

O

~EWG 36

O-N

DABCO" Ar rain. EWG=CO2R,CN,CONH2 15-30

Ar.

CN

AF

O

O.~ N..~N,O 40k~EWG Me" N cat TEA " OJ", " ",K 39 Me EtOH,• 41 Me O

5.7.2

N'O~co2R 38 OPh

EWG OH 37 77-95% R

F,

0

42 R=Me,CI,CF3,CN,CO2Et, NHAc CONH2,CONMe2

ISOXAZOLINES

Chiral dipolarophiles such as 43 <03TL1071> and 45 <03SL1358>, derived from carbohydrates, react with nitrile oxides to afford spiro- and bicyclic-isoxazolines 44 and 46, respectively, with high regio- and diastereoselectivity.

287

Five-Membered Ring Systems with 0 & N Atoms

R

N_

AF

OTBDMS

+

""

O ~'~OBn OBn OBn 43

DCM

OBn

O

OBn OBn R = Me, Ph 44 76-85% Ar = 2,4,6-Me3C6H2 dr > 95:5

....OR1 45

OTBDMS

RC-N-O DCM"

O

" OR1 '. . . . . . . H

R-J-~N.O R = Me, Et R1 = Et, c-C5H9, c-C6Hll 46 78-89%

The chiral isoxazoline derivatives 49 were prepared in a highly enantioenriched form by 1,3-DC of benzonitrile oxide and pivalonitrile oxide with acrylate 47 followed by reductive removal of the D-glucose-derived auxiliary R*OH which was recovered in high yields <03SL1865>. O "~OR* 47

R-C-N-O DCM, rt R=Ph

N"O~f cO2R* LiB(Et)3H N"O~ cH2OH R

48

THF, rt

96%; dr 9 9 1

R = t-Bu 90%; dr 9 9 1

R

T#OO-

49

TBSO

99%

98%

89%

92%

OMe

R*OH

The cycloaddition of carbethoxylformonitrile oxide with different alkenes was shown to be easier when performed in an ionic liquid such as [bmin][BF4] or [bmin][PF6] <03TL5327>. A parallel array of 16 differently substituted isoxazoline diamides 53 was prepared through a three-step procedure (Schotten-Baumann, 1,3-DC, ester amidation with A1C13) using [bmin][BF4] as common phase without isolation of any of the intermediates. The final products were extracted with diethyl ether in 38-51% overall yields, pure by NMR analysis <03OL4029>. CI ~_COCI

50

CO2Et

CONHR 2

N R2NH2toluene R1NH2 = ( \CONHR1 He.. N~.~CO2Et ~ ~ O KHCO3 ,,,, KHCO3 Me3A, in [bmin][BF4] [bmin][BF4] CONHR 1 [bmin][BF4] 51

52

R1, R2 = c-Hex, Ph, Bn,/-Bu

N

6 CONHR 1 53

38-51% overall yields

Isoxazolines 54, prepared by stereoselective 1,3-DC of nitrile oxides and enantiopure allylic alcohols, were converted into 13-amino acids 56 and 58 by nucleophilic addition to the C=N bond followed by reductive cleavage of the N-O bond and oxidative cleavage of the diol moiety. The facial selectivity in the nucleophilic addition was dictated by the C-5 substituent in either a directed (hydride addition) or a sterically (Grignard reagents addition) controlled manner <03JA6846>.

288

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

a1 ~'"'NHBoc

R1 i)LiAIH4 ....NHBoc NalO4 RuCI3 /,~qOH ii) BoC20 CO2H HO--~ 56 59-76% 55 40-64% 7-15"1 dr

R1

R2MgCI R2,,,71 i) LiAIH4 R1 N BF3"OEt2 H"~//E-NHii)BOC20_ R2,,?NHBoc THF - 78 ~

iii) Nal04 iv) NaClO2 CO2H

/ , HO

58

57 81-95% 9->20"1 dr

54

48-69%

An electrocatalytic method for the reductive N-O bond cleavage of 3-methoxyisoxazoline in the presence of Ni~ was studied. The nickel complex, generated in situ, acts as the actual electron source. Under these conditions, isoxazoline 59 afforded a mixture of [3hydroxyester 60 and ]3-hydroxynitrile 61 in high overall yields, and in different ratios depending on the amount of Ni~ used <03TL8217>.

N-'O Ph 1) Ni~ / DMF O OH OH N~/~ Zn anode / 2e~ + .,,j,,, " MeO Ph N.-..C Ph Me 2) 0.2 M HCI 60 61

"~" CO2Me ~1~ %Fe(CO)2eeh3 + ..~

~

O2N" 62

(OC)3Fe

63

Nillbpy (%) Yield (%) 6 0 61 7 15 30 100

90 99 90 99

TBSO, ~)3

MeO2C ?TBS

TEA Ph3P(OC)2Fe., 63%

4:1 1.9 1 2.2 1 13 1

N-O

64

Fe(CO)3

The bimetallic tetraene isoxazoline 64 was prepared through a highly diastereoselective intermolecular nitrile oxide-olefin cycloaddition and used as an intermediate in the synthesis of the C7-C24 segment of macrolactin A. The addition of the nitrile oxide on the less hindered face of the s-trans triene rotomer of 63 was the key to controlling the absolute configuration of the new formed stereocenter <03S2064>. The isoxazoline skeleton is frequently present in biologically active compounds and is used as a building block in the synthesis of new potential drugs. New libraries of isoxazoline derivatives have been recently prepared by solution-phase or solid-phase synthesis and their activity as factor Xa inhibitors <03BMCL1795>, antibacterial <03JMC284> or antifungal agents <03BMC4539> was evaluated. 3,3-Disubstituted 4-isoxazolines 65 were easily converted to ct,[3-enals 66 by treatment with MeI in THF at reflux temperature. When the same reaction was performed in polar solvents such MeOH, DMF or MeCN the formation of minor amounts of t~,13-unsaturated amides 68 was observed. The amides 68 were obtained as sole products in high yields by heating the preformed isoxazolinium salts 67 in MeOH. The new process is believed to proceed through the heterolytic cleavage of the C3-N bond of 67 assisted by the solvent with formation of an allylic tertiary carbocation intermediate <03JOC3718>.

289

Five-Membered Ring Systems with 0 & N Atoms

R2

2

CO2Et Mel R1 reflux

66

65

O2EtTfOMe

oc;

rt, 2 h

Rl co2Et 2

MeOH reflux 1h

67

O2Et R1

CONMe2 68

95-100%

R1, R2:-(CH2)5-; Ph, Me; p-MeOCsH5, Me; Some stable azomethine ylides were prepared by photochemical excitation of a series of differently annulated 4-isoxazolines. For example, irradiation of a ca. 10-3 molar solution of 69 in C6H6 with a high-pressure mercury lamp afforded the azomethine ylide 72 in 88% yield after chromatographic purification. The proposed pathway for the transformation is based on the photochemically induced N-O bond cleavage of 69 to the diradical 70 followed by bond reorganization to aziridine 71, which undergoes C-C cleavage to afford the final product 72 <03EJO1438>.

H

A

Phil

P h ~ H

36 min

O

69

5.7.3

o

hv

70

O 71

hv Ph

H O

O 72

88%

ISOXAZOLIDINES

Isoxazolidines are useful and versatile intermediates in the synthesis of highly functionalized compounds. Frequently, they are prepared by 1,3-DC of enantiomerically pure nitrones derived from compounds belonging to the chiral pool such as carbohydrates, amino acids, and hydroxy acids. Several examples have been reported also this year, and among them there are the total syntheses of the natural products (+)-hyacinthacine A2 (73) <03TL2315> (for an analogous approach to 73 see <03SL35>), (-)-monatin 77 <03CC2678>, and (+)-heliotridine 81 <03EJO4373>. In all these cases, the reductive opening of the N-O bond of cycloadducts 75, 79, and 83 was followed by a spontaneous cyclization to afford 7-1actam 74, 3t-lactone 78, and pyrrolizidine 82, respectively. The cycloaddition of the enantiopure nitrone 85 with diversely substituted dipolarophiles 86 afforded bicyclic isoxazolidines 87 with a very high anti-facial selectivity <03TL523>.

290

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

/...j~OH

/ . . . ~ 0 Bn

H OBn BnO OBn .. (a) Me2NOC. / ~ ~ L-xylose ....OH::=:>HO" <~I~I< ....OBn ~ H,%..~,5 ~ ~ or D-arabinose %~3 < " ' 7 <' "-oBnO~n OH s 74 LOBn -0760Bn HO2C../___(CO2H ~H2 OO~ N HO"~ "NH2~ 0 % ~ OH(a) p h S H O O ~ - ~ ~ ~ ~ / ~:> ~ OH:~:>Ph"~NYZ=> IS)-phenylglycino 77

aN--~ i78

9

HQ _H /--OH t-Bu~CO2Et ~:> 81

~""ILI"~OH

800

t.Bu~CO2Et ::~

t-BuQ

~ N - d ....\Br ~

+"0- ==> L-malicacid

82 83 84 (a): reductivecleavageof the N-ObondbyZn/AcOH,H2/Pd(OH)2and 1-12/RaNi

+ R2" ,,,H OBn ~R' O- OBn

D-glyceraldehyde

85

R2 =- ',',..R, /L-C~

OBn

OBn

87

86

N-Benzyl-C-glycosyl nitrones reacted with acrylate to give glycosyl isoxazolidines which were easily converted to glycosyl pyrrolidines by reduction of the N-O bond with Zn in acetic acid. The best result was obtained with pyranosyl nitrone 88 which quantitatively afforded the cycloadduct 89 with complete regio- and stereoselectivity <03TA3731 >.

~CO2Me Sug Zn Sug /~ AcOH,H20 /~ neat ,- Bn-N lJ ,. Bn-N O "',C02Me60 ~ 5 h ~OH - o..N.Bn 25 ~ 4 h 100% 89 90% O 90 88

Sug~] +

CO2~ a O-

91

92

DCM

rt, 24h

OZHP

:

CO2 ,z

93

CO2Me oO/~ C'}

Sug=

92

~-",/>C 02-7~ le----~n es ~N"d reflux 94 7h

O,,,"o~O

OH O CO2Me

95 42% overallyield

Insoluble polymer-supported dipolarophiles such as 92 were used to mask the nitrone moiety of the chiral pyrroline N-oxide 91 to prevent racemization at the vicinal stereogenic center by temporary formation of the resin linked isoxazolidines 93. A thermally induced 1,3dipolar cycloreversion was used to cleave the product from the resin and restore the 1,3dipole functionality which underwent intramolecolar 1,3-DC to afford the enantiomerically pure tricyclic isoxazolidine 95 <03SL1889>.

291

Five-Membered Ring Systems with 0 & N Atoms

Some approaches to chiral 5-isoxazolidinones, useful precursors of [3-amino acids, have been studied. Diastereomeric 5-isoxazolidinones 97 were prepared by cyclization of chiral hydroxylamines 96, separated and then converted to enantiomerically pure cz-substituted-[3amino acids by hydrogenolysis of the N-O bond and concurrent removal of the chiral auxiliary <03JOC1575>.

ph/~N ~ O

phi..N~.~.CO2R,LiHMDS OH

R

97a

THF

96

P

R

:. hO ~ N: & 97b

1) 10% Pd/C

HCO2NH4 FmooHN~'~-CO2 H

2) Fmoc-OSu

98a

R

1) 10~ Pd/C HCO2NH4 F m o c H N / ~ / C O 2 H ~

%

:

2) Fmoc-OSu

R

98b

15,

Chiral nitrone 99 reacted with ynolates such as 100 at low temperature to give 5isoxazolidinones with good diastereoselectivity. The 4,4-dimethyl-5-isoxazolidinone 103 could be obtained in high yield and with good diastereoselectivity by treating the initially generated enolate 101 with MeI <03S1441>.

o / ~

H,

i) THF

~N+

-78 oc l~n

103 95% dr: 94:6

ii) Mel

o-

O ~ ,O 99

Oki

iiI -=8 oc

+ [

100

O

H,

THF [---~ 0

O

13n 101

t-BuOHO

J

H, "

= / I~

Bn

102 91% dr: 84 : 10::6

A stereoselective synthesis of 5-isoxazolidinones was achieved through addition of lithiated chiral oxazolidines to nitrones followed by intramolecular addition of the resulting lithiated hydroxylamines to the oxazoline C-N double bond and acidic hydrolysis of the resulting spiro-fused isoxazolidines. For example, the 2-oxazolidinyloxirane 104 gave the epoxy 5-isoxazolidinone 106 which was quantitatively reduced to the epoxyamino acid 107 <03OL2723, 03T9713, 03JOC9861>. Upon treatment with LDA, the 4-chloro spiro-fused isoxazolidine 108 underwent stereoselective ring contraction to give oxazolidinyl[1,2]oxazetidine 109 which is a masked form of an cz-hydroxy-[3-amino acid <03JOC10187>.

292

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

,s.uu

TMEDA -98 ~ THF _ t-Bu +..O 104 ii) "N I_ dr 98:2 ILL. Ph ee > 99%

_

_NH O O ~ t.B/L) J [- t-Bu

t-BuI 106 60%

t-BuI 105

"~NH O THF I H,,,N--O ,Li Okr"k--J'~ H Ar -98~ ~Ar ~1/~ ~ J \ J~ C

NH t-BUll07

ee > 99%

-I

108

O _O H2 __~H+O"N~eh ed HO2C...~ Ph ee >

,t-Bu

,,o ,,~-~H/~r 109

MeOH,. - ~ O 20 bar

O~

99%

H

,~,r \t-Bu 110

The highly strained 5-spirocyclopropane isoxazolidines show a peculiar reactivity caused by the presence of the small ring spiro-fused next to the weak N-O bond. The thermal rearrangement of spirocyclopropanated isoxazolidines has been recently used to prepare a variety of tetrahydropyridone derivatives with up to three spiroannelated cyclopropane rings. For example, compound 111 was cleanly converted into 112 upon heating at 140 ~ <03EJO2001>. In the presence of a protic acid 3,4-cis ring fused 5-spirocyclopropane isoxazolidines 113 underwent ring contraction to 3,4-cis-fused bicyclic azetidin-2-ones 114 with concomitant extrusion of ethylene <03JOC3271>. Both processes are believed to occur through the homolysis of the N-O bond of the neutral and protonated isoxazolidine, respectively.

TFA 70-110 - v - - ~-

oc, , , p-xylene 111

112

I~ H 113

80%

02H4

O HH~~.N

114 47-92%

A variety of N- and C-nucleoside derivatives in which the sugar unit has been replaced by a functionalised isoxazolidine have been synthesized. The synthetic approaches to different classes of nucleoside analogues such as 115 were all based on 1,3-DC of nitrones <03TA2717, 03TA2419, 03T4733, 03T5231, 03JMC3696>.

115a

'"B

"O

115b

,CO2Et

B

OH 115e

N~N..o/ ..../ 115d

oH

B = nucleobase

Isoxazolidines 118, prepared from enantiopure cyclic nitrones 116 and isolevoglucosenone 117, were used as key intermediates in the synthesis of a new class of directly linked (1--*3)imino-C-disaccharides belonging to D-gulo and D-allo series such as 119 and 120.

293

Five-Membered Ring Systems with 0 & N Atoms

o o

,+ O116

O

o ~

Ho ~

o

RO

=

>

(RO)"~118

117

OH

HO

OH or HO

(HO~"

119 D-gulo series

(HO~"

120

D-allo series

During the last year, new aspects of enantioselective synthesis of isoxazolidines using chiral auxiliaries derived from sugar <03EJO4152>, and by chiral induction of either cationic Co(Ill) complexes <03S1462, 03BCJ2197> and organocatalysts <03EJO2782> in the reaction of simple acyclic nitrones with ct,13-unsaturated aldehydes have been analysed. The enantio- and diastereoselectivity of 1,3-DC of nitrones with 3-crotonyl-2-oxazolidinone catalysed by Ni(II)-binaphthyldiimine complexes have been studied <03BCJ327>. 5.7.40XAZOLES 2,4,5-Trisubstituted oxazoles 123, widely distributed as subunits of biologically active natural products, have been efficiently synthesized from various carbonyl compounds 121, using sequential treatments with [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]benzene (HDNIB) and amides, under solvent-free microwave irradiation conditions. These regioselective reactions proceed in high to excellent yields in short reaction times through sulfonyloxy carbonyl intermediates 122 <03TL123>. Trisubstituted derivatives were also obtained through a new silyl-promoted variant of the Passerini reaction. New multiple component condensation (MCC) reactions of unsubstituted isocyanoacetamides 124 with aldehydes and ketones, or their derived iminium ions, led to 2-substituted-5-aminooxazoles 126 and 125, respectively <03TL6825>. From 124, a one-pot four-component process affording 127 has been developed based on the in situ hydroxyarylation and acylation of 126 with aromatic aldehydes and acid chlorides, respectively <03TL6829>. O 0 HDNIB _~ RI.J~R 2 MVVl 20-40 sec 121

NR1R2 R3R4~NI~ 125

R2

R1

ODNs 122

R3R4CO

O R1., HNR1R2 I~N..R2 N T~.HCI NO ,1 2 MeOH, rt 73-92% 124

R3

NH2 R D. MW! 1-2 min

O

,R3=Me,Ar R2 R2=H,Me,Ph,COMe,CO2Et,CONEt2 DNs=2,4_(NO2)2CsH3SO 2

R1 123 58-94%

OSiR3 R5CHO R3-~)-....j O R1 R3R4CO OSiR3 R3SiCI R3SiC' R3~-..../O R1 o r = !~ [ N I ~ N , R2 Zn(OT~2 R4 I N I ~ ~ R 2 R5COC, R5 ~yX NEM 35-72% X! Y= O DCM, rt 126 29-84% X=H Y=OSiR3 127

294

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

N

s~~O 1.n-BuLi,THF,-78~

n-Be

CuON

3. RX (X-Br, I) 128

N~R

TBSOA

n_,,ujLO

R= Me, allyl,propargyl 129

o ,,CliO o

,o

6

47-96%

Copper salts such as CuCN, CuBr'SMe2 and CuCN'2LiC1 were demonstrated to mediate the regioselective allylation, alkylation, and propargylation of the lithium anion of nbutylthiooxazole 128 providing 2,5-disubstituted systems 129. Desulfurization with deactivated W2-Raney nikel produced 5-substituted derivatives <03TL7395>. #

H H ~O Z~I1/ O 132

PY , R (RCO)20

R

20-98%

(,~,

133

134

R1

R2~X_ DMF-

OLN ~ k~

24-61%

135

55-65 oc ,7K2CO3 ~~ _ - : - j ,

R1

The synthesis of oxazole C-nucleosides in moderate yields by Tosmic addition to sugar derived aldehydes and concomitant cyclization has been reported. In particular, aldehyde 130 gave 131 in 48% yield <03SL1619>. 5,5'-Bisperfluoroalkyl-2,2'-bisoxazoles 133, with different alkyl and aryl spacers Z, were obtained by treatment of diamides 132 with perfluoroalkyl anhydrides <03S2211 >. Reactions of tx-oxo-oximes 134 with electrophiles (X - Br, I, OSO3Me) in the presence of anhydrous K2CO3 gave 2-substituted benzoxazoles 135 in a new general route <03JOC9093>. 2-Substituted oxazolo[4,5-b]pyridines 138 (and quinolines) were synthesised in high yields from zwitterion or hydroxyamidine derivatives 137, obtained by treatment of nonenolisable amides 136 with the complex base NaNH2-t-BuONa, via hetaryne intermediates. Intramolecular cyclization and NH3 elimination to give 138 were performed in dimethylacetamide by heating or microwave irradiation <03S2033>. Different approaches to oxazolo[4,5-c]quinoline-4(5H)-ones from ethyl 2-chlorooxazole-4-carboxylate have also been described <03OL2911 >.

Bro N 136 H

NaNH2-t-BuONaI " ~ ~ q NH2 ~"'i1/O NH2* DMA R (2 equiv) '~N"~%N//"" a N R Aor MWl R=t-Bu,Ar, Het 137 45-80% H -NH3 138 55-88%

295

Five-Membered Ring Systems with 0 & N Atoms

R3

R3

OH O

o R 4 ~ R2= 100 ~ O+ 120 ~ 1 II I. I 1 ~ R ~"~..O ~.,~O.,."% O Rs=OH R1 R5/ ~"~-/~O"~O RI=Me,Bn RI=Me r~ NHBz 141 61-91% 139 140 R2=H

.lAr 0;r H20 ~ ' ~ O

139a

N.R4

60_6;O/oH N ~ , o H

MeCN, A Ph 16-24h 1

- u u Bz 14240-80%

Ph

r

144

J

R4

N OO H

+~I/~--()I R3/~-R~ NX/--R 3

R~

O

145

146

Solventless reactions of 5(4H)-oxazolones 139 with hydroxycoumarins 140 exhibited excellent control of chemoselectivity leading to O- and C-acylation products 141 and 142 <03SL1710>. 4-Arylideneoxazolones 139a behaved as imines in [2+2] cycloaddition with benzyne, generated from benzenediazonium carboxylate, to afford mainly benzoxazepine-2-ones 144, through ring-opening of the cycloadduct 143, followed by water addition <03T6067>. 1,3-DC of imines and mtinchnones 145, in situ generated by treatment of 5(4H)oxazolones with chlorotrimethylsilane, allowed a diastereoselective multicomponent synthesis of highly substituted imidazolines 146, containing a four-point diversity and two stereocenters. The process is applicable to aryl, alkyl, acyl, and heterocyclic substitutions and only the trans distereomers (with respect to R 2 and R 3) of 146 were observed in almost all cases <03S 1433>.

RI~O 148 v v= AcOD-x~~ K2CO3Me2CO ~nUBr , 147a 147b

2OAc ARI~sBox

Bzg(,OH

BzO~SEt OBn OBz RI=OAc,R2=H 149a92% Box=- - < O ~ 150 R1=H, R2=OAc 149b 90%

OAc AcO~O AcO--~~ 149a AgOTf B Z ~ Q DCM B z O ~ S E t 98~ otonly 151 OBz

BnOo

Novel glycosyl donors, 1,2-trans-S-benzoxazolyl (SBox) glycosides 149a,b have been synthesized by reaction of D-glucopyranosyl bromide 147a and D-galactopyranosyl bromide 147b with 2-mercaptobenzoxazole 148. They allow selective 1,2-cis glycosylation of Opentenyl and thioglycosides, such as 150 that reacted with 149a to give 151 with complete stereoselectivity <03OL455>.

296

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

R I ~O N C.~CO2R2Me2AI - H

51-91%

R~'3 R1~\~ I~CO R3

2R2

152

153

iPr, ~,.

RI=Me,Ph,C6H11,PhtN~,,H,'~ R2=H,n-Bu,allyl R3=C6H13,Ph,TMS,CH2OMe o

~~N

+roc

~N'x,/~CONH2 o~ ~NH

154

155 (-)-muscorideA

An iterative oxazole assembly via ot-chloroglycinates 152, obtained from primary amides by treatment with glyoxylate esters and SOC12, has been reported. Compounds 152 reacted rapidly with dimethylaluminium acetylides to give oxazoles 153. This technique allows polyoxazole construction and has been exploited for the total synthesis of (-)-muscoride A 155, by application of the same sequence to the intermediate oxazole amide 154 <03AG(E)1411>.

Ph ph~N

1. t-BuOK CI- H3~I E N-protected-aa R2 H THF, -78 ~ T t-BuOCOCI ,~NTE ~--E 2.Fm0c-aa-CI O'~~. NHgmOc NMM'THF'-20~ R3HN O .~v..NHFm0c 156 3. HCI,-78 ~ to rt 157 R1 57-73% 158 O |1 68-82% R E=CO2Me AIlO2q O Ph3P R3HN

THF, 0 ~

N...,./E

159 63-85%

i~1

N

NHFmoc

MeO2C

NHBoc

O~"')~NH H N - - ~ ~ N

160

NHZ

The synthesis of a new family of densely functionalised oxazole-containing amino acids 159 has been described starting from imine 156. Treatment with t-BuOK and acylation of the anion with Fmoc protected amino acid chlorides afforded intermediates 157, converted to 158 by coupling with N-protected amino acids. Cyclization allowed the construction of the oxazole ring with diverse functional groups orthogonally protected. These behaved as useful building blocks for the preparation of macrocyclic peptides such as 160 <03OL4567>. The total synthesis of the peptide derived macrocycle dendroamide A 163 has been accomplished in 19% overall yield from appropriately protected heterocyclic amino acids. The oxazole amino acid 162 resulted from cyclodehydration of ]3-ketodipeptide 161 with bis(triphenyl)oxodiphosphonium triflate, with notable chemo- and stereoselectivity <03JOC9506>. A highly stereocontrolled total synthesis of the cytotoxic 18-membered macrolide (+)leucascandrolide A has been reported <03T6833> as well as the second total synthesis of

297

Five-Membered Ring Systems with 0 & N Atoms

diazonamide A <03AG(E)1753>. The first enantiospecific total synthesis of pseudopteroxazole 164 allowed the revision of the previously assigned stereochemistry <03JA13486>.

FmocHN

~]~0~_.1 ~

Ph3PO

OBn

1,1~." ~

Tf20

_

Frn~

N

/2

oc~,_~0o~ 1,~% ~ ~-~~

o _~ O,4. N > ,,,'"~NH

0~~

5.7.5

i

n "..~ HN/'~O

N~S~I~' dendroamide A

164

J'~

OXAZOLINES

Several new ligands containing the oxazoline nucleus were synthesized in enantiopure form. Compounds of general structure 165 were obtained from L-serine or L-threonine and found application as catalysts for the zinc addition to aldehydes <03TA3292> or were derived from f3-amino alcohols and used in diethylzinc addition to N-(diphenylphosphinoyl) imines <03JOC4322>. Also, compound 166 was derived from a commercially available amino acid and afforded good selectivity in allylic alkylation <03TL6469>.

Ar

0--" 165 HO

R 1, R2 - Me, Ph, H R 3 = H, Ph

166

167 X = Ar, H

R = alkyl R1= Ph, H

;~ R

169

R

R

170

171

'R 1

~ 0 1.

R1

R

R 1= Cbz, Boc,Ac, Ts

R2 = Me, i-Pr

9

o

172/)'-~-~

.~

R R

R

175

R

173

R

298

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

Compound 167 was obtained by aziridine expansion, a known synthetic transformation, applied on ferrocenyl derivatives <03TA3321>. The new bisoxazoline ligands 168 were decorated with secondary binding sites to enhance the selectivity in asymmetric cyclopropanation of furans <03TA765>. Ligand 169 also found application in cyclopropanation reactions <03T1933>. Ligand 170 is a new example of the small family of sulfur-containing oxazoline ligands <03TA339>. Compound 171 was used in the synthesis of a series of iridium-carbene complexes for the asymmetric hydrogenation of arylalkenes <03JAl13>. High selectivity and yields were obtained in Nozaki-Hiyama allylation and methallylation catalyzed by chromium complexes with ligand 172 <03JA1140>. Compound 173 found application in the formation of rhodium(II) catalysts for the preparation of aziridines and in the cyclopropanation of olefins with ethyl diazoacetate <03JOC9705>. The well known bisoxazoline ligands of general structure 174 found application in several new reactions forming complexes with different metals. Copper complexes were used in asymmetric polymerization of 2,3-dihydroxynaphthalene <03MM2604>, Mannich reactions of glycine derivatives with imines <03JOC2583>, enantioselective Henry reactions <03JA12692>, enantioselective Diels-Alder reactions <03JA13942>, asymmetric Michael reactions <03JOC5067>, Nazarov reactions <03OL5075> and [3+2] cycloadditions with azomethine imines <03JA10778>. Nickel complexes were used in the enantioselective syn aldol reactions of N-propionylthiazolidinethiones in the presence of silyl triflates <03JA8706>, while mercury complexes found application in the enantioselective mercuriocyclization of y-hydroxy-cis-alkenes <03JA4684> The C2-symmetric bisoxazolinate 175 formed complexes with lanthanides for the catalysis of enantioselective intramolecular hydroamination/cyclization <03JA14768>.

Pyridine bisoxazoline ligands of general structures 176 were widely used and only the most outstanding results are reported here. Samarium and gadolinium complexes were employed to catalyze quinone Diels-Alder reactions <03JA10162> while other lanthanide(II) triflates were used in enantioselective Diels-Alder reactions <03JOC7862>. Scandium(III) triflate complexes were used for enantioselective indole Friedel-Crafts alkylations <03JA10780>. A derivative of the pyridine-bisoxazoline ligand was linked to a polymer to afford compound 177, used for the silylcyanation of benzaldehyde <03OL3663>. A pyridine bis(oxazoline)-copper(II) complex was able to perform amino acid recognition in aqueous solution <03TL4335>. Some interesting applications of oxazoline derivatives in supramolecular chemistry were also described in the literature. Compound 178 was revealed as an efficient receptor for fluorescence sensing of ammonium and organoammonium ions <03OL1419>. Bisoxazoline

299

Five-Membered Ring Systems with 0 & N Atoms

179 showed a highly biased P-type helical conformation in solution and in the solid state <03JOC22>. Compound 180 was used as a ligand for palladium and copper to obtain supramolecular helical stacking of metallomesogens <03JA4527>.

R

N.-,, 0

Cl

O./.N

HO

O

0 R,,.~~O~

0

R ~O~~f'Njo~

178

C12H250" "lv, 180 O012H25

179

MeO,.,~N~ OMe \ /

"-~<'[IH2N/~O,,H

N.~N

181

/

-T

O

.R

R = Ar, AIk

50-89%

"~ "OC12H25 O012H25

N~O R

A mild and straightforward method was described for the synthesis of oxazolines using the triazine ester 181. The reaction of 181 with a [3-aminoalcohol afforded the corresponding oxazoline in high yield <03TL2331>. A novel cobalt-catalyzed carbonylation of 2-aryl-2oxazolines 182 was described affording the corresponding 4,5-dihydro-l,3-oxazin-6-ones <03OL1575>.

R1

R1

N"~ gnCo(CO)4 . , . . , ~ a Ar/~ Oj)~R +200 COpsi 30-95% Ar ,, "O" "O 182

183

Aminosugars can be activated by formation of the corresponding trichloro-oxazolines, which are excellent glycosyl donors as they form disaccharides with good t r a n s selectivity under mild conditions <03OL4995>.

5.7.6

OXAZOLIDINES

Several new syntheses of oxazolidinones as well as the application of these procedures for the synthesis of natural products were published. The Rh-catalyzed synthesis of

300

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

oxazolidinones developed by Du Bois was successfully applied to the synthesis of Lvancosamine <03OL3891 > and tetrodotoxin <03JA11510>. A new metal-catalyzed exocyclic carbonylation of cycloimino esters 184 was reported. The reaction proceeded without HI in relatively mild conditions affording the expected Nacyl oxazolidin-2-ones 185 <03OL3955>. An improved procedure for the palladium catalyzed oxidative carbonylation of 13-aminoalcohols to oxazolidin-2-ones was published <03JOC601>. R N

O t-Bu.. O

R = H,/-Pr ,.

50-70 %

184

O

O~NH

I ~ ~ ~ R~186

Co2(CO)8

0

HN/JL-o

OEt Ph3P-CCl4'TEA

)7----OEt O 187

87-90%

OH

A simple stereoselective synthesis of trans-2-oxazolidinones, such as 187, was reported using a PPh3-CCla-TEA mediated cyclization of N-Boc-13-aminoalcohols 186. In the same work cis derivatives were converted into trans by the use of DBU <03TL6323>.

0 0 (EtO)2P~/NCS + R H 188

189

INaH

THF, 0 ~

o

O II

R

O II

I( E t O ) 2 P . ~ o _

L

1910\[~"NH

19O" "0ff NH

N.C~s

S

S

R = t-Bu,/-Pr, PhCH=CH,2-furyl, Ph Ts O=C=N HO\ ~ "r R

192

193

EWG

O

Ts I NH O\ ~ R 194

DBU

O

~N

Ts

EWG 75-88~/o O-..~ ....'\EWG R

195

Through a diastereoselective addition of diethyl isothiocyanomethylphosphonate 188 to aldehydes it was possible to obtain differently substituted 2-oxazolidinethiones 190 and 191, which were converted into the corresponding a-amino phosphonic acids <03TL4747>. The intramolecular Michael addition of N-tosylcarbamates 194 afforded selectively trans substituted oxazolidinones 195 <03H(60)1173>. A well known reaction for the synthesis of oxazolidinones, cycloaddition of isocyanates to epoxides, was applied to resin linked substrates for the synthesis of libraries of isoxazolidinones 198 <03JCC789>.

301

Five-Membered Ring Systems with 0 & N Atoms

~~

NL

196

"~O

iT-R xylene'95~ ..

N~-c~'O 197

R1--

K+

R

00~176

N O L ~ O~==O " ~ P h N" N H 198 ~ Br 199 R1

--" Ag+ 82%

= O~. N'Ph "j 201 O

2-Bromopropanamides 199 reacted with potassium enolates of different [3-dicarbonyl compounds. The reaction with the potassium salt of 2,4-pentanedione 200 afforded oxazolidin-4-one 201 in good yield <03TL4121>. O

O CF3CO3H

O'~NH O

O/JJ',.NH ~--~. R J204

O BrMg~

/

54%

OANH

":~'2R 85"90~176 "AcOY" R ~eOH R = biphenyl 95% NaBH4 87% O O/JJ,..NH ~_J 206 R

O oJ.L. NH.-

MeO

R

205

The Baeyer-Villiger oxidation of oxazolidinone 202 afforded the previously unknown 5acyloxyoxazolidin-2-one 203. This intermediate allowed an easy access to several other oxazolidinone derivatives by reaction with different nucleophiles <03 SL1903>.

Ph 0 PLhN R1..R2 1) Nail, 0 ~ ....../.~.N...J/~ ~'.... i ,.-2) phosgene, -78 ~ - O / ~OH = CI~,_R1 H 207 80-92 % 208 Rz Ph

O

......L"N R

R

CI~"-OMe, MeCN Boc,,

L-serine

=_ 211 ~)

O

,,,,'"

DBAL-H

0

Boc\

TBDMS

-N o H

Access to enantiopure oxazolidinones was afforded by treatment of the corresponding aziridines 207 or 209 with phosgene or methyl chlorocarbonate <03JOC 104, 03JOC43>.

302

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

Oxazolidine 212, obtained by DIBAL reduction of the protected serine 211 is a configurationally stable derivative of serinal. Its orthogonal protecting groups make it a useful chiral synthon <03JOC2979>. An efficient synthesis of chiral ynamides 214 was performed using catalytic CuCN and bromoalkynes. The variety of substituents R and R 1 used demonstrated that these reaction conditions are tolerated by several functional groups. These compounds found application in highly stereoselective Saucy-Marbet rearrangement for the synthesis of highly substituted chiral homoallenyl alcohols. <03JA2366, 03OL2663>. An analogous reaction was performed on different amides, a single example concerned an oxazolidin-2-one and the catalyst was CuI in the presence of KHMDS at room temperature <03OL4011>. Pdz(dba)3 was instead used for the arylation of oxazolidin-2-ones 216 using aryl chlorides 215. A detailed study was completed to choose the best ligand on the basis of the stereoelectronic nature of the aryl substituent <03OL2207>.

0

O A

~/

NH

213

R

/---k ~NH HN~ O Br "---- R1 ,,,J,L,, CuCN 0 N m

K3PO4

~/

52-85 %

R1

214"~R

PR2 CI

215

R1

R~/R2 216 O

Pd2(dba)3 Cs2CO3

217

R2 ~[],,,O

218

O

toluene

Oxazolidinones were used in an efficient dioxygen-coupled oxidative amination of styrene derivatives using Pd(II) and Cu(II) salts in the presence of a base. These results, see for example compound 218, are remarkable due to the complete inversion of regioselectivity with respect to the same reaction in the absence of base <03JA12996>. Potassium trimethylsilanolate induced the cleavage of 1,3-oxazolidin-2- and 5-ones affording the corresponding 13-amino alcohols and amino acids. A N-benzoyl group was shown to be stable to this reagent, while a benzyloxycarbonyl group was easily removed <03OB 1106>. Oxazolidin-5-ones were key intermediates in the synthesis of N-methyl amino acids through their reduction with EtaSiH <03JOC2652>.

303

Five-Membered Ring Systems with 0 & N Atoms

S

HO

o

o

O~/N..~ NaH ~ O Ph l ~ ~ o % h = 219

h

=

p~h~O

Me' ~

''O ~/N~' Ph O 220

~~ o

Phi% ....,~Ph

HO O

N

C0H,

221

"

Me

Zn(CH21'2/Et20 Ph..~/O~"L n-BuLi ,.....\N_/'Ph 223 / 72 %

\

222

Compound 219 underwent an easy and novel oxazolidinone rearrangement upon treatment with Nail <03JOC6268>. The oxazolidinone protected N-acetyl glucosamine 4-OH derivative 221 exhibited enhanced reactivity as a glycosyl acceptor in a variety of coupling methods. The products were finally converted to the target N-acetylglucosaminyl saccharides under very mild conditions <03OL 1297>. Tertiary amines form complexes with Simmons-Smith reagents. These complexes are activated by n-BuLi to undergo [2,3]-rearrangements. Using oxazolidine 222 this process afforded compound 223 as the main product with very high diastereoselectivity <03OL1757>.

ph/~ N/~O Ph ""~J-%~ 224

O

[C3H5PdCI]2 (R)-BINAP O

"

226

NH

O

ph/[L, NH P h ~

+

NPht

ph/U..N :H P h ~ 227

955 98%

NPht

5-Vinyloxazolidin-2-ones 224 were used as substrates for palladium catalyzed allylic substitutions showing an unexpected regioselectivity towards the branched product 226. This effect was rationalised on the basis of an hydrogen bond interaction<03JA5115>.

0

O O

o~.JLy~Ph DIBAL-H.. ---/

2281

/~

hydrolysis/ OH // 2::t'O)20 / ~ e O 2 C Li +

230

O i i

L~

Ph

231

~ ~ ~ a . Ph 232

304

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

N-Acyl-5,5-dimethyloxazolidin-2-one 228 can be considered as a latent aldehyde equivalent. Its reduction with DIBAL-H afforded the corresponding l'-hydroxyalkyloxazolidinone 229 as the sole product. The product can react under the WadsworthHomer-Emrnons protocol to afford the ot-[3 unsaturated ester 232 or the free aldehyde 231 could be isolated after hydrolysis <03OB2001 >. This methodology was also employed in the asymmetric synthesis of tx-alkyl and [3-alkyl aldehydes <03OB2886>. N-Boc protected oxazolidines found application in the enantioselective synthesis of aminosugars <03OL3001>. Oxazolidin-2-ones were also used as tethers for the stereoselective [4+3] cycloadditions of nitrogen-stabilised oxyallyl cations via epoxidation of allenamides <03JA12694>. Various kinds of oxazolidin-2-ones were used as chiral auxiliaries in reactions such as Diels-Alder cycloadditions <03JOC9809>, alkenylation with alkenylselenonium salts <03OL565>, aldol reactions <03OL591>, asymmetric conjugate additions <03OL3539>, radical additions to aldohydrazones <03OL2461>, reactions with singlet oxygen <03OL4951> and halo aldol reactions <03OL329>.

5.7.7

OXADIAZOLES

An efficient solvent-free synthesis of 1,2,4-oxadiazoles 235 was described using microwave irradiation by reaction of acyl chlorides with amidoximes <03H(60)2287>. The same kind of condensation was used for the synthesis of unnatural [3- and tx-amino acids, 237 and 239 respectively, with an oxadiazole nucleus, using different derivatives of aspartic acid <03JOC7316>. 5-Perfluoroalkyl-l,2,4-oxadiazoles 240 underwent an uncommon reaction with hydrazine to afford the corresponding triazoles 241 <03JOC605>.

N"OH

O

MgO

R

R..-~NH2 RI-JJ'-.Cl Microwave 67-86% 233

Fm~

v _c O 2 H

t-BuO2c j 236

R1

234

==Fm~

cO2H

235

Fmoc-HNvCO2t-Bu

N-" O

_

HO2c /

238

R

R1 R---X~,O.N 240

Fmoc-HNvCO2H

_

R1 MeOH

R-'~ N.

R = perfluoroalkyl

H

241

239 N-~ R

Five-Membered Ring Systems with 0 & N Atoms

5.7.8

305

REFERENCES

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

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Five-Membered Ring Systems with 0 & N Atoms

03OL3891 03OL3955 03OL4011 03OL4029 03OL4567 03OL4951 03OL4995 03OL5075 03S1347 03S1433 03S1441 03S1462 03S1586 03S2033 03S2064 03S2211 03S2325 03S2518 03SL35 03SL1358 03SL1619 03SL1710 1710. 03SL1746 03SL1865 03SL1889 03SL1903 03 SL2213 03T663 03T1933 03T4733 03T5215 5215. 03T5231 03T6067 03T6833 03T9713 03TA339 03TA765 03TA2419 03TA2717 03TA3291 03TA3321 03TA3731 03TL123 03TL523 03TL1071 03TL1847 03TL2315 03TL2331

307

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308

03TL3555 03TL4121 03TL4335 03TL4747 03TL5327 03TL6323 03TL6469 03TL6825 03TL6829 03TL7395 03TL7763 03TL8217 03TL8901

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

J.W. Bode, Y. Hachisu, T. Matsuura, K. Suzuki, Tetrahedron Lett. 2003, 44, 3555. P. Marchetti Tetrahedron Lett. 2003, 44, 4121. H.-J. Kim, R. Asif, D.S. Chung, J.-I. Hong, Tetrahedron Lett. 2003, 44, 4335. K. B|a~ewska, D. Sikora, T. Gajda, Tetrahedron Lett. 2003, 44, 4747. D. Conti, M. Rodriquez, A. Sega, M. Taddei, Tetrahedron Lett. 2003, 44, 5327. G. Madhushudan, G.O. Reddy, J. Ramanatham, P.K. Dubey, Tetrahedron Lett. 2003, 44, 6323. C. Blanc, J. Hannedouche, F. Agboussou-Niedercorn, Tetrahedron Lett. 2003, 44, 6469. Q. Wang, Q. Xia, B. Ganem, Tetrahedron Lett. 2003, 44, 6825. Q. Wang, B. Ganem, Tetrahedron Lett. 2003, 44, 6829. J.P. Marino, H.N. Nguyen, Tetrahedron Lett. 2003, 44, 7395. A.J. Clark, D. Patel, M.J. Broadhurst, Tetrahedron Lett. 2003, 44, 7763. V.F. Caetano, F.W.J. Demnitz, F.B. Diniz, R.M. Mariz, M.Navarro, Tetrahedron Lett. 2003, 44, 8217. J.L. Stevens, T.D. Welton, J.P. Deville, V. Behar, Tetrahedron Lett. 2003, 44, 8901.

309

Chapter 6.1

Six-Membered Ring Systems" Pyridines and Benzo Derivatives Daniel L. Comins* and Jason Dinsmore

Department of Chemistry, North Carolina State University, Raleigh, NC, USA danie l_comins @ncsu.edu Sean O'Connor

ATK Thiokol, Inc., Brigham City, UT, USA sean.oconnor@ atk.com

6.1.1 INTRODUCTION Pyridines and their benzo-derivatives continue to play an important role in the synthesis of biologically active compounds. This chapter is a summary of methods developed for the preparation and reactions of pyridines, quinolines, isoquinolines and piperidines that were reported in the literature in 2003. This review covers selected recent advances in the field and is not an exhaustive coverage of the literature. In contrast to previous volumes, more schemes have been added at the expense of text. Several pertinent reviews appeared during 2003: <03CHE825>, <03AHC31>, <03CRV3787>, <03PAC1403>, <03RCR69>, <03AHCI>, <03PAC19>, <03EJ03693>, <03T2953>.

6.1.2 PYRIDINES 6.1.2.1 Preparation of Pyridines Tandem oxidation-annulations of propargylic alcohols yield pyridines via a one-pot synthesis <03SL1443>. R3 HO

__

R3

+

NH2 R1J,~R 2

R4

IBX heat 60-96%

_-R

IBX = o-iodoxybenzoic acid R 1 = Me, Ph

R3= H, Et

R 2 = CO2Et, CO2-t-Bu

R4 = Me, Ph, 4-CIC6H4, 4-MeOC6H4

R4

310

D. L. Comins, J. Dinsmore and S. O'Connor

A wide variety of pyrido[2,3-b][1,4]oxazin-2-ones were synthesized from reaction of a 2haloacetamide with a 2-halo-3-hydroxypyridine through the Smiles rearrangement <03JOC7918>.

R1 I OTNH

X

I.N~

R2"~Cl + HOI ~

R1

R1

O==~ - -NH X'ff'N~ ,, --"] BE)

thl(~R2~O, i ~ N,,~

R2

-

0e~ x) N. ~'Z~ I -~

R2"X',,O~ Smiles rearrangement

I >90% R~O I N~ O~N I~

R1 = alkyl R2 = H, CH3 Olefin-containing esters of pyridine-3,5-dicarboxylic acid are able to form macrocycles using a ring-closing metathesis reaction if the pyridine was protected with complexing Pt. The method was applied to 69- and 75-membered macrocycles <03ZOR449>. An example of a 17membered ring formation is shown below.

O % //)'--Pt--N~ //~

~NMe2

~/'-O~-'.v.",...~

O

O

1. CI2(PCy3)Ru=ChPh,5 mol % 2. NaCI(aq)

99%

O

O O

An elegant one-step synthesis of fused isoxazolo[4,5-b]pyridine-N-oxides was reported. Deoxygenation to the pyridines proceeded by treatment with PCI 3 <03IJC(B)1742>. @

1 -~H3C O_~ R2 R1 o IIcH2.R2 IH3C N ~No2 " R2 N~~I N,~

H3C, NO2 N% CH3 piperidine

80%

R' ]

~.~R

1

PCI3" N

N _R2 R1

With an eye toward more lipid-soluble bioactive molecules, various trifluoromethylsubstituted fused pyridines were synthesized <03S 1531>.

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

MeN.N~ ~1

O NH2 +

O

MeN.NN~ F3C~ ~ . .

F3C"JL'~R2

~

~1

R2

NH2

311

M 74-94%=

~

R1

R2

R1 Me,Ph =

R2 =

Ph, 2-thienyl, 3-pyridyl, OF 3, Me, OH

1,4-Dihydropyridine-2-thiones are available by reacting cyanothioacetamide with chalcones. Subsequent glycosidation and oxidation yields glycosylthiopyridines <03SC2243>.

I~

CN S NH2

~

Ar

O Ph

I=,

EtOH,0PiperidineocPh

A~CN ~ H

S|

R-Br

:

70-73% h

A~CN EtOH/heat air/3min A~CN H

S"R

Ph

S"R

R = glycopyranosyl Ar = Ph, 2-furanyl,2-thienyl

6.1.2.2 Reactions of Pyridines Several 6-aminoimidazo[1,2-a]pyridines were prepared from 6-iodoimidazo[1,2-a]pyridines via copper- and palladium-catalyzed aminations <03JOC4367>.

~.N

F

HNR1R2 Cul -

69-85% R1, R2=

R1N ~2

F

H, alkyl

A general synthesis of 1-aryl/heteroaryl-l,2,4-triazolopyridines from cyclization of aryl/heteroaryl-2-pyridylhydrazones by oxidation with hypervalent iodine in moderate to good yield was described <03EJM533>.

N..N~ / R

R = Ar, 5-nitro-2-furyl, 2-thienyl

Iodobenzenediacetate 50-82~

N __..,

312

D. L. Comins, J. Dinsmore and S. O'Connor

Depending on reagent and reaction conditions, 2- and 4-trifluoromethylpyridines can be regioselectively deprotonated and reacted with electrophiles in good yield <03EJO1569>. Deprotonation was followed by carboxylation with CO2 and acid hydrolysis. CO2H NLiTMP, THF ~ -75 min

27%

LiTMP, THF -75 *C, 6 h

73%

~ 15

~"-CF

-CF3

"N -/~CF3

N-

"CF3

HO2C'~CF3

41%

3 LiTMP, DEE ,. -75 *C, 2 h

23%

18%

BuLi, LiDMAE DEE

71%

y

-75 *C, 2 h

~

CF 3

LiTMP, THF

CF3

-75 ~ 2 h

,.CO2H

C.F3 BuLi,DEELiDMAE -75 ~ 2 h 41%

CO2H

A series of 3-aminoimidazo[ 1,2-a]pyridines were synthesized by the reaction of substituted pyridines with 1,2-bis(benzotriazolyl)-l,2-(dialkylamino)ethanes <03JOC4935>.

R3 R2..~R

4

R 1" ~ N " f ~ N H 2

+

Bt ~ Bt

R 1 = H, ell3, NH2 R 2 = H, Cl R 3 = H, CH 3 R4 = H, OCH2Ph

L---~O

Bt = benzotriazolyl

~" 64-92 %

R

R4

R 1"-~ N ~ % N

y

oC5

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

313

The amine-capping reagents 4-cyano- and 4-nitro-2,6-bis(bromomethyl)pyridine were synthesized in three steps from 2,6-1utidine <03JOC7661>.

N.O2

NO2

HNO

Me

Me 98% Me

O

|

Me H2SO4 Me

Me

86%

44% H2 Br

CN 1(MeO)2SO22. KCN e ~ 16% M

H2 Br CN

Me

NBS~44% C ~ N ~ C H2 H2 Br Br

A new method for the synthesis of C-3-substituted tetrafluoropyridines was reported <03NJC313>. The reaction utilized a nickel catalyst which effected regioselective substitution.

F F~F

F 1.2.MeLi[Ni(COD)2]PEt_~ 3 F~~[~F

F F Commercially available

F F Et3P-Ni-PEt3 Me

F 1Air6% ~ F~Me F- -N- F

I

C~

F

O

F ~ M e F

Intramolecular cyclizations of iodobenzenes tethered to pyridines via a two-carbon linkage yields quinolines and isoquinolines. Radical initiators are employed and yields as high as 98% are reported <03OBC4047>. Pyridines substituted in the 2- and 3-positions gave complex mixtures in lower yields. o

O

AIBN PhMe heat 98%

In order to assemble the imidazo[1,2-a]pyridine scaffold, 2-amino-3-chloropyridine was reacted with 2-bromo-p-fluoroacetophenone <03OL1369>. The product was transformed in five steps to a desired antiviral template.

314

D. L. Comins, J. Dinsmore and S. O'Connor

CI +

NH2

F

ma . c o 3 IPA heat 87%

Br

F

N

Lithium aminoborohydride has proven to be a mild reagent to generate 2dialkylaminopyridines from 2-fluoropyridine. This reaction is generally applicable to the introduction of unhindered secondary amines <03OL3867>. LiH3BNR1R2

F

1=

RT, 1 h

NR1R2

60-99%

R 1 = R2= Me, Et, Pr, C4H8, C5H10, C6H12

An improved synthesis of pyridyl boronic esters, valuable synthetic intermediates in crosscoupling reactions, has been reported. The critical element is the use of tris-trimethylsilylborate instead of the usual trialkylborates <03SC795>. ~.R

i-PrMgCI

[(CH3)3SiO]3B =

r R = H,

HCl 67 62-75%

6-Br, 6-Me-C4H 4

(OH)2

A general method for the preparation of 2,3,5-trisubstituted furo[3,2-b]pyridines via Pd(0)catalyzed intramolecular cyclization was reported <03TL725>. CI Cl

Pd(OAc)2

..N.y,,,I R e

N

78-98%

O2Me R

R = H, Me, n-Pr,/-Pr, Cy

2-(Fluorinatedphenyl)pyridines were prepared by coupling 2-halopyridines with multifluorinated phenylboronate. Pd(0) and AgO were the coupling agents necessary for optimal yield <03TL 1503>.

I

+

F~~

Pd(PPh3)4 ~ AgO 32%

F

F

~N

F

315

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

The important synthetic intermediates, 1-aminopyridinium ylides, are available from reaction of pyridines with a nitrene precursor <03TL4385>.

R +

Ph ~I=N-Ts

Cu(Omf)2 _-75% i

oN.

Ts

R = H, 2-CH3,3-CH3,4-CH3,4-CN C3-Substituted N-benzhydrylpyridiniums were utilized as sources for 3,5-disubstituted pyridines through 1,4-dihydropyridine intermediates <03TL4711>.

Na2S204 R ~ Br

(0130002)O R ~ C O X TEA

= CHPh2

i CHPh 2

CHPh2

R1= electron-withdrawinggroup

1. MeONa R 2. TFA,phenol,

/CO2Me

Pd/C

75-80%

50-60%

5-Nitropyridine-2-sulfonic acid was utilized as starting material for the preparation of 2alkoxy- and 2-amino-5-nitropyridines in fair to excellent yields. 2-Chloro-5-nitropyridine was also realized, whereas attempts with bromo, iodo, or cyano substituents were not successful <03OBC2710>.

R1-OH

O3S

.,•

R10~

45-94% NO2

R2R3NH 45-92%

PCls 164 *C 87%

"NO2

~,,NO2 R2R3N

_-.-

,~NO2 Cl

Allyl-palladium complexes of pyridine derivatives cyclize to yield pyridinium compounds <03JOM313>.

316

D. L. Comins, J. Dinsmore and S. O'Connor

R2

R1

R1~ I I1" O 2 C ~ R2 H3C~c_-CH2 R, ..~ vCO2Et 1. Pd(OAc)2 Et H3C I~N I~L ~ R2 2~LiCI ~ "N-Pd-X 2. heat 80% overall R2

R1

R1 = H, OMe

R1~~CO2 |174 X

al

Et R2 R2

R2 = H, OCH20 X = OAc A regioselective halogenation of pyridinols to provide bromo- and iodohydroxypyridines in excellent yields has been developed. These heterocycles are useful intermediates to other substituted pyridines <03SL1678>.

~__ R

OH

NBS, 2 equiv

86.95%

Br ~ Br I/,\ ~""1 R3T --OH t1"-N/--"I

~

ar

H20 35-80%

,~/-~

RT

~.N ~)

RLi

R=H, Me

--OH

R

89-95%

I..,~ Br OH

Castanet and co-workers have transformed a series of 2-halopyridines to 2-benzoylpyridines via a unique carbonylative cross-coupling reaction <03SL 1874>.

Pd(OAc)2_lmd CO, PhB(OH)2" base 80-95%

X

Ph O

X = 2-Br, 2-CI Imd =

At" N~CIN..Ar

Chiral 3-acyl-N-methylpyridinium salts have been used in the asymmetric synthesis of 4substituted dihydropyridines <03TA469>. Diastereomeric ratios ranged from 2.5"1 to 9:1. These compounds served as an entry to the ervitsine ring system.

~~~_jNM%

.OM% 2. 1.34-62% TCAA "RCu"

R_ o

~ N ~ C V ICel l 3 R = CH2Ph

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

317

Pyridinium salts are converted to 4-phenylpyridines by treatment with methylammonium sulfite and 4-methylpyridinium compounds through a ring-opening mechanism <03IZV 1522>.

Me

~X

| (MeNH3)2SO3 b heat

H3Me ? j ~ SO3N

O

'"NHR1

base ~

29-57% overall

O3NH3Me~ X base

_=

NHR1 RINH2 =

i~2 XO

Me, Et, i-Pr

R1, R 2 =

0

|

X=l, Br

I~2 XO

The authors utilized mild reaction conditions and a Co(II) Schiff-base complex to oxidize a number of pyridines to pyridine N-oxides <03AG(E)1265>.

(,~

R

Co(II) Schiff-basecomplex ~ CICH2CH2CI,02, 1 atm, 20 ~

R (,,~~,~

50-85%

R1

~ |

Co(ll) Schiff-basecomplex

R = 2-Me,3-Me,4-Me,3-CONH2,4-CN

Harano and co-workers found that the cascade reaction of pyridine N-oxides with allenes, after 1:1 cycloaddition and 1,5-sigmatropic rearrangement, added ketene in what they determined was a stepwise [2+2] cycloaddition <03CPB 1068>. In some cases the addition of the ketene is stereoselective.

R ~

RL HC" P hSO2 c",, =

O|

CH2

R1

_

R2

CHCI3

SO2Ph Me

R3 kF=C=O R4

45-98%

--I

R2 R1 O ~ ~ M e R3~4--~'" H SO2Ph O

_~

[1,5]

~N u , ~ M e n SO2Ph R1 = H, Me R2 = H, Me R3 = H, OMe,OPh R4 = H, Ph

318

D. L. Comins, J. Dinsmore and S. O'Connor

6.1.3 QUINOLINES

6.1.3.1 Preparation of Quinolines A high-yield preparation of 2- and 4-trifluoromethyl-2-quinolinones was sought. Depending on reaction conditions, the condensation of anilines with ethyl 4,4,4-trifluoroacetoacetate <03S2005> led to two different quinolinones as shown. F3C',,1..~~,O Et

U

F3C..r, OEt + O

.

R

81-96~0 R

O

CF 3

H 0~ polyphosphoric acid

110 ~ 55-690/0 ~

R = H, Me, MeO, F

0

R ~\"~

F3C,,~~,

0

.CF3

Y

NH

R

0

A

Diallylaniline, when heated with a catalytic amount of Co2(CO)8 under an atmosphere of CO, produces 2-ethyl-3-methylquinoline exclusively. Further examination of this reaction found that diallylaniline is in fact a source of the allyl group in this transformation <03JOC3563>.

0

002(00)8 CO

2-ethyl-3-methylquinoline

An efficient asymmetric synthesis of six-membered quinoline derivatives bearing a quaternary carbon center or a spiro-ring by an ene-type cyclization of 1,7-enynes catalyzed by the cationic BINAP-Pd(II) complex was reported <03JA4704>. R

[(MeCN)4Pd](BF4)2 (5 mol%) S-BINAP (10 mol%) HCOOH, (leq) DMSO, 100 *C, 1-3 h

I

Ts R = CO2Me, 99%, >99% ee R = H, 99%, > 99% ee

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

319

A series of 2-naphthyl-4-aminoquinolines was synthesized to support studies concerning DNA binding <03JA7272>. This gave rise to oxy-functionalized naphthyl substituents.

~

I~

O CF3 + Me ~

O

-NH2

R

CF3

Me2N~

Me

R

NHLi

THF 89%

HN~NMe2 R = Me, H, O(CH2)6OSiMe2Bu-t, O(CH2)6OH OR

In order to maximize yields and regioselectivity in the Friedlander synthesis of quinolines, the bicyclic pyrrolidine base 1,3,3-trimethyl-6-azabicyclo[3.2.1 ]octane (TABO) was utilized to good effect. The reaction was carded out with unactivated methyl ketones <03JOC467>. The ratios of the two products were ~86% 2-substituted and 14% 2,3-disubstituted. RI~cHO

1.1 equiv TABO 0.05 equiv H2SO4

+ o1~R3

R2 -NH2 R1 = Br, CI R2 = Br, H R3 = n-Pr, CH2CO2Et

EtOH, 65-70 ~ 90-93% both products

=

R3 + R~

R"

A convenient synthesis of substituted, chlorinated quinolines by electrolysis has appeared. The starting materials are readily available and yields are good <03JOC3706>. O

~~01 R1

+

Ph R2 = Me, Et, i-Pr

R1 = Me,

Ila, Junjappa, and coworkers described an efficient route to highly functionalized quinolines. Their starting materials are ct-oxoketene N,S-anilinoacetals and Vilsmeier reagents <03JOC3966>. Optimized conditions require R groups to be methoxy, except for the cases where naphthylamine rather than aniline is the parent compound. In that case the yields are also excellent.

320

D. L. Comins, J. Dinsmore and S. O'Connor

R1

Ar

DMF or DMA POCI3, 80 *C > 90% (optimized)

R1 = H, OMe

R2 = H, OMe, CI R3 = H, OMe, F

R1 R2*~~~'~

Ar O

R3" R~~4~N~"~"SM e

R4= H, OMe Ar = C6H5, 2-BrC6H4 (best yields)

A polyhalogenated quinoline C-nucleoside is assembled by reaction of a 2-aminophenone with a ketene ylide, through an intramolecular Wittig reaction. The nucleoside unit is already attached and is evidently not damaged under reaction conditions <03JOC4170>. CI,,,~~NH2

o• RO._~

H Ph3P=C=C=O benzene, reflux 50%

O

I

I

R = TBDMS

Ionic liquids (imidazolium salts) were utilized as "green" solvents in the Friedlander synthesis. Reactions of o-amino-substituted aromatic carbonyls with a variety of ketones (cyclic, acyclic, aromatic) result in the desired quinolines in uniformly high yield. Conditions are mild and no hazardous acids or bases are used <03JOC9371>. O R ~ R 2 v

-NH2

RI= H, CI R2 = Me, Ph

R2

O J~R R4+

Ionic Liquid= 3

R

100 *C > 90%

~ ~

R3 ~N"/~R 4

R3 = CH3, CH2R', Ar R4 = H, CO2Et, COCH3, CH2-R'

Attempts to cyclize unsaturated Fischer chromium carbenes to quinolines met with mixed results. The yields are poor, and the products were often mixed with tetrahydroquinolines and indoles. It appears there are too many competing side reactions for this to be an effective synthetic method <03T8775>.

Cr(CO)5 H

)t--Me

toluene. 90 ~

Me

+

+ Me

H 15%

21%

H 12%

Me

321

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

Two separate methods for preparation of quinolinophanes were described. The reactions are straightforward and proceed in good yields <03T1739>.

I

NH2

NaOH-acetone

N

O

hv,12

95%

O

80% Ph

ROOOH2OOOH3 NH2

EtOH

=-

@I

N~ CH3 PPA ID-

reflux 2 h 93-95%

N ,,CH3

120 ~ 75-80%

Nucleophilic ring-opening of benzoxazinones by enolates of arylacetic esters followed by deacylation of the amine group resulted in cyclization to the desired 3-arylquinolin-2-ones <03JOC4567>. O O O R' " ~ N H O O OH

R3"v~oR4

O

LDA, THF

R1

R2

R4

lira

-78 ~

R2

MeONa

D

toluene reflux

R2= H, CI R3 = Ph, 3-MeOPh, 4-MeOPh

R2

H 57-93% overall

The Baylis-Hillman reaction has been carded out to synthesize 3-carboalkoxyquinolines in two steps. Previous efforts in this area have yielded indoles, 2-quinolines, 4-quinolines, unsubstituted quinolines, and dihydroquinolines <03JOC6427>. The yields are only fair, but the reaction is very clean, with only unreacted starting material found with product.

~_.I~N R1

OH O2,,R2 A cOl/pyridine 71-99%

R 1 = H, CI, di-MeO R2 = CO2Me, CN

OAc ~

__.~I~N R1

R2

[Cp*Fe(CO)2]2 10 mol%

R2

CO, 6 atm, 42 h, 150 ~ 39-89%

Isomerization of enyne-isonitriles to enallene-isonitriles resulted in a formal [4 + 1] cycloaddition to indenoquinolines <03OL3277>. Starting material is prepared in two steps. Application to other related systems resulted in low yields and/or exclusive formation of indoles.

322

D. L. Comins, J. Dinsmore and S. O'Connor

H "- ' ~ 1

H

.fo

H

Poc,3. i-Pr2NH ph 1 h, 0 *C

Pd(PPh3)2CI2,2 mol % Cul, Et3N, DMF

| @ ~C'.

N ~ . ~ p

h

t-BuOK t-BuOH 5h, rt 51% overall

Fluorine-substituted quinolines can be formed in good yields from readily available starting materials. The reaction proceeds by generating nucleophiles through addition to multiple bonds, in this case, nitriles and isonitriles <03OL1455>. R1

R1

F2C~

R2M, toluene, -_

c..N- v

r.t., 15 min

R1 = n-Bu, sec-Bu R2 = n-Bu, Et,/-Pr, t-Bu

toluene, HMPA, 0 *C, 1 h, then r.t., 4 h ._

F2 C |

v

R1 F R

R2

M= Mg, Li

Readily available thiocarbamates, thioamides, and thioureas provide direct routes to quinolines in moderate to good yields <03OL1765>. The reactive intermediate postulated is the synthetic equivalent of an imidoyl radical, but with greater utility.

tris(lrime~ylsilyl )silane N H

44-88%

X = O, CH2, NH A synthesis of quinolines from reaction of 2-isopropenylaniline hydrochloride with cyclic ketones was described. The method employs a hydrothermal process with no organic solvents involved <03OL1605>. The authors suggest this as an environment-friendly process. The product yields and side product formations are heavily dependent upon reaction temperature. NH2 I~.~J HCI

O~)n H20, heat

C5Hll 64% n=3 200 ~

C3H7 27% n =1 100 ~

36% n =2 150 ~

323

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

The cyclopentaquinoline core of a series of alkaloids has been reported. An intramolecular hetero Diels-Alder reaction proceeds with high diastereoselectivity and forms up to four contiguous stereocenters <03OL2509>. Care was taken to avoid formation of undesirable regioisomers.

x

/Y

MeOy.~~~

,

TsOH, 5 mo160. %'79% 80 ~ lh =

NH2

MeoX~H~,:/'~,/~~IVle "

Me racemic

A solventless synthesis of substituted quinolines occurs when anilines are reacted with alkyl vinyl ketones in the presence of indium(Ill) chloride on silica gel and with microwave radiation <03T813>. The mechanism proposed involves Michael addition of aniline to the vinyl ketone followed by cyclization and aromatization under the catalysis of InC13/SiO2. The reactions are fast, clean, and high-yielding.

O RI~NH2

+

R4R2~I R3

R4

InCl3/SiO2 microwave 5-30min 45-87%

RI~

~ R3 q/-.~...R2

R1= H, Me, OMe,OH, Cl, Br, CO2Me,OTs R2 = H, Me,n-Pr,di-Me2 R3 = H, Et R4 = Me, 4-OMeC6H4 A successful ruthenium-catalyzed oxidative coupling and subsequent cyclization between 2aminobenzyl alcohol and secondary alcohols in the presence of KOH and 1-dodecene leading to quinolines has been reported <03T7997>. After optimization of conditions, yields were fair to good. The reaction is widely applicable to a large series of 2-substituted quinolines.

~ g H 2

+

OH

r

R

[Ru], KOH

1-dodecene, dioxane, R = Ph, 2-, 3-, 4-MeC6H4,4-MeOC6H4, 80 ~ 20 h 4-FC6H4,4-pyridyl,2-thienyl,2-furanyl, 42-90% 2-naphthyl,Me,i-Pr, phenethyl,pentyl

R

An efficient, diverse synthesis of oxazolo[4,5-c]quinoline-4-ones and thiazolo[4,5c]quinolines-4-ones is carried out in two steps from readily available starting materials <03OL2911>. The Suzuki-Miyaura coupling reaction was employed.

324

D. L. Comins, J. Dinsmore and S. O'Connor

EtO2C

2.NH2C6H4B(OH)2

Br

Ph Pd(PPh3)4,DME, H20 K2CO3, 80 ~ 78%

i

EtO2C.

/

N ~p

O~kPh

NH2

H

A rapid, high-yielding procedure for the conversion of o-nitrobenzaldehydes to quinolines (a modification of the Friedlander synthesis) has been reported <03OL4257>. The method appears to be limited in that the ketones utilized must be symmetrical. An example is shown below.

H R

~

O O

+

I~

SnCI2 (5 equiv)' ZnCI2(5 equiv)=

R2"/""'~"~'NO 2 R1 = H, OH, OMe,

R2 = H, OMe

EtOH, 70 ~ 4 A mol sieves 70-98%

R

~

R

CI

N-Phenyldiazoketolactams cyclized via carbenoid insertion to a pyrrolo[ 1,2-a]quinoline-l,4dione. The reactions are highly regioselective and proceed in good yields, though the C-H insertion does not always occur at the same location on the phenyl ring <03TL7433>. The "normal" insertion product is shown below. R1

R1

O

"'~,r

CH2CI2 67-71%

N '"H O-"J'Nv---~ :-"Ar :H"

RI= Me, F, CI R2= H, F, CI Ar = C6H5,2-thienyl, 2-naphthyl, 2-furyl Because the 2'-aminochalcones are known to form 2-aryl-4-quinolones, the authors undertook an investigation of possible reductive coupling reactions of 2'-hydroxy-2-nitrochalcones <03TL5893>. With a limited number of examples, the reactions were carried out via a one-pot synthesis. Quinoline-N-oxides formed as side products are likely intermediates and can be carried on to the final material.

325

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

R2

R2

nc, 2H20

OH O

NO 2

HCI (Conc.), AcOH, 90 ~ 23-66%

OH N / ~ , , .

R1 = H, OH, OCH 3, OBn R2= H, Br

A mild, highly efficient, scalable synthesis of 4-arylquinolin-2-ones from 2aminobenzophenones was reported <03TL4271>. By reacting the starting material with lactones and two equivalents of LiHMDS, the desired compounds are formed in good to excellent yields. O RI__~~.~ ,~

NH2 O

~_jO R3

H ,2-4.5 eq

LiHMDS,1 M in THF, 5-7.5 eq, 0 *C to r.t., then H20, r.t., 2-3 h 65-96%

R

I

~

R2

O R3

R1 = H, 4-Me, 5-CI, 5-CF3 R2= H, 5'-CI R3 = H, OMe, OBn, MOM

The Buchwald-Hartwig palladium-catalyzed aryl-amino coupling reaction was applied to the synthesis of functionalized N-phenyl-2-quinolinones <03TL4207>. This was especially powerful because known methods of cyclization preclude anilines with electron-withdrawing groups para, or any ortho substituents, for steric reasons.

326

D. L. Comins, J. Dinsmore and S. 0 'Connor

R3 R2..~

~

O

R1

1. NaOEt, EtOH, reflux, 4 h = 2. Tf20, Et3N, CH2Cl2, r.t., 2 h

R

I

~

NH2 o

R3

OEt

.

Pd2(dba)3(25 mol %), (• Cs2CO3, toluene, reflux 38-80%

R3

R2

RI~

R4

f,~,OTf

NaOMe, MeOH,

N~

refluxr 1-4 h ,, 43-84%

OEt

R2

R1

N~O

R1 = H, 6-Me, 6-NO2, 7-Me, 7-OMe R2=H, Cl R3 = H, CO2Me R3 = H, OMe

O

6.1.3.2 Reactions of Quinolines

Singh and co-workers have repeated an earlier reported quinoline annulation reaction and obtained a different product. A mechanism is proposed <03IJC(B)1456>. CH3

CH3

N-N--C-Ar H H

A = AcOH

~NII~"N~N

NaNO2 AcOH 72-80% C H3 Ar = C6H5, 4-CH30-C6H 4, 4-C1-C6H4, 4-C H3-C6H4, 3,4-(OCH20 )-C6H3, alpha-Naphthyl t

Oxazoloquinolines were obtained from 2-amino-3-bromoquinolines by successive acylation, amination, and cyclization <03S2033>.

327

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

R-COX

~

81%

heat (90-96%) or microwave

(85-94%)

B

r

O

"ComplexBase"

N'JI'-R H

81%

~ O \ I[~..N~L,.N//~--R

.o~ |

NH2

N"~R H

R = t-butyl, Ph

The Sonogashira cross-coupling reaction was applied to p-phenylethynes and 2chloroquinoline. The resulting compounds are blue-green emitters. Their electrogenerated chemiluminescence properties were reported <03CC2146>.

,PPh,,,P0C,,,cu,

9

R = H, Me, OMe, NMe2, NEt2 N-pyrrolidinyl, N-piperidinyl N-morpholinyl

"-O

_

THF, TEA, reflux, 24 h

Asymmetric hydrogenation of quinolines by iridium catalysis was explored <03JA10536>. Nineteen compounds were reported with excellent yields and enantiomeric excesses.

R

~

[Ir(COD)Cl]/(R)-MeO-Biphep R1

toluene/12/H2(700 psi), r.t. 86-94% ee mostly > 90%

RR1 H

R1 = Me, Et, n-Pr, n-Bu, 3-Butenyl, n-Pentyl, 2-ethylaryl, Ph, CH2OH, i-Pr, CHOCOCH3 R2 = H, F, Me, MeO

A regioselective transformation of quinolines to indoles was developed. The 1,4-dihydro Meisenheimer salts were prepared, to the exclusion of the 1,2-isomer. Yields were poor to excellent <03TL6241>.

328

D. L. Comins, J. Dinsmore and S. O'Connor

PO(OPh)2

A

R1 ~ / ~ ~ ~ , v

/CHO

R1 = H, 6-Me, 7-Me, 6-MeO

i~1 I

CO2Ph Pyrrolo[3,4-c]quinolines are synthesized by ],5-electrocyclisation of azomethine ylides. 2Aryl-3-formylquinolines were reacted with sarcosine in refluxing xylene. The products were purified in fair yields. Trapping with N-phenylmaleimide <03TL2343> showed presence of the azomethine ylide intermediate.

R2",,,~CHO sarcosine(2 eq)=

R2~~.

O ~ ,,CH3

xylene, 140 *C 40-60%

R']R1 -N- -Ph

L

'

CH3 2 R

-H2 =

~ R~I "N-

R1 = H, CH3 R2 = H, OCH3 -Ph

6.1.4 ISOQUINOLINES

6.1.4.1 Preparation of Isoquinolines The preparation of 3,4-disubstituted isoquinolines by a general process involving the palladium-catalyzed cross-coupling of N - t e r t - b u t y l - 2 - ( 1 - a l k y n y l ) a r y l b e n z a l d i m i n e s and organic halides was examined <03JOC920>. Conditions were optimized to prevent the formation of 3phenylisoquinolines. The method was generally successful, except in the cases where the aryl halides were electron-rich or o-substituted. Forty-seven examples are given.

~-

+ R2X

~'~R1

R1 = Ar, n-Bu, 1-cyclohexenyl R2= Ar, allyl, alkynyl, vinyl X = I, Br, CI, OAc

K2CO3, 100 *C, 12 h 23-80%

R'~

R1

329

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

A route to 4-(1-alkenyl)isoquinolines and 4-alkyl-3-arylquinolines via palladium(II)-catalyzed cyclization, followed by olefination, was developed through many trials. Substrates were chosen for their ability to stabilize the Pd(II) intermediate, and to promote the Pd-catalyzed cyclization. An o-methoxy substituent on the aryl group was found to be necessary <03JOC980>. Forty-one examples are given.

H2C=CHR (5 eq) PdBr2 10 mol %, CuCI2 10 mol %

0 ~~--~N-'t-Bu

~ ~Tii~-~"~N

NaHCO3 (3 eq), DMSO, 70 *C, 02, 5-24 h 48-89%

OMe

R

R = CO2-t-Bu, CONMe2, CH(OH)CH3 The application of zirconocene-copper-mediated coupling of benzocyclobutadiene with nitriles was shown to be effective in one specific case <03OL877>. The only successful transformation is shown below. In contrast, benzonitrile only yielded traces of 3phenylisoquinolines.

{~~Br

1.Mg

Me , CP2Zr~

1. t-BuCN toluene 70*0

2. Cp2ZrMeCI

2. CuCI/THF 61%

[~~.~

t-Bu

'/<...~,M,,~N

Various 13,13-difluoro-o-isocyanostyrenes react with organolithiums to yield quinolines. The paper also describes the formation of isoquinolines from o-cyano-13,13-difluorostyrenes in a similar manner <03OL1455>.

RI F2Cp~ N~,.,

r.t., 15 min R1 = n-Bu, sec-Bu R2 = n-Bu, Et, i-Pr, t-Bu M=Mg, Li

toluene, HMPA, 0 ~ 1 h, then r.t., 4 h

20

R2M, toluene,

/'N~c~

L

I

J

62-88o/o

F

R"

Coupling of a cyanocarbene complex with an alkyne-aldehyde yielded isoquinolines. This occurs through an isobenzofuran intermediate followed by an intramolecular Diels-Alder reaction. Yields are poor to moderate and the reactions with good yields are plagued by product mixtures <03OL4261>. Preparations of benzo analogues were more successful.

330

D. L. Comins, J. Dinsmore and S. O'Connor

Cr(CO)5

j

R2

R2

X

X

R2

toluene, heat

+

0 1

Cr(0)

R'

_1

X

R2

R 1 =H, Ph R2 = Bu

20-59%

X = OMe, NMe2 R"

A stereoselective Friedel-Crafts type cyclization was used in a strategy to prepare enantioenriched 1,4-dihydro-4-phenylisoquinolines. The products are formed in fair yields and variable ee <03T8049>. Substrates are prepared from (S)-mandelic acid.

O H2SO4/CH2CI2 ~ N'R2

R1

-15 *C, 4 h

20-70% yield 90-97% ee

~N~N. R1

O R2

Tetrahydroisoquinolonic acids are formed in good yields and enhanced rates from threecomponent coupling reactions of benzaldehydes, amines, and homophthalic anhydride. The key feature of this approach is the use of ionic liquids <03T1805>.

X-ArNH2 + Y-ArCHO

+

o ~ o

~ 'n~~11~0.~ c'~.-~.~. 87-95%

o~~_ x ~ J~" _ Y

bmim = 1-butyl-3-methylimidazolium X = H, 4-Me, 4431, 4-Br, 4-MeO, 3,4,5-(MEO)3 Y = H, 4-MeO, 2-Me, 4-N(Me)2

An efficient single-step synthesis of isoquinolines was achieved by a three-component reaction of aromatic ketone with benzylamine and alkyne. Rhodium (I) is used as the catalyst and o-functionalization of the aromatic rings is not necessary, indicating an extended scope for this method <03OL2759>. The reaction is complicated by a sizable amount of phenethyl-substituted side product.

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

.CH3

Me

, ~ ~ D

H2N~Ph

+

R

Rh(PPh3)3Cl toluene, 170 ~ 12 h 82-89%

Ph ~

Ph

331

(C.H2)2Ph +

R

Ph

Ph

54-63% of product

R = H, CF3, OMe

R

Ph

Ph

46-37% of product

A titanium "precatalyst" is described which the authors use in a one-pot synthesis of tetrahydroisoquinolines from phenethylamines and alkynes <03OL4733>. The reaction is a modification of the Pictet-Spengler reaction.

//

MeO~

NH2

,,Q-,~ ./NEt2

,2

,FA

5 mol%

95%

MeO

R =/-Pr, t-Bu, 2,6-Me2C6H3, 2,6-di-i-PrC6H3

MeO'~~~

The Ritter reaction has been applied to the reaction of a-naphthyl carbinols with nitriles. Rather than finding a mixture of regioisomers as feared, the only products were the 3,4dihydrobenzo[h]isoquinolines <03CHE184>.

Me { ~ ~ ~ M

Me e

RCN H2SO4

Me Me ~ R V l e /

R = CH2CO2Et,SMe, CH2CONH2

"~ R,,~r~N~Me

Me

= 20-55%

Me Me

332

D. L. Comins, J. Dinsmore and S. O'Connor

Reaction of isothiocyanatocarbonyl compounds with aromatic ethyl amines is found to be a satisfactory route to pyrimidoisoquinolines <03CHE277>. The reaction is mild as it only requires heating in acetic acid.

MSO

= H2NR

Me .OH N.R

Me Me/ "NCS R=

M e O ~ ~

Me~.,.,~ Me N S H

MeO" v

M e O ~

AcOH, heat

M e O . ~ ~ M e N.~S

52%

M ~ M IHe

NH2

Primary amines reacted via a "palladium-catalysed allene insertion-nucleophilic incorporation-Michael addition cascade" to give isoquinoline derivatives. The yields were good and fifteen examples are reported <03TL7445>.

~[~~ EWG

I

[~~

EWG NH2

Pd(OAc)2(10 mol%) PPh3 (20 mol%),K2CO3, toluene, reflux36 h 60-76% b

EWG = CO2Me,PhCO,CN, NO2 6.1.4.2 Reactions of Isoquinolines Reactive 1-isoquinolylnitrenes are generated from FVT of tetrazolo[5,1-a]-isoquinoline. The reaction proceeds from the nitrene through a carbodiimide to two nitrile compounds. The mechanism was studied by ~SN enrichment <03JOC1470>.

N + [15N--N+~I**]@ '" CI -

~15N~I~N

~- ~ N

N3

~

~ i

= ~N

N.:

N

N

~ ~ ~Njj N

~ ~ C N.N.: ~- ~~~CNcN 40%

25%

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

333

Several 3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium inner salts undergo reaction with dipolarophiles in 1,3-cycloaddition reactions <03JOC8700>. The best yields with the cleanest mixture of compounds is when R ~ = PMB and dimethyl acetylenedicarboxylate (DMAD) is the dipolarophile.

CF3

S

R2 ~

N-N ~ O ~/12~~~1~1+R1

R3

toluene, heat 32-89%

~

N"N O ~ IR H" \' N

R1= PMB,Et, CH2CO2Me R2 = H, CO2Me R3= H, CO2Me

3 "R2

IR1

A three-component one-pot synthesis of highly substituted spiro[1,3]oxazino[2,3a]isoquinolines has been demonstrated <03TL729>. The starting materials are quinoline, DMAD, and either 1,2- or 1,4-quinones. An example is shown.

CO2Et ~ N

III §

O . ~

CO2Et

~

DME r.t, 6 h 76%

O

J

CO2Et

I ....

02Et

0 A route to the dihydrobenzo[d]azepin-3-one ring system from isoquinoline in three steps was shown to be feasible. The method has been applied to the synthesis of zatebradine, an antianginal <03TL4203>.

~ N

PhCH2Br,MeOH 2 weeksreflux " quantitative

AgNO3,MeOH -40 ~ to r.t., 16 h 44%

~ N

~

O RO

| |"Bn Br

CH3CN/H20 HCBr3, aq.min KOH, r.t., 45 89%

NH R=H, Me

~ N "Bn CBr3

334

6.1.5

D. L. Comins, J. Dinsmore and S. O'Connor

PIPERIDINES

6.1.5.1 Synthesis of Piperidines Substituted piperidines are obtained by an intramolecular cyclization of vinylsilanes with acyl amines <03SL143>. Ratio of piperidine to pyrrolidine products depends on the acid used, time and temperature. The silyl group is easily converted to a hydroxyl group.

I~

P u

Bu

acid catalysis=

SiMe2Bn

65-88%

v

"SiMe2Bn

SiMe2B n

P = Ts, Ms, Boc As an approach to the synthesis of piperidines with stereocontrol, multiple functionality, and flexibility, the authors employed a [3+3] cycloaddition reaction of a silylpropenyl acetate with aziridines in the presence of a palladium catalyst. The key intermediate is a palladiumtrimethylenemethane (Pd-TMM) complex <03JOC4286>. Optically active aziridines gave enantiomerically pure piperidines.

~N--Ts

+

10% Pd(OAc)2 60% P(O'i'Pr)3b

AcO~SiMe3

20% n-BuLl THF, 65 ~

R

, ~ R

l"s

44-82%

R = Me, i-Pr, n-Pr, Bn, Ph, TBDMSO,allyl

L,.0 o |

AcO,v~SiMe 3

PdLn

Pd-TMM A stereospecific route to enantiopure a l l - c i s - 2 , 3 , 6 - t r i s u b s t i t u t e d piperidines was described <03TL3963>. The cyclization step is dependent upon reaction temperature, choice and amount of base.

/N n-C12H2

OH O ~

1 cBr4/Ph3P/Et3N/CH2cl ~ to r.t. 2'0 _

H

2. Et3N/MeCN,80-85~ 52%

O n.C12H25= ~ ~ J~ COCF3

5 ~ ~ n-C12H2

H

1.95% H202/(CF3CO)20 Na2HPO4,CH2CI2 II.

2. HCI/MeOH 45%

O "~

1. PtO2/H2,HOAc

=

2. (CF3CO)20/Et3N DMAP 71%

n.C12H25,~~ OH H

335

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

A three-component Diels-Alder reaction has been reported. Depending on the chiral auxiliary on the nitrogen end of the 1-aza-4-borono-l,3-butadiene, diastereomeric excesses can exceed 95% in moderate yield. The method was applied to solid-phase synthesis of piperidine derivatives with acceptable results <03MI466>.

qL/

/ \ O,,B,,O

0

~ N

~

+

i~ R

R

0

Toluene NPh + PhCHO 80~ 72h 0

~.~OMe

_.~~NPh Ph C)H

55%

I

0

~._~C(R)2OMe

R= H, 80% de R = Me, > 95% de A 2-aminoalkylfuran was utilized as starting material in a synthesis of a piperidine-containing natural product. The desired stereochemistry is attained by taking advantage of A(l'3)-strain <03JOC4371>.

~ O~

~ Ph N.-.j Ph

1. n-BuLi,THF, BrCH2CH2CH2OTBDPS

86%

.,

2. HCl 95% 3. TsCI, NEt3,CH2CI2 90%

OTBDPS m-CPBA , NH Ts'

CH2CI;

CH2 4 steps HO'"

"~ Ts TBDPSO

v

Ts

~OTBDPS

A ring-closing metathesis (RCM) strategy was utilized in the synthesis of 5-hydroxypiperidin2-ones <03JOC2432>. Stereoselectivity is observed with optically active amino acid derivatives as starting materials.

336

D. L. Comins, J. Dinsmore and S. O'Connor

Ph

O

L"NH

O

Ph

CH2CI2

Ph

ph/~.N.,~.,J

4oo,o-

Ph

"Grubbs' Catalyst" 78%

Ph O O l,..N.,-~A.ph oxone, NaHCO3 p h ~ [ ~ ~ . p h Me2CO, H20 54% Grubbs' Catalyst =

O

O Ph p h ~ . . . , ~ ./J

LDA, THF,-78 ~ 91%

OH

PCy3 Cl,,, I Ru=~

CIS I Ph PCy3

Polyhydroxylated piperidines are valued as inhibitors of carbohydrate-processing enzymes. Dioxanylpiperidine, identified as a precursor, is synthesized in good yield, stereoselectively, in 5 steps from Garner's aldehyde. The key step is a ring-closing metathesis with Grubbs' catalyst <03OL2527>.

HO O~NBoc Me Me

~ZnBr,

THF

78% after ReX 92% de

,.

"~

,.N/~O Boc

"~Me

9 O. NBoc Me/NMe

HCI

Grubbs' Catalyst CH2CI2,r.t. "excellent yield"

~

Boc

o . fe

e

i=

Nail, THF 0~ 76%

Me

Boc dioxanylpiperidine

Highly-functionalized piperidines are available from readily-available pyrazinones by way of Diels-Alder cyclization and acid-catalyzed methanolysis. Products are reported as single stereoisomers <03T5047>.

337

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

Bn

H2C=CH2.

Ph~ N ~ O CI

N

R

Bn

P h ~i ~

35 atm toluene

H30 |

Bn Ph. ~ O

82-92% O" Noverall H

CI

R = H, Me, Ph

-R

0Ph

H|

0

BR

N i

";

84-94%

Me

R

NH3§

el"

A variety of piperidines are formed by intramolecular cyclization of y-aminoolefins via bromination of the double bond. Chiral secondary amines provide diastereoselectivity <03CC 1918>. H N

1. Br2, CH2CI2,-78 ~ "R 2. K2CO3, Acetone, 70 *C= 70-85%

)m R

R = protecting group It.,.,.~II

,It

Ph N.~Me HH

1. Br2, CH2CI2, -78 ~ 2. K2CO3, Acetone, 70 ~ 74% one diastereomer

~H'J" ~IyHh '~ Me

Enantiomerically pure 2-azetidinones are applied to the asymmetric synthesis of nonracemic 2-piperidones. This is a novel application of 2-azetidinones <03T6445>. Because 2-azetidinones are valued as antibacterials and chiral building blocks for amino acids, peptides and 2pyrrolidinones, they are readily accessible for application to this transformation.

O~ R 1 ,,,R2 LiAIH4 ,. BnO RR2 BnO; , THF, 0 oc H O ~ ) ~ ' ~ N -'Boo "Boc 87% H BnO RR2 N~MHe "B~

BnO IBX " . ~ ~ , RR2 93%~O = = ( ~ N-Boo H

Ph3P=CHCO2Me y

87%

1. TMSOTf r,~,,,OBn ... 2'6-1utidine'0 ~ ~ . ~ N ~ . , R a 1 2. DMAP O 2 95%

Enantioenriched radical precursors are trapped by amines intramolecularly to give 2substituted piperidines with 60% ee. The authors propose a tight radical ion pair mechanism to account for these results <03OL3767>.

338

D. L. Comins, J. Dinsmore and S. O'Connor

0 ~jO

OPh Bn MejNO2 'Pk~o OPh Bu3SnH

6 steps

AIBN 41%

70% overall

II(PhO)~,P'/NI oHI|~ L

"/'

1I

,H

"Bn J

Tight RadicalIon Pair

T r a n s - 2 , 6 - d i s u b s t i t u t e d piperidines are building blocks for complex bioactive alkaloids and are available in good yield from an acyclic polyfunctional sulfinimine <03OL3855>. The authors suggest that an intermediate alkoxy aluminum species shields one face of the imine bond during the reduction to afford the observed stereoselectivity.

P-T~

OH i

OMe

HO

Me--I~lLi 90%"

Ph~OMe

P-T~

OH i

HO Ph~N'Me

C)Me

MeMgBr 88~176

OH I

P-T~

ph- v

.,~"~ILH "O 1. HCI _v -Me 2. NH4OH 0 *C

~ Ph" -N- Me

DIBAL-H ~ H n-BuLi 68% Ph" -N- '"Me H

Because many 4-benzylpiperidines are physiologically and pharmacologically active, an efficient route to these compounds was developed <03TL8249>. Cyclization of imines containing an allylsilane with aldehydes in a one-pot reaction resulted in 4-methylenepiperidines in good yields. Heck-type arylation of arylboronic acids with 4-methylenepiperidines afforded the styryl derivatives, which gave the desired piperidines on reduction.

O ~NH2

1. LewisAcid, r.t. I ~ 2. TsCI, pyridine 73-96%

"i's

ArB(OH)2

_-

R 10 mol%Pd(OAc)2 02, Na2CO3, DMF 62-88%

10% Pd/C Ts

R MeOH,H2 85-90%

"i's

R = H, CH(OCH3)2,n-Pr, i-Pr, t-Bu, C6H5, Ar = C6H5,4-t-BuC6H4,4-MeOC6H4,4-FC6H4, 4-MeOC6H4,4-CIC6H4,PhCH=CH2,2-pyridyl 4-Me2NC6H4, 4-MeCOC6H4 Ring-closing metathesis of N-acyl-2,6-dialkenylpiperidines has been applied to the synthesis of bridged azabicyclic structures <03JOC8867>.

339

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

H O~,~.O

1. NaBH4, H EtOH,HCl O ~ S O 2 P h 2. PhSO2Na, HCO2H

THF,RMgX-20 ~

c~z ~

~o,~,., " -7800

H

1. n-BuLi, -78 ~ 2. Cbz-CI,-78 ~ 76-92%

63-74%

70%

O ~ ) n

O

PCy3 =-

h

c~z~

c,~-tu; ''c' i ~k~---Ph

~ ) + n

2. AllyI-TMS, BF3OEt2, -78 ~ 59-67%

Cy3P

_

~1)

trans isomer CH2CH2, r.t.

N'Cbz n

82-91% (yield includes

trans-precursor)

6.1.5.2 Reactions of Piperidines An entry to cyclopentane-annulated piperidines, ubiquitous in natural products, is available from 4-nitroalkyl-3-allylthiolactams <03SL1673>. As shown, the 2-nitropropyl group adds trans to the substituent at C-6 if either the substituent at C-6 or the N-substituent is bulky.

" • -NO2 R2

i~1

-22 ~ 24 h

R2

~..o~

2. Et3N

~'

z7-89O/o

" ~ . NO2

80-90%

-~__ ~o~

R2

~'

~.,,i e pe~

R2

41

72-80% R2 R1 = CH2COCH3, CH3 R2 = Bu, H

I~1

AIBN toluene 100 ~ 39-43%

R2- "N" ~'O i~1 84 82

R2- "N" ~'O " "

16 18

340

D. L. Comins, d. Dinsmore and S. 0 'Connor

The nitrone of piperidine reacts with phenyl vinyl ether to yield a 1,3-dipolar cycloaddition product. Benzylation led to a ring-opened product which was converted to a hydroxamic acid. This is desired functionality in medicinal chemistry because it is a metal-binding ligand <03S1221>.

oI+

~_~

~/OPh O :_ ~ , ~

OPh

oh

OPh

BnBr

OyOPh

500OD.

58%

Ph O~NHOH

NH2OH.

65%

9O%

Arylation of piperidine by Ni-catalyzed coupling of aryl nitriles proceeds in good yield. An amidine intermediate is suggested <03S 1643>.

R~N-Li

; I.-CN :I' ]

+ PhCN

Ni catalyst Cs salt

R

--~/N

-Ph

THF 61-73%

A precursor to the pharmaceutical Paroxetine was obtained in good yield and 96% ee. Addition of phenyl Grignard to a chiral et, 13-unsaturated enoylsultam followed by epimerization to the thermodynamically more stable C-3, C-4 t r a n s isomer provides the desired compound <03TL5355>. Other chiral auxiliaries gave lesser or negligible ee.

F

F

CMe

O O~.o. II ~..~Me Me 1. F - - ~ - - M g B r 2. KO-t-Bu 75%

Ii.1

o o

0 ~3~Me

O'k

....~0~ 0

Me

H

- HCI

Paroxetine Starting from a common precursor, either c i s - or t r a n s - 2 - m e t h y l - 4 - a r y l p i p e r i d i n e s can be prepared <03TL4531>. Yields and selectivity depended on the aryl group, reaction time, temperature and amount of catalyst used.

CH3 OH Boo--N~ ~ ~ A r

H2 N._toluene i/SiO2

CH3 Boc-N/~~'~Ar

trans-2,4 CH3 OH Boc..

N ~

H2

A

r

Pd/C

EtOH

CH3 Ar BoC..N~ ~

cis-2,4

Ar = 2-naphthyl,Ph, (2-CH3)-Ph (4-OCH3)-Ph, (4-CF3)-Ph

341

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

The authors desired cis-3-hydroxy-2-phenylpiperidines as starting materials for the synthesis of a large number of bioactive products. They accomplished this task, starting with protected 3hydroxyglutarimide, available in 5 steps from S-glutamic acid <03OL1927>. The epimeric hydroxyl compound is converted to the cis-phenyl through an acyliminium ion, thus the two isomers did not need to be separated, simplifying the synthetic route.

. ~~omgges

O" N"OI~MB

NagH4

=

O ~

MeOH, 940/-20 0 *C

OmegeS eF3.OEt2 "

PMBOH

"'Ph THF,r.t. 81% PMB

CH2012, r.t.800/o

,,,O-S'~ u

?'-NM B"Ph - ~

""Ph I~MB

i

A three-step synthesis of a precursor of paroxetine is described. An aza double Michael reaction was used to form the piperidine ring <03TL7429>.

0

O ~ Bn

NHBn 1. methyl acrylate, TBSOTf, Et3N,

t-BuOH,DCE,r.t.

.

.

.

.

.

"'CO2Me LAH,THF,reflux,,

,,,,/OH

.

2. NaOMe,58% MeO e,overall H-toluen reflux F

0 ~ . ~Bn

~

quantitative F

F

Enantiopure cis- and trans-2,6-dialkylpiperidines were synthesized from the same 6alkylpiperidine-2-one. In order to relieve A (~'2) strain in the intermediate iminium ion, the 6-alkyl substituent is in a pseudo-axial disposition and nucleophilic attack occurs from the axial direction to give the cis product <03JOC 1919>.

342

D. L. Comins, J. Dinsmore and S. O'Connor

R2G"

1

R1

~ ~ 6 H5

C6H 5 "H

H C6H5,1/"'OH

OR

~

R = H, MgBr R 1 = CH 3, n-Pr R 2 = H, alkyl

C~H~H~.1oH

R 3 = alkyl, when R 2 = H, R 3 = H, when R 2 = alkyl

The synthesis of spirocyclic aminochromans are described. From an optically active oxazolopiperidine, the desired compounds are realized in eight steps, with 32% overall yield and greater than 99.5% enantiomeric purity <03JOC 1401>.

Boc i

NC~.~o,s.e0s~HO~ Ph,

Boc i

THFHO~

" OTBMS Bu,;Foo _-

~~oc R

TFA, CH2CI2

Ph3P, DEAD toluene, reflux 85%

R

72%

The key step in a synthesis of rigid azabicyclic piperidines was a ring-closing metathesis <03TL2995>. Starting from 3-hydroxypiperidine, the transformation was accomplished in six steps, each in good yield.

343

3ix-Membered Ring Systems: Pyridines and Benzo Derivatives

~

~/Br OH 2steps

H

~ O ~

~

~ I

O .,~

Br

OH

Mg,-60 ~ THF, 1 h

11,

KHMDS, THF -78 ~ to reflux 69%

74% /-Pr

..•

(F3C)2MeCO'"~i~~ ~J'%Ph (F3C)2MeCO _-

Bu3SnH, AIBN toluene, 80 ~

O

Br

CH2Cl2, r.t., 1 h 54%

N

79%

Syntheses of new analogues of diphenylpyraline are described. The strategy is flawed by a non-stereospecific hydrogenation. This results in a 50:50 mixture of diastereomers requiring purification by HPLC <03T1403>. R1 R1 R1 MeS Nt .R 2 Raneynickel W-2, N0 R2 2~ 1" N--~-H CH3I' CHCI3' ~11-0~C~ r't"2 h18 h I ~ R3 EtOH' r.t.,306 psi h (H2)-" ~ <~R3 NMe2

O

R1 =Me, Ph R2 = H, i-Pr, Ph R3 = H, i-Pr, Ph

H OH single diastereomer separated by HPLC

A synthetic entry to enantiopure cis- and trans-3,5-disubstituted piperidines was reported. The key steps are a cyclocondensation, which involves a dynamic kinetic resolution, and a stereoselective alkylation of the resulting bicyclic 6-1actam <03OL3139>.

Pho R ~. O~N~sO

LiHMDS,-78 ~ 1 h, Mel or BrCH2CO2tBu,

~'"1

-78 ~ 2 h 60-800/0

1. MeOH-HCI 2. H2/Pd(OH)2 78%

Ph,

Ph,

~ O~N~,,O R'"~'""

H R" . . . . .

9

1M BH3-THF, -78 ~ I

r.t. 47-570/0

~__~OH

~ R'"

....I

HCI

I

R = Me, CH2CO2t-Bu, CH2CO2Me

344

D. L. Comins, J. Dinsmore and S. O'Connor

6.1.6

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03JA10536 03JOC467 03JOC920 03JOC980 03JOC1401 03JOC1470 03JOC1919 03JOC2432 03JOC3563 03JOC3706 03JOC3966 03JOC4170 03JOC4286 03JOC4371 03JOC4567 03JOC4935 03JOC6427 03JOC7918 03JOC8700 03JOC8867 03JOC9371 03JOM313 03MI466 03NJC313 03OBC2710 03OBC4047 03OL877 03OL1369 03OL1455 03OL1605

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

03OL1765 03OL1927 03OL2509 03OL2527 03OL2759 03OL2911 03OL3139 03OL3277 03OL3767 03OL3855 03OL3867 03OL4257 03OL4261 03OL4733 03PAC19 03PAC1403 03RCR69 03S1221 03S1531 03S1643 03S2005 03S2033 03SC795 03SC2243 03SL143 03SL1443 03SL1673 03SL1678 03SL1874 03T813 03T1403 03T1739 03T1805 03T2953 03T5047 03T6445 03T7997 03T8049 03T8775

03TA469 03TL725 03TL729 03TL1503 03TL2343 03TL2995 03TL3963 03TL4203 03TL4207 03TL4271

345

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346

03TL4385 03TL4531 03TL4711 03TL5355 03TL5893 03TL6241 03TL7429 03TL7433 03TL7445 03TL8249 03ZOR449

D. L. Comins, J. Dinsmore and S. O'Connor

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347

Chapter 6.2 Six-Membered Ring Systems: Diazines and Benzo Derivatives

Michael P. Groziak

California State University at Hayward, Hayward, CA, USA mgroziak@csuhayward, edu

6.2.1 I N T R O D U C T I O N The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine were once again central to a great many chemical and biological investigations. Progress on the syntheses and reactions of these heterocycles, and their continued use as intermediates toward broader goals was abundant. An even larger number of studies than last year relied on solid-phase, microwave irradiation, or metal-assisted approaches. Also, as expected, more progress of an X-ray, computational, spectroscopic, natural product, and biological nature was made. Like last year, these have been grouped together as much as possible.

6.2.2 REVIEWS AND G E N E R A L STUDIES Methods for synthesizing furazano[3,4-b]pyrazines and their analogues were summarized in one review <03RCR87>, and the synthesis and reactionsmincluding rearrangements---of pyrazino[2,1-b]quinazoline-3,6-diones was the subject of another <03MI149>. A review of the polarographic behavior of pyrimidine derivatives concentrated heavily on azo-pyrimidines <03MI13>. Reviews of a biological nature included one examining the role ofpyrimidines as antiinfective bioactive compounds <03MI269>, another the regulation of bone resorption and formation by purine and pyrimidine nucleotides acting at receptors <03MI290>, and still another pyrimidinones as nonpeptidic chymase inhibitors <03MI1191>. In the nucleoside field, the use of calorimetric, volumetric, and structural data for describing the properties of pyrimidine nucleic acid bases and their derivatives was the subject of a specialized review <03MI155>, and pyrimidine nucleoside analogs as cancer chemotherapeutics <03MI717>

348

M.P. Groziak

and bicyclic furo[2,3-d]pyrimidine nucleoside analogues as antiviral agents were examined <03MI253>. Finally, purine and pyrimidine nucleotide metabolism <03MI1271> and biosynthesis <03MI297> in higher plants were each discussed in separate reviews. Some investigations applied to more than one type of diazine and so were general in nature. The relative ortho-directing metalation ability of the F, C1, and OCH3 groups in the diazines 2chloro-6-methoxypyrazine 1, 2-fluoro-6-methoxypyrazine 2, and 3-fluoro-6-chloropyridazine 3 was studied, and the order was found to be F > OMe > C1 <03JHC855>. Also, the synthesis and Pd-catalyzed cross-coupling reactions of (tributylstannyl)fluoropyrazines 4 enabled access to new fluorinated diazine liquid crystals like 5 <03T6375>. Bis(2-quinolyl) and bis(2[ 1,8]naphthyridyl) derivatives of the diazines pyrimidine and pyrazine were prepared as bridging ligands for mononuclear and dinuclear mixed-ligand Ru(II) complexes <03EJI3547>. An unusual ring expansion of intermediate imidazolidines 7 to 1,4-diazines 8a-c was discovered in the preparation of fully saturated piperazin-3-ones and quinoxalin-3-ones from 2-anilino-2-ethoxy-3oxothiobutanoic acid anilide 6 with aliphatic 1,2-diamines <03JOC2334>.

1

2

3

..~ N ~ F

N..~ Ar2

Bu3Sn.~N~ N~..,']-....- F----~ = Ar 1

N

Ar2

N

I

Ar I 5

EtO_ NHPh

H2N HN-R1

Me@~.~NHPh

EtOH

0

S

/

.

J L

.

.

HN _

.

.

.

_

N-R1

~1" ]1~ O S 7

_

/

'l J

Me Iq~ CSNHPh 8a, RI= R2=H

b, R 1 = Et, R 2 = H;

r R1 = H, R2= Me

6.2.3 PYRIDAZINES AND BENZO DERIVATIVES X-ray crystallography has continued to expand our knowledge of the solid state structures of pyridazines and their derivatives. Substituted 3,6-di(2-pyridyl)pyridazine metal-coordinating ligands, synthesized via inverse electron-demand Diels-Alder reactions, were characterized by Xray <03EJO4887>. Upon treatment with cationic Rh(I) precursors, these tetradentate ligands generated mono- and binuclear cyclometalated complexes which were characterized by a wide variety of methods, including X-ray <03EJI70>. In addition to these, X-ray structures of 3,6dichloro-4-[2-(4-thiamorpholino)ethanesulfanyl]pyridazine 9a and 3,6-bis(pyrazol-1-yl)-4-[2-(4thiamorpholino)ethanesulfanyl]pyridazine 9b <03AX(C)293>, and 1,2,3,4-tetrahydro-2,6diphenyl-3,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine-l,4-dione <03ZK235> were reported.

349

Six-Membered Ring Systems." Diazines and Benzo Derivatives

Finally, silver(I) complexes of 3,6-di(2-pyridyl)pyridazines were prepared and characterized in the solid state <03AJC653>.

N-N 9a, R = CI;

S /---.._/ /'--.--N S--"--J 6.2.3.1 Syntheses

Condensation reactions continued to be popular routes to pyridazines. For instance, pyridazino[4',3':4,5]thieno[3,2-d][1,2,3]triazine, pyrimido[4',5':4,5]thieno[2,3-c]pyridazine, 5aminothieno[2,3-c]pyridazine, and phthalazines were all accessed in this way <03BKC1181>. A dipolar cycloaddition reaction of quinazolinones constituted a new route for the synthesis of annelated pyrrolo- and pyridazinoquinazolines 10 and 11, respectively <03MOL401>. Symmetric and unsymmetric 1,3,4-oxadiazoles were synthesized in situ from NH2NH2 and 2acyl-4,5-dichloropyridazin-3-ones <03S560>. Sonogashira Pd-catalyzed cross-coupling reactions were used to prepare some 6-phenyl-3(2H)-pyridazinones 12 with various C5 alkynyl substituents <03T2477>. Pyrido[l',2':l,2]imidazo[4,5-d]pyridazines 13 were among the heterocycles synthesized from 2,3-dicarbonylimidazo[1,2-a]pyridines <03T5869>, and pyridazino[3,4-h]psoralens and pyridazino[3,4-j]angelicins 15---nitrogen isosteres of potent DNA inhibitors--were synthesized from resorcinols like 14 <03T8171 >. 0

0

~ ~ N - A r 10

r~'~N

O

R~

0

L~ L~''~N'N<'~Ar i~ ~ ~, ~"~-~""N-" "',--~""N O2 11 Me

R2

13

0

14

O Me

R'N~N

0

~R'N~N

Br R1 Ph Ph 12 R1= C-C-R,CH=CHCOPh Me

O ~

MeO2C. ~N, ,,~ ~ /N ~CO2Me Me 15

The preparation of the first stable crystalline isobenzofuran containing two ring-nitrogen atoms, 4,7-di(2-pyridyl)-5,6-diazaisobenzofuran, was reported <03AJC811>. New pyridazine N- and O-glycosides were synthesized under phase transfer catalytic conditions <03SC1155>. New perfluorinated (2H)-pyridazin-3-ones and 3-(alkyl- or arylamino) substituted pyridazines were prepared from perfluoroketene dithioacetals <03S436>, and N-benzoyl-N-tert-butyl-N'-

350

M.P. Groziak

[(1,4-dihydro-6-methyl-4-oxo- 1-phenyl-3-pyridazinyl)carbonyl]hydrazines were prepared from 1,4-dihydro-6-methyl- 1-phenyl-3-pyridazinecarboxylic acids via two separate routes <03IJC2608>. Imidazo[1,2-b]pyridazines 17 were obtained in an efficient manner from 3,6dichloropyridazine 16 by imidazole ring formation under Swern oxidative conditions <03TL2919>, and functionalized 3(2H)-pyridazinones were prepared in an Ugi four-component condensation reaction <03S691>. An intramolecular diazo-coupling reaction generated pyrazolo[4",3":5,6][4',3'-e]pyrido[3,2-c]pyridazine--a new heteroaromatic tetracyclic ring system <03HEC271 >.

CI CI

HO R2 ~ DMSO, EtaN, CI 0H2012

16

N" 17 R2

Efficient one-pot syntheses were reported for some pyridazines. One of 2-substituted pyridazino[4,3-h]psoralen derivatives relied upon the Diels-Alder reaction of 3,6-dichloro1,2,4,5-tetrazine and 8-methoxypsoralen <03SL2225>, and another of 4,5-disubstituted-3(2H)pyridazinones 19 relied upon bis-functionalization of the 4,5-positions of 3-pyridazinones 18 in a retro-ene-assisted Pd-catalyzed reaction <03TL4459>. A zeolite-HY catalyzed synthesis of 1,8-naphthyridinyl-3(2H)-pyridazinones in dry media under microwave irradiation was developed <03SC1067>, as was a photochemical one of [2.2](3,8)-pyridazinophane 20 and related compounds <03T1739>. A new synthesis of pyridazino[4,5-b][ 1,4]oxazin-3,8-diones 21 via the Smiles rearrangement was reported <03TL8995>, as was a method for the direct conversion of unsubstituted and 4-substituted y-bicyclic lactams 22 to 4,5-dihydro-2Hpyridazin-3-ones 23 <03TL7799>. A "traceless" solid phase synthesis of 4,5- and 5,6-diaryl3(2H)-pyridazinones was developed <03SL1113>. 6-Substituted imidazo[4,5-d]pyridazin-7ones were synthesized from 1,2-disubstituted 4-aroylimidazole-5-carboxylate intermediates <03H(60)1329>. 3-Cyano-2-diazo-4,5,6,7-tetrahydrobenzo[b]thiophene was shown to react with 3-imino-butyronitrile to give an azo derivative which could lead to pyridazines, among other heterocycles <03PS 1667>.

O H'N x ~' I N

O HOCH2"N~""/X" ' I X

O " H ' N ~ RI '

N~X

=

19

18, X = CI, Br O

20

O N

X

N~R

N

X, Y = O H , CI

Y C H 2 C O NH =R CsCO3,Z~CH3CN O

AF

N ..THP N lq

N 21

R4 22

Ar~R1 0

R1

-

R2

N. N ,.,~..0 23

351

Six-Membered Ring Systems: Diazines and Benzo Derivatives

6.2.3.2 Reactions

The reactivity of pyridazine-3(2H)-thiones toward nucleophilic and electrophilic species was investigated <03HAC334>. Tetrazolo[1,5-b]pyridazine-8-carbohydrazides were prepared, and their condensation with aromatic aldehydes, sulfonyl chlorides, and aryl/alkyl isothiocyanates was explored <03H(60)1873>. N(2)-Oxide and 3-amino derivatives of 6,8-dimethylpyrimido[4,5c]pyridazine-5,7(6H,8H)-dione 24 were shown to react with primary alkylamines in the presence of an oxidant to produce condensed imidazolines 25, imidazoles 26 and 27, or pyrroles 28 <03T7669>. Heterocyclic analogs 29 of the still unknown dibenzo[a,o]pycene were obtained as a byproducts when cyclohexylamine was used. The inverse-Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate 30 with unsaturated bicyclic endoperoxides gave p-quinonefused pyridazines like 31 <03JOC7009>. 5-Alkynyl-4-chloro- and 4-alkynyl-5-chloro-2methylpyridazin-3(2H)-ones were shown to be convenient precursors for preparing 2substituted pyrrolo[2,3-d]pyridazinones <03H(60)2471>. 3(2H)-Oxo-, 3(2H)-thioxo-, and 3aminopyridazines were coupled with N-phthaloyl- or N-tosyl-amino acids using DCC to afford 3-(N-phthalyl- and N-tosyl-aminoacyl)pyridazines <03PS 1911>.

O Me'N ~~~',T'NHR_~, Me

24

25

Me Me"N ~

R3 ff.~R2 ~ ~kN -~N -"-~ , ~ 1

~

Me N

'

M

N"N "fl"" N~ N ~

e

"~N"N

R3 R2 ,~ "N~N 26

CO2Me I~,,,~.I~! + G CO2Me 30

R2 R3 R2 N~---~N R ~ . ~ N RI 27

28

MeO2C

O

N

MeO2C

O

31

29

6.2.3.3 Applications

A couple of specialized applications of pyridazines were disclosed. For instance, carboxylic anhydrides can be prepared from the corresponding carboxylic acids using 4,5-dichloro-2-[(4nitrophenyl)sulfonyl]pyridazin-3(2H)-one <03S 1517>. The lipase-catalyzed resolution of 2(acyloxymethyl)-4,5-dihydro-5-methylpyridazin-3(2H)-ones 32 was shown to be a practical way to obtain a chiral pyridazinone like 33 bearing a pyrazolopyridine ring <03TA529>, and the biochemical properties of a novel 5,6,7,8-tetrahydropyrimido[4,5-c]pyridazine nucleoside were described <03HCA 1193>.

352

M.P. Groziak

CH2OCOR ~ N ,I~ \ ~ 1] N~____ Me

H

1. lipase -"

2. deprotect

32

, N--

I Me

98%

ee

Et" b, R = But

A nice collection of biologically active pyridazines and benzo-fused derivatives was reported. The pyridazinone nucleus emerged as a key central unit in the development of melanocortin subtype-4 receptor agonists <03BMCL4431 >, and the imidazo[ 1,2-b]pyridazine one was a key component in a new class of broad spectrum antirhinoviral agents <03JMC4333>. cisTetrahydrophthalazinone/pyridazinone hybrids were developed as dual PDE3/PDE4 inhibitors <03JMC2008>, and a Stille-based approach generated 5-substituted-6-phenyl-3(2H)pyridazinone platelet-aggregation inhibitors <03CPB427>. 6-(5-Chloro-3-methylbenzofuran-2sulfonyl)-2H-pyridazin-3-one was developed as a novel aldose reductase inhibitor <03JMC2283>, and [(arylpiperazinyl)alkyl]pyridazinones were synthesized as selective aladrenoceptor antagonists <03JMC3555>. Among the other pyridazine-based bioactive agents investigated were [(3-chlorophenyl)piperazinylpropyl]pyridazinones as antinociceptive agents <03JMC1055>, pyridazinones as COX-2 inhibitors <03BMCL597>, pyridazinonearylpiperazines as C~l-adrenoceptor antagonists <03BMCL 171 >, a 5H-indeno[ 1,2-c]pyridazin-5one derivative as a rationally designed monoamine oxidase B (MAO-B) inhibitor <03BMCL69>, 7-chloro-2,3-dihydro-2- [ 1-(pyridinyl)alkyl]pyridazino[4,5-b]quinoline- 1,4,10(5H)-triones as NMDA glycine-site antagonists <03BMCL3553>, 5-aryl-pyrazolo[3,4-b]pyridazines as inhibitors of glycogen synthase kinase-3 <03BMCL1581>, and 3-arylamino- and 3cycloalkylamino-5,6-diphenylpyridazines as ACAT inhibitors <03AP563>.

6.2.4 PYRIMIDINES AND BENZO DERIVATIVES

A large collection of pyrimidine-based compounds were examined by X-ray crystallography. An X-ray crystal structure of 6-amino-2-methyl-4-pyrimidone was obtained, and its N-amination of with O-(mesitylenesulfonyl)hydroxylamine was shown to give the corresponding 3-amino derivative <03CHE195>. The X-ray crystal structure of a monocyclopentadienyl complex of tantalum(V) with a chelating pyrimidinethiolate ligand was reported <03EJI493>. X-ray crystallography was used to study the intermolecular stacking in pyrazolo[3,4-d]pyrimidinebased pentamethylene-linked flexible molecules like 34 <03AX(C)42>. The effect on stacking of a bulky i-propyl group in comparison with a methyl or ethyl one in the related molecules 35 was also revealed by X-ray crystallography <03AX(C)523>. The crystal structures of ethyl 4'-(4methoxyphenyl)- 1',7"-dimethyl-2,3"-dioxo-5"-phenyl-2,3,2",3",4",5"-tetrahydro- 1H-indole-3spiro-2'-pyrrolidine-3'-spiro-2"-(thiazolo[3,2-a]pyrimidine)-6"-carboxylate 36 <03AX(E) 1416> and its closely related 37 <03AX(E)1618> revealed the two spiro junctions linking a planar 2oxindole ring, the pyrrolidine ring in an envelope conformation, and the thiazolidine and oxindole tings slightly distorted from planarity. Crystal structures of 4'-(4-chlorophenyl)<03AX(E) 1624> and 4'-(4-methoxyphenyl)- 1'-methyl-4",5",6",7"-tetrahydro- 1H-indole-3-spiro-

353

Six-Membered Ring Systems: Diazines and Benzo Derivatives

2'-pyrrolidine-3'-spiro-2"-(thiazolo[3,2-a]pyrimidine)-2(3H),3"(2"H)-dione <03AX(E) 1418>, 38a and b, respectively, showed similar features. Compound 38a was synthesized by the intermolecular [3+2] cycloaddition of 2-(4-chlorobenzylidene)-6,7-dihydro-5H-thiazolo[3,2a]pyrimidin-3-one and an azomethine ylide derived from isatin and sarcosine.

~ MeS

SIPr SMe

SiPr

i1:)rS

34

SIPr 35

OMe

R

,

Me'~N / ' / ~ O ~ 36

H

Me"~N / ' / ~ O ~ 37

H

N/~N'"OS ~N H b,R=OMe

38a, R = CI

The supramolecular structures of the isomers 5,7-dimethoxyimidazo[ 1,2-c]pyrimidine 39 and 7-methoxy- 1-methylimidazo[ 1,2-a]pyrimidin- 5( 1H)-one were determined by X-ray crystallography <03AX(C)363>. The hydrogen bonding in 2-amino-4-methoxy-6methylpyrimidine, 2-benzylamino-4-benzyloxy-6-methylpyrimidine, and 4-benzylamino-2,6bis(benzyloxy)pyrimidine 40 were examined by X-ray crystallography <03AX(C)9>. The crystal structure of 4-(2-pyridyl)-lH,2H-pyrido[1,2-c]pyrimidine-l,3-dione 41 revealed this heterocycle to have a reasonably planar ring system <03AX(E)511 >. Some C-N axially chiral Naryl-2(1H)-pyrimidinones were resolved by spontaneous crystallization in the absence of an outside chiral source <03AG(E)4360>. Folded and fully extended conformations were discovered by X-ray crystallographic examination of dissymmetric propylene-linker compounds like 42 containing pyrazolo[3,4-d]pyrimidine and phthalimide units <03AX(C)409>. Different hydrogen-bonded supramolecular structures were determined by X-ray crystallographic examination of 4-amino- 1-benzyl-2-(methylsulfanyl)pyrimidin-6 ( 1//)- one, 4-amino-6benzyloxy-2-(methylsulfanyl)pyrimidine, and 4-amino- 1-benzyl-2-(methylsulfanyl)- 5nitrosopyrimidin-6(1H)-one 43 <03AX(C)454>. By X-ray, 4,6-bis(methylsulfanyl)-l-(4phenoxybutyl)-lH-pyrazolo[3,4-d]pyrimidine 44 does not show any intramolecular aromatic pistacking interactions <03AX(C)494>.

354

M.P. Groziak

BnOOn

OMe

N MeO

N

N

~ N

O

N NHBn

39

H

40

O 41

R

N.H2

R1

N MeS

MeS 42

O

N

MeS

R2

I~n

O

43

44a, R ~ = SMe, R 2 = CH2OPh; b, R 1 = OH, R 2 = Ph

The crystal structure of 6-amino-3-bromo-l-(2-deoxy-2-fluoro-[3-D-arabinofuranosyl)-l,5dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 45, a fluorinated 2'-deoxyguanosine analogue, revealed it to have the sugar conformation of a ribonucleoside <03AX(C)406>. By X-ray, 2amino-4-(4-chlorophenylthio)-5-phenyl-6-(1-piperidyl)pyrimidine 46 exists as a convoluted Hbonded polymer chain <03AX(E)222>. The metal complex [4-amino-N-(pyrimidin-2yl)benzenesulfonamido-tcN](triphenylarsine-rAs)gold(I) 47 was examined by X-ray crystallography <03AX(E)707>. The major product of the reaction of K2[PtC14] with pyrimidine-2-thiol was reinvestigated, and the major product was shown to be the cis isomer of [Pt(III)2C12(pymS)4], supported by an X-ray crystal structure determination <03BCJ549>. The metal complex [4-amino-N-(pyrimidin-2-yl)benzenesulfonamido- ~cN](triphenylphosphine-toP)gold(I) 48 was examined by X-ray crystallography <03AX(C)95>. The crystal structure of the metal complex diaquabis(nitrato-tcO)bis(4,7-dihydro-l,2,4-triazolo[1,5-a]pyrimidin-7one-tcN3)copper(II) 49 was determined <03AX(E)903>. The tautomerism of 1,4-diazepines fused with pyrimidine rings was studied by NMR, X-ray, and computational methods. In 6,8diphenylpyrimido[4,5-b][1,5]diazepin-4-ols, the enamine was found to be more stable than the diimine form, but the opposite was found true for 6,8-diaryl-2,3,4,7-tetrahydro-l,3-dimethyl1H-pyrimido[4,5-b] [ 1,5]diazepine-2,4-diones <03JHC25>.

Br O

O

..2 5

"'r 46

c,

355

Six-Membered Ring Systems: Diazines and Benzo Derivatives

"" Ph3As- AuTN~S'~O

PhaP-Au-N' O~~<~

47

~ ."'~OH2 "N ~'~"N~H H20""'(~u"~''~ N.~]k h

48

Manganese(II) and copper(II) hexafluoroacetylacetonate 1:1 complexes 50 and 51 with 5-(4exhibit strong exchange coupling between the paramagnetic dication and the nitroxide unit <03JA10110>. Ab initio studies have suggested that 4-cyano-5-isocyanoimidazole 53 and 4,5-dicyanoimidazole might be formed to some extent in nitrosative deaminations of adenine via facile pyrimidine ring-opening in the dediazoniation of the adeninediazonium ion 52 <03OL4077>. The H-bonding and solvent effects in the alkylation of pyrimidine bases by a quinone methide (54 --* 55 --- 56 or 57) was the subject of a DFT computational study <03JA3544>. The influence ofheteroatom substitution in the aromatic ring of aminopyrimidines on amino group characteristics in both free and H-bonded molecules was investigated <03JMS125>. NMR analysis of the protonation of N , N , N ' , N ' , N " , N " h e x a m e t h y l 2,4,6-pyrimidinetriamine 58a showed that an equilibrium of C5- and N l-protonated forms predominated. NMR titration data revealed the pKa of these species to be 6.87 and 6.89, respectively <03JA2535>. [N-tert-butyl-N-aminoxyl]phenyl)pyrimidine,

hfac2 hfac2 Mn But,,N..O-Cu "N-'~ N ".N.,,'~N

O But_N'

+

,) N

h

--

"Mn- 0 "N'Bu t I 50 hfac2

N"C

N

"C~"N

N

-

H

52

N ~,,,,N.

"Cu- O" N "But I 51 hfac2

O'-.H. _--

54

55

R

53

OH or ~ N H

56

57

Iq

356

M.P. Groziak

R Me2N.,.~~NMe2 NMe2

H R + H+ M e 2 N . 7 ~ N M e NMe2

2

58a, R= H;

N_

NMe2

,~

NMe2

6.2.4.1 Syntheses Solid-phase syntheses of pyrimidines continue to appear at a rapid pace. A solid-phase synthesis of 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide was directly scaled up in excellent yields and high purity <03OPRD553>. The synthesis of imidazo[1,2-a]pyrimidines 59 via condensation of a solid-supported c~-bromoketone and 2-aminopyridines was reported <03TL6265>. Pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones have been accessed via a versatile solid-phase synthetic route <03S1739>. A microwave-assisted solid support synthesis of 5methyl-6-ethylcarboxylate-2-thioxothieno[3,2-d]pyrimidine-4(1H)-ones from 2-amino-3,5diethyl carboxylate-4-methylthiophene and monosubstituted thioureas was reported <03BKC1038>.

Microwave irradiation is by now an established tool in organic synthesis, and its use in pyrimidine syntheses is particularly valuable. A one-pot reaction for annulating a pyrimidine ring onto thiazoles 60 under microwave irradiation and solventless conditions was reported <03T5411>. A one-pot annulation of pyrimidine rings onto azoles under microwave irradiation and solvent-free conditions was reported <03S63>. A microwave-assisted, one-pot cyclocondensation of a,[3-unsaturated esters, amidines, and malononitrile or ethyl cyanoacetate was shown to be a high-yield, three-component synthesis of pyrido[2,3-d]pyrimidines 61 <03TL5385>. A very high yield microwave-assisted synthesis of 2,4-disubstituted and 2,4,6trisubstituted pyrimidines from amidines and alkynones was described <03SL259>. A synthesis of 2-amino-4,6-diaryl-substituted pyrimidines was improved via the use of microwaves <03IJHll5>. A one-pot, 3-component synthesis of pyrano[2,3-d]pyrimidines 62 and pyrido[2,3-d]pyrimidines 63 relied upon microwave heating in the solid state <03TL8307>. The synthesis of 2-substituted isomers of the meridianins, bioactive indole alkaloids from the tunicate Aplidium meridianum, relied upon a microwave-assisted Fischer cyclization as the key step <03CPB975>. The microwave-assisted Biginelli cyclocondensation of [3-ketoester, aryl aldehydes, and thiourea derivatives led to bi- and tricyclic pyrimidine derivatives <03PS1269>. The direct microwave-assisted Sonogashira coupling of pyrimidinones 64 and uridine with alkynes gave the corresponding 5-alkynyl derivatives 65 or the furano-fused pyrimidines 66 with propargyl alcohol <03TL9181>. The classical thermal and microwave assisted Negishi crosscoupling synthesis of pyridinyl-pyrimidines were compared, and the latter was found to allow

357

Six-Membered Ring Systems: Diazines and Benzo Derivatives

efficient access to di-coupled compounds <03SL1862>. Polyphosphate ester was found to be a useful reaction moderator in the microwave assisted synthesis of pyrimidines via the Biginelli reaction <03PS1241>. The C5 iodination of substituted pyrimidinones and pyrimidine nucleosides has been improved in a microwave-assisted protocol <03S 1039>. 1. Gly, Ac20 Arl

60

RL.....CO2Me

CN

x O RO~"~ "N

In.

MW

MeOH

04J~"N" "0" -NH2 or R2

X.~N~R "1 M

65

2

3

R

PdC/2(PPh3)2, Et3N, Cul, DMF MW, 5 min

R4

O,,~N_ "N- "NH 2 R2 63

O N

N...:

R2 R3 61 R3 = NH2, OH O Ph

62 R3

I

I~~N-~

.:

Ph

X = OH, NH2, NH2OH J R

O--N

MW, 10 min 100-140 *C

O

PhCHO, R3CH2CN

H2N,J,,~N~Ar'I 0 1 H

NaOMe,

NH + H2N " ~ R 4

X = CN, CO2Me

x

2. H 3 0 +

Ar2~/N<.v-S

OH

/

CH2OH ~O-~k O

1

. . j ~ N ~ R2 ~ same/ X N R1 conditions (a 1 = H)

2

I

64

66

In the first example of an anionic domino reaction in the indole series, indolo[3,2e][1,2,3]triazolo[1,5-a]pyrimidine derivatives were smoothly prepared from ethyl 2-azido-1methyl-lH-indole-3-carboxylate and substituted acetonitriles <03H(60)2669>. Imidazo[1,2a]pyrimidines and imidazo[1,2-c]pyrimidine 68 were among the heterocycles prepared in regiospecific fashion using 1,2-bis(benzotriazolyl)- 1,2-(dialkylamino)ethanes 67 <03JOC4935>. Hexa- and octahydropyrido[3'2':4,5]thieno[3,2-d]pyrimidines have been prepared <03CHE 110>, as have heteroaryl-substituted pyrimidinyl-imino-4-thiazolidinones <03IJH209>. Cyclization of 3-alkenylpyrido[1,2-a]pyrimidines 69 was shown to lead to furo[2,3-d]pyrido[1,2a]pyrimidines 7t) <03TL 1939>, and convenient syntheses of 3-substituted pyrido[4',3':4,5]thieno[2,3-d]pyrimidines and some of their fused thiazolo derivatives were reported <03HAC201>. Condensed pyrimidine derivatives were obtained from N-chloroacetyl derivatives and malononitrile <03PS649>. Bridged-head azolo[3,2-a]pyrimidines 71 and 73 have been obtained through ring transformation of 2H-pyran-2-ones 72 <03T7141 >, and benzopyrano pyrano pyrimidines and benzopyrano pyrano thiopyrimidines were prepared from 4hydroxycoumarin and barbituric or thiobarbituric acid, respectively <03IJC 184>.

358

M.P. Groziak

'-~N)n

R3 R2X~<.y.R4 R I ~ N i~,,"NH2 +

X =C,N; Y =C, N

H

~.._?

I

.OH

RI

-'-

4

0

X-N R-~S ~.~NH2 SMe

HS.~

"R 2 70

NC

H N

0

72

68

~L,,~_.jkl . ~ ~

69 O

R4

CN

Z

n=0,1

Ar

71

)n

67, Z = O, N"

Me~ N

NG

Bt

R3 R2X'~Y"

Bt

Ar 73

Condensation and cyclization routes to pyrimidines proved fruitful. An oxidative cyclization route to cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates 74 and 75 was reported <03T3709>. An efficient synthesis of pyrido[3,2-d]pyrimidine-2,4-diones 77 was based upon the conversion of 2,3-pyridinedicarboxylic anhydride 76 into its half-ester, followed by Curtius rearrangement and condensation with amino acids <03TL2745>. Alkynylsubstituted pyrimidines 79 were synthesized in a practical manner by cyclocondensation of diacetylenic ketones 78 and amidines <03T2197>. A one-pot, 3-component synthesis of pyrimidines by a coupling-addition-cyclocondensation sequence was developed <03S2815>, and a facile synthesis of 2-substituted imidazo[1,2-a]pyrimidines by cyclocondensation of alkynyl(phenyl)iodonium salts and 2-aminopyrimidine was reported <03JHC909>. Triazolo[4,3-a]pyrimidines were prepared via cyclocondensation of a 2-thioxopyrimidin-4(3H)one with hydrazonoyl halides <03HCA739>. The condensation of (Z)-2-benzoylamino-4dimethylamino-2-oxo-3-butene with amidines was shown to afford pyrimidines 80 and 81, as well as other heterocycles <03ARK77>. A regioselective synthesis of 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones 82 by radical cyclization was reported <03T2151>. A convenient route to trifluoro[chloro]methylated 2-(5-hydroxy-5-trifluoro[chloro]methyl-4,5dihydro-lH-pyrazol-l-yl)pyrimidines via regiospecific cyclization was reported <03S894>. 2H1,2,3-Triazolo[4,5-d]pyrimidine-5,7-diones were prepared from uracils via cyclization of [3-azoct,13-unsaturated sulfilimines <03H(60)2677>. An alternative synthesis of 5-aminopyrazolo[4,3d]pyrimidin-7(6/-/)-one was accomplished via an intramolecular cyclization reaction <03BKC1365>. Novel 7-oxo-7H-pyrrolo[3,2-d]pyrimidine 5-oxides were prepared via cyclization in 1-(5-nitro-6-pyrimidinyl)-2-arylacetylenes <03SL 1151>. Pyrido[2,3-d] pyrimidine oxides 84 were synthesized via ring transformation of isoxazolo[3,4-d]pyrimidine 83 <03TL 1847>.

359

Six-Membered Ring Systems." Diazines and Benzo Derivatives a 1

~ N R1

~O~l~x,~.Oo ~ N , R 2 BF474

N'R~20 O

76

O

A

O BF4-v

75

NN"R1 c,R ~=Ph,R2=H; ,/~O d, R 1 = R 2 = M e ; e, R ~ = R 2 = Et; ' ~=12 f, R 1 = R 2 = Ph

Hi 1. CIC02Et, NaN3 ~ ~ N ~ . O

MeOH = ~~.-C02H

"N" "CO2Me2" aminoacid, tt'.-N~,,N,~CO2H 1 N NaOH O R 77 a1

0 R"

+

a, R 1 = M e , R 2 = H; b, R 1 = B u , R 2 = H;

~ I N ~ A r (NH2)

78

C02Et

O

R R2N J~ 0

R3 O J N I ~ 82

BzNH

Me

80

R1 0 Me"N"~--~"X +H~ 2

O

R2N...~,O----~ O"~N~ B r ~

C02Et

R3

~'~N"~%SH

B z N H ~ N'N Me 81 CN 0 Me-N~R2

O~-NIL~NP-RICH(~ O"~NIVle 83

84

-N- -NH2

IVle

+_

0

One-pot and catalytic syntheses of pyrimidines continued to be developed as attractive, efficient routes to pyrimidines. For example, a one-pot synthesis of pyrimidines by tandem oxidation-heteroannulation of propargylic alcohols was reported <03SL1443>, as was a one-pot conversion of pyrimidinones to substituted pyrimidines using diphenylphosphinic chloride <03H(60)413>. One-pot syntheses of pyrimidinylidenamidomonothiophosphoric esters <03PS851> and of 2,4-disubstituted 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidines 86 via a (CF3CO)zO-mediated reaction of 1-benzosuberone 85 and nitriles were also reported <03TL2149>. A rapid synthesis of 6-alkyl-5-(4'-aminophenyl)pyrimidine-2,4-diamines without the need for chromatography was reported <03SC3467>. A KF/AI203 catalyst was used in a synthesis of polysubstituted pyrimidines from ketene dithioacetals <03SC3989>. An asymmetric autocatalytic synthesis of pyrimidyl alkanols 87 without added chiral substances was developed <03TA185>.

R Tf20-

85

R.~Ng

86

i-Pr2Zn N -- R

"'OH (S)-alkanol

87, R = C=CBut

360

M.P. Groziak

Other efficient pyrimidine syntheses were developed. A modular synthesis of functionalized pyrimidinones 88 and 89 via a selective sulfide and halide cross-coupling protocol was reported <03OL4349>. A series of benzyl 2,4-dioxo-2,3,4,5-tetrahydro-lH-pyrrolo[3,2-d]pyrimidine-6carboxylates 91 were prepared in four steps from the diprotected 4-oxoproline 90 by a general method in which diversity is readily added to the pyrimidine ring nitrogens <03JOC6984>. A solution-phase parallel synthesis of 4,6-diarylpyrimidine-2-ylamines 91 via a rearrangement reaction was developed <03T655>. A fluorous approach in which the fluoroalkylthiolate moiety of pyrimidine 92 was used as a phase tag facilitated the synthesis of disubstituted pyrimidines 93 <03OL1011>. A "catch and release" synthesis of fused 2-alkylthiopyrimidinones 94 was mediated by the polymer-bound base P-BEMP <03TL5041 >. A new entry to a three-component synthesis of 2,4-disubstituted pyrimidines 95 was developed using TMS-ynones and Sonogashira coupling conditions <03OL3451>. A highly efficient (5 step) and scalable route to trisubstituted pyrido[2,3-d]pyrimidin-7-ones 96 was described <03TL4567>.

Br,~

O

O RI,~N,CH2CO2But

N,,CH2CO2But

~N~L~sR

=

~N~sJ,~sR

Br,~ or

O

~N~...R 1 89

88

~

, PhF

CO2Bn

O

>=

N,,CH2CO2But

R1 N

~ ""~'~CO2Bn R2N~ " N : O H

1. EtOH, Ar,,..~~l- Ar2 50% aq. KOH, ~I ~, ~O J~ +H2N,~.NH reflux, 1-3 h '"-~r~'' Ar1" ".,..~ ~Ar2 NH2 2. 30% aq. H202 NH2

89

90

/

91

CF3~'N-'-H CF3(CF2)7CH2CH2.,.S~ , , ~ Me m N N 92

"~ CI

Nuc..~~Me OXONE ~

Nuc:

N

N

Nq~~ CF3

93

361

Six-Membered Ring Systems: Diazines and Benzo Derivatives

R2NCS, .--. -CO2Me electrophile

O -- ./,IL,. R2 R1 ,'~. . R1,'-~" "IliON/~N "-" NH2 P-BEMP "" - ' SR3 "catch & release" 94 CI

~

I

N CI"J~'N//LxsMe

O RI.~..CI

I

~

1. ---- TMS, Pd/Cu,Et3N

RI-.~ N...F~N R2

NH R2

R2LNH2

95

R1 = (heter)aryl, R2 - various

I t. ~-" O ~ N ~ N H R 3 R1 96 !

Pyrimidines were sometimes obtained using atypical reagents or starting materials. 5,7Dialky•-4•6-di•x•-4•5•6•7-tetrahydr•is•thiaz•l•[3•4-d]pyrimidine-3-carb•nitriles 99 have been synthesized from 6-amino-l,3-dialkyluracils 97 and 4,5-dichloro-SH-1,2,3-dithiazolium chloride 98 (Appel's salt) <03OL507>. A carbodiimide-mediated preparation of the tricyclic pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine ring system led to the total synthesis of the marine antitumor alkaloid Variolin B 100 and its analogs <03JOC489>. 1-(N-Alkylidene or benzylideneamino)-l,6-dihydro-2-methylthio-6-oxo-pyrimidines were prepared from Meldrum's acid derivatives <03SC927>. The reaction of dimethyl N-cyanodithioiminocarbonate with cyanoacetanilides was shown to constitute an efficient synthesis of N-aryl-6-methylsulfanyl-4pyrimidinones, among other compounds <03SC2095>. Pyrimidine derivatives were obtained by the reaction of chalcones and urea or thiourea <03PS475>. 1,2,4-Triazolo[4,3-a]pyrimidine derivatives were obtained from hydrazonoyl halides <03HAC421>, as were 1,2,4-triazolino[4,3a]pyrimidines and other heterocycles <03PSll01>. Pyrimidinylideneamidothiophosphoric dichlorides were obtained by sulfurization of the corresponding aminodichlorophosphines, generated in situ from N-alkyl-2-aminocycloiminium halides and PCI3 <03HAC498>. Under mild conditions, addition of substituted 2-aminopyridines 101 to activated alkynoates led to the formation of 4-trifluoromethylpyrido[1,2-a]pyrimidin-2-ones 102 <03TL3659>. Pyrimidinyl nitronyl nitroxides featuring the bis-N-oxy fragment included in a 6-membered ring have been prepared along a multi-step route from diacetonamine. One of them was analyzed by X-ray crystallography <03CC2722>. CI

O

+ ~..

R - l / ~ N ~I O

NH2

Me 97

CI

98

O

CN

~5"sN" CI- R- N.~~N,S pyr, CH2CI2 O 23 ~ 24 h

IVle

O

Nuc

Nuc :~ R-/~.N~~N8 O IVle 99

362

M.P. Groziak

H2N" N

R I~N/~ 100

F3C~CO2Et I~N~ N NH F3C~,,,,J,.,~~O

101

H2N

102

Regioselectivity was often addressed in pyrimidine syntheses. A regioselective method for preparing substituted hydroxyspiro([1]benzopyran-2,4'(l'H)-pyrimidine)-2'(3'H)thiones and hydroxyspiro-([1]benzopyran-2,4'(l'H)-pyrimidin)-2'(3'H)ones was reported <03CHE233>. 5H-Thiazolo[3,2-a]pyrimidines 103 and 2H,6H-pyrimido[2, l-b][ 1,3]thiazines 104 were among the heterocycles accessed from thiourea in an efficient regioselective synthesis of biheterocyclic compounds <03JOC4912>. Regioisomeric pyrimidine annulated heterocycles have been obtained from 6-cyclopent-2-enyl-5-hydroxy-l,3-dimethylpyrimidine-2,4(1H,3H)-dione and 5-cyclopent2-enyl-6-hydroxy- 1,3-dimethylpyrimidine-2,4(1 H,3H)-dione <03M 1137>.

N~T'~ss~R1 R2J'~,,X. N-..~ 103

N~.S. R2~X " N ~ R 1 104

Among the fused thiazoles obtained from 2-(4-phenyl-3H-thiazol-2-ylidene)malononitrile were thiazolo [3,2-c] pyrimidines and pyrazolo [3,4-d]- 1,3-thiazolino [2,3-f] pyrimidines <03SUL35>. A versatile synthesis of pyrido[4',3':4,5]thieno[2,3-d]pyrimidines and fused derivatives was developed <03PSI>. A series of new benzo[4,5]thieno[2,3-d]pyrimidines equipped with a C2 propanoic acid substituent and a C3 amino, aryl, aminosugar, or arylmethylideneamino substituent have been prepared <03PS245>. A new approach to the synthesis of 2,5-diamino-5,6-dihydro- 1H-pyrimidine-4-ones 105 related to TAN- 1057A/B 106 was developed <03TL5871>. Facile syntheses of 5-arylpyrazolo[4,3-d]pyrimidin-7-ones <03IJC343> and 3-substituted-2,3-dihydropyrido[3,2-d]pyrimidine-2,4-diones <03SC4259> were reported. 4,6-Disubstituted thieno[2,3-d]pyrimidines were prepared from 4,6-dichloro-2methylthiopyrimidine-5-carbaldehyde <03HEC89>. 3H-Quinazolin-4-ones 107a and b containing pyrimidinone moieties were synthesized <03MOL363>, and 3-substituted pyrido[4',3':4,5]thieno[2,3-d]pyrimidines and related fused thiazolo derivatives were prepared <03PS667>. Me

Me

RINHC(=NH)NH2 Boc,.Ni .~,--,.N.R1 B~ ~CO2Et ' O-~N//L'-NH2 105

NH Me H 2 N ~ N ~ N ~ R1 ~ H ~H2 ~ O ~ N L N L N H 2 106

R2

Six-Membered Ring Systems: Diazines and Benzo Derivatives HMe

363

~N..~O

N.N~~~N Me 107a, R = H; b,R=Br

2,3-Dihydroxypropyl derivatives of 4-aryl-6-methyl-5-nitro-l,4(3,4)-dihydropyrimidin-2ones were synthesized <03CHE 188>, as were thieno- and pyrrolo[2,3-d]pyrimidines peri-fused with pyrimidine, 1,4-diazepine and 1,4-thiazepine rings <03S1377>. The synthesis and structure of isomeric 5(1H)-oxo and 7(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates were reported <03JHC93>. The preparation of benz[4,5]imidazo[1,2-c]pyrido[3',2':4,5]thieno[2,3e]pyrimidine, a member of a new heterocyclic ring system, was reported <03CHE255>. Pyrimido [3,2-c] tetrahydroisoquinoline-2,4-dione s were obtained from 1,3-dialkyl- 5[(bromobenzyl)methylamino]pyrimidine-2,4-diones by treatment with aryl radicals <03S920>. Pyrazolo[3,4-d]pyrimidines have been obtained by reaction of 3,5-bis(dimethylaminomethylene)amino-4-methoxycarbonylpyrazole and 4-cyanopyrazole with amines <03CHE238>. New routes to pyridino[2,3-d]pyrimidin-4-one and pyridino[2,3-d]triazolino[4,5-a]pyrimidin-5ones 108a-c were described <03MOL333>. N-Alkyl-6-hydroxy-5-(2,3,4,9-tetrahydro-lH-fScarbolin-l-yl)-lH-pyrimidine-2,4-diones and their 2-thio analogs were prepared from 3,4dihydro-f~-carboline and N-substituted barbituric or 2-thiobarbituric acids, respectively <03RJO596>. Ph

O

R1

'N~L~N~N~-~

P~

108a, R 1 = CO2Et, R 2 = NH2; b, R 1 = CN, R 2 = NH2; c, R 1 = Ph, R2= CN

(+)-R-7-Benzyloxymethyl-cyclopenta-cis-[4,5][ 1,3 ] oxazolo [3,2-a]pyrimidinone s 109a-c versatile carbocyclic nucleoside precursorsmwere prepared rapidly from 1-hydroxymethyl-3cyclopentene <03T671>. Pyrene-modified purine and pyrimidine nucleosides were obtained via Suzuki-Miyaura cross-couplings, and their fluorescent properties were characterized <03S2335>. Pyrimidine nucleoside analogs 112 have been prepared by [4+2] cycloaddition reaction of glycosyl isothiocyanates 110 and the diazadienium salt 111 <03JOC8583>. An efficient route to 2,3-anhydro-13-D-lyxofuranosyl pyrimidine nucleosides was described <03SL1271>. A straightforward synthesis of labeled and unlabeled pyrimidine didehydro-dideoxynucleosides via the use of a ring-closing metathesis reaction <03EJO666>. Novel deoxy phospha sugar pyrimidine nucleosides 114 were synthesized in high yield by treating the (+)-2aminophospholane 1-oxide 113 with various acrylamide derivatives <03TL3455>. m

364

M.P. Groziak

R

9 '%O F ' ~ N

%H

x

109a, R = Me, X = O;

b, R=H,X=O; c,R=H,X=NH

+

SMe ~~ N ,.-

-

SNH21 ~ C,I + ..1~ MeS NMe2 S Sugar Sugalr 110 111 112

~

Ph

~ Me

=~

Ph

O a~ JJ.. a2

NH~

=

OH 113

I

"~H 114

6.2.4.2 Reactions

1,3-Dipolar cycloadditions of mesitylnitrile oxide to the exocyclic double bond of 7methylenepyrrolo[ 1,2-c]pyrimidin- l(5H)-ones led to spiroisoxazolinyl nucleosides in good yields <03SL2364>. Cyclization of conjugated azomethine ylides at the periphery of pyrido[ 1,2a]pyrimidines 115 led to stereoselective pyrroline-ring formation to give tricyclic products 116 <03T4581>. Irradiation of thiobarbiturates possessing an alkenyl or benzyl group in their Nalkyl side chain generates bi- and tricyclic fused pyrimidines <03H(59)303>, the synthesis of 5,5'-(pyridin-2-ylmethylene)dipyrimidinetrione from barbituric acid and 2pyridinecarboxaldehyde was shown to proceed via the reactive intermediate (pyridin-2ylmethylene)pyrimidinetrione <03JHC167>, and y-radiolysis of pyrimidine nucleobase 117 giving radical 118 has been shown to lead to tandem lesions as the major DNA damage product <03JA13376>.

O

NPh

O NHPh I ~ N ~ " ~ ~ .,,CO2Me

"~CO2Me - 115

fin

116 O N"H

0

~ 1..N.H

.,.-..,

u,mctr

(y-radiolysis) 0

\

117

,o

Bn

02

v

H20 0

\

,,Nvu

118

tandem lesions

3 6~

Six-Membered Ring Systems." D iazines and Benzo Derivatives

Treatment of pyrimidinethiones with gaseous Sell2 leads to 1,4,6-trisubstituted 2[1H]pyfimidineselenones <03H(60)2749>. Reaction of 2-ethoxycarbonylmethyl- 1,4,6trimethylpyrimidinium iodide with isoniazide and aminoguanidine gives bicyclic adducts <03CHE275>. The reaction of 2-substituted-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde oximes 120 with electron-deficient olefins to give pyrimidinones 119 and acetylenes to give pyrimidinones 121 was investigated <03T4113>, as was the chemical reactivity of [1,2,3]triazolo[1,5-a]- and [ 1,5-c]-pyrimidinium salts like 122 toward nucleophiles like morpholine, water, and NaOCH3, uncovering new 1-aza- and 2-azabutadienes 123 substituted by a 1,2,3-triazole ring <03T4297>. The Pd-catalyzed C3-regioselective arylation of imidazo[1,2a]pyrimidine 124 with aryl bromides to give substituted derivatives 125 was reported <03OL4835>, and spiroheterocycles 127 were obtained by treating 5-aryloxymethylene-6,7,8trihydropyrido[2,3-d]pyrimidines-2,4(1H,3H)diones 126a with H2SO4 or by treating 5-(0bromoaryloxymethylene)-6,7,8-trihydropyrido[2,3-d]pyrimidines-2,4(1H,3H)diones 126b with Bu3SnH <03T4309>. SNAr displacement reactions in pyrimidines and purines were found to be dramatically accelerated using CF3CO2H in CF3CH2OH <03CC2802>.

H O H'N--O _ I-

R1 NI

O

o

NOH ,

O

R3

120

119

[/

Me Ar1 N"~I--I~, NUC Me~N2 . /MeaN BF4- Ar L 122

121

Nuc Me Ar1 N'~N "N, Ar2

I,,~N,,,~l,q/~ ~k~..~N...,,~

+

~gr

AH

t

~

123

R

124

125 / ~ ~ R R1

Me. N O

R2

a 1

O~ ./~

O

~e

Ar1

O N"N, Me Me N''1~, H20 .J], IJ~," N,, Me" v ~Ar2 Ar"

4 Me '

126a, X = H;

b,X=Br

.

~ R2

Me.N

O.-J~,.N

IVle I~le

R3 127

366

M.P. Groziak

6.2.4.3 Applications Pyrimidines were valuable to the macromolecular and macrocycle fields. Dendritic macromolecules based on repeating units of the 2-arylpyrimidine 128 were prepared using 4,6dichloro-2-(4-methoxyphenyl)pyrimidine as the building block <03T3937>, and new macrocyclic pyrimidine derivatives were prepared for future use <03RJO257>. The preparation and use of stable isotope-labeled pyrimidines was valuable as well. The synthesis of fully [13C/15N]-labeled pyrimidine nucleosides was achieved from 13C-glucose and labeled nucleobases <03JOC1867>, and, using [13C/15N/2H]-labeled substrates, the pyrimidine unit of thiamin 131 (vitamin B1) in yeast has at last been shown to originate biosynthetically from a C5N fragment derived from a portion of pyridoxol 129 (vitamin B6) and an N-C-N fragment derived from L-histidine, the latter originating from urocanic acid 130 <03JA13094>.

CO2H N_

CH2OH

128

130

NH2

Me" "N"

.eJ%J

129

131

Me

-oH

As is typical, pyrimidine chemistry featured prominently in the nucleoside/nucleotide fields. New pyrimidine bi- and tricyclic nucleosides with conformationally locked sugars were prepared <03JOC6695>, and a triplex-forming oligonucleotide containing modified 1-isoquinolone as a nucleobase was used to selectively recognize a CG interruption in a homopurine-homopyrimidine tract of double-stranded DNA (dsDNA) <03T5123>. Nucleophilic ring-opening and rearrangement of the furanopyrimidine nucleoside 132 with NH2NH2 gave the new 6,6-bicyclic pyrimidopyridazin-7-one nucleoside 133. This thymidine mimic was analyzed by X-ray crystallography, and it was incorporated into DNA for biochemical studies <03TL3387>. A pyrimidine motif DNA triple stranded structure was studied by FTIR and UV spectroscopy <03JMS 183>. The 5'-amino-5'-phosphonate analogs of pyrimidine nucleoside monophosphates were prepared from their corresponding aldehydes <03JOC6108>. Me

,~IN~~ O N O HO

HN~~ jN'N~Y Me

H2NH2 132

O"~ N''J HO

133

367

Six-Membered Ring Systems: Diazines and Benzo Derivatives

Oligodeoxyribonucleotides bearing 2,2'-anhydro-13-D-arabinofuranosyluracil derivatives were conveniently converted into their arabinofuranosyl pyrimidine-based counterparts <03BMCL2441>. Mitsunobu condensations gave a series of 1,6-heptadienes substituted in the 4-position with purine and pyrimidine nucleic acid bases. Copolymerization products of these were obtained <03JOC1235>. The synthesis of the doubly-modified pyrimidine ribonucleoside 134 containing a 2'-aminoethoxy side-chain on the ribose and a 5-methyl-lH-pyrimidin-2-one base unit was reported <03TL5065>. Modified analogs of 2'-deoxyuridine and 2'-deoxycytidine triphosphate bearing a 7-amino-2,5-dioxaheptyl linker at the C5 position were synthesized as thermostable DNA polymerase substrates during PCR <03BMCL3735>. 3-Bromopyrazolo[3,4d]pyrimidine 2'-deoxy-2'-fluoro-~-D-arabinonucleosides like 135 were prepared as modified DNA constituents <03JOC5519>. 2'-Deoxy-3'-deutero pyrimidine nucleosides 136 prepared via stereospecific NaBH(OAc)3 reduction were incorporated into DNA oligomers <03OL917>. And finally, in an extremely intriguing report, random medium-size RNA analogs 138 with mixed pyrimidine and purine sequences were shown to arise via eutectic phase polymerization of activated monomers like pyrimidine 137 <03JA13734>.

DNA

N

Br

O

N

0..~. O f ,

DNA

NH3

HO ~.,,r

F/

N-H 2

NH

HO""--~ 7 '

134

0 M e . . , ~ N.H

o"

135 O I-+,N-P-O--~ 0

H'W 6- HO~OH

DNA 136

Mg 2+ pb 2+

-18 ~

(PN)n 138

137 Once again, a great many pyrimidines were prepared for their potential biological activity. Fluorophenyl-substituted thiazolo[4,5-d]pyrimidines <03AP216>, and C-2 sulfonamido pyrimidine nucleosides 139 <03T4047> were prepared as anticancer agents. 5HPyrido[3',2':5,6]thiopyrano[4,3-d]pyrimidines were among the planar heterocycles prepared as potential antiproliferative agents <03JHC783>. A new and efficient synthesis of Alimta 140 and other pyrrolo[2,3-d]pyrimidine anticancer agents was reported <03JOC9938>. 3'- and 5'Nitrooxy pyrimidine nucleoside nitrate esters as nitric oxide donor agents as anticancer and antiviral agents <03JMC995>, and 2,4-diamino-6-(arylaminomethyl)pyrido[2,3-d]pyrimidines <03JMC5074>, 2,4-diamino-5-(2',5'-disubstituted benzyl)pyrimidines <03JMC1726>, 6substituted 2,4-diaminothieno[2,3-d]pyrimidines like 141 <03EJM605>, 2,4-diamino-6(substituted benzyl)pyrido[2,3-d]pyrimidines like 142a,b <03BMC59>. quaternized 2aminopyrimido[4,5-d]pyrimidin-4(3H)-ones <03EJM719>, and novel pyrimidine-based glutamate derivatives as dihydrofolate reductase (DHFR) inhibitors <03JMC591>. The crystal

368

M.P. Groziak

structures of two polymorphs of the potent N9-C10 reversed-bridge pyrido[2,3-d]pyrimidine antifolate 143 in complex with DHFR were determined <03AX(D)654>.

X fi~ i arabinose

x = O or NH,R= 4-Me-C6H4SO2N X = NH,R = CONMe2 "N"

OH I H2N""~N ~

N

"SO2--

140

139

N,H2 Me "N ~ .,,,~N j~. H.,,jLN / ~ I (CH2)n--Ar H2N H2N 141 R

-

H.N ;-H2N

O

H "~N%.......~

O

(

"CO2Na CO2Na

NO~ ~ H.N H2N

R 142a, R = Me;

b,R=Et N/~,..,"N<.,[/NH2

CH O N, N I

CH30.,,~~ OH3 OCH3 143

NH2

In the antiinfective field, the synthesis and evaluation of pyrimidinone antibiotics with a broader spectrum against Gram-positive bacteria was reported <03BMCL2641>. New pyrimidines <031JC910, 03IJH217>, pyrimidine-incorporated 1,3,4-thiadiazoles <03IJH245>, pyrazolo[3,4-dJpyrimidines <03HAC530>, N-[5-(2-furanyl)-2-methyl-4-oxo-4H-thieno[2,3d]pyrimidin-3-yl]carboxamides and 3-substituted 5-(2-furanyl)-2-methyl-3H-thieno [2,3d]pyrimidin-4-ones 144 <03EJM89>, pyrimidine derivatives of 1,8-naphthyridine <03IJC636>, substituted thiazolyl-, oxazolyl-, and condensed pyrimidines derived from 4-aminophenyl-2H1,2,3-triazole <03IJH371>, substituted 1H-pyrazolylthiazolo[4,5-d]pyrimidines 145a,b <03EJM27>, and tetrahydrobenzothieno[2,3-d]pyrimidines <03PS439> were all prepared and examined as antimicrobial agents. Specific pyrazolo[3,4-d]pyrimidine-based inhibitors of microbial DNA polymerase-III were also designed and prepared <03JMC1824>. 2,3-Dihydro5H-5,7-diarylthiazolo [3,2-a]pyrimidine-3-ones <03IJC173>, benzofuro[3,2-d]pyrimidines <03JIC 187>, 2-substituted [ 1,3,4]thiadiazolothieno[3,2-e]pyrimidin-5(4H)-ones <03IJH33 5>, 3-aryl- 1-(5-methyl-4-acetyl-3-isoxazolyl)-2-thioxo-( 1H,3H, 5H)-pyrimidine-4,6-diones, and pyrazolo[3,4-d]pyrimidines featuring sulfur moieties <03PS1795> were prepared as both antibacterials and antifungals <03IJH357>.

369

Six-Membered Ring Systems: Diazines and Benzo Derivatives

N

O~N.,(NHCOR, N=CHR) <S.~ N~,,,,Me R=aryloralkyl

~

Me O

~N'N==~~~~NLHMe ~

144

R

145a,R=H; b, R=Me

2-(Methylsulfenyl)pyrido[1,2-a]pyrimidin-4-ylidenamines were prepared as 5-HT6 antagonists <03JMC4834>, pyrazolo[3,4-d]pyrimidines 146 related to olomoucine 147 <03EJM525>, and pyrazolo[4,3-d]pyrimidines <03BMCL2989> were prepared as cyclindependent kinase 2 inhibitors. Chemical modification and X-ray crystallography were used to identify 4,6-bis-anilino <03BMCL2955> and 2,4-bis-anilino <03BMCL2961> pyrimidines as cyclin-dependent kinase 4 (cdk4) inhibitors. Pyrimidinopyridine-triazene conjugates were examined as abl tyrosine kinase inhibitors <03BMCL3297>, pyrido[2,3-d]pyrimidin-7-ones are under development as antiresorptive bone-targeted inhibitors of Src tyrosine kinase <03BMCL3071>, and 2-amino-4-(3-bromoanilino)-6-benzylsubstituted pyrrolo[2,3d]pyrimidines are of interest as tyrosine kinase receptor inhibitors <03BMC5155>. N-(2,4Dioxo-l,2,3,4-tetrahydrothieno[3,2-d]pyrimidin-7-yl)guanidines were designed to be thymidine phosphorylase inhibitors <03BMCL 107>.

HN"~F , H

NHCH2CH2OH 146

NHBn M~

Nz NHCH2CH2OH 147

Thieno[2,3-d]pyrimidine-2,4-diones were prepared as gonadotropin-releasing hormone (GnRH) receptor antagonists <03BMCL3617>, and sulfonylamido-substituted pyrimidines were prepared as endothelin receptor antagonists <03BMCL955>. The solid-phase synthesis and structure-activity relationships of 1-substituted 4-amino-lH-pyrimidin-2-ones as antagonists of the receptor integrin etv133 were reported <03BMCL165>. New 3-aryl-6-(3thienyl)pyrazolo[1,5-a]pyrimidin-7-ones were synthesized as benzodiazapine receptor ligands <03JMC310>, and C9- and C2-substituted pyrazolo[4,3-e]-l,2,4-triazolo[1,5-c]pyrimidines were prepared as A2A and A3 adenosine receptor antagonists <03JMC1229>. Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines were shown to be adenosine receptor antagonists <03JMC4287>, and a thieno[2,3-d]pyrimidine-2,4-dione beating a C6 p-methoxyureidophenyl group was shown to be a highly potent and orally bioavailable antagonist for the human luteinizing hormone-releasing hormone (LHRH) receptor <03JMC113>.

370

M.P. Groziak

The combined effects of pyrimidine and purine antiviral agents were examined in the duck hepatitis B virus infection model <03AAC1842>. Acyclic bis-vinyl pyrimidines were shown to undergo ring closure metathesis, leading to a general route to the antiviral agent d4T <03T941>, and 5-substituted-2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines were prepared as acyclic nucleoside phosphonates antivirals <03JMC5064>. Structural analogs of C5- or C6substituted pyrimidine acyclo-nucleosides were prepared as anti-HIV-1 agents <03CPB630>. Pyrimidines were also used to construct phosphodiesterase inhibitors like the chloropyrimidinones 148 and 149 <03TL2717>. A 3D-QSAR study of 29 thieno[3,2d]pyrimidines as phosphodiesterase IV Inhibitors was undertaken to provide information for predicting affinities of still more potent compounds <03BMCL1403>. Compounds based on the [1]benzothienol[3,2-d]pyrimidin-4-one unit were examined as cyclooxygenase (COX-1 and COX-2) inhibitors <03AP429>. Bicyclic pyrimidinones as hepatitis-C virus NS3 protease inhibitors <03BMCL785>. 4(3H)-Pyrimidinone-based bicyclic and tricyclic heterocycles were selected as antiplatelet agents <03BMC123>, 2,4-disubstituted pyrimidines as KDR kinase inhibitors <03BMCL1673>, and 5,6,7-trisubstituted 4-aminopyrido[2,3-d]pyrimidines as adenosine kinase inhibitors <03JMC5249>.

o Me-N~ h O/,~NLNH2

0 POOl3 Me-N~... , A =-

Cl ..J.......NL N H 2 ~ 148

cI Me.N- ~ O.,~ N/~'...NH2 149

Barbituric acids and uracils equipped with a dimethoxyphenol or dimethylphenol unit were synthesized as anti-inflammatory agents <03CPB1451>, as were 6-dimethylamino-lHpyrazolo[3,4-d]pyrimidines <03BMC863> and pyrimidines equipped with a di-tert-butylphenol unit <03CPB309>. New steroidal derivatives 151a-e featuring a pyrimidine ring fused to the 16,17 position were synthesized from the steroid ketone precursor 150 <03MOL444>, but their biological activity remains to be investigated.

R 0

RC(=NH)NH2, NaOMe

151a, R = H;

b,R=Me; c, R = Ph; d, R = NH2;

e, R = O M e 150

6.2.5 PYRAZINES AND BENZO DERIVATIVES An large number of pyrazines were subjected to X-ray crystallographic analysis. Those in the realm of metal complexes included [/~-2,3,5,6-tetrakis(2-pyridyl)pyrazine]bis[chloroplatinum(II)] bis[trichloro(dimethyl sulfoxide-tcS)platinate(II)] 152 <03AX(E)411>, tetraaqua-l,2,4,5benzenetetracarboxylato(pyrazine)dicobalt(II) dihydrate <03AX(E)841 >, polymeric

371

Six-Membered Ring Systems." Diazines and Benzo Derivatives

tetraaqua( 1,2,4,5-benzenetetracarboxylato)(pyrazine)dinickel(II) dihydrate <03AX(E)734>, disodium bis( 1,2,4, 5-benzenetetracarboxylato)dihydroxytetrazincate(II) pyrazine 153 <03AX(E)731>, trans-lt-pyrazine-bis[bromotetrapyridineruthenium(II)] dihexafluorophosphate dimethylformamide disolvate 154 <03AX(E)679>, dipotassium disodium trans-bis(pyrazine2,3-dicarboxylato)cuprate(II) dithiocyanate dihydrate 155 <03AX(E)212>, dipotassium aquabis(pyrazine-2,3-dicarboxylato-tceN, O)cuprate(II) hexahydrate <03AX(E)800>, and catenapoly[[[tetraaquacobalt(II)]-~-pyrazine] phthalate] <03AX(E)961>.

'~"" N

CI I~t--N~'~h

2-

2+

0 /H- -NI~---~N- - HJO I

...~.Zn

~Zn/'/ (~

I

Zn~

~=0

b d~o ,-----( ,9 o ~ o o~/--~'/~~--~o-

CI I CI-Pt-Cl ,,,,~ N - - P t - - N , ~ ) Cl

~

O~-%Me

I

2

I

152

o=<

r

0

0

o

Zn -i\

\ 153

trans-

/ ~ N-Ru(py)4Br J2 .2PF6Br(py)4Ru-Nk~k

I:

N, , .(9---Cu-.o

2K+. 2Na+.

2-

-2SCN-2H20

154

0 155

New coordination polymers were prepared by hydrothermal reaction of squaric acid, pyrazine, and the metal halides FeC12.o4H20, CoBr2, and NiBr2. X-ray crystallography revealed their structures to be based on a metal atom coordinated by four water molecules and two pyrazine ligands in a slightly distorted octahedron <03ZN(B)52>. A pyrazine-pillared coordination cage that selectively binds planar guest molecules by intercalation was prepared by multicomponent assembly, and was shown to be stable even when the template was removed. The empty cages 156a,b strongly bind pyrene as well as 1,3-bis(4-methoxyphenyl)-3hydroxyprop-2-ene- 1-one <03AG(E)3909>.

372

M.P. Groziak

~X'NH2

H2N-M

tN~" ~

H2N N

%1

H2

156a, M : Pt; b,M=Pd

Spontaneous assembly of In(Ill) and the bidentate ditopic ligand pyrazine-2,3-dicarboxylic acid gave {[Ina(pzdc)6]3-}= which was shown by X-ray crystallography to have a metal-organic framework with a distorted NbO-like net <03CL796796>. The electronic absorption spectrum and reduction behavior of a multicomponent, trinuclear Ru(II) species containing 2,3-bis(2'pyridyl)pyrazine bridging ligands and 2,2'-biquinoline peripheral ligands were investigated <03CCC1677>. The FTIR spectra of pyrazinamide complexes of Mn 2+, Co 2+, Fe E+, Ni 2+, and Cd 2+ tetracyanonickelate were examined and found to suggest that they are similar in structure to Hofmann-type 2D coordination polymeric compounds <03JMS541 >. 2-Chloropyrazine and 2,6-dichloropyrazine were the subjects of a vibrational spectroscopic and quantum chemical study <03TC73>, and the physicochemical properties of 2-methyl- and 2phenylimidazo[1,2-a]pyrazin-3(7/-/)-one and their N- and O-alkylated derivatives were investigated by X-ray crystallography, as well as by UV/Vis and NMR spectroscopies, and computational methods <03BCJ236 l>. New, highly fluorescent heterocycles based on pyrazinofused 1,4,5,8-tetraazafulvalenes have been prepared and characterized by a variety of methods, including X-ray crystallography. They exhibit a strong red fluorescence at 605 nm <03H(60)2457>.

6.2.5.1 Syntheses Some very clever syntheses of pyrazines were reported. Tandem MnO2-mediated oxidation followed by in situ trapping with aromatic or aliphatic 1,2-diamines was shown to give rise to quinoxalines, dihydropyrazines, pyrazines, and piperazines without the need to isolate highly reactive 1,2-dicarbonyl intermediates <03CC2286>. A new intramolecular cyclization route to highly substituted chiral 6,7-dihydro-SH-imidazo[1,5-a]pyrazin-8-ones like 157 from Meldrum's acid was developed <03OL3907>, and 5-chloropyrido[3,4-b]pyrazines were prepared from 1,2dicarbonyl compounds and 2-chloro-3,4-diaminopyridine <03H(60)925>. A synthesis of

Six-Membered Ring Systems." Diazines and Benzo Derivatives

373

thieno[2,3-b]pyrazines based on the acylation-deacylation of 3,4-dihydro precursors was developed, and the X-ray structures of some of the products were obtained <03H(60)337>. O

Me

o

OMe

157

The synthesis of unusual pyrazine-phosphonates 158 along an aza-Wittig route was described <03T2617>, and new pyrido [3',2':4,5]thieno[2,3-e]pyrrolo[ 1,2-a]pyrazines were prepared from methyl 3-aminothieno[2,3-b]pyridinecarboxylates via a Curtius rearrangement <03HEC123>. The synthesis and excellent antioxidative properties of lipophilic N-alkylated 2-amino-5-(phydroxyphenyl)- 1,4-pyrazine and 2-amino-3,5-bis(p-hydroxyphenyl)- 1,4-pyrazine were reported <03S513>. New oxazolo[3,2-a]pyrazin-5-one scaffolds 159 possessing angular, ring junction substituents were prepared via bicyclocondensation of 3-aza-l,5-keto acids and amino alcohols <03OL2727>. 2,3,5,6-(Tetrapyridin-2-yl)pyrazine, an excellent tridentate ligand for Fe 2+, was prepared via aerial oxidation of a cobalt(II)-2-aminomethylpyridine complex <03H(59)283>. A Chiral intermediate (+)-5-substituted-6-(5-chloropyridin-2-yl)-7-oxo-5,6dihydropyrrolo[3,4-b]pyrazines 160 useful for the synthesis of (S)-(+)-zopiclone, a hypnotic agent, were obtained via enzymic resolution using immobilized C a n d i d a antarctica B lipase (CAL-B) <03TA429>.

O P(O)(OEt)2 RI"jj''R2

.o c

I~R3

0:~"/ R

P(O)(OEt)2 R1I~" R2

o "PG

159a, R = Me;

b, R =aryl

P(O)(OEt)2 Me2N Rll,~-.R2

p(o)(OEt)2 ~,~ p(o) (OEt)2 158

CI

RCO2

H20 CAL-B

0

O

~t~,, H N--~ RCO2 160

~'~H HO

N'-~

M.P. Groziak

374

6.2.5.2 Reactions The nucleophilic substitution, amination, aldol-type condensation, oxidation, and hydrolysis of the 1H-pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide system, structurally related to pteridine, were studied in detail <03HCA139>. Chlorinated pyrazines were directly oxidized to their corresponding N-oxides using dimethyldioxirane in a completely regioselective fashion <03HEC221 >. 1,6-Dibenzoyl-5H, 10H-diimidazo[ 1,5-a; l',5'-d]pyrazine-5,10-dione, prepared under Friedel-Crafts conditions, was shown to react with NH2NH2 to give a substituted imidazo[4,5-f]pyridazine <03CHE250>. Pyrazinones 161 were stereoselectively transformed via Diels-Alder reactions into substituted analogues of cis-5-amino-6-oxo-2-piperidinemethanol and cis-5-amino-2-piperidinemethanol 162 <03T5047>.

Ph CI

Bn ,

.N...O N

Bn ,

Ph~ . ~ O

R

161

O-"- "N- "R H

Ph

CF3

Bn

N~.O - R NHAc

Ph

Bn

_ F3C~ ' ~ ~ O / ' " ~ . 162 X = CO, CH2 R = aryl, alkyl

R NHAc

6.2.5.3 Applications There are a wide variety of applications for pyrazines and their benzo derivatives. Chemiluminescent 3,7-dihydroimidazo[1,2a]pyrazine-3-ones 164 have been prepared from 2amino-3,5-dibromopyrazine 163 <03T8129>. Poly(pyrazine-2,5-diyl), a new poly(p-phenylene) type polymer with a coplanar structure, was prepared by organometallic dehalogenative polycondensation of 2,5-dibromopyrazine in a microwave-assisted procedure <03MI4487>. Without added base, the deep navy-blue dimeric Cu complex [Cu(II)(H2L)(MeCN)]2(BF4)4 of the nondeprotonated bis-terdentate diamide ligand N, N'-bis(pyridylmethyl)-2,3pyrazinedicarboxamide was shown to self-assemble, but in the presence of base a grass-green grid complex [Cu(II)(HL)]a(BF4)4 of the monodeprotonated ligand was found to form. The latter is a rare example of a discrete grid of pyrazine-bridged metal ions <03CC2992>. 1,8-Pyrazine-capped 5,12-dioxocyclams were synthesized using 2,6-bis(bromomethyl)pyrazine, and they were complexed to Cu 2+ to give 5-cooordinate complexes featuring a distorted square pyramidal geometry <03IC4346>. The chiral auxiliary (2R)-2,5-dihydro-2-isopropyl-3,6dimethoxypyrazine was employed in Pd-complex-mediated 5-exo-trig-spiroannulations <03EJO332>. Pyrazine analogues 165 and 166 of dipyrrolylquinoxalines were synthesized and their anion binding properties were examined <03OL4141 >. Ruthenium complexes of substituted pyrazino[2,3-j'][1,10]phenanthrolines were prepared and characterized as potential solar-cell dyes <03HCA2110>. The binuclear complex [Ru(II)(NH3)5(pz)Ru(II)(bpy)2(NO)](PF6)5 167 was prepared, and this pyrazine-bridged nitrosyl ruthenium complex was shown to release NO upon irradiation with visible light by laser flash-photolysis <03JA 14718>. A pyrazinone core was used as a starting scaffold in the development of antithrombotic selective inhibitors of the tissue factor VIIa complex <03JMC4050>.

375

Six-Membered Ring Systems." Diazines and Benzo Derivatives

R30~ H2N..,N.. Br~,,N~Br

H2N,~N~,,] ~ RI~,.N/I,,,,.Br

H2N

O N

N

N

R1 N H

~ R "~N/~.R 2

163

R2

164

-

(H2N)5Ru--N,k 165

~

Z

--Ru.- - N

')

166

Among the bioactive pyrazines prepared were pyrazinoic acids as antifungals, antituberculars, and antibacterials <03IJH229>, pyrazino[1,2-a]indole-l,4-dione analogs of the mycotoxin gliotoxin as selective inhibitors of prenyltransferases <03BMCL3661>, and 5,6,7,8tetrahydropyrido[3,4-b]pyrazine hydroxamic acids as heparin-binding epidermal growth factor (HB-EGF) shedding inhibitors <03BMC433>. Substituted pyrazinones were found to be antagonists of the integrin etv[33 <03BMCL1809>. Using X-ray methods, pyrazinones were refined into antithrombotic inhibitors of the tissue factor/Factor VIIa complex <03BMCL2319>, and using computational ones, arylpiperazines were optimized to S-(-)-2-[[4-(naphth-1yl)piperazin-l-yl]methyl]- 1,4-dioxoperhydropyrrolo[1,2-a]pyrazine 168 as a 5-HT1A receptor agonist <03BMCL1429>. Finally, a poly(lactide-co-glycolide) microsphere-encased form of pyrazinamide 169 was developed as an oral agent for treating murine tuberculosis <03AAC3005>, and clinical Mycobacterium tuberculosis isolates were examined for pyrazinamidase activity, pyrazinamide susceptibility, and p n c A mutations <03AAC3672>. O

''N/~ N,v ~ 168

N O

N

NH2 169

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03BMCL2989 03BMCL3071

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03PS1 03PS245 03PS439 03PS475 03PS649 03PS667 03PS851 03PSl101 03PS1241 03PS1269 03PS1667 03PS1795 03PS1911 03RCR87 03RJO257 03RJO596 03S63 03S436 03S513 03S560 03S691 03S894 03S920 03S1039 03S1377 03S1517 03S1739 03S2335 03S2815 03SC927 03SC1067 03SCl155 03SC2095 03SC3467 03SC3989 03SC4259 03SL259 03SLl113 03SLl151 03SL1271 03SL1443 03SL1862 03SL2225

M.P. Groziak E.K. Ahmed, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 1. A.A.S. E1-Ahl, M.A. Ismail, F.A. Amer, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 245. A.M.S. E1-Sharief, J.A.A. Micky, N.A.M.M. Shmeiss, G. E1-Gharieb, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 439. O.S. Moustafa, R.A. Ahmad, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 475. A.M.M. Soliman, A. Khodairy, E.A. Ahmed, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 649. E.K. Ahmed, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 667. N. Gupta, V. Kabra, V. Saxena, S. Jain, K. Bhatnager, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 851. N.M. Rateb, N.A. Abdel-Riheem, A.A. A1-Atoom, A.O. Abdelhamid, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 1101. N. Foroughifar, A. Mobinikhaledi, H. Fathinejadjirandehi, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 1241. N. Foroughifar, A. Mobinikhaledi, H.F. Jirandehi, S. Memar, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 1269. K.M.H. Hilmy, R.M. Mohareb, A. E1-Torgman, Y.M. Sharawy, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 1667. Z.H. Ismail, S.M. Abdel-Gawad, A. Abdel-Aziem, M.M. Ghorab, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 1795. A.A. Aly, A.A.F. Wasfy, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 1911. A.B. Sheremetev, I.L. Yudin, Russ. Chem. Rev. 2003, 72, 87. V.P. Krivonogov, G.G. Kozlova, G.A. Sivkova, L.V. Spirikhin, I.B. Abdrakhmanov, Y.I. Murinov, G.A. Tolstikov, Russ. J. Org. Chem. 2003, 39(2), 257. K.A. Krasnov, V.G. Kartsev, M.N. Yurova, Russ. J. Org. Chem. 2003, 39(4), 596. L.D.S. Yadav, S. Singh, Synthesis 2003, 63. C. Brule, J.-P. Bouillon, E. Nicolai, C. Portella, Synthesis 2003, 436. P. Jeanjot, F. Bruyneel, A. Arrault, S. Gharbi, J.-F. Cavalier, A. Abels, C. Marchand, R. Touillaux, J.-F. Rees, J. Marchand-Brynaert, Synthesis 2003, 513. Y.-D. Park, J.-J. Kim, H.-A. Chung, D.-H. Kweon, S.-D. Cho, S.-G. Lee, Y.-J. Yoon, Synthesis 2003, 560. C.F. Marcos, S. Marcaccini, R. Pepino, C. Polo, T. Torroba, Synthesis 2003, 691. N. Zanatta, D.C. Flores, C.C. Madruga, D. Faoro, A.F.C. Flores, H.G. Bonacorso, M.A.P. Martins, Synthesis 2003, 894. K.C. Majumdar, P.P. Mukhopadhyay, Synthesis 2003, 920. L. Paolini, E. Petricci, F. Corelli, M. Botta, Synthesis 2003, 1039. S. Tumkevicius, Z. Sarakauskaite, V. Masevicius, Synthesis 2003, 1377. J.-J. Kim, Y.-D. Park, W.S. Lee, S.-D. Cho, Y.-J. Yoon, Synthesis 2003, 1517. N. Graveleau, T. Masquelin, Synthesis 2003, 1739. E. Mayer, L. Valis, R. Huber, N. Amann, H.-a. Wagenknecht, Synthesis 2003, 2335. A.S. Karpov, T.J.J. Mueller, Synthesis 2003, 2815. X. Huang, Z. Liu, Synth. Commun. 2003, 33, 927. K. Mogilaiah, N.V. Reddy, Synth. Commun. 2003, 33, 1067. J.-Q. Feng, C.-J. Sun, L.-Q. Qu, Synth. Commun. 2003, 33, 1155. G.H. Elgemeie, S.R. E1-Ezbawy, S.A. Sood, Synth. Commun. 2003, 33, 2095. D.D. Holsworth, M.S. Jeremy, J. Edmunds, W. He, S. Place, S. Maiti, Synth. Commun. 2003, 33, 3467. S.-Y. Yu, Y.-X. Cai, Synth. Commun. 2003, 33, 3989. R. Mamouni, M. Akssira, M. Aadil, A. Elhakmaoui, J. Lasri, E. Zaballos-Garcia, Synth. Commun. 2003, 33, 4259. M.C. Bagley, D.D. Hughes, P.H. Taylor, Synlett 2003, 259. E. Sotelo, E. Ravina, Synlett 2003, 1113. I. Susvilo, A. Brukstus, S. Tumkevicius, Synlett 2003, 1151. C.S. Callam, R.R. Gadikota, T.L. Lowary, Synlett 2003, 1271. M.C. Bagley, D.D. Hughes, H.M. Sabo, P.H. Taylor, X. Xiong, Synlett 2003, 1443. P. Stanetty, M. Schnuerch, M.D. Mihovilovic, Synlett 2003, 1862. J.C. Gonzalez-Gomez, E. Uriarte, Synlett 2003, 2225.

Six-Membered Ring Systems." Diazines and Benzo Derivatives

03SL2364 03SUL35 03T655 03T671 03T941 03T1739 03T2151 03T2197 03T2477 03T2617 03T3709 03T3937 03T4047 03T4113 03T4297 03T4309 03T4581 03T5047 03T5123 03T5411 03T5869 03T6375 03T7141 03T7669 03T8129 03T8171 03TA185 03TA429 03TA529 03TC73 03TL1847 03TL1939 03TL2149 03TL2717 03TL2745 03TL2919 03TL3387 03TL3455 03TL3659 03TL4459

3 83

R. Fischer, E. Hyrosova, A. Druckova, L. Fisera, C. Hametner, M.K. Cyranski, Synlett 2003, 2364. A.S. El-Din, Sulfur Lett. 2003, 26, 35. L. Varga, T. Nagy, I. Kovesdi, J. Benet-Buchholz, G. Dorman, L. Urge, F. Darvas, Tetrahedron 2003, 59, 655. N. Perez, B. Gordillo, Tetrahedron 2003, 59, 671. D.F. Ewing, V. Glacon, G. Mackenzie, D. Postel, C. Len, Tetrahedron 2003, 59, 941. A.A. Aly, Tetrahedron 2003, 59, 1739. K.C. Majumdar, P.K. Basu, P.P. Mukhopadhyay, S. Sarkar, S.K. Ghosh, P. Biswas, Tetrahedron 2003, 59, 2151. M.F.A. Adamo, R.M. Adlington, J.E. Baldwin, G.J. Pritchard, R.E. Rathmell, Tetrahedron 2003, 59, 2197. A. Coelho, E. Sotelo, E. Ravina, Tetrahedron 2003, 59, 2477. F. Palacios, A.M. Ochoa de Retana, E. Martinez de Marigorta, M. Rodriguez, J. Pagalday, Tetrahedron 2003, 59, 2617. S.-I. Naya, M. Nitta, Tetrahedron 2003, 59, 3709. W. Maes, D.B. Amabilino, W. Dehaen, Tetrahedron 2003, 59, 3937. I. Krizmanic, A. Visnjevac, M. Luic, L. Glavas-Obrovac, M. Zinic, B. Zinic, Tetrahedron 2003, 59, 4047. M. Shirai, H. Kuwabara, S. Matsumoto, H. Yamamoto, A. Kakehi, M. Noguchi, Tetrahedron 2003, 59, 4113. S. Batori, E. Gacs-Baitz, S. Bokotey, A. Messmer, Tetrahedron 2003, 59, 4297. K.C. Majumdar, S. Sarkar, T. Bhattacharrya, Tetrahedron 2003, 59, 4309. M. Noguchi, M. Shirai, K. Nakashima, I. Arai, A. Nishida, H. Yamamoto, A. Kakehi, Tetrahedron 2003, 59, 4581. J. Rogiers, W.M. De Borggraeve, S.M. Toppet, F. Compernolle, G.J. Hoomaert, Tetrahedron 2003, 59, 5047. Y. Hari, S. Obika, M. Sekiguchi, T. Imanishi, Tetrahedron 2003, 59, 5123. L.D.S. Yadav, S. Dubey, B.S. Yadav, Tetrahedron 2003, 59, 5411. J.M. Chezal, E. Moreau, O. Chavignon, C. Lartigue, Y. Blache, J.C. Teulade, Tetrahedron 2003, 59, 5869. F. Toudic, A. Heynderickx, N. Ple, A. Turck, G. Queguiner, Tetrahedron 2003, 59, 6375. V.J. Ram, P. Srivastava, A. Goel, Tetrahedron 2003, 59, 7141. A.V. Gulevskaya, O.V. Serduke, A.F. Pozharskii, D.V. Besedin, Tetrahedron 2003, 59, 7669. M. Adamczyk, S.R. Akireddy, D.D. Johnson, P.G. Mattingly, Y. Pan, R.E. Reddy, Tetrahedron 2003, 59, 8129. J.C. Gonzalez-Gomez, L. Santana, E. Uriarte, Tetrahedron 2003, 59, 8171. K. Soai, I. Sato, T. Shibata, S. Komiya, M. Hayashi, Y. Matsueda, H. Imamura, T. Hayase, H. Morioka, H. Tabira, J. Yamamoto, Y. Kowata, Tetrahedron: Asymmetry 2003, 14, 185. J.M. Palomo, C. Mateo, G. Fernandez-Lorente, L.F. Solares, M. Diaz, V.M. Sanchez, M. Bayod, V. Gotor, J.M. Guisan, R. Femandez-Lafuente, Tetrahedron: Asymmetry 2003, 14, 429. N. Yoshida, M. Aono, T. Tsubuki, K. Awano, T. Kobayashi, Tetrahedron: Asymmetry 2003, 14, 529. H. Endredi, F. Billes, S. Holly, THEOCHEM 2003, 633, 73. P.J. Bhuyan, H.N. Borah, R.C. Boruah, Tetrahedron Lett. 2003, 44, 1847. M. Gullu, S. Uzun, S. Yalcin, Tetrahedron Lett. 2003, 44, 1939. A. Herrera, R. Martinez-Alvarez, R. Chioua, M. Chioua, Tetrahedron Lett. 2003, 44, 2149. D. Gala, D.J. DiBenedetto, M. Kugleman, M.S. Puar, Tetrahedron Lett. 2003, 44, 2717. R. Mamouni, M. Aadil, M. Akssira, J. Lasri, J. Sepulveda-Arques, Tetrahedron Lett. 2003, 44, 2745. P. Raboisson, B. Mekonnen, N.P. Peet, Tetrahedron Lett. 2003, 44, 2919. D. Loakes, D.M. Brown, S.A. Salisbury, M.G. McDougall, C. Neagu, S. Nampalli, S. Kumar, Tetrahedron Lett. 2003, 44, 3387. M. Yamashita, V.K. Reddy, P.M. Reddy, Y. Kato, B. Haritha, K. Suzuki, M. Takahashi, T. Oshikawa, Tetrahedron Lett. 2003, 44, 3455. G.C.B. Harriman, S. Chi, M. Zhang, A. Crowe, R.A. Bennett, I. Parsons, Tetrahedron Lett. 2003, 44, 3659. E. Sotelo, A. Coelho, E. Ravina, Tetrahedron Lett. 2003, 44, 4459.

384

03TL4567 03TL5041 03TL5065 03TL5385 03TL5871 03TL6265 03TL7799 03TL8307 03TL8995 03TL9181 03ZK235 03ZN(B)52

M.P. Groziak

J. Kasparec, J.L. Adams, J. Sisko, D.J. Silva, Tetrahedron Lett. 2003, 44, 4567. G.L. Adams, T.L. Graybill, R.M. Sanchez, V.W. Magaard, G. Burton, R.A. Rivero, Tetrahedron Lett. 2003, 44, 5041. S. Buchini, C.J. Leumann, Tetrahedron Lett. 2003, 44, 5065. N. Mont, J. Teixido, J.I. Borrell, C.O. Kappe, Tetrahedron Lett. 2003, 44, 5385. L. Zhang, L. Xu, C.U. Kim, Tetrahedron Lett. 2003, 44, 5871. S. E1 Kazzouli, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet, Tetrahedron Lett. 2003, 44, 6265. Y.J. Lim, M. Angela, P.T. Buonora, Tetrahedron Lett. 21)03, 44, 7799. I. Devi, B.S.D. Kumar, P.J. Bhuyan, Tetrahedron Lett. 2003, 44, 8307. S.-D. Cho, S.-Y. Song, Y.-D. Park, J.-J. Kim, W.-H. Joo, M. Shiro, J.R. Falck, D.-S. Shin, Y.J. Yoon, Tetrahedron Lett. 2003, 44, 8995. E. Petricci, M. Radi, F. Corelli, M. Botta, Tetrahedron Lett. 2003, 44, 9181. A. Kochel, W. Malinka, A. Redzicka, Z. Kristallogr. 2003, 218, 235. C. Naether, J. Greve, I. Jess, Z. Naturforsch., B: Chem. Sci. 2003, 58, 52.

385

Chapter 6.3.

Triazines, Tetrazines and Fused Ring Polyaza Systems Carmen Ochoa, Pilar Goya and Cristina G6mez Instituto de Qufmica M~dica (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain e-mail: [email protected], [email protected]

6.3.1.

TRIAZINES

A novel dinuclear ruthenium(II) complex [(bpy)(2)Ru(bdptb)Ru(bpy)(2)](4+), where bpy = 2,2'-bipyridyl and bdptb = 2,2'-bis(5,6-diphenyl-l,2,4-triazin-3-yl)-4,4'-bipyridine), has been synthesized and characterized <03ICC773>. Binuclear and star-burst organoplatinum(II) complexes of 2,2'-dipyridylamino derived ligands containing a 1,3,5-triazine core have been described <03OM3781>. New tris(pyrazolyl)-l,3,5-triazine gold(l) and palladium(II) derivatives have been reported <03EJI2693>. Synthesis and characterization of coordination polymers of 1,2-bis(4-thio-l,3,5-hexahydrotriazin-l-yl)ethane have been described <03SRI775>. The structure of tris(3',5'-dimethylpyrazol-l-yl)-l,3,5-triazine and its use as a ligand in coordination chemistry have been studied <03KGS1584>. 1,3,5-Triazine derivatives having styryl or higher oligo(phenylenevinylene) chains in the 2, 4, and 6 positions have been described as star-shaped push-pull compounds <03EJO4173>. Melamine derivatives bearing a guanidinium ion were able to recognize nucleotides through hydrogen bondings <03H2217>. Permeable molecularcrystals of tetra(p-melamin-2-ylphenyl)methane were able to react with extemal agents to give crystalline products <03AG(E)5303>. Studies on covalent linkage of melamine and cyanurate, which improves the thermodynamic stability of hydrogen bonded double rosettes in polar solvents, have been carded out <03EJO1463>. A novel type of hydrogen bonded assembly based on the melamine-cyanuric acid motif has been reported <03JOC1097>. Cyanuric and thiocyanuric esters have been evaluated as boron-containing fragments and their fragmentation in mass spectrometry studied <03TL8689>. Facilitated forward chemical genetics using a tagged 1,3,5-triazine library and zebra fish embryo screening have been developed <03JA11804>. Competition reactions for the substitution of monochloro- 1,3,5-triazines with different amines provide relative reactivity data that can be used to identify new groups for the chemoselective syntheses of dendrimers based on melamine <03OL2359>. Structural investigations of three model 2,4,6-tfis(amino)-l,3,5-triazines, using solution and solid-state NMR studies plus a full structure determination by powder X-ray diffraction have been carried out <03MRC324>. Determination of dealkylated hydroxy-1,3,5-triazines has been developed by an enzyme-linked-immunosorbent assay <03MI156>. The capability of discriminating between Zn(II) and Co(II) by a new polydentate ligand, 2,4,6-(di-pyridin-2-ylamino)-l,3,5-triazine, has been studied <03POL205>. A 1,3,5-triazine-2,4,6-trione bearing three short side sulfonamide arms has been designed as a host for selective binding of chloride <03NJC172>. The

386

c. Ochoa, P. Goya and C. G6mez

preparation and characterization of a chromophore group containing cyclotriphosphazenes have been reported <03PS549>. The synthesis, structure and electrochemistry of cyclophosphazene hydrazides as scaffolds for multi-ferrocenyl assemblies have been studied <03OM976>. The determination of 31p coupling constants in cyclotriphosphazenes and their influence on 1H and 13C NMR spectra of phosphorus substituents have been evaluated <03MRC183>. The molecular ordering of photoreactive non-mesogenic 1,3,5-triazine compounds into columnar mesophases by charge-transfer interaction has been described <03TL7493>. Polymers containing terminal hydrogen bonding recognition motifs based on diamino-l,3,5-triazine in their side-chains for the self-assembly of appropriate receptors have been prepared by ring opening metathesis polymerization (ROMP) of norbornenes <03CEJ992>. A new template, (R)2-hydroxyethyl-l,3,5-triazine, has been used to design novel sorbitol dehydrogenase inhibitors <03BMC4179>.

6.3.1.1. Synthesis For the first time, the synthesis of 2-methyl-4,6-dialkyl-l,2,3-triazin-5-ones 3 from the corresponding cyclopropenones 1 via triazines 2, using Nakamura's method, has been achieved <03H477>.

R.~O

Et..N,,Et 0 Et3~)BF4 R~ I ~ N H R ,,R .. Mel ~. _'~ NaN3 NaOH ~e

+ Et- NH I R Et

1

2

3 (a-e)

R an'Pr b n-Bu c (CH2)4Me d (CH2)5Me 9cyclohexyl

Nucleophilic displacement of readily available ct,c~-dibromoketone 4 with excess of morpholine 5 gave the corresponding ketoaminals 6, which upon condensation with aminoguanidinium salts 7 afforded 5-substituted-3-amino-1,2,4-triazines 8 with more than 95% regioselectivity <03OL2271>.

O__~r r

R--

4

+

~t~

THF

~

R_~~

5

+

6

R = Ph,5-MeO-l-naphthyl

+ ~L. NH+, H3N.N__I~IH3 CO32_ 7

I AcOH MeOH R

N~

NH2

8 (45-76%) A general protocol for the rapid and high yield synthesis of diverse 3,5,6-trisubstituted-1,2,4triazines, by microwave assisted technology, has been developed <03TL1123>.

387

Triazines, Tetrazines and Fused Ring Polyaza Systems

The synthesis and biological activity of 2,4,6-triamino-substituted-l,3,5-triazines have been described <03JIC138>. The synthesis of N-substituted 2,4-diamino-6-(benzothiazolyl-2thiomethyl)-l,3,5-triazines 11 has been achieved from guanidine derivative 9 through intermediate 10 <03KGS730>. NH2 [~N~.._S_CH2CON S

H~

H C'3CC(:NH)OMe

~\~"-S

/ X b

NH2 9

10

~ ~

heat

.NH2

11

a b r d

CI3

R R R NHMe e NH(cyclohexyl) i morpholino NMe2 f NHPh j piperidino N(Me)(CH2)17Me g NHC6H4-P-Me k NH(CH2)FMe N-(n-Bu)2 h NBn2 I NHCH2(2-furyl)

An efficient method to synthesize a solution-phase 96-membered combinatorial library of 1aryl-4,6-diamino-1,2-dihydro-1,3,5-triazines has been developed. The strategy involved an acidcatalyzed cyclocondensation between 6 arylbiguanide hydrochlorides and 16 carbonyl compounds in the presence of triethyl orthoacetate as water scavenger <03BMC217>. The synthesis of N-4-alkyl-5-azacytidines and their base-pairing with carbamoylguanidines contributed to explain the mutagenicity of 2'-deoxy 5-azacytidine <03CCC711>. Cycloaddition reactions of 2,4-diphenyl-l,3-diazabuta-l,3-dienes with aryl and alkyl isocyanates and isothiocyanates afforded a variety of 1,3,5-triazin-2-one and 2-thione derivatives <03T7397>. To improve upon the previous orthogonal method for the solid-phase synthesis of a 1,3,5-triazine library, an alternative strategy has been developed <03OLl17>. The synthesis of 2,6bis(trichloromethyl)-l,2,4,6-thiotriazine 1,1-dioxide ammonium salts has been reported <02MI1702>. The synthesis and ansa substitution of novel examples of aryl hydrido fluorophosphazanes have been described <03ICC584>. 6.3.1.2. Reactions

Synthesis of N-monosubstituted 1,2,3-triazinium salts 13, from 1,2,3-triazines 12, and their reaction towards C-nucleophiles have been described <03S413>. Et I+ NsN'N

R1

-20 ~ 3 d R2

12a, 12b, 12c, 12d,

Ar, Et30*X-

R 1 = Ph, R 2 = H R 1 = H, R 2 = Ph R 1 = Me, R 2 = H R 1= H, R 2 = Me

N"N" N

J

R1

X"

R2

BF4, 95% 13b, X- = BF4, 98% 13c, X = PF6-, 56% 13d, X- = PF6-, 57%

13a, X =

Reactions of 3-hydrazino-l,2,4-triazin-5-one derivatives with carbonyl compounds to give triazolotriazine derivatives have been reported <03KGS1376>. Intramolecular inverse electron demand cycloadditions of 2-substituted imidazoles with various 1,2,4-triazines produced both imidazo[4,5-c]pyridines (3-deazapurines) and pyrido[3,2-d]pyrimidin-4-ones (8-deazapteridines

388

C. Ochoa, P. Goya and C. Grmez

<03JOC4345>. 5,6-Unsubstituted-3-aryl-l,2,4-triazines were found to react with aminovinyl ketones and aminovinyl esters to form tetrahydropyrrolo[3,2-e][ 1,2,4]triazine derivatives in good yields <03TL2421>. Transformations of 6-benzoyl-2H-1,2,4-triazine-3,5-dione and 6-benzyl-5thioxo-3,4-dihydro-2H-1,2,4-triazin-3-one into fused 1,2,4-triazine systems have been studied <03PS 1143>. Nucleophilic substitution of 4-amino-6-(t-butyl)-3-methylthio-4,5-dihydro-l,2,4triazin-5-one with carboxylic acid hydrazides to yield triazolotriazines has been described <03KGS950>. Synthesis of 3-(l'-hydroxyiminoethyl)-l-phenyl-4H-1,2,4-triazine-5,6-dione from 3-(l'-hydroxyiminoethyl)-5-benzyl-l-phenyl-4,5-dihydro-l,2,4-triazin-6-one in the presence of organotin(IV) compounds has been performed <03H2123>. A versatile strategy for the synthesis of functionalized 2,2'-bipyridine and 2,2'/6',2"-terpyridine via their 1,2,4-triazine analogues through inverse electron demand Diels-Alder reaction has been reported <03JOC2882>. More examples of the synthesis of 2,2'-bipyridyl derivatives using aza DielsAlder methodology have been described <03TL693>. Parallel synthesis in solution of an insecticidal 1,2,4-triazine library starting from 3-methylthio-6-substituted-l,2,4-triazines has been developed <03C262>. Several reactions of 3-hydrazino-l,2,4-triazin-5(2H)-one with compounds containing carbonyl and active methylene groups have been carried out to give different 3-substituted-l,2,4-triazin-5-one derivatives and a 1,2,4-triazolo[4,3-b][1,2,4]triazinone derivative <02MI1686>. In a one-pot microwave reaction, an acylhydrazide tethered indole underwent a three-component condensation to form 1,2,4-triazine followed by an inverse electron demand Diels-Alder reaction to deliver novel unnatural [3-carbolines <03T4495>. The synthesis of heterobicyclic nitrogen compounds derived from 6-methyl-5-styryl-l,2,4-triazine3-thione has been described <03PS279>. A new pathway to the synthesis of 6-aza-5-methyl-(2'deoxy)isocytidine and 6-aza-(2'-deoxy)isocytidine together with isomeric 3-glycosyl derivatives from the corresponding silylated 1,2,4-triazine derivatives has been developed <03JOC367>. Glycosylation reactions of 1,2,4-triazin-6-ones or thiones <03MI1825> and 3-thioxo-l,2,4triazin-6-one <03MI21>, <03MI1805> have been performed. Consecutive photolysis of triazido-l,3,5-triazine, in a low-temperature nitrogen matrix, yielded dicyanocarbodiimide and trinitreno-l,3,5-triazine <03AG(E)5206>. Chemical reduction of 2,4,6-tricyano-l,3,5-triazine yielded novel 4,4',6,6'-tetracyano-2,2'-bis-triazine and its radical anion <03JOC3367>. Reactions of 2,4,6-tris[di(t-butoxycarbonyl)nitromethyl]-l,3,5-triazine with nucleophiles have been reported . A 1,3,5-triazine scaffold bearing free and protected amino groups has been used for connecting two different and differently derivatized amino acids to obtain two diastereoisomeric chiral systems, which have been used in the chromatographic resolution of racemic analytes <03TA1345>. A new synthetic route, via the Suzuki cross-coupling of resin-bound chlorotriazines 14, using various arylboronic acids and palladium catalysts has been developed to prepare a triazine library expanded to biaryl scaffold 16 <03TL6141>.

Triazines, Tetrazines and Fused Ring Polyaza Systems

389

Halogen derivatives of 1,3,5-triazines reacted with potassium salts of N(thio)phosphorylthioamides to give the products of substitution of one, two or three halogen atoms with imidothiyl structures <03JGU638>. Several nucleophilic substitutions of halogen derivatives of 1,3,5-triazines to yield the corresponding amino derivatives have been described <03IJC(B)53>, <03IJC(B)621>, <03SC2599>. The synthesis of novel rigid triazine-based calix[6]arenes from 2-amino-4,6-dichloro-l,3,5-triazine derivatives has been reported <03TL1359>. Synthesis of novel disubstituted exocyclic 1,3,5-triazin-2-ylamino nucleoside libraries (1152 compounds 23), from 2,4,6-trichloro-l,3,5-triazine, by a parallel solid-phase combinatorial approach have been reported. The pathway followed is shown in Scheme 1, once intermediate 21 was obtained, 64 primary amines were selected for the first substitution step, g, by fixing one building block for the second step, and 32 secondary amines were selected for the second substitution step, h, by fixing one building block for the first step <03T2297>.

Conditions: a) SnCI4, NAN3; b) NaCN, MeOH; c)polystyrene MMT-CI resin, DMAP, pyridine; d) t-butyldimethylsilyl chloride, imidazole; e) PMe3; f) diisopropylethylamine; g) Set A: amine building blocks, diisopropylethylamine, 0 ~ to rt; h) Set B: amine building blocks, diisopropylethylamine, 75-80 ~ i) 1M tetra-n-butylammonium fluoride in THF; j) 2% trifluoroacetic acid in 1,2-dichloroethane, 1 min

Scheme 1 Thiol-disulfide exchange on cyanuric chloride yielded multivalent dendrimers of melamine <03OL1245>. Cyanuric chloride was loaded on polyethylene glycol 4000 to give a new supported reagent to carry out the liquid-phase Sonogashira coupling reaction <03SC403>. The reaction of a bis-spirocyclic phosphazane with thiophenols in the presence of alkali carbonates has been reported <03PS 1549>.

390

C. Ochoa, P. Goya and C. G6mez

6.3.2.

TETRAZINES

6.3.2.1. Synthesis Treatment of O-benzylated ribono(arabino)-l,4-lactone oxime methanesulfonate 24 with NH3 in MeOH gave the crystalline 1,4-dihydro- 1,2,4,5-tetrazines 25, (1S)-erythritol- 1-yl isomer from the ribono and (1R)-isomer from the arabino derivative <03HCA1488>.

o = o.s

BnO

Bn

BnO/

NH 3 or

N-NH 7 /,

OBn

MeNH2

"I'OBn 24

25(21o)

Reaction of nitrilimines 26 with 1-substituted-l-methylhydrazines 27 yielded the acyclic adducts 28. Thermal cyclization of adducts gave tetrahydro-l,2,4,5-tetrazines 29 in 70-80% yields. Dihydro-l,2,4,5-tetrazines 30 were obtained (22-25% yield) upon elimination of formaldehyde from tetrahydrotetrazines 29a <03SC1245>.

R1CO-CN,-N-Ar + H2 N ~ N

26

27

Ar = 4-CIC6H4 R1 = Me, Ph, 2-naphthyl

/

Me

~co.2

>R1CO~

Ar N--N" charcoal H Me 1100CNH-N ,.CO R2

28

Ar N-N' R1CO---~ > HN - N "(:;OR 2 29a, R2 = H

29b, R2 = Me

R2 = H, Me

29a I -HCHO

Ar N_N ~ R~CO--( / > N=N

30 6.3.2.2. Reactions

A series of chlorotetrazines 31 reacted with different terminal alkynes 32 under Sonogashira coupling conditions to furnish alkynyltetrazines 33 in good to moderate yields <03OL3495>. R1 N ~

5% (PPh3)2PdCl 2

I

II

.

__

.2

2 eq. TEA DMA

CI

31

,.cu,

32 R1 = morpholinyl, pyrrolidinyl, diethylamino R2 = C(CH3)2OH, Ph, n-C4H9

N=N

,>

N 33

__

.2

391

Triazines, Tetrazines and Fused Ring Polyaza Systems

A variety of 1,6-dihydro-3,6-dialkyl-l,2,4,5-tetrazines have been obtained from the corresponding perhydrotetrazines <03SC2769>. Novel bridgehead nitrogen heterocyclic systems containing the 1,2,4,5-tetrazine ring have been synthesized from 1,2,4,5-tetrahydrospiro3-( 1',7',7'-trimethylspiroadamantan-2'-yl)-1,2,4,5-tetrazine-6-thione <03IJC(B) 1176>, <03IJC(B)1460>. Inverse electron demand Diels-Alder reactions of 3,6-bis(3,4dimethoxybenzoyl)-l,2,4,5-tetrazine have been studied. This represents the first systematic study of the [4+2] cycloaddition reactions of 3,6-diacyl-l,2,4,5-tetrazines <03JOC3593>. Reaction of 3,6-disubstituted-l,2,4,5-tetrazines with fullerene C60 yielded the first nonclassical fullerene C62 incorporating a 4-membered ring <03JA2066>. Oxidation reactions of 3,6-diaryl1,2-dihydro-l,2,4,5-tetrazines afforded the corresponding bis-substituted tetrazines with two pendant 2-pyrrolyl or 2-thienyl groups, which are precursors of new conjugated polymers <03T4761 >.

6.3.3.

FUSED [6]+[5] POLYAZA SYSTEMS

New dinuclear phosphane complexes stabilized by 8-thiotheophylline have been described <03EJI348>. The metal ion complexes Co(II), Ni(II), Cu(II) and Cd(II) of some azopyrazolopyrimidine derivatives have been prepared and characterized <03SRI1351>. Coordination chemistry of aminomethylphosphine derivatives of adenine has been studied <03EJI2426>. The DNA binding properties of imidazo[4,5-b]pyridines have been evaluated <03JA5707>. Novel series of arylpyrazolo [3,4-b]pyrimidines <03BMCL1577>, <03BMCL3055>, arylpyrazolo[3,4-b]pyridazines <03BMCL1581> and heteroarylpyrazolo[3,4b]pyridines <03BMCL3059> have been identified as potent inhibitors of Glycogen Synthase Kinase-3 (GSK-3).

6.3.3.1. Synthesis The synthesis of a panel of pyrrolo[2,1-d][1,2,4,5]tetrazinones of type 36, which present potent antitumor activity, has been accomplished by reaction of 2-diazopyrroles 35 with isocyanates, using the most convenient method to obtain azolotetrazinones <03BMC2371>.

R2~N NaNO2ICH3COOH, R~R .~ Na co

34

35

R1 R3NCOIDMF R2~N R

36

The synthesis of 7-benzoyl-3,4-dihydroisoxazolo[4,3-d][1,2,3]triazin-4-one has been achieved from 4-diazo-5-benzoylisoxazole-3-carboxamide <03PJC1001>. Treatment of a 3amino-(2'-thiazolyl)-4-amino-6-styryl-l,2,4-triazin-5-one derivative with ethyl chloroformate afforded the corresponding N-substituted triazolotriazinone <03PS2025>. Other triazolo-l,2,4triazin-5-one derivatives have been synthesized by cyclization reactions of diaminotriazoles <03IJC(B)2054>. Reactions of 3-bromoacetylazulene with 2-amino-l,2,4-triazines gave the corresponding imidazo[1,2-b][1,2,4]triazine substituted azulenes <03H359>. A highly diastereoselective synthesis of 6-functionalized dihydroimidazotriazines has been described <03OIA595>. The synthesis of (14C)-labeled vardenafil hydrochloride, an imidazotriazinone derivative with selective phosphodiesterase inhibitory activity, has been reported <03MI1019>.

392

c. Ochoa, P. Goya and C. G6mez

Synthesis of 4-amino-3-(2'-pyridyl)pyrazolo[5,1-c][ 1,2,4]triazine and some of its derivatives has been achieved from appropriate pyrazolohydrazones <03JHC71>. A 2,6-diaminoimidazo[3,4a][1,3,5]triazine has been synthesized as a constitutional isomer of the natural nucleobase 2,6diaminopurine <03OL2067>. Reaction of 2-hydroxylamino-4,5-dihydroimidazolium-Osulfonate with phenyl isothiocyanate gave the corresponding tetrahydroimidazo[1,2a] [1,3,5]triazine-4-thione derivative <03JOC4791>. A pyrazolo[2,3-a][1,3,5]triazine derivative has been synthesized as a nonpeptide radioligand used to visualize corticotropin-releasing hormone type-1 <03JMC3559>. Pyrazolo-, thiazolo- and tfiazolo[1,3,5]triazines have been prepared in a straightforward one-step procedure by a ring chain-transformation reaction from the corresponding 2-aminoazoles <03S 1201>. Pyrazolo[ 1,5-a][1,3,5]triazines were prepared, as corticotropin-releasing factor (CRF) receptor ligands, by couplings of aminopyrazoles with aroylthioimidates <03BMC4093>. Novel solution-phase and solid-phase synthesis of pyrazolo[1,5-a][ 1,3,5]triazin-4-ones and pyrazolo[ 1,5-a][ 1,3,5]triazines have been described <03C248>. Syntheses of thiadiazolo-l,3,5-triazines have been performed by cyclizations of aminothiadiazole derivatives and ammonium thiocyanate. Their antiviral activity has been evaluated <03IJC(B)2583>. Preparation of a dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylate has been described <03JOU753>. Some triazolopyrimidine derivatives have been synthesized <03KGS949>, <03HCA739>, <03PS1101>, <03JCO653>. Many examples of the synthesis of diverse purine derivatives have been reported <03BMC1299>, <03BMC3607>, <03BMC3641>, <03CC1452>, <03CPB608>, <03MI365>, <03JOC276>, <03MI373>, <03OBC1354>, <03T47>, <03TL8361>. Other imidazopyrimidines have been described <03JMC1769>, <03TL6265>. Syntheses of several pyrazolopyrimidine derivatives have been developed <03SC2095>, <03JMC310>, 03IJC(B)343>, <03MI620>, <03H413>, <03PS1413>, <03BMC863>, <03BMCL2989>. Palladium catalyzed reaction of 4-amino-6-chloro-5nitropyrimidine 37 with arylacetylenes 38 afforded the corresponding 1-(4-amino-5-nitro-6pyrimidinyl)-2-arylacetylenes 39, which in dry pyridine underwent smooth cyclization to give pyrrolo[2,3-d]pyrimidine 5-oxides 40 <03SL 1151>. NH2

37

38 R = H , Me, F

R

o

Py R

40

One-pot synthesis of 9-deazaxanthines from 1,3-di-n-propyl-5-nitro-6-arylvinyl-pyrimidine2,4-dione has been accomplished <03TL2121>. Syntheses of new azolopyrimidines <03S63>, <03T7141>, isothiazolopyrimidines <03OL507> and thiazolopyrimidines <03EJM27> have been reported. Efficient preparation of imidazo[4,5-d]pyridazin-7-ones <03H1329> and imidazo[1,2-b]pyridazines <03TL2919> have been described. Synthesis and antihistaminic activity of new imidazo- and triazolopyridazines have been reported <03CPB122>. A new approach to the synthesis of fused pyrazolopyridazines, triazolopyridazines and

393

Triazines, Tetrazines and Fused Ring Polyaza Systems

tetrazolopyridazines has been attempted <03PS199>. Synthesis and SAR evaluation of oxadiazolopyrazines as selective Haemophilus influenzae antibacterial agents have been described <03BMCL3233>. Some 1,2,4-triazolothiadiazine derivatives have been synthesized <03PS1987>. Syntheses of diverse imidazopyridine derivatives have been reported <03BMCL129>, <03BMCL289>, <03JHC569>, <03JHC585>. Synthesis of 1H-pyrazolo[3,4b]pyridines 46, as inhibitors of Cyclin-Dependent Kinases, has been carried out following the pathway shown in Scheme 2 <03BMCL1133>.

CN

I~

0

a,b

~N,N i)c HCIH2N O PMB ii) d, Ph~ C 0 2 E t 42

41

0

e v,.._

~

p h ~ \Nf~

H

43 ~OEt

CI

P h ~ N

f, g

0

N ~

PMB

44 0

X-Y

P h ~ ~ N ~ N/~'~ N' H 46

PMB 45

PBM =p-methoxybenzyl; X = S, NMe, O Y = n-butyl, n-propyl,n-pentyl, (1-methyl)butyl,cyclohexyl,benzyl,phenyl, (2-hydroxy)ethyl, (2-dimethylamino)ethyl a) NH2NH2H20(1 equiv), THF,0-25 ~ 2 h; thenp-methoxybenzaldehyde(1 equiv)25 ~ 2 h; b) nBuONa (1 equiv)/n-BuOH,25-120 ~ 3 h then HC1,42% fromacrylonitrile;c) 10%K2CO3;d) 43 (1 equiv), 120 ~ 1.5 h then Ph20, 250 ~ 1.5 h, 40%; e) POC13,110 ~ 60%; f) NaX-Y,CH2C12,25 ~ 6 h; g) TFA, 65 ~ 2.5 h, 50-80%from45 Scheme 2 New pyrazolopyridine derivatives have been synthesized <03SC253>, <03BMCL3367>, <03JIC311>. An elegant one-step synthesis of 5,6-disubstituted isoxazolo[4,5-b]pyridine Noxides has been carded out <03SC3077>. 6.3.3.2. Reactions

Several 2-arylthio-5-(4-oxo-benzo[d][1,2,3]triazin-3-ylmethyl)cyclopentane carboxylates and the corresponding carboxylic acids have been prepared from the appropriate benzotriazines and arylthiocyclopentanes as specific matrix metalloproteinase inhibitors <03JMC3840>. Intramolecular [4+2] cycloaddition reactions of suitable thieno[2,3-c][1,2,4]triazines yielded new condensed thienopyridine ring systems <03T8489>. Reaction of some 8aminopyrazolo[1,5-a][1,3,5]triazine derivatives with various acyl chlorides has been developed as a general approach towards the synthesis of 8-acylamido-pyrazolo[1,5-a][1,3,5]triazines, which could be applied to high-throughput synthesis <03TL703>. Glycosylation reactions of 2aryl-l,3,4-oxadiazolo[3,2-a][1,3,5]triazine-5,7-dithione with different sugars have been described <03IJC(B)215>. Selective C-arylation of free (NH)-purines via catalytic C-H bond functionalization has been developed <03JA5274>. Substitution at the 2 or 8 positions of 9-ethyladenine with a variety of side-chains was accomplished in order to obtain non-xanthine adenosine receptor antagonists

394

c. Ochoa, P. Goya and C. Grmez

<03MI629>. An unusual oxidative ring transformation of purine to imidazo[ 1,5-c]imidazole has been described <03OL4265>. SNAr Displacement reactions of 2,6-disubstituted-purines with weakly nucleophilic substituted anilines were dramatically accelerated in the presence of trifluoracetic acid in trifluoroethanol <03CC2802>. Regioselective N-9-arylation of purines using arylboronic acids in the presence of Cu(II) has been carried out <03TL3359>. 2Aminoalkyl-6-aminoaryl-9-isopropyl-8-substituted purines were obtained from the corresponding 2,6,9-trisubstituted purines as new CDK1 inhibitors <03BMCL2993>. Other substituted purines have been synthesized from appropriate purine derivatives as MAP kinase inhibitors <03BMCLll91>, interferon inducing agents <03BMC5501> and selective phosphodiesterase type-4 inhibitors <03EJM199>. Alkylation of 2-amino-6-chloropurine with allyl-protected bromohydrins afforded 7-hydroxy(phenyl)ethyl-guanines <03OL637>. Preparation of 2,6,9-trisubstituted purines 50 from 2,6-dihalogenopurine 47 has been carried out as novel inhibitors of Src Tyrosine Kinase <03BMCL3067>.

OH

CI

CI

FJ~N/~L~N" -N'I~N -..-

>

R1-NH2(1 eq.) DIEA/DMSO, 110 *C

DIAE/PPh3/THF

FJLLN//L-N H

47

,.

48

N, N>

R~NH

R~NH

N,I~N >

R2-NH2(excess)

F/LLN//L..N 49 ~

"-

DIENDMSO,110 *C

,,. R2 N ,~N//I~N H

Rl, R2= aryl, phosphonicacids Reaction of 9-benzyl-6-iodopurine 51, in toluene at -80 ~ with i-PrMgC1 gave, almost quantitatively, the purine-derived Grignard reagent, which reacted selectively with aldehydes 52 affording the corresponding alcohols 53 in 25 to 62% yield <03OIA289>.

HO _Ar

'

51

"Ph

ii) ArCHO/toluene 52

~"Ph 53 (25-62%)

Application of a phase-transfer catalysis procedure on 2-amino-6-chloropurine afforded 6O-benzylguanine derivatives <03SC941>. Cross-coupling reactions of 2,6-dichloropurines yielded carba-analogs of myoseverin <03T607> and 2-substituted 6-methylpurine bases and nucleosides <03JOC5773>. Electrocyclization of 8-hydrazino derivatives of caffeine yielded 3substituted 1,2,4-triazolo[4,3-e]purines <03M565>. N 1 / N 9 Alkylation of different purine nucleobases has been carried out using potassium fluoride-doped natural phosphate as catalyst <03MI109>. Coupling reactions between p a r a - mono or bis-amino calix[4]arenes and thymin-

395

Triazines, Tetrazines and Fused Ring Polyaza Systems

1-ylacetic acid afforded mono or bis-thymine-substituted calix[4]arenes <03T2539>. New (S,Z)-2-aminopurine methylenecyclopropane analogues have been synthesized, from 2-amino6-chloropurine derivative, as anti-herpes viruses agents <03JMC1531>. A method for preparation of 6-alkylpurines via [2+2+2] cyclotrimerization of 6-alkynylpurines with diynes has been developed <03TL785>. S-Alkylation of 2-acetamido-9-(2-acetoxyethoxymethyl)-6oxo-8-thioxopurine yielded new 8,9-disubstituted guanine derivatives <03KGS274>. Substitution reactions on adenine <03TL3755> and guanine <03IJC(B)651> have been reported. Several transformations on pyrazolo[3,4-d]pyrimidines to yield new cyclindependent-kinase-2 inhibitors <03EJM525>, Staphylococcus aureus DNA-polymerase III inhibitors <03JMC1824> and antimicrobial agents <03PS1795> have been reported. One-pot two-step microwave-assisted reactions of 4,5-dihalogen substituted pyrazolo[3,4-d]pyrimidines to obtain new 4,5-disubstituted derivatives have been developed <03OL3587>. Substitution reactions on pyrrolopyrimidines <03JMC591>, <03CCC751> and pyrrolopyrazines <03TA429> have been described. The reaction of an 8-carbohydrazide derivative of tetrazolo[1,5-b]pyridazine with aromatic aldehydes gave the corresponding 8arylidenecarbohydrazide derivatives <03H1873>. A detailed thermodynamic and kinetic study of the reaction of 4,6-dinitrotetrazolo[1,5-a]pyridine with water and methanol has been carded out <03OBC2764>. Transformations of imidazo[4,5-b]pyridines afforded new derivatives which act as corticotropin releasing factor receptor ligands <03BMCL125>.

6.3.4.

FUSED [61+[61 POLYAZA SYSTEMS

The mechanism by which benzo[1,2,4]triazine 1,4-dioxides, a class of anticancer drugs, produce oxidizing radicals following their one-electron reduction has been investigated <03JA748>. In relation with protein dimerizers, a flexible methotrexate dimer has been synthesized and the crystal structure of this bis-MTX in complex with E. coli DHFR published <03JA1501>. Analogs of methotrexate (MTX) encompassing bridging ester groups have been synthesized and evaluated as DHFR inhibitors <03JMC3455>.

6.3.4.1. Synthesis Some new 1,2,4-triazin-5-ones fused to 1,2,4-triazines 54, 1,2,4-triazin-5-ones 55, 1,2,4,5tetrazines 56 and 1,2,4,5-tetrazin-3-ones 57 have been synthesized from 4-amino-6-styryl-3thioxo- 1,2,4-triazin-5(4H)-ones <03PS2055>.

N-N N"U"NH

%-.N-,N 2 O"J"N'J"N'" HL.J

-o

%N-,N O N'LNH

I'~ N ~ R' 3

R4 54

55

R1 OH

H=CH'-

56

H

NH

%'

N,,.R3

O

57

R2 = 4-(NH2SO 2)C6H 4, R3 = H, 2,4-(NO2)2C6 H3, R4 = 2-furyl 4-CIC6H 4

396

c. Ochoa, P. Goya and C. G6mez

The synthesis and biological activity of pyrimido[1,2-b]-l,2,4,5-tetrazin-6-ones as HCMV protease inhibitors has been reported <03BMCL3483>. Novel 6-azapteridines from bifunctional 1,2,4-triazines have been synthesized <03CCC965>. Pyrimido[5,4-e][1,2,4]triazines with oral tyrosine phosphatase inhibitory activity have been described <03BMCL2895>. In order to establish structure-activity relationships, analogs of tirapazamine (1,2,4-benzotriazin-3-amine 1,4-dioxide), a bioreductive hypoxic cytotoxin currently in clinical trials, have been synthesized <03JMC169>. Efficient solid-phase syntheses of 1,2,3-benzotriazin-4-ones using t-butyl nitrite <03TL5539> and with SynPhase TM lanterns <03MI452> have been published. Solid phase syntheses have also been reported for pteridines <03OBC 1909>. In an example, a traceless reaction starts by linking pyrimidines to polystyrene supports via either a 2- or a 4thioether. Oxidative cleavage (dimethyldioxirane) followed by nucleophilic substitution by amines, azides or water completes the synthesis <03TL1267>. Tetrahydropteridinediones 59 were obtained in a ring transformation reaction of diazepines fused to uracil rings 58 <03H2511>.

o

H

I~le ~

Heat

MeoN

-'-

0

H

~e

~02

le 58

59

R=Ts, H

A novel and versatile solid-phase synthesis of pyrimido[4,5-d]pyrimidine-2,4-diones has been reported <03S 1739>. The key step is the reaction of the support-bound pyrimidine with isocyanates, involving formation of a carbamate intermediate, followed by a base-catalyzed intramolecular ring closure to give the polymer-bound pyrimidopyrimidines which are used in subsequent reactions providing 1,3-disubstituted 7-amino derivatives. 6.3.4.2. Reactions

Wittig reactions using 2-thioalkyl-6-formylpteridines as substrates were the first step in providing highly functionalized 6-substituted pteridines <03OBC664>. Rearrangement of 5,8dihydro-6H-pteridin-7-ones into pteridin-6-ylideneacetic acids has been described <03H2115>. In an extensive paper, Pfleiderer has reported on the improvement of the solubility of pterins by preparing the N-2-acyl- or N-2-[(dimethylamino)methylene]-derivatives, and on the use of 2-(4nitrophenyl)ethyl (npe) as a suitable blocking group <03HCAI>. The reactivity of pyrazino[2,3c] [1,2,6]thiadiazine 2,2-dioxides, sulfur dioxide analogs of pteridines, has been studied <03HCA139>. N-Oxide and 3-amino derivatives of pyrimido[4,5-c]pyridazinedione 60 have been shown to react with primary alkylamines in the presence of an oxidant to produce condensed imidazolines 61 based on a nucleophilic aromatic substitution of hydrogen (SNH) strategy. Heterocyclic analogues of the still unknown dibenzo[a,o]picene 62 were obtained as by-products <03T7669>.

Triazines, Tetrazines and Fused Ring Polyaza Systems

O

~e

397

?NH2 AgPy2MnO4

60

O

Me I

o.

I~le

61a, R = n-Pr (19%) 61b, R : n-Bu (14%)

6.3.5.

R

Me

R

62a, R = n-Pr (11%) 62b, R = n-Bu (2.5%)

MISCELLANEOUS FUSED RING POLYAZA SYSTEMS

6.3.5.1. Synthesis Derivatives of thienotriazine, thienoimidazotriazine, thienotriazolotriazine and thienotetrazolotriazine have been synthesized <03PS1211>. Several reports have dealt with pyridothienopyrimidines and pyridothienotriazines, synthesis <03PS89>, and synthesis and evaluation as antimicrobial <03PHA372> and as antiprotozoal agents <03EJM265>. A new quinoxalino[1,2-c][1,2,3]benzotriazine system has been obtained through an anomalous course of the reduction of 2-(3-oxo-3,4-dihydroquinoxalin-2-yl)benzene diazonium salt <03JHC357>. Two new heterocyclic systems, 3-phenyl-3,4-dihydrobenzimidazo[2,1-~[1,2,4]triazine <03KGS948> and 8,9,10,11-tetrahydroindolo[2,1-c]benzo[1,2,4]triazine <03H2519> have been described. The synthesis and reactivity of 8-fluoro-4-hydroxy-lH-[1,2,4]triazino [4,5-a]quinoline-l,6(2H)-dione has been reported <03JHC789>. Bridgehead nitrogen heterocyclic systems containing a triazolo-l,3,5-triazine moiety have been prepared <03IJC(B)2003>. Derivatives of [1,2,4]triazino[4,3-a]benzimidazole have been synthesized as constrained analogs of high affinity ligands at the benzodiazepine receptor <03AP413>. Novel annelated 2,3-benzodiazepine derivatives containing [1,2,4]triazines have been synthesized <03JMC3758>. Synthesis of 9-substituted tetrahydroazepinopurines as asmarine analogs has been described <03T6493>. In relation to adenosine receptor antagonists, new derivatives of pyrazolo[4,3e][1,2,4]triazolo[1,5-c]pyrimidines have been synthesized <03JMC1229, 4287>. A one-pot synthesis of 1,2,4-triazolo[ 1,5-c]quinazoline thiones 65, consisting of a domino cyclization of 2isothiocyanatobenzonitrile 63 with hydrazides 64 has been published <03EJO 182>.

398

C. Ochoa, P. Goya and C. G6mez

0 ~

S"yr":" N solv64ent > wN N"N~R 2-6 refluhx II/~~HIHIHI~O 1 l II~J~/H~ 63

R1 H

--~

H 65

The aza-Wittig reaction of resin-bound iminophosphoranes 66 with aryl isocyanates has been studied. Depending on the temperature and on the nature of isocyanate employed, a significant amount of 2,4-dioxo-l,3,5-triazino[ 1,2-a]benzimidazoles 68 were formed along with the normal aza-Wittig products 67. The mechanism of the reaction may involve the loss of triphenylphosphinimide instead of triphenylphosphine oxide, resulting in the formation of isocyanates instead of carbodiimides as intermediates <03TL3705>.

6.3.5.2. Reactions

Cleavage of [ 1]benzofuro[2,3-e][ 1,2,4]triazine ring was employed to obtain oxygen, nitrogen and sulfur derivatives of 1,2,4-triazines <03JHC805>. The formation of highly reactive triazinium-imidothiolate zwitterions 70 and their role as key intermediates for novel SN(ANRORC) reaction pathways has been reported. These intermediates, isolated from the reaction between bis([ 1,3,4]thiadiazolo)[ 1,3,5]triazinium halides 69 and benzylamines can yield unusual bis([ 1,2,4] triazolo) [ 1,3,5] triazinium halides 72, [1,2,4]triazolo[1,3,4]thiadiazolo[1,3,5]triazinium halides 73, or highly substituted guanidines 71 <03EJO1389>, <03SL1459>.

399

Triazines, Tetrazines and Fused Ring Polyaza Systems

1

--~

2

N~N,,,,,~N,,~~ R 1" \ \ u H..N..R3"N---N 71

a1 N~ ~

,S ~|

69

H2NR3

9

R1

.J...., ,,.

H..N.,,~N-~S"

"

72

70

R1 X -

R4_SH

6.3.4.

h3

~3

73

REFERENCES

02MI 1686 02MI 1702 03AG(E)5206 03AG(E)5303 03AP413 03BMC217 03BMC863 03BMC1299 03BMC2371 03BMC3607 03BMC3641 03BMC4093 03BMC4179 03BMC5501 03BMCL125

03BMCL129

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400 03BMCL289 03BMCLll33 03BMCL1191 03BMCL1577 03BMCL1581 03BMCL2895 03BMCL2989 03BMCL2993 03BMCL3055 03BMCL3059 03BMCL3067

03BMCL3233 03BMCL3367 03BMCL3483 03C248 03C262 03CC1452 03CC2802 03CCC711 03CCC751 03CCC965 03CEJ992 03CPB122 03CPB608 03EJI348 03EJI2426 03EJI2693 03EJM27 03EJM199 03EJM265 03EJM525

C. Ochoa, P. Goya and C. G6mez

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03EJO182 03EJO1389 03EJO1463 03EJO4173 03H359 03H413 03H477 03H1329 03H1873 03H2115 03H2123 03H2217 03H2511 03H2519 03HCA1 03HCA139 03HCA739 03HCA1488 03ICC584 03ICC773 03IJC(B)53 03IJC(B)215 03IJC(B)343 03IJC(B)621 03IJC(B)651 03IJC(B)1176 03IJC(B) 1460 03IJC(B)2003 03IJC(B)2054 03IJC(B)2583 03JA748 03JA1501 03JA2066 03JA5274 03JA5707 03JAl1804 03JCO653 03JGU638 03JHC71 03JHC357 03JHC569 03JHC585 03JHC789 03JHC805 03JIC138 03JIC311 03JMC169 03JMC310 03JMC591

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402 03JMC1229 03JMC1531 03JMC1769 03JMC1824 03JMC3455 03JMC3559 03JMC3758 03JMC3840 03JMC4287 03JOC276 03JOC367 03JOC1097 03JOC2882 03JOC3367 03JOC3559 03JOC3593 03JOC4345 03JOC4791 03JOC5773 03JOU753 03KGS274 03KGS722 03KGS730 03KGS948 03KGS949 03KGS950 03KGS1376 03KGS1584 03M565 03MI21 03MI109 03MI156 03MI365 03MI373 03MI452 03MI620 03MI629 03MI1019 03MI 1805 03MI1825 03MRC183

C. Ochoa, P. Goya and C. G6mez

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Triazines, Tetrazines and Fused Ring Polyaza Systems 03MRC324 03NJC172 03OBC664 03OBC1354 03OBC 1909 03OBC2764 03OL 117 03OL507 03OL637 03OL1245 03OL2067 03OL2271 03OL2359 03OL3495 03OL3587 03OL4265 03OL4289 03OL4595 03OM976 03OM3781 03PHA372 03PJC1001 03POL205 03PS89 03PS199 03PS279 03PS549 03PSll01 03PSl143 03PS1211 03PS1413 03PS1549 03PS1795 03PS1987 03PS2055 03S63 03S413 03S1201 03S1739 03SC253 03SC403 03SC941 03SC1245 03SC2095 03SC2599 03SC2769 03SC3077 03SLl151 03SL1459 03SRI775

403

H.E. Brikett, J.C. Cherryman, A.M. Chppendale, J.S.O. Evans, R.K. Harris, M. James, I.J. King, G.J. McPherson, Magn. Reson. Chem. 2003, 41,324. F. Hettche, R.W. Hoffmann, New J. Chem. 2003, 26, 172. D. Guiney, C.L. Gibson, C.J. Suckling, Org. Biomol. Chem. 2003, 1,664. K. Hirota, K. Kazaoka, I. Niimoto, H. Sajiki, Org. Biomol. Chem. 2003, 1, 1354 C.L. Gibson, S. La Rosa, C.J. Suckling, Org. Biomol. Chem. 2003, 1, 1909. T. Boubaker, R. Goumont, E. Jan, F. Terrier, Org. Biomol. Chem. 2003, 1, 2764. J.T. Bork, J.W. Lee, S.M. Khersonsky, H.S. Moon, Y.T. Chang, Org. Lett. 2003, 5, 117. Y.G. Chang, H.S. Cho, K. Kim, Org. Lett. 2003, 5, 507. J. Novak, I. Linhart, H. Dvorakova, V. Kubelka, Org. Lett. 2003, 5, 637. J.A.P. Umali, E.E. Simanek, Org. Lett. 2003, 5, 1245. Z. Wang, H.K. Huynh, B. Han, R. Krishnamurthy, A. Eschenmoser, Org. Lett. 2003, 5, 2067. J. Limanto, R.A. Desmond, D.R. Gauthier, P.N. Devine, R.A. Reamer, R.P. Volante, Org. Lett. 2003, 5, 2271. M.B. Steffensen, E.E. Simanek, Org. Lett. 2003, 5, 2359. Z. Novak, A. Kotschy, Org. Lett. 2003, 5, 3495. T.Y.H. Wu, P.G. Schultz, S. Ding, Org. Lett. 2003, 5, 3587. N. Pojoe, M. Pojoe, Org. Lett. 2003, 5, 4265. T. Tobrman, D. Dvorak, Org. Lett. 2003, 5, 4289. E. Gamier, J. Guillard, E. Pasquinet, F. Suzenet, D. Poullain, C. Jarry, J.M. Leger, B. Lebret, G. Guillaumet, Org. Lett. 2003, 5, 4595. V. Chandrasekhar, G.T.S. Andavan, S. Nagendran, V. Krishnan, R. Azhakar, R.J. Butcher, Organometallics 2003, 22, 976. Q.D. Liu, W.L. Jia, G. Wu, S.I. Wang, Organometallics 2003, 22, 3781. A.E. Abdel-Rahman, E.A. Bakhite, E.A. A1-Taifi, Pharmazie 2003, 58, 372. E. Wagner, A. Opolski, J. Wietrzyk, Pol. J. Chem. 2003, 77, 1001. E.W. Ainscough, A.M. Brodie, A. Derwahl, Polyhedron 2003, 22, 205. A.E. Abdel-Rahman, E.A. Bakhite, O.S. Mohamed, E.A. Thabet, Phosphorus Sulfur 2003, 178, 89. A.A. Shalaby, Phosphorus Sulfur 2003, 178, 199. T.M. Abdel-Rahman, A.A. Shalaby, I.F. Nassara, Phosphorus Sulfur 2003, 178, 279. M. Odabasoglu, S. Cakmak, G. Turgut, H. Icbudak, Phosphorus Sulfur 2003, 178, 549. N.M. Rateb, N.A. Abdel-Riheem, A.A. A1-Atoom, A.O. Abdelhamid, Phosphorus Sulfur 2003, 178, 1101. A.M. E1 Massry, Phosphorus Sulfur 2003, 178, 1143. H.M. Moustafa, A. Khodairy, A.M.M. A1-Saghier, Phosphorus Sulfur 2003, 178, 1211. M. Abass, Phosphorus Sulfur 2003, 178, 1413. G.A. Carriedo, F.J.G. Alonso, S.L. Vizcaino, C.D. Valenzuela, N. Yutronic, Phosphorus Sulfur 2003, 178, 1549. Z.H. Ismail, S.M. Abdel-Gawad, A. Abdel-Azeim, M.M. Ghorab, Phosphorus Sulfur 2003, 178, 1795. A.A.B. Hassanien, Phosphorus Sulfur 2003, 178, 1987. Z E1-Gendy, J.M. Morsy, H.A. Allimony, W.R. Abdel-Monem, R.M. Abdel-Rahman, Phosphorus Sulfur 2003, 178, 2055. L.D.S. Yadav, S. Singh, Synthesis 2003, 63. M. Mattner, H. Neunhoeffer, Synthesis 2003, 413. M. Karanik, M. Patzel, J. Liebscher, Synthesis 2003, 1201. N. Graveleau, T. Masquelin, Synthesis 2003, 11, 1739. G.H. Elgemeie, A.H. Elghandour, A.M. Elzanate, G.W.A. Elaziz, Synth. Commun. 2003, 33, 253. M. Xia, Y.G. Wang, Synth. Commun., 2003, 33, 403. X. Liu, O.H. Zheng, G.D. Hutchins, X.S. Fei, L.C. Erickson, K.D. Miller, B.H. Mock, B.E. Glick-Wilson, K.L. Stone, K.A. Carlson, Synth. Commun. 2003, 33, 941. A.R.S. Ferwanah, A.M. Awadallah, E.A. E1-Sawi, H.M. Dalloul, Synth. Commun. 2003, 33, 1245. G.H. Elgemeie, S.R. E1-Ezbawy, S.A. Sood, Synth. Commun. 2003, 33, 2095. Y.W. Shu, Y.Y. Dong, Synth. Commun. 2003, 33, 2599. Y.Q. Sun, W.X. Hu, Q. Yuan, Syn. Commun. 2003, 33, 2769. E. Rajanarendar, M. Srinivas, K. Ramu, Synth. Commun. 2003, 33, 3077. I. Susvilo, A. Brukstus, S. Tumkevicius, Synlett 2003, 1151. K. Wermann, M. Walther, H. G6rls, E. Anders, Synlett 2003, 1459 W.B. Gumule, L.J. Paliwal, R.B. Kharat, Synth. React. Inorg. Met-Org. 2003, 33, 775.

404 03SRI1351 03T47 03T607 03T2297 03T2539 03T4495 03T4761 03T6493 03T7141 03T7397 03T7669 03T8489 03TA429 03TA1345 03TL693 03TL703 03TL785 03TL1123 03TL1267 03TL1359 03TL2125 03TL2421 03TL2919 03TL3359 03TL3705 03TL3755 03TL5539 03TL6141 03TL6265 03TL7493 03TL8361 03TL8689

C. Ochoa, P. Goya and C. G6mez

H.M.A. Salan, A.A. Mohamed, S.A. Ibrahin, A.A. Hadmed, Synth. React. Inorg. Met-Org. Chem. 2003, 33, 1351. S. Weyler, A.M. Hayallah, C.E. Muller, Tetrahedron 2003, 59, 47. M. Hocek, I. Votruba, H. Dvorakova, Tetrahedron 2003, 59, 607. C.V. Varaprasad, Q. Habib, Y. Li, J. Huang, J.W. Abt, F. Rong, Z. Hong, H. An, Tetrahedron 2003, 59, 2297. C.C. Zeng, Q.Y. Zheng, Y.L. Tang, Z.T. Huang, Tetrahedron 2003, 59, 2539. C.W. Lindsley, D.D. Wisnoski, Y. Wang, W.H. Leister, Z.J. Zhao, Tetrahedron 2003, 59, 4495. J. Soloducho, J. Doskocz, J. Cabaj, S. Roszak, Tetrahedron 2003, 59, 4761. D. Pappo, Y. Kashman, Tetrahedron 2003, 59, 6493. V.J. Ram, P. Srivastava, A. Goel, Tetrahedron 2003, 59, 7141. G. Abbiati, A.C. Carvalho, E. Rossi, Tetrahedron 2003, 59, 7397. A.V. Gulevskaya, O.V. Serduke, A.F. Pozharskii, D.V. Besedin, Tetrahedron 2003, 59, 7669. Y.A. Ibrahim, B. A1-Saleh, A.A.A. Mahmoud, Tetrahedron 2003, 59, 8489. J.M. Palomo, C. Mateo, G. Fernfmdez-Lorente, L.F. Solares, M. Dfaz, V.M. S~inchez, M. Bayod, V. Gotor, J.M. Guis~in, R. FernAndez-Lafuente, Tetrahedron: Asymmetry 2003, 14, 429. A. luliano, C. Lecci, P. Salvadori, Tetrahedron: Asymmetry 2003, 14, 1345. S.P. Stanforth, B. Tarbit, M.D. Watson, Tetrahedron Lett. 2003, 44, 693. P. Raboisson, D. Schultz, C. Lugnier, R. Mathieu, J.J. Bourguignon, Tetrahedron Lett. 2003, 44, 703. P. Turek, M. Kotora, M. Hocek, I. Cisarova, Tetrahedron Lett. 2003, 44, 785. Z.J. Zhao, W.H. Leister, K.A. Strauss, D.D. Wisnoski, C.W Lindsley, Tetrahedron Lett. 2003, 44, 1123. C.L. Gibson, S. La Rosa, C.J. Suckling, Tetrahedron Lett. 2003, 44, 1267. X.P. Yang, C.R. Lowe, Tetrahedron Lett. 2003, 44, 1359. J. Tae, K.O. Kim, Tetrahedron Lett. 2003, 44, 2125. V.N. Charushin, N.N. Mochulskaya, A.A. Andreiko, V.I. Filyakova, M.I. Kodess, O.N. Chupakhin, Tetrahedron Lett. 2003, 44, 2421. P. Raboisson, B. Mekonnen, N.P. Peet, Tetrahedron Lett. 2003, 44, 2919. A.K. Bakkestuen, L.L. Gundersen, Tetrahedron Lett. 2003, 44, 3359. C.E. Hoesl, A. Nefzi, R.A. Houghten, Tetrahedron Lett. 2003, 44, 3705. E. Coutouli-Argyropoulou, P. Pilanidou, Tetrahedron Lett. 2003, 44, 3755. T. Okuzumi, E. Nakanishi, T. Tsuji, S. Makino, Tetrahedron Lett. 2003, 44, 5539. J.T. Bork, J.W. Lee, Y.T. Chang, Tetrahedron Lett. 2003, 44, 6141. S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet, Tetrahedron Lett. 2003, 44, 6265. S.J. Lee, J.Y. Chang, Tetrahedron Lett. 2003, 44, 7493. L.G.J. Hammmmarstom, M.E. Meyer, D.B. Smith, F.X. Talamas, Tetrahedron Lett. 2003, 44, 8361. Y.A. Azev, T. Dulcks, D. Gabel, Tetrahedron Lett. 2003, 44, 8689.

405

Chapter 6.4 Six-Membered Ring Systems" With O and/or S Atoms

John D. Hepworth James Robinson Ltd., Huddersfield, UK Email."j. d.hepworth@tinyworld,co. uk B. Mark Heron Department of Colour and Polymer Chemistry University of Leeds, Leeds, UK Email: [email protected]

6.4.1

INTRODUCTION

Reviews of the thio-Claisen rearrangement <03T7251>, the application of Lawesson's reagent in synthesis <03S1929> and the role of 1,3-dithianes in natural product synthesis <03T6147> have been published. Reviews of biosynthetic Diels-Alder (DA) reactions <03AG(E)3078>, cycloaddition reactions of vinyl oxocarbenium ions <03T2371>, the synthesis of 6-membered heterocycles from alkoxyethylenes <03RJOC757> and of new antimalarial drugs <03AG(E)5274> include much O-heterocyclic chemistry. Material pertinent to this chapter can be found in reviews of the ring opening of heterocycles by arenecatalysed lithiation <03PAC1453>, natural product hybrids as new leads for drugs <03AG(E)3996> and synthetic efforts toward the phomoidrides <03CR2691>. An account of bicyclic ketals discusses not only their synthesis and functionalisation, but also their transformation into a range of useful products <03SL1759>; a one-pot synthesis of frontalin is illustrative <03T8551 >. Work on naturally occurring spiroketals includes the total synthesis of attenol A and B <03SL2185>, aspects of the synthesis of the spongistatins <03CC462; 03JA12836; 03JA12844; 03OL761; 03OL4815; 03OL4819; 03TL7741; 03TL7747>, azaspiracid <03AG(E)3643; 03AG(E)3649; 03T8963>, y-rubromycin <03OL4425>, spirofungin A <03TL4965> and tautomycin <03T9609>. An account of the desymmetrisation of centrosymmetric molecules as a tool for asymmetric synthesis includes its application to tetracyclic tetrahydropyrans <03SL1213>; a synthesis of an intermediate pyranopyran in a route to hemibrevitoxin B is illustrative of this approach <03JOC747>. Developments in marine ladder polyethers include synthetic studies on brevetoxin <03JA7822; 03TL7929>, ciguatoxin <03JOC3225; 03TL5229>, gambierol <03JA46; 03JAl1893; 03OL913>, gymnocin-A <03JA14294; 03TL4351>, and yessotoxin <03JOC9050; 03TL8935>. A divergent synthesis of tetracyclic ethers of varying ring size

406

J.D. Hepworth and B.M. Heron

involves the neutral coupling of an alcohol and an a-chlorosulfide derived from the same precursor <03T5645>. Total syntheses of the macrolides phorboxazole A <03AG(E)1258; 03AG(E)2711; 03OBC4173>, phomactin <03JA1712; 03OBC3949>, leucascandrolide A<03AG(E)343; 03AG(E)3934; 03OL5035>, and apicularen A <03CEJ6177; 03OBC104> have been published. 6.4.2

HETEROCYCLES CONTAINING ONE OXYGEN ATOM

6.4.2.1 Pyrans Spiro-cyclobutene derivatives prepared from the intramolecular Wittig reaction of DMAD with ethyl oxo-(2-oxocycloalkyl)ethanoates yield cycloalka[b]pyrans via a thermal electrocyclic ring-opening ring-closing sequence (Scheme 1) <03T2001>. Cycloalka[b]pyranones result from the one-pot reaction of DMAD, dimedone and Ph3P at room temperature <03PSS2627>. A trans-annular DA of a pyranophane pseudobase is the key feature of a total synthesis of (+)-chatancin, a soft coral metabolite <03JOC9983>. O

O

O CO2Et

n = 3- 9

(i)

CO2R ~J..,,,./ CO2R

CO2Et CO2R

=

L;I-12)n CO2R

Reagents: (i) Ph3P, DMAD, CH2CI2,-5 ~ Scheme 1

\(0H2r n

CO2Et 8 examples 77- 94%

RT; (ii) PhMe, reflux

Depending upon reaction conditions, the Pd-catalysed isomerisation of alkylidene cyclopropyl ketones can lead to furans or pyrans. In acetone and in the absence of added salts, proximal bond cleavage occurs exclusively and 4H-pyrans are formed <03AG(E)183>. The 4H-pyran unit has been spiro-linked into the indanoparacyclophanes <03T1739>. 1

R . ~ _ _ < ~ R2 C)~/~R3

5 mol% [PdCI2(MeCN)2] . . ~ Me2CO RT -" ' R1

R2 R3

8 examples 60 - 91%

Good yields of 3,4-dihydropyrans are produced with high regioselectivity in a ring closing metathesis (RCM) and double bond isomerisation sequence using a Ru complex activated by the addition of a hydride donor (Scheme 2) <03EJO816>. A chiral Moadamantylimido alkylidene complex catalyses the asymmetric ring-opening- RCM reaction of the norbornyl triene 1 which leads to the chiral spirocyclic dihydropyran <03JA2591>. The first example of a quadruple RCM is high yielding and exhibits both regio- and stereoselectivity; octaene 2 produces mainly the bis-spirocycle 3 <03TL2145>.

407

Six-Membered Ring Systems." With 0 and~or S Atoms

(i) 5 mol% Grubbs' cat. PhMe, 20 ~ I" I"1 14 examples --Ph 36- 95% (ii) 30 mol% Nail MeO_J--hoy 100 ~

""

MeO--

Scheme

~~~~--~/~"

2

5mol%chiralMocat.= 22 ~

O,,~

96%ee

Phil, 3 h.

80%

1

--o,_

ru,,s' ca,.

65%

C H O,2, T,24 . 2

3

Cyclobutenes possessing an angular O-functionality, obtained from a Lewis acidmediated [2+2] cycloaddition of cyclic silyl enol ethers to ethyl propynoate and subsequent reduction and butenylation, undergo a ring-opening metathesis that produces a substituted dihydropyran that forms part of a cis-diene. After desilylation, an oxy-Cope rearrangement leads to the fused tetrahydropyran 4 <03JA14901 >.

_OTBS

O -

H

j

H-

~.

(ii), (iii)

-

4

Reagents: (i) 2 mol% cat. 5, Phil, 60 ~ lh., (83%); (ii) TBAF; (iii) KHMDS, 18-crown-6,-40 ~ then MeOH (64%)

.esN

NMes

Cl~" P C y 3 Ph 5

The in situ reaction of aldehydes with a chiral amine generates chiral enamines that function as electron-rich alkenes in an enantioselective hetero Diels-Alder (hDA) reaction with enones (Scheme 3) <03AG(E)1498>. An elimination- addition sequence is proposed to account for the production 2-alkoxy-5-trifluoroacetyl-3,4-dihydro-2H-pyrans rather than the 3-trifluoroacetyl derivative during the DA reaction of [3-trifluoroacetylvinyl ethers with heterodienes (Scheme 4) <03T2899>. Vinyl allenes with an aldehyde function tethered at the allene terminus undergo an intramolecular hDA reaction; the stereochemistry of the tricyclic dihydropyran adduct is consistent with an exo approach of the C=O to the dienic portion of the vinyl allene (Scheme 5) <03TL8471>. Functionalised 3,4-dihydro-2H-pyrans have been obtained through e n d o - s e l e c t i v e hDA reactions using supported vinyl ethers <03EJO4118>. The Cu-catalysed hDA reaction between cyclohexadiene and ethyl glyoxalate occurs with high ee using a Cl-symmetric sulfoxime ligand <03CC2826>. a-Hydroxyalkyl dihydropyrans are formed with high enantio- and diastereo- selectivity in a one-pot, three component reaction. An initial hDA involving 3-boronopropenal and ethyl vinyl ether affords a cyclic allylboronate and an allylboration reaction ensues on addition of an aldehyde. Oxidation of the allylboronate provides the 4-hydroxydihydropyran (Scheme 6) <03CC276; 03JA9308>.

408

J.D. Hepworth and B.M. Heron

O ,~

O'-~/CO2 R3 (i) 10 mol% cat. 6, silica -15 ~ - RT, CH2CI2

4-

R1

(ii) PCC, CH2CI2

/ O ' . ~ 002R3

R1~

10 examples

-

80- 94% ee

I~ 2

65 - 81%

Scheme 3

/COCF3

R32"~fCHO RIo ~

R

R2 R3~/~

sealed tube 140 ~ 8 h.

J

R10'~O /

Scheme 4

R

II

COGF3

5 examples 30 -42%

R

BF3.OEt2

R = Me, 45% R = t-Bu, 48%

CH2CI2, RT O

+

H

H202, NaOAc I THF " BPin

BPin ~O

H

Scheme 5

~ OEt

Cr cat., mol. sieve_RT

6 examples OEt

,

RCHO

BPin = mB~o

OH

40 ~

24 h.

,, R

8 examples OEt 61-92%

~H H

Scheme 6

There are several examples of annulation of a dihydropyran on to other ring systems using cycloaddition methodology. Thus, 4-hydroxypyranones react with t~,]3-unsaturated iminium salts to give pyrano[3,2-c]pyranones in a formal [3+3] cycloaddition. The pyran ring behaves as a diene with DMAD and gives aromatic compounds <03JOC1729>. This approach features in a total synthesis of (+)-arisugacin <03T311> and in the synthesis of the ABD ring system of phomactin A <03OL4843>. AcO

/___~/

R

O

4-

HO

sealed tube EtOAc, 85 ~ 24 - 48 h.

O

>

R

25 examples 52 - 84%

The conjugate addition of dithiols to hexa-l,4-diyn-3-ones yields [3,[Y-bis-l,3-dithiane ketones, masked 1,3,5-triketones, which have been converted into dihydro- and tetrahydropyrans <03OL 1147>. The enol triflates derived from tetrahydropyran-2-ones undergo a cross-coupling with benzenethiols catalysed by Ni(0) that gives the 6-arylsulfanyl-3,4-dihydro-2H-pyrans, readily oxidised to the stable sulfoxides. The latter undergo facile conversion to the t~-lithiated enol ethers <03S584>.

409

Six-Membered Ring Systems: With 0 and~or S Atoms

R

O (i) - (iii),. R

S..ph

,.

,.

3 examples, 61 - 80% Reagents: (i) PhN(Tf)2 and KHMDS, THF, -78 ~ (ii) PhSNa, 10 mol % Ni(0), -78 ~ - RT; (iii) m-CPBA, NaHCO3, CH2CI2, -78 ~ (iv) n-BuLi, THF,-78 ~ (v) MeOH,-78 ~

The Heck arylation of 2-substituted 3,4-dihydro-2H-pyrans with diazonium salts exhibits and leads to the 2-aryl-5,6-dihydro-2H-pyrans (Scheme 7) <03CC1656>. Tris(dihydropyranyl)indium undergoes Pd-mediated cross coupling reactions with aryl halides to give mainly 6-aryl-3,4-dihydro-2H-pyrans (Scheme 8) <03OL2405>. trans-diastereoselectivity

R.~

(i) = R , , . ~ ~ A r

6 examples 71 - 83% Reagents: (i)[ArN2]BF4, Pd2(dba)3.CHCI3, NaOAc, MeCN, 20 ~

Scheme 7

(i)

~ 3

~ A

In

r 17 examples 27 - 100% Reagents:(i)ArBr, (PPh3)2PdCI2, THF, reflux

Scheme 8

A Nazarov cyclisation of 1-(3,4-dihydro-2H-pyran-6-yl)-3-phenylpropenones affords cyclopenta[b]pyranones (Scheme 9) <03OL4931 > and the conjugated ethoxytriene 7 derived from tetrahydropyran-2-one also yields a fused cyclopentenone <03JOC9728>. O

O

OEt

O

O

12 examples 40- 92% Reagents: (i) 10% AlCl 3, CH2Cl2, RT

Scheme 9

7

62%

Reagents: (i) Amberlyst 15, CHCI3, 25 ~

Homoallenic alcohols 8 yield 3,4-dimethylidenetetrahydropyrans in a Prins reaction with aldehydes <03CC346> and an intramolecular Prins cyclisation occurs in water using a Lewis acidic surfactant <03OL4521>. Application of the Prins reaction to alkynols instead of alkenols yields 5,6-dihydro-2H-pyrans (Scheme 10) <03OL 1979>. =_ RI~"'/J~SiMe3 19 examples 60 - 100% Reagents: (i) R2CHO, TMSOTf, Et20, -78 ~

FeX3 RCHO

CH2X2, Rs

8

X 8 examples 30 - 98%

Scheme 10

An iterative sequence of propargylation, enantioselective epoxidation of the resulting silylated skipped enynes, an endo selective hydroxyepoxide cyclisation and protodesilylation in which a SiMe3 group plays a pivotal role produces the tris-tetrahydropyran 9 in 18 steps <03OL2339>. The stereoselectivity of the endo selective oxacyclisations of 1,4-di- and

410

J.D. Hepworth and B.M. Heron

1,4,7-tri- epoxides is controlled by the nature of the terminal nucleophile; a tert-butyl carbonate affords the cis-fused bis-tetrahydropyran, but the N,N-dimethylcarbamate gives the trans-fused bicycle <03OL2123>. A key feature in a convergent approach to trans-fused tetracyclic ethers is a SmIz-induced intramolecular reductive cyclisation <03TL5259>.

o H

H

H

H -

H

,,,OH (i) = ,,,OH

OH

79%

O

+

sttl

HO O

9

10

OH

OH

Reagents: (i) (+)-L-DET, Ti(O/-Pr)4, t-BuOOH

Sharpless asymmetric oxidation of the meso 1,4-diol 10 results in its desymmetrisation to the pyran-3-one, which exists as a mixture with the dihydrofuran, and the doubly oxidised bis-pyranone. Each of these hemiacetals can be individually trapped in good yield by careful choice of reaction conditions <03OBC2393>. 6.4.2.2 [1]Benzopyrans and Dihydro[1]benzopyrans (Chromenes and Chromans)

In a variation of the RCM approach to chromenes, allylphenols are isomerised to the vinylphenol prior to O-allylation and subsequent treatment with a Grubbs' second generation Ru catalyst. Application to bis(O-allylated)catechols affords 1,4-benzodioxins <03TL6483>.

~~OH~

(i),(ii)~~O~......~ =

(iii)= ~

Reagents: (i) RuCIH(CO)(PPh3) 3, PhMe, 80 ~ (90%); (ii) allyl bromide, K2CO3, Me2CO, reflux (86%); (iii) Grubbs' cat. 5, CDCI 3, RT (>80%)

The Mitsunobu reaction of o-vinylphenols with chiral epoxyalcohols, derived from allylic alcohols using Sharpless methodology, affords epoxyethers 11. Removal of the epoxy function, which serves as a protecting group for the vinylic double bond, and a ring-closing metathesis gives 2-substituted chromenes with good enantiomeric purity. It is noted that the chiral chromenes are photoracemised, presumably through the light-induced opening of the pyran ring <03TL435>. Both 2H-chromen-4-yl and thiochromen-4-yl enol phosphates have been synthesised using RCM <03TL4275>. Aryl vinyl ethers also undergo RCM, affording 4H-chromenes in high yields (Scheme 11) <03TL311 >. [~~OH

+ O , , . ~1OH ~ R

(i),(ii)= ~~~,,o~O".,,R1 (iii)= ~~]~O"]",R1

11 6 examples Reagents: (i) DEAD, PPh 3, THF (63 - 72%); (ii) Zn, CP2TiCI2, N2 (44 -62%) (iii) Grubbs' cat. 5, CH2CI2, RT (88 - 97%)

Six-Membered Ring Systems: With 0 and~or S Atoms

411

R1

R

R 5 examples, 80- 98% Reagents: (i) Grubbs' cat. 5, CH2CI 2, RT

Scheme 11

O '~R 2

R1 I R2 8 examples, 13 - 87%

Reagents: (i) PtCI4, 1,2-DCE, RT- 70 ~ Scheme 12

No racemisation is observed during the Pt(IV)-catalysed cyclisation of chiral propargyl ethers to chromenes. The PtC14 catalyst appears to activate selectively the triple bond to nucleophilic attack by the arene and enables this well-established route to chromenes to be carried out under mild, neutral conditions and with a variety of substrates (Scheme 12) <03T8859>. A Pt-catalysed 6-endo hydroarylation of an alkynone combined with an intramolecular Michael addition are the key steps in a synthesis of the rotenoid deguelin <03OL4053>. In the synthesis of 2H-naphtho[1,2-b]pyrans from 1-naphthols and 1,1-diarylprop-2-yn-1ols, initial protonation and loss of water from the latter generate an alkynyl carbocation, normally converted to the aryl propargyl ether. However, the concomitant formation of the highly coloured propenylidenenaphthalenones 12, a new class of merocyanine dyes, suggests attack of the allenic form of the cation at the 4-position of the naphthol followed by a 1,7-H shift <03EJO 1220>. R Ar, Ar OH O I + R = H , Me

Ar

Ar

OH

PhMe, reflux

Ar

12

Ar

A Suzuki coupling of 2,6-dimethoxyiodobenzene with the dihydroaromatic boron compound 13 forms the basis of a synthesis of the dibenzo[b,d]pyran ring system <03AG(E)2795> and naphtho[2,3-c]chromenes result from an intramolecular dehydro DA reaction on the diarylalkynes 14 <03SL1524>.

PhMe.

13 Reagents: (i) PdCl2(dppf), 2,6-dimethoxyiodobenzene, aq. NaOH, THF; (ii) DDQ, Phil (83%); (iii) TMSI (97%)

R

160 oc14

3 examples 54 - 72%

A study of the synthesis of chromans from allylic carbonates involving Pd-catalysed asymmetric allylic alkylation has established that the addition of acetic acid results in a pronounced increase in enantioselectivity. Furthermore, (E) allylic carbonates afford (R) chromans and the (Z) substrates the (S) heterocycle (Scheme 13) <03JA9276>. This approach to chromans has been combined with a radical epoxide cyclisation in a total synthesis of (-)-siccanin <03AG(E)3943>.

412

J.D. Hepworth and B.M. Heron

R

Br

"'//" R 9 examples 73 - 89% ee 62 - 99% Reagents: (i) 2 mol% Pd2dba3. CHCI3, ligand, AcOH, CH2CI2 (i)

"
0~/~

"OCO2Me

~ ~ .

~0

(jCH2)2OAc L'~~O~/~ BF3OEt2HO -" " I OH 15

Br (CH2)2OAc H

S c h e m e 13

A lipase-mediated asymmetric acylation features in a total synthesis of the 4-vinylchroman, (-)-heliannuol, from a prochiral diol; the hetero ring results from a Pdcatalysed intramolecular aryl ether cyclisation <03SL2395>. An altemative approach to this sesquiterpene family is based on the ring expansion of spirodienones 15, derived by anodic oxidation of the corresponding phenols, and manipulation of the 4-side-chain in the resulting chromans. The natural product was shown to have an R-configuration at the benzylic function <03SL411, 03TL4877>. An In-mediated allylation of a chroman-4-one is part of yet another route to these molecules present in sunflowers <03T8375>. A three-component Pd-catalysed reaction involving a 3-iodophenyl ether, an alkyl halide and an electron-deficient alkene proceeds with the creation of three new C-C bonds resulting in the formation of chromans (Scheme 14). When applied to benzylic ethers, isochromans are formed <03OL4827>. I

CO2t-Bu

I

~~~.O1~

+

~CO2t-Bu 620/o -(i) gu

Reagents: (i) n-Bul, Pd(OAc)2, PPh3, Cs2CO 3, DME, norbornene, 80 ~ Scheme

14

~ ~ H O

NOy '''' I~~CH2!O2. +R "v2 (i)= ~L.~~.o .,, 0 2

16

14 examples 21 - 99% Reagents: (i)DABCO, THF, reflux

Sequential inter- and intramolecular Michael additions are proposed to account for the formation of 3-nitro-4-nitromethylchromans from the reaction of nitroalkenes with 2-(2-hydroxyaryl)-l-nitroethene derivatives 16 that proceeds with high stereoselectivity. Treatment of the products with base yields chromenes <03TL3813>. Developments in the synthesis of chromans through cycloaddition reactions continue. The thermal degradation of 4H-1,2-benzoxazines, available by the cyclisation of 1-nitro-2arylethane derivatives, in the presence of styrene leads to 2-phenylchromans via generation of a quinone methide <03JA5282>. The tetracyclic system akin to that found in the quassinoids has been constructed using a diene-transmissive DA approach <03CJC81>. A combination of a Knoevenagel condensation between the tx,13-unsaturated iminium salt derived from farnesal and a 1,3-cyclohexadione and a 6n-electrocyclisation, which constitutes a formal [3+3] cycloaddition process, forms the essential part of the synthesis of the daurichromenic ester 17. A subsequent [2+2] photoaddition affords the chroman, saponification of which completes total syntheses of the rhododaurichromanic acids <03OL3935>. In a variation of

Six-Membered Ring Systems: With 0 and~or S Atoms

413

this synthesis, the microwave-assisted condensation between farnesal and orsellinic acid is used to construct the chromene ring and so produce daurichromenic acid <03OL4481 >. / ~ ~ ~ C02Me

(i), (ii) ~ C O 2 M e O H

" - . ~

(iii)

17 Reagents: (i) LDA, THF, -78 ~ NCCO2Me (71%); (ii) DDQ, PhMe, reflux (44%); (iii) hL), hexane, RT, 65 h. (79%) A complex multistep synthesis of the 8-CD3 analogue of 8-tocopherol has been described <03EJO2840>. The super Lewis acid, Me3Si[C6FsCTf2], is an effective catalyst for the regioselective condensation between trimethylhydroquinone and isophytol that yields (~)-a-tocopherol <03AG(E)5731 >.

6.4.2.3 [2]Benzopyrans and Dihydro[2]benzopyrans (Isochromenes and Isochromans) A wide variety of 4-iodo-lH-2-benzopyrans results from treatment of 2-alkynylbenzaldehydes with iodonium species followed by reaction with O- or C- centred nucleophiles. Furthermore the 4-I function can undergo cross-coupling reactions (Scheme 15) <03JA9028>. Competition between 5-exo-dig and 6-endo-dig cyclisation modes is observed in the Pdcatalysed cycloisomerisation of 2-alkynylbenzyl alcohols under neutral conditions. The formation of isochromenes through the latter mechanism is favoured by alkyl rather than aryl substitution at the triple bond terminus and also by low concentrations in a solvent of low polarity and higher reaction temperatures (Scheme 16) <03T6251 >. ~

(i) . v

Bu

O

~"~R

OH R1

I

15 examples, 35 - 87% Reagents: (i) IPY2BF4/HBF4, CH2CI2, 0 ~ - RT, then either O or C nucleophile (X) Scheme

Pdl 2 - KI dioxane, 80 ~

O

I=,

Bu

74%

Bu

Scheme 16

15

An efficient synthesis of 1H-2-benzopyran-5,8-diones is based on the Michael addition of enamines to 2-(1-hydroxyalkyl)-l,4-benzoquinones. The initially formed 3aminoisochroman-5,8-diol is oxidised and deaminated to the isochromenoquinone during work-up, but prior oxidation with Ag20 yields the isochromanoquinone as a single diastereoisomer (Scheme 17) <03S673>. Benzologues of these quinones are readily synthesised by the Pd-catalysed intramolecular cyclisation of 2-bromo-3-aryloxymethyl-l,4naphthoquinones under basic conditions <03T5941 >.

414

J.D. Hepworth and B.M. Heron

O

R10\

R2

OH

OH

+

DMF, RT R3

O

Ar

R2

,.

a3

/ u OH

R4

ol4.,N--.~ R :~

air SiO2

=.

O

O R3

O

R'*

5 examples, 46 - 80%

Scheme 17

6.4.2.4 Pyrylium Salts A facile synthesis of two naturally occurring 3-deoxyanthocyanidins from 2,4,6-triacetoxybenzaldehyde has been described <03S1878>. A one-step route to pyranoanthocyanins, molecules that have been found in red wine <03TL4887>, involves initial reaction under aqueous conditions of cinnamic acids at the electrophilic 4-position of anthocyanins followed by an intramolecular cyclisation and decarboxylation <03TL7583>. A tri-(E)-caffeoyl anthocyanin present in the blue petals of morning glory, Ipomoea tricolor, is resistant to E,Z-isomerisation by UV-B irradiation, a property that may be important in plant survival <03TL7875>. A detector for sulfide ion in aqueous conditions is based on the pyrylium - thiopyrylium conversion with its associated red shift of the charge transfer band <03JA9000> and the formation of trisubstituted thiophenes from pyrylium salts through reaction with Na2S and I2 has been elaborated <03SC2849>. Di- and trisubstituted furans have been obtained from pyrylium salts prepared from benzoic acids or their methyl esters and acetophenones <03TL9271> and a naphtho[1,2-b]furan results from the ring-opening of a 1-(3-chloropropyl)benzo[c]pyrylium salt with MezNH.HCI followed by an intramolecular cyclisation <03CHC386>.

6.4.2.5 Pyranones The product from the Pd-catalysed reaction of (Z)-3-substituted 3-iodoprop-2-enamides with tributylstannyl ethynides depends on the substituent present on the latter. Heterocyclisation to pyran-2-ones by the 6-endo mode occurs with the C-5- and C-6-alkyl and (CH2)2OSiMe3 derivatives (Scheme 18) <03TL7633>. SnBu3

R1

R1

= R2

NH2

Ph R2

O

5 examples, 49 - 62% Reagents: (i) 5 mol% Pd(PPh3)4, DMF, RT then NH4CI

Scheme 18

.;o ~,~/,j,

O

(i) (ii) ' = 74%

18

O..

Ph O

Reagents: (i)C02(CO)8, Phil, RT; (ii) Phil, 50 psi CO, Phil, 80 ~

cis-Epoxyalkynes and the related ene-ynes 18 undergo a Co2(CO)8-mediated reaction that yields pyran-2-ones and the corresponding 5-hydroxy-5,6-dihydropyranones from the former substrates and tricyclic dihydropyranones from the tethered alkenes. A tandem

Six-Membered Ring Systems: With 0 and~or S Atoms

415

cyclocarbonylation- [2+2+1] cycloaddition is proposed for this stereocontrolled coupling reaction <03JA9610>. Moderate yields of 6-substituted 3,4-diarylpyran-2-ones result from the reaction of a diarylcyclopropenone with pyridinium salts; initial ylide formation is followed by ring expansion <03BMCL2205; 03JMC4872>. L A Ph

r

Phil, Et3N

+

L.... cIC(O)R

25 ~

Ar R = alkyl, alkoxy, alkylthio

D,

R

22 examples, 8- 38%

O

The nucleophilic 1,4-addition of activated methine compounds to 2-alkynones is a facile route to highly substituted pyran-2-ones; a cyclobutenoxide intermediate is suggested (Scheme 19) <03TL2061>. 1,2-Allenic ketones also undergo a base-catalysed 1,4-addition reaction with malonic ester and, provided the allene moiety is unsubstituted, a double bond isomerisation and cyclisation follow and pyran-2-ones are formed (Scheme 20) <03JOC8996>. 2,3,3-Trimethylindoles and -indolines also react with diethyl malonate, yielding fused pyran-2-ones <03JHC297>. The base-catalysed cyclisation of a malonate features in a total synthesis of photodeoxytridachione <03AG(E)549>.

toct~

O

R3

O

R2 EtO2C

R2

R3" ~O/ ~"O 10 examples, 9 - 87% Reagents: (i) Nail or NaOEt, 1,4-dioxane, reflux Scheme 19

EtO2C

F1

~R

2

(i) = R

%

CO2Et

i

R 2" ~O f ~ O 18 examples, 33 - 92% Reagents: (i) 10 mol % K2CO3, solvent, reflux Scheme 20

3,6-Bridged pyran-2-ones 19, paracyclophanes, and the analogous crown ethers are formed by the intramolecular [4+2] cycloaddition ofbis-ketenes generated thermally from the products of the reaction of Meldrum's acid with dicarboxylic acid dichlorides. On heating with hydrochloric acid, ring transformation to 2,6-bridged pyran-4-ones occurs <03H(60)899; 03T2651>. Thermal decarbonylation of 5-aryl-4-phenyl-2,3-dihydrofuran-2,3-diones generates aroylphenylketenes that cyclodimerise to dihydropyran-2,4-diones at 140 ~ which at higher temperature afford 4-aroyloxypyran-2-ones as a result of a 1,3-shift <03RJOC103>. r-

A - " I

OH O '

reflux o

O

reflux

L ~CH2n)n~

J

19 5 examples 60 - 89%

5 examples 76 - 90%

Alkynes and carbon suboxide react to initially form a cyclobutenone derivative 20. If the alkyne is in excess, a second reaction with alkyne leads to cyclobuta[b]pyran-4-one and the

416

J.D. Hepworth and B.M. Heron

corresponding pyran-2-one. When C302 is in excess, cyclobuta[b]pyrano[2,3-d]pyran-2,5diones are formed <03JHC321>. O R R

I, ",.

I + I

o

CII _ 70oc C CHCI-"=

oc II

I,o R

R ~

-~

R + R / ~

4 examples, 45-55%

,

=

R

L_

~

R

o

4 examples, 30-60% R 4 examples

O Both 3- and 5-bromopyran-2-ones have been used as substrates in Suzuki coupling reactions <03BMCL2667; 03SL253> and 4-bromo- and 6-chloropyran-2-ones couple with alkynes <03S2564; 03TL607>. 3,5-Dibromopyran-2-one is aminated regioselectively at C-3 <03TL65> and conditions have been found to allow Stille coupling selectively at either C-3 or C-5 <03JA14288>. (Bromo-q4-2-pyranone)-tricarbonyliron complexes have been prepared <03SL1693>. Syntheses based on the destruction of the pyranone ring include those of tetrahydrofluorenes <03TL4439>, tropolones <03TL4543>, benzisoindoles <03OL2833> and oligoarenes <03TL3363>. The application of Heck, Stille and Suzuki methodologies to kojic acid gives access to a variety of 5-substituted pyran-4-ones <03TL7349>. Chiral Zr complexes are effective catalysts for asymmetric DA reactions involving a wide range of aldehydes and variants on Danishefsky's diene (DD); the reactions proceed in a stepwise manner. Of particular note is the formation of the 2,3-trans-dihydropyranone with 2,4-diMe-DD with high diastereo- and enantioselectivity, whereas 4-benzyloxy-DD similarly affords the analogous cis-derivatives (Scheme 21) <03JA3793>. The DA reaction has been achieved using a diene supported on a Merrifield resin <03TL3645>. New catalysts that bring about high stereoselectivity in DA reactions include a Ce(III)-(R)-BNP complex <03CL608>, a dendritic Ti-NOBIN <03CEJ5989>, rare earth phosphates <03T10509>, and a Cr(III)Schiff base complex <03OL2563>. A Zn-BINOL catalyst simultaneously effects the DA reaction of benzene dicarboxaldehydes with DD and reduces the second carbonyl function <03OL1091>.

OSiMe3 !~~ O . , J

Ot-Bu

~

6 examples, 79 - 98% ee 23 - 99%

(i), (ii)

II O

R"~'~"H

~OSiMe3 BnO~ot_Bu

(i), (ii)

(i)10 mol% chiral Zr cat., (ii) H+ or Sc(OTf)3

BnOO~o ) R 6 examples, 81 - 97% ee 54 - 100%

Scheme21

6.4.2.6 Coumarins

Electron-rich phenols are converted into coumarins under mild conditions in a Pd(0)catalysed reaction with alkynoate esters, offering a facile route to naturally occurring

Six-Membered Ring Systems: With 0 and~or S Atoms

417

molecules; incorporation of formic acid into the reaction mixture is necessary presumably to maintain the catalytic cycle (Scheme 22) <03JA4518>. In TFA, the reaction appears to be catalysed by Pd(II) and to involve hydroarylation of the esters <03BCJ 1889>. A wide variety of internal alkynes undergo a Pd-catalysed carbonylative annulation with 2-iodophenols yielding 3,4-disubstituted coumarins with no formation of chromones (Scheme 23) <03JOC9423>. CO2Et

OMe

rl +/3.0. R

MeO

MeO

R

R

eO O 5 examples, 41 - 69%

R

R

30 examples, 9 - 78%

Reagents: (I) CO, Pd(OAc)2, py, n-Bu4NCl, DMF

Reagents: (I) Pd(OAc)2, NaOAc, HCO2H Scheme 22

Scheme 23

Salicylaldehydes and some o-hydroxyaryl ketones react with Meldrum's acid to give coumarin-3-carboxylic acids <03TL1755>. 3-Cyanocoumarins, and thus the 3-carboxylic acids, are available in high yield from a Knoevenagel reaction between salicylaldehydes and malononitrile in water <03S2331>. 3-Chlorocoumarins result from the cathodic reduction of trichloroacetyl esters of o-hydroxyacetophenones <03T9161 >. RCM of the unsaturated aryl esters 20 obtained by the acylation of allylphenols provides a general route to coumarins <03PAC421; 03TL4199>.

mo

R

oru

s ca

,

CH2Cl 2, reflux

O

MeO" . ~

5 examples, 70 - 90%

"O" "O

'2

20

21

Three naturally occurring isomeric coumarin dimers have been obtained from one precursor, methyl 2-hydroxy-4-methoxy-6-methylbenzoate through an initial unselective coupling promoted by FeC13 adsorbed on silica gel. After chromatographic separation, the coumarins were prepared by attack of -CHzCN on the ester function of the three biaryls. One of the biaryls was resolved and the individual atropisomers converted into (+)- and (-)kotanin 21 <03AG(E)931; 03S1803>. Nitrocoumarins undergo [4+2] cycloadditions with dienes, behaving as 2n components in water and giving the exo adducts 22. Dihydrodibenzofurans are formed through a Nef cyclodehydration following hydrolysis and decarboxylation. However, 3-nitrocoumarin reacts as the 4n fragment with 2,3-dimethoxybuta-l,3-diene and 4-substituted 3-nitrodihydrocoumarins are formed <03JOC9263>. ~

N "~

O

2

"O" "O

//~--I - ~

~

H

NaOH

solvent, heat

02 22

9 examples, 55 - 95%

,.

(ii) H2SO 4 8 examples, 40 - 60%

418

J.D. Hepworth and B.M. Heron

The influence of high intensity ultrasound on various reactions of 4-hydroxycoumarin in aqueous conditions has been studied <03S1286>. 4-Hydroxycoumarins and -thiocoumarins undergo an asymmetric Michael addition to a,[3-unsaturated enones in the presence of imidazoline catalysts. High yields and enantioselectivities are observed and the method has been used to prepare kg quantities of enantiopure warfarin (Scheme 24) <03AG(E)4955>. OH

OH R1 +

(i)

O RI

_-=

,.>" L,-. v

(O)R2

17 examples, 65- 99% Reagents: (i) imidazoline cat., CH2CI2, RT

O

2R1

(i)

--

~'~... R2

0

F:'"

i.... v

E

82

21 examples, 6- 98% Reagents: (i) electrophile (E), CH2CI2, -78 ~

Scheme 24

Scheme 25

Various electrophiles bring about the cyclisation of o-(1-alkynyl)benzoates and (Z)-2alken-4-ynoates to isocoumarins and pyran-2-ones in high yields; extension to the synthesis of bis-coumarins and hetero-fused pyranones is successful (Scheme 25) <03JOC5936>. 3Aryl-4-iodoisocoumarins, prepared in a similar manner, undergo Stille reactions and can readily be deiodinated <03T2067>. Spiro 3-substituted dihydroisocoumarins are formed in high yield when benzocyclobutenones are treated with Li dialkylphosphides through spontaneous trapping of the distal anion. Reverse addition of the reagents allows complete conversion to the anion that can then react with added aldehyde, affording simple 3-substituted heterocycles. The reaction also proceeds with tricarbonylchromium complexes of the cyclobutenone <03EJO4363>. [

R1 O ~ ~

[

LiP(i-Pr)2 ~

R1 { ~~ O

THF,-78 ~

R1 .

O

LiP(i'Pr)2 , ,. THF,-78 ~ R2CHO

R 1 = H (79%) R 1 = OMe (83%)

R2

R 1 = H, R2 = n-Pr (57%) R 1 = H, R2 = 4-NO2CsH4 (78%)

6.4.2.7 Chromones

Sonogashira coupling of alkynes with 3-iodoflavones leads to 3-alkynylflavones and is best effected using (S)-prolinol; it is successful in aqueous conditions <03T9563>. The ylide phenyliodonium bis(phenylsulfonyl)methylide inserts into the 2,3-double bond of flavones and offers a direct route to 3-substituted flavones <03T7929>. O

~~]O~A

O + r

+ _

PhI--C(SO2Ph)2

SO2Ph 7 examples

Rh2(OAc)4 ~

SO2Ph 42 - 66%

MeCN, 20 ~

~"

0"

"Ar

Chromone-3-carboxaldehydes react with benzylic ylides to yield diastereomeric mixtures of 3-styrylchromones in which the (Z)-isomer is predominant <03NJC1592>; subsequent DA reactions with maleimides under microwave irradiation are stereo selective with the

419

Six-Membered Ring Systems: With 0 and~or S Atoms

(Z)-diastereoisomer giving the endo cycloadduct and the (E)-isomer the exo xanthone derivative <03SL1415>. Conjugate addition of Li dialkynylcuprates to the 3-formyl and 3-ethoxycarbonyl derivatives of chromone gives 2-alkynylchromanones, but rearrangement to the 2-hydroxychromanone 23 often accompanies work-up. However, addition to 3-cyanochromone results in ring opening and the formation of an eneynonitrile; transformation to a bis-benzopyranopyridine follows in the case of the propylcuprate <03TL 1461 >. OH

O

O

O

=cN

OH

X=CHO

O

=

R

R 4 examples, 21 - 90%

R = SiMe3, 68% Reagents: (i)(R

--)2CuLi

23 R = SiMe3, 79%

, Et20, N2,-10 ~ then H3 O+

In order to achieve good enantioselectivity in the Stetter synthesis of chroman-4-ones, it appears that a carbonyl function is necessary in the unsaturated side-chain of the salicylaldehyde-derived starting materials (Scheme 26) <03SL 1934>. O I

EWG

O O) =

~,,

EWG

O hv

3 examples, 58 - 90%

Reagents: (i)chiral triazolium salt, KHMDS, PhMe Scheme 26

)

ROH R

24

O

R = Me, 20%

Chalcones can be prepared by a Heck reaction between an aryl iodide and an aryl vinyl ketone. Demethylation allows spontaneous cyclisation to the flavanone <03TL9107>. An arene-alkene photocyclisation is observed during the irradiation of dihydro-2-methyl-2vinylnaphtho [ 1,2-b]pyran-4-one and benzotricyclo [5.3.1.06'1]undecenes 24 result <03TL2011 >. Oxidation of chroman-4-one and its thio analogue with Mn(OAc)3 gives the 3-acetates and subsequent basic hydrolysis yields the 3-hydroxychroman-4-one. Enzymatic hydrolysis of the O-heterocycle using Amano PS lipase in a phosphate buffer selectively cleaved the (+)isomer <03TA1489>. Enol ethers derived from chroman-4-one are converted into the 3hydroxy-chromanone with high enantioselectivity, optimal with the pentyl ether, using a modified Sharpless asymmetric dihydroxylation reaction <03JOC8088>. 6.4.2.7 Xanthones and Xanthenes

Intramolecular cyclisation following halogen-metal exchange in the benzonitrile derivatives 25 provides a route to xanthones and thioxanthones. Incorporation of a second aryl halide function into the benzonitrile substrate allows an anionic cascade ring-closing sequence and the formation of pentacyclic xanthene derivatives 26 <03JOC4091>.

420

J.D. Hepworth and B.M. Heron (ii), (iii)

CN

Ar=H : CN

Br

F~Ar

(i)

O

~

[ ~ 2 5 ~ ~i A r (ii)

X= O(95% ) X = S (99%)

N

Ar = 2-FC6H4

X = O (89%) X = S (91%) 26

Reagents: (i) 2-bromo(thio)phenol, K2CO3, DMF, 100 ~ (ii) t-BuLi, THF, -78 ~ - RT; (iii) aq. HCI, 70 ~ Dihydrobenzoxanthenes 27 result from the photolysis of 2-(1-naphthyl)phenols; a quinone methide intermediate is postulated. The twisted nature of the o-hydroxybiaryl system facilitates excited-state intramolecular proton transfer (ESIPT) at both the 2'- and 7'positions <03JA 1164>. The anion derived from furobenzopyrandione 28 reacts with Michael acceptors regiospecifically to yield xanthones and various annulated derivatives <03OL3753> and intramolecular trapping of the anion by a carbamate side-chain leads to spiro- pyrrolidine and piperidine 9-xanthene derivatives <03TL9291 >.

O

hv

300 nm aq. MeCN-

O

OH

OH O 4 examples, 67 - 88% Reagents: (i) R1CH=CHC(O)R2, LiOt-Bu 28

27 (80%)

6.4.3

SPh

O

HETEROCYCLES CONTAINING ONE SULFUR ATOM

6.4.3.1 Thiopyrans and analogues

Products from the cyclisation of sulfur-containing substrates can depend on the reaction conditions. Thus, although the 13-keto thioamides 29 yield piperidine-2-thiones when boiled with 2-methylbut-2-enal in ethanol containing triethylamine, thiopyrans are formed in pyridine <03T4183>.

O

S

Rl " ] J ' ' ~ N" 29

R1

R2 +

R3

O

R4~ . / ] j

PY reflux"

C ~ N/I~S/~_,H .. R3 ~2 R'*

4 examples 55 - 68%

The electrophilic 6-endo cyclisation of derivatives of 1-sulfanylpent-4-en-2-ol leads to thiopyrans when effected by I2, but to tetrahydrothiophenes by a 5-exo route when induced by Se reagents (Scheme 27) <03EJO209>. Similarly, the conditions used for the ICl-promoted cyclisation of bis(4-methoxybenzylthio)acetylene influence the competition between Ar2-6 (ortho) and Arl-5 (ipso) routes. In the strict absence of water, the exclusive product is the 1H-2-benzothiopyran 30, whereas in the presence of nucleophiles ipso attack is favoured and

421

Six-Membered Ring Systems: With 0 and~or S Atoms

the spirocyclohexadienone results; a common c~-complex is proposed. The spiro compounds can be rearranged to 1H-2-benzothiopyrans and 2-benzothiopyrylium salts <03EJO47>.

PhSe~ +

PhSe OAc OAc Ratio 57:34 (67%) O~...'~.. ] .[~.CH2Ar S.,

~

PhSeCI CH2CI2

_OH A c S ~ -

12,NaHCO3 CH2CI2

53%

Scheme 27

,SCH2Ar

ICl

\~---I H20, NaHCO3 A r ~ S ~ S~---Ar MeOH,ICIcH2Cl2 9M e O ~ l ~S MeOH,CH2CI2 ~ ~ ' ~~/ "S 8 4 % 72% Ar = 4-MeOC6H4 30

The thiochromene 31 is the final product arising from the photoirradiation of tris-(2benzo-[b]thienyl)methane. The primary photoproduct is a cyclopropane derivative formed by a di-~-methane rearrangement <03TL751 >. The disulfide 32 is a stable source of o-thiobenzoquinone methides. In the presence of I2, alkenols undergo an intramolecular cycloaddition under ambient conditions to give tetrahydrofuro- and tetrahydropyrano[3,2-c]benzothiopyrans <03TL6513>. a3

S ""~

~

:)

S

~CHO ~'~""" 32 S3)--2

R3 R4 I-4 ,0--~"R4 + "'(--OH 300m01%12,. ~ ( C H 2 ) 2 R1~0H2)2 R2

0H2012,RT ~I...~~S~R'H 2 3 examples 70- 93%

Exploration of helical sterically overcrowded alkenes containing thioxanthene units continues in the search for molecular devices. The donor-acceptor substituted thioxanthene derivatives 33 behave as molecular modulators <03JA15659>, motors <03OBC33> and switches <03CEJ2845>, and a low barrier to rotation around the cumulenic bonds is observed for the thioxanthene 34 <03OL3371>. The new heterocyclic bis-tricyclic aromatic alkenes 35, synthesised using Barton's two-fold extrusion diazo-thione coupling technique, adopt mono-folded conformations <03OBC2755>.

Ph Ph ph~~'~ ph

S Me2N'~~ /

02 33

34

35 X = S, Se, Te

422 6.4.4

J.D. Hepworth and B.M. Heron

H E T E R O C Y C L E S CONTAINING TWO OR MORE OXYGEN ATOMS

6.4.4.1 Dioxins and Dioxanes

1,2-Dioxins are readily ring-opened under a variety of conditions and thus function as masked cis-y-hydroxy enones. On treatment with malonate nucleophiles, the initial ring opening of naphtho[2,1-c][1,2]dioxin is followed by Michael addition of malonate to the enone and two lactonisations which furnish fused dihydrocoumarins 36 <03S668>. Ringopening of the readily prepared epoxy-l,2-dioxins with either Et3N or Co(II) complexes affords 4-hydroxy-2,3-epoxyketones with good stereocontrol in both steps <03JOC5205>.

O iO

(i) =

O

R3

R,H~~O

36

.

i

R3

O

(i)=

amples

23 - 84%

,.r ~ o,:..j,

a3

(ii)

o

7 examples

~'

O,~?OH

O

10 examples 77 - 100%

51 - 92%

Reagents: (i)m-CPBA, CH2CI2;(ii)Co(ll)salen, CH2CI2

Reagents: (i) diethyl malonate, NaOEt, THF

Reaction of trimethylhydroquinone with aldehydes yields 1,3-benzodioxins, oxa analogues of the tocopherol system, as a separable mixture of two diastereoisomers. The trans-isomer is formed preferentially with bulky aldehydes <03T2687>.

NO

RCHO NO OH

H+ =

O

~ O

''~R

[ ~

O

HCHO BF3.OEt2=

O

CH2CI2

O~O tr--0"~0---~

O"

7 examples, 52- 81%

~k~

/O81%

37

The hydroxymethylation of 1,2-cyclohexanedione leads to the complex fused 1,3-dioxane 37. 3-Methyl- 1,2-cyclopentanedione yields a similar tetracycle <03 EJO4146>. An asymmetric synthesis of 2,3-disubstituted 1,4-benzodioxanes is based on the cyclisation of the protected diol 38, a Mitsunobu-derived substrate, which probably involves a quinone methide <03TA701>. An efficient resolution of 1,4-benzodioxane-2-carboxylic acid has been described <03TA3779>. Substituted benzene-l,2-diols react with propargylic carbonates under Pd-catalysis to yield 2-substituted 3-alkylidene-l,4-benzodioxins either as a mixture of regioisomers or as a single isomer depending on the substituents present <03EJO2813; 03TL557>.

Ph ~O ~.--O.,I

Ar-.~3H2OH

A rI / " I' r ~ OBn AcOH,HCl O~11~

38

CHO

O

O

65 ~ 1 h

CHO 53%

R._~~OHoH +

(i)

R

O

9 examples OCO2Me 50 - 100% Reagents: (i) [Pd2(dba)3], dppb, THF, RT

423

Six-Membered Ring Systems: With 0 and~or S Atoms

6.4.4.2 Trioxanes

The photoisomerisation of (E,E)-arylidene-13-ionones to the fused pyrans 39 is well known, but it has now been shown that [2+4] photoaddition of 02 to the pyran occurs regioselectively forming stable trioxanes <03TL 1943>. The polycyclic 1,2,4-trioxane 40 is formed when H202 is added to the hDA dimer of methylene cyclohexanone <03OBC2859>.

~

A

r

dryhv Phil ~

0-0

02

A

r

4 examples,85 - 90%

39

OH

HO u

40

Artemisinin has been converted in two steps into the stable trioxane isobutene dimer 41. Reactions at the linking unit leave the trioxane fragments intact and allow the synthesis of a variety of dimers that possess desirable pharmacological properties <03JMC1060>. 10-Bromoalkyl and 10-aminoalkyl derivatives of deoxoartemisinin have been prepared and used to form dimers and a trimer in which artemisinin residues are linked through alkylamide and alkylthio functions <03JMC987>. A variety of 10-aryl <03EJO2098> and 10-CF3 <03JOC9763> derivatives of dihydroartemisinin and 9-substituted derivatives of artemisinin <03JMC4244> have been synthesised and their reactions and stereochemistry studied. "

O

,,,

b

...... 41

"

HOO

OOH

~

~ O-O R2 4 examples 45-64%

Reagents:(i)o,30)~H202/ methyltrioxorhenium, TFE,RT; (ii) R1R2CO,HBF4 Scheme 28

6.4.4.3 Tetraoxanes

Controlled oxidation of a mixture of two carbonyl compound to the gem-dihydroperoxide of the more reactive substrate followed by the acid-catalysed addition of the second carbonyl compound provides a reliable route to unsymmetrically substituted tetraoxanes (Scheme 28) <03TL6309>. 6.4.5

HETEROCYCLES CONTAINING TWO OR MORE SULFUR ATOMS

6.4.5.1 Dithianes and Trithianes

424

J.D. Hepworth and B.M. Heron

The first examples of 3,6-(perfluoroalkyl)-l,2-dithiins have been obtained through the oxidative deprotection and cyclisation of (Z,Z)-l,4-bis(t-butylthio)-l,4-bis(perfluoroalkyl)1,3-butadienes. They adopt a similar twist geometry to the parent dithiin and during electrochemical oxidation appear to form a planar radical cation (Scheme 29) <03JOC8110>. Thiopropenoylsilanes 42, readily accessible from silylated allenes, self-dimerise in a head-to-head fashion to give silylated 1,2-dithiins; sometimes the corresponding 1,3-dithiin is also formed <03TL2831>.

RF

RF

~L ~ St-B St-Bu CH2cI2MecNNBS ~Ss, . RF

Me3Si l ...OTHP , . m:- [r I ~iS ,M i e3S

RF 2 examples,65- 68%

42

S c h e m e 29

_ ~ SSirMe3s SiMe3 8 examples 29 - 65%

S+SLj" OF3 " CF3SO3 43

Treatment of propane-l,3-dithiol with trifluoroacetic anhydride and then with trifluoromethanesulfonic acid affords 2-trifluoromethyl-l,3-dithianylium triflate 43. This first ct-perfluoroalkylcarbenium salt is thermally stable and acts as an electrophilic polyfluoroalkylating agent <03TL5995>. Ketene dithioacetals, available by the Peterson olefination of 2-trimethylsilyl-1,3-dithiane with aldehydes and ketones, are oxidised to the trans-l,3-dithiane 1,3-dioxides 44 with virtually complete diastereo- and enantioselectivity using Sharpless methodology <03JOC4087>.

,o

k-- S

R2

k--S. R2 44 "b 6 examples,98+%ee, 60 - 75%, Reagents:(i) Ti(Oi-Pr)4,(+)-DET, PhC(Me)2OOH,CH2CI2, -40 ~

o

R1-"

Rl"X'-v--'~-R2 10 examples 48 - 95% Reagents:(i) HS(CH2)3SH,MeOH-CH2CI2 S c h e m e 30

The double conjugate addition of dithiols to propargylic ketones offers a facile route to [3-keto 1,3-dithianes that can function as masked 1,3-dicarbonyl compounds and provide access to spiroketals. When the alkynic substrate contains an additional electrophilic centre, a tandem cyclisation can accompany thiane formation (Scheme 30) <03OBC 15>. 6.4.6

HETEROCYCLES CONTAINING BOTH OXYGEN AND SULFUR IN THE SAME RING

6.4.6.10xathianes

Vinyl and allyl sulfonates derived from primary and secondary alkenols and from propargylic alcohols undergo an RCM in the presence of Ru catalysts to give dihydro 1,2-oxathiane 2,2-dioxides <03SL667>.

425

Six-Membered Ring Systems: With 0 and~or S Atoms

+

.o

;

"~0

.

R

R

R

5 examples, 67- 100% Reagents: (i) EtaN, CN2CI2; (ii) Grubbs' cat. 5, Phil, 70 ~ The cycloaddition reaction of o-thioquinones with acyclic 1,3-dienes is a finely tuned process that can involve either reagent behaving as the diene component. It has now been established that formation of a 2-spiro-linked thiopyran by a [2+4] reaction is kinetically controlled and that the [4+2] alternative leads to the thermodynamic product, a 1,4-benzoxathiin (Scheme 31). Cyclic dienes yield only the oxathiin <03T5523>. Incorporation of the thionocarbonyl diene unit into furan and pyran rings and reaction with carbohydrate glycols leads to tricyclic oxathianes, desulfurisation of which yields 2-deoxydisaccharides <03T4249>. a2

R2

R' O

R'

thermodynamic control

--

a2

kinetic

control

O

25 examples, 17 - 9 3 %

Scheme 31

Adamantane-2-thione undergoes a concerted regioselective cycloaddition reaction with alkynoic acids to give 2-spiro-linked 1,3-oxathiin-6-ones (Scheme 32). When applied to thiofenchone, the reaction also appears to be stereospecific <03EJO3727>. PhMe ,.

+

CO2H

R

reflux

O 3 examples, 65- 100%

Scheme 32

+ "~R 3

R1

R1

TiCI4 = ~~'R CH2CI2 R3 -78 ~ 2 13 examples, 24 - 88%

R2

Scheme 33

2-Alkenyl-4,4-dimethyl-l,3-oxathianes are synthetic equivalents of the highly reactive t~,D-unsaturated thioaldehyde system. As such, they react with alkenes in a tandem cationic [4++2] polar cycloaddition- elimination sequence to yield 3,4-dihydro-2H-thiopyrans (Scheme 33) <03T1859>. Reactions subsequent to lithiation at C-2 of the 1,3-oxathianes derived from 5-hydroxy-1tetralone 45 <03EJO337> and from myrtenal 46 <03JOC6619> result in the equatorial product.

~

'

b 45

H (i) s-BuLi, THF, -78 ~ (ii) electrophile

~ 46

E 4 examples, 83 - 99%

Triflic anhydride effects the cyclisation of methylthioethyl phenyl ethers to the sulfonium salt, demethylation of which affords the 2,3-dihydro-l,4-benzoxathiin (Scheme 34). The

426

J.D. Hepworth and B.M. Heron

method is also successful with the corresponding ethers derived from naphthalene, benzothiophene and indole <03S1191>. o-Methylsulfanyl O-aryl N,N-diethyl carbamates, accessible using directed metallation methodology, undergo an anionic ortho-Fries rearrangement yielding 2-(hydroxyaryl thio)acetamides, which on refiuxing with AcOH afford [1,4]benzoxathiin-2-ones (Scheme 35) <03SL1474>. R

O

(i) Tf20

s

R

OH

AcOH

s

I

R _r'"~';T~ ,, O "_~_ O

- - ~ ~ s ~J

3 examples, 86 - 94% Scheme 34

6.4.6

O

4 examples, 81 - 84% Scheme 35

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03JOC3225

427

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428 03JOC4087 03JOC4091 03JOC5205 03JOC5936 03JOC6619 03JOC8088 03JOC8110 03JOC8996 03JOC9050 03JOC9263 03JOC9423 03JOC9728 03JOC9763 03JOC9983 03NJC1592 03OBC15 03OBC33 03OBC104 03OBC2393 03OBC2755 03OBC2859 03OBC3949 03OBC4173 03OL761 03OL913 03OL1091 03OL1147 03OL1979 03 OL2123 03OL2339 03OL2405 03OL2563 03OL2833 03OL3371 03OL3753 03OL3935 03OL4053 03OL4425 03OL4481 03OL4521 03OL4815 03OL4819 03OL4827 03OL4843 03OL4931 03OL5035 03PAC421 03PAC1453

J.D. Hepworth and B.M. Heron V.K. Aggarwal, R.M. Steele, Ritmaleni, J.K. Barrell, I. Grayson, J. Org. Chem. 2003, 68, 4087. J.L. Kristensen, P. Vedsa, M. Begtrup, J. Org. Chem. 2003, 68, 4091. B.W. Greatrex, N.F. Jenkins, D.K. Taylor, E.R.T. Tiekink, J. Org. Chem. 2003, 68, 5205. T. Yao, R.C. Larock, J. Org. Chem. 2003, 68, 5936. A. Solladi6-Cavallo, M. Balaz, M. Salisova, R. Welter, J. Org. Chem. 2003, 68, 6619. B.J. Marcune, S. Karady, P.J. Reider, R.A. Miller, M. Biba, L. DiMichele, R.A. Reamer, J. Org. Chem. 2003, 68, 8088. E.D. Lorance, R.S. Glass, E. Block, X. Li, J. Org. Chem. 2003, 68, 8110. S. Ma, S. Yu, S. Yin, J. Org. Chem. 2003, 68, 8996. Y. Mori, K. Nogami, H. Hayashi, R. Noyori, J. Org. Chem. 2003, 68, 9050. D. Amantini, F. Fringuelli, O. Piermatti, F. Pizzo, L. Vaccaro, J. Org. Chem. 2003, 68, 9263. D.V. Kadnikov, R.C. Larock, J. Org. Chem. 2003, 68, 9423. E.G. Occhiato, C. Prandi, A. Ferrali, A. Guarna, P. Venturello, J. Org. Chem. 2003, 68, 9728. G. Magueur, B. Crousse, M. Our6vitch, J.-P. B6gu6, D. Bonnet-Delpon, J. Org. Chem. 2003, 68, 9763. P. Soucy, A. L'Heureux, A. Tor6, P. Deslongchamps, J. Org. Chem. 2003, 68, 9983. A. Sandulache, A.M.S. Silva, D.C.G.A. Pinto, L.M.P.M. Almeida, J.A.S. Cavaleiro, New J. Chem. 2003, 27, 1592. M.J. Gaunt, H.F. Sneddon, P.R. Hewitt, P. Orsini, D.F. Hook, S.V. Ley, Org. BiomoL Chem. 2003, 1, 15. R.A. van Delden, N. Koumura, A. Schoevaars, A. Meetsma, B.L. Feringa, Org. Biomol. Chem. 2003, 1, 33. A. Lewis, I. Stefanuti, S.A. Swain, S.A. Smith, R.J.K. Taylor, Org. Biomol. Chem. 2003, 1, 104. S. Bartlett, R. Hodgson, J.M. Holland, M. Jones, C. Kilner, A. Nelson, S. Warriner, Org. Biomol. Chem. 2003, 1,2041. A. Levy, S. Cohen, I. Agranat, Org. Biomol. Chem. 2003, 1, 2755. J.-F. Berrien, O. Provot, J. Mayrargue, M. Coquillay, L. Cic6ron, F. Gay, M. Danis, A. Robert, B. Meunier, Org. Biomol. Chem. 2003, 1, 2859. C.M. Diaper, W.P.D. Goldring, G. Pattenden, Org. Biomol. Chem. 2003, 1, 3949. G. Pattenden, M.A. Gonz~ilez, P.B. Little, D.S. Millan, A.T. Plowright, J.A. Tornos, T. Ye, Org. Biomol. Chem. 2003, 1, 4173. A.B. Smith III, W. Zhu, S. Shirakami, C. Sfouggatakis, V.A. Doughty, C.S. Bennett, Y. Sakamoto, Org. Lett. 2003, 5, 761. U. Majumder, J.M. Cox, J.D. Rainier, Org. Lett. 2003, 5, 913. H. Du, K. Ding, Org. Lett. 2003, 5, 1091. H.F. Sneddon, M.J. Gaunt, S.V. Ley, Org. Lett. 2003, 5, 1147. P.O. Miranda, D.D. Diaz, J.l. Padr6n, J. Bermejo, V.S. Martin, Org. Lett. 2003, 5, 1979. F. Bravo, F.E. McDonald, W.A. Neiwert, B. Do, K.I. Hardcastle, Org. Lett. 2003, 5, 2123. T.P. Heffron, T.F. Jamison, Org. Lett. 2003, 5, 2339. U. Lehmann, S. Awashi, T. Minehan, Org. Lett. 2003, 5, 2405. D.E. Chavez, E.N. Jacobsen, Org. Lett. 2003, 5, 2563. K. Kranjc, S. Polanc, M. Ko~evar, Org. Lett. 2003, 5, 2833. Y. Kuwatani, G. Yamamoto, M. Iyoda, Org. Lett. 2003, 5, 3371. F.M. Hauser, W.A. Dorsch, Org. Left. 2003, 5, 3753. A. Kurdyumov, R.P. Hsung, K. Ihlen, J. Wang, Org. Lett. 2003, 5, 3935. S.J. Pastine, D. Sames, Org. Lett. 2003, 5, 4053. K.Y. Tsang, M.A. Brimble, J.B. Bremner, Org. Lett. 2003, 5, 4425. Y. Kang, Y. Mei, Y. Du, Z. Jin, Org. Lett. 2003, 5, 448 I. D.L. Aubele, C.A. Lee, P.E. Floreancig, Org. Lett. 2003, 5, 4521. M.J. Gaunt, D.F. Hook, H.R. Tanner, S.V. Ley, Org. Lett. 2003, 5, 4815. M.J. Gaunt, A.S. Jessiman, P. Orsini, H.R. Tanner, D.F. Hook, S.V. Ley, Org. Lett. 2003, 5, 4819. S. Pache, M. Lautens, Org. Lett. 2003, 5, 4827. K.P. Cole, R.P. Hsung, Org. Lett. 2003, 5, 4843. G. Liang, S.N. Gradl, D. Trauner, Org. Lett. 2003, 5, 4931. D.R. Williams, S. Patnaik, S.V. Plummer, Org. Lett. 2003, 5, 5035. A.K. Chatterjee, F.D. Toste, S.D. Goldberg, R.H. Grubbs, Pure Appl. Chem., 2003, 75, 421. M. Yus, Pure Appl. Chem., 2003, 75, 1453.

Six-Membered Ring Systems: With 0 and~or S Atoms

03PSS2627 03RJOCI03 03RJOC757 03S584 03S668 03S673 03Sl191 03S1286 03S1803 03S1878 03S1929 03S2331 03S2564 03SC2849 03SL253 03SL411 03SL667 03SL1213 03SL1415 03SL1474 03SL1524 03SL1693 03SL1759 03SL1934 03 SL2185 03SL2395 03T311 03T1739 03T1859 03T2001 03T2067 03T2371 03T2651 03T2687 03T2899 03T4183 03T4249 03T5523 03T5645 03T5941 03T6147 03T6251 03T7251 03T7929 03T8375 03T8551 03T8859 03T8963 03T9161 03T9563 03T9609 03T10509 03TA701 03TA1489

429

I. Yavari, F. Nasiri, H. Djahaniani, Phosphorus Sulfur Silicon 2003, 78, 2627. E.S. Vostrov, E.V. Leont'eva, O.P. Tarasova, A.N. Maslivets, Russ. J. Org. Chem. 2003, 39, 103. V.D. Dyachenko, R.P. Tkachev, Russ. J. Org. Chem. 2003, 39, 757. J.E. Milne, P.J. Kocienski, Synthesis 2003, 584. B. Greatrex, M. Jevric, M.C. Kimber, S.J. Krivickas, D.K. Taylor, E.R.T. Tiekink, Synthesis 2003, 668. K. Kobayashi, K. Nomura, T. Ogata, M. Tanmatsu, O. Morikawa, H. Konishi, Synthesis 2003, 673. N.E. Shevchenko, V.G. Nemajdenko, E.S. Balenkova, Synthesis 2003, 1191. G. Cravotto, G.M. Nano, G. Palmisano, S. Tagliapietra, Synthesis 2003, 1286. W. HtRtel, M. Nieger, M. MOiler, Synthesis 2003, 1803. T. Mas, Synthesis, 2003, 1878. M. Jesberger, T.P. Davis, L. Barner, Synthesis 2003, 1929. F. Fringuelli, O. Piermatti, F. Pizzo, Synthesis 2003, 2331. I.J.S. Fairlamb, F.J. Lu, J.P. Schmidt, Synthesis 2003, 2564. J.-X. Wang, X. Shi, X. Men, L. Zhao, Synth. Commun. 2003, 33, 2849. E.C. Gravett, P.J. Hilton, K. Jones, J.-M. P6ron, Synlett 2003, 253. F. Doi, T. Ogamino, T. Sugai, S, Nishiyama, Synlett 2003, 411. A. Le Flohic, C. Meyer, J. Cossy, J.-R. Desmurs, J.-C. Galland, Synlett 2003, 667. M. Anstiss, J.M. Holland, A. Nelson, J.R.Titchmarsh, Synlett 2003, 1213. D.C.G.A. Pinto, A.M.S. Silva, L.M.P.M. Almeida, J.R. Carrillo, A. Diaz-Ortiz, A. de la Hoz, J.A.S. Cavaleiro, Synlett 2003, 1415. C. Mukherjee, S. Kamila, A. De, Synlett 2003, 1474. D. Rodriguez, M.F. Martinez-Esper6n, L. Castedo, D. Dominguez, C. Sa~, Synlett 2003, 1524. I.J.S. Fairlamb, S.M. Syvfinne, A.C. Whitwood, Synlett 2003, 1693. J.-G. Jun, Synlett 2003, 1759. M.S. Kerr, T. Rovis, Synlett 2003, 1934. D. Enders, A. Lenzen, Synlett 2003, 1698. T. Kamei, M. Shindo, K. Shishido, Synlett 2003, 2395. R.P. Hsung, K.P. Cole, L.R. Zehnder, J. Wang, L.-L. Wei, X.-F. Yang, H.A. Coverdale, Tetrahedron 2003, 59, 311. A.A. Aly, Tetrahedron 2003, 59, 1739. S. Ohsugi, K. Nishide, M. Node, Tetrahedron 2003, 59, 1859. I. Yavari, M. Bayat, Tetrahedron 2003, 59, 2001. R. Rossi, A. Carpita, F. Bellini, P. Stabile, L. Mannina, Tetrahedron 2003, 59, 2067. M. Harmata, P. Rashatasakhon, Tetrahedron 2003, 59, 2371. M. Sato, T. Oda, K. Iwamoto, E. Murakami, Tetrahedron 2003, 59, 2651. C. AdelwOhrer, T. Rosenau, L. Gille, P. Kosma, Tetrahedron 2003, 59, 2687. S. Zhu, G. Jin, W. Peng, Q. Huang, Tetrahedron 2003, 59, 2899. T.S. Jagodifiski, J.C. So~nicki, A. Weso|owska, Tetrahedron 2003, 59, 4183. M. Tamarez, R.W. Franck, A. Geer, Tetrahedron 2003, 59, 4249. S. Menichetti, C. Viglianisi, Tetrahedron 2003, 59, 5523. M. Inoue, J. Wang, G.-X. Wang, Y. Ogasawara, M. Hirama, Tetrahedron 2003, 59, 5645. T.N. Van, N. De Kimpe, Tetrahedron 2003, 59, 5941. M. Yus, C. N~jera, F. Foubelo, Tetrahedron 2003, 59, 6147. B. Gabriele, G. Salerno, A. Fazio, R. Pittelli, Tetrahedron 2003, 59, 6251. K.C. Majumdar, S. Ghosh, M. Ghosh, Tetrahedron 2003, 59, 7251. W. Adam, E.P. Gogonas, L.P. Hadjiarapoglou, Tetrahedron 2003, 59, 7929. S.K. Sabui, R.V. Venkateswaran, Tetrahedron 2003, 59, 8375. X. Yang, S. Luo, C. Hua, H. Zhai, Tetrahedron 2003, 59, 8551. S.J. Pastine, S.W. Youn, D. Sames, Tetrahedron 2003, 59, 8859. R.G. Carter, T.C. Bourland, X.-T. Zhou, M.A. Gronemeyer, Tetrahedron 2003, 59, 8963. D.B. Batanero, F. Barba, Tetrahedron 2003, 59, 9161. M. Pal, V. Subramanian, K. Parasuraman, K.R. Yeleswarapu, Tetrahedron 2003, 59, 9563. M. Kurono, M. Isobe, Tetrahedron 2003, 59, 9609. H. Furuno, T. Hayano, T. Kambara, Y. Sugimoto, T. Hanamoto, Y. Tanaka, Y.Z. Jin, T. Kagawa, J. Inanaga, Tetrahedron 2003, 59, 10509. X. Chen, X. Ren, K. Peng, A.S.C. Chan, T.-K. Yang, Tetrahedron: Asymmetry, 2003, 14, 701. A.S. Demir, A. Aybey, O. Sesenoglu, F. Polat, Tetrahedron: Asymmetry, 2003, 14, 1489.

430 03TA3779 03TL65 03TL311 03TL435 03TL557 03TL607 03TL751 03TL1461 03TL1755 03TL1943 03TL2011 03TL2061 03TL2145 03TL2831 03TL3363 03TL3645 03TL3813 03 TL4199 03TL4275 03TL4351 03TL4439 03TL4543 03TL4877 03TL4887 03TL4965 03TL5229 03TL5259 03TL5995 03TL6309 03TL6483 03TL6513 03TL7349 03TL7583 03TL7633 03TL7741 03TL7747 03TL7875 03TL7929 03TL8471 03TL8935 03TL9107 03TL9271 03TL9291

J.D. Hepworth and B.M. Heron

C. Bolchi, L. Fumagalli, B. Moroni, M. Pallavicini, E. Valoti, Tetrahedron: Asymmetry, 2003, 14, 3779. l J.-H. Lee, C.-G. Cho, Tetrahedron Lett. 2003, 44, 65. W.A.L. van Otterlo, E.L. Ngidi, E.M. Coyanis, C.B. de Koning, Tetrahedron Lett. 2003, 44, 311. C. Hardouin, L. Burgaud, A. Valleix, E. Doris, Tetrahedron Lett. 2003, 44, 435. C. Damez, J-R. Labrosse, P. Lhoste, D. Sinou, Tetrahedron Lett. 2003, 44, 557. M. Biagetti, F. Bellina, A. Carpita, R. Rossi, Tetrahedron Lett. 2003, 44, 607. N. Tanifuji, H. Huang, Y. Shinagawa, K. Kobayashi, Tetrahedron Lett. 2003, 44, 751. D.E. Daia, C.D. Gabbutt, B.M. Heron, J.D. Hepworth, M.B. Hursthouse, K.M.A. Malik, Tetrahedron Lett. 2003, 44, 1461. A. Song, X. Wang, K.S. Lam, Tetrahedron Lett. 2003, 44, 1755. R. Singh, M.P.S. lshar, Tetrahedron Lett. 2003, 44, 1943. G.P. Kalena, P. Pradhan, V.S. Puranik, A. Banerji, Tetrahedron Lett. 2003, 44, 2011. I. Hachiya, H. Shibuya, M. Shimizu, Tetrahedron Lett. 2003, 44, 2061. D.J. Wallace, Tetrahedron Lett. 2003, 44, 2145. A. Capperucci, A. Degl'Innocenti, S. Biondi, T. Nocentini, G. Rinaudo, Tetrahedron Lett. 2003, 44, 2831. D. Sil, A. Goel, V.J. Ram, Tetrahedron Lett. 2003, 44, 3363. C. Pierres, P. George, L. van Hijfte, J.-B. Ducep, M. Hibert, A. Mann, Tetrahedron Lett. 2003, 44, 3645. C.-F. Yao, Y.-J. Jang, M.-C. Yan, Tetrahedron Lett. 2003, 44, 3813. T.N. Van, S. Debenedetti, N. De Kimpe, Tetrahedron Lett. 2003, 44, 4199. A. Whitehead, J.D. Moore, P.R. Hanson, Tetrahedron Lett. 2003, 44, 4275. M. Sasaki, C. Tsukano, K. Tachibana, Tetrahedron Lett. 2003, 44, 4351. S.-H. Min, S.-J. Pang, C.-G. Cho, Tetrahedron Lett. 2003, 44, 4439. J.E. Baldwin, A.V.W. Mayweg, G.J. Pritchard, R.M. Adlington, Tetrahedron Lett. 2003, 44, 4543. F. Doi, T. Ogamino, T. Sugai, S, Nishiyama, Tetrahedron Lett. 2003, 44, 4877. A.E. Hhkansson, K. Pardon, Y. Hayasaka, M. de Sa, M. Herderich, Tetrahedron Lett. 2003, 44, 4887. T. Shimizu, J. Kusaka, H. lshiyama, T. Nakata, Tetrahedron Lett. 2003, 44, 4965. A. Tatami, M. Inoue, H. Uehara, M. Hirama, Tetrahedron Lett. 2003, 44, 5229. K. Kawamura. H. Hinou, G. Matsuo, T. Nakata, Tetrahedron Lett. 2003, 44, 5259. D.V. Sevenard, P. Kirsch, E. Lork, G-V. R6schenthaler, Tetrahedron Lett. 2003, 44, 5995. J. Iskra, D. Bonnet-Delpon, J.-P. B6gu6, Tetrahedron Lett. 2003, 44, 6309. W.A.L. van Otterlo, E.L. Ngidi, C.B. de Koning, Tetrahedron Lett. 2003, 44, 6483. T. Saito, T. Horikoshi, T. Otani, Y. Matsuda, T. Karakasa, Tetrahedron Lett. 2003, 44, 6513. T. Kamino, K. Kuramochi, S. Kobayashi, Tetrahedron Lett. 2003, 44, 7349. M. Schwarz, P. Winterhalter, Tetrahedron Lett. 2003, 44, 7583. S. Rousset, M. Abarbri, J. Thibonnet, J.-L. Parrain, A. Duch~ne, Tetrahedron Lett. 2003, 44, 7633. T. Terauchi, T. Terauchi, I. Sato, W. Shoji, T. Tsukada, T. Tsunoda, N. Kanoh, M. Nakata, Tetrahedron Lett. 2003, 44, 7741. T. Terauchi, T. Tanaka, T. Terauchi, M. Morita, K. Kimijima, I. Sato, W. Shoji, Y. Nakamura, T. Tsukada, T. Tsunoda, G. Hayashi, N. Kanoh, M. Nakata, Tetrahedron Lett. 2003, 44, 7747. K. Yoshida, M. Mori, M. Kawachi, R. Okuno, K. Kameda, T. Kondo, Tetrahedron Lett. 2003, 44, 7875. I. Kadota, N. Nishina, H. Nishii, S. Kikuchi, Y. Yamamoto, Tetrahedron Lett. 2003, 44, 7929. D. Regas, J.M. Ruiz, M.M. Afonso, A. Galindo, J.A. Palenzuela, Tetrahedron Lett. 2003, 44, 8471. I. Kadota, H. Ueno, Y. Yamamoto, Tetrahedron Lett. 2003, 44, 8935. A. Bianco, C. Cavarischia, A. Farina, M. Guiso, C. Marra, Tetrahedron Lett. 2003, 44, 9107. A.M. Bello, L.P. Kotra, Tetrahedron Lett. 2003, 44, 9271. D. QuintUs, A. Garcia, D. Dominguez, Tetrahedron Lett. 2003, 44, 9291.

431

Chapter 7

Seven-Membered Rings

John B. Bremner

Director Institute for Biomolecular Science Department of Chemistry University of Wollongong Wollongong NSW 2522 AUSTRALIA e-mail: j [email protected]

7.1

INTRODUCTION

Seven-membered heterocycles continued to be a focus of significant activity through 2003, with fused systems again a particular highlight. Ring closing metathesis methodology has been further exploited in the syntheses of seven-membered rings. The number of ring heteroatoms, with an emphasis on nitrogen, oxygen and sulfur, again form the basis for the divisions in this Chapter. Sections on systems of pharmacological interest or significance, and on future directions, are also included.

7.2

SEVEN-MEMBERED SYSTEMS CONTAINING ONE HETEROATOM

A number of interesting preparations and reactions have been described, although activity in this particular area has not been especially high. As was done previously, some of the following material is divided into non-fused and fused ring examples.

7.2.1

Azepines and derivatives

Microwave-assisted reactions have become well established in contemporary synthetic methodology. Non thermal microwave effects, though, have been shown not to be a factor in the observed rate enhancement with the ring-closing metathesis reaction to form the azepine derivative 2 (88% coversion; 20 minutes, 100 ~ from the acyclic diene 1 precursor with the ruthenium catalyst 3 <03JOC9136>.

43 2

J.B. Bremner

Ru catalyst CH2Cl2

m( n

1

2

m = n = 2; X = NTs

TfO-

c",:ru.. i

CY3P " C~C.~ Ph Ph

An altemative to ring-closing metathesis to access seven-membered rings has been described by Ohno et al. <03H(61)65>. Thus, reaction of the bromoallene 4 containing a nucleophilic moiety and Pd(PPh3)4 in the presence of methanol affords the azepine derivative 5 in good yield (76%). Oxepine derivatives can also be made in a similar way using an alcohol as the nucleophilic moiety in the allene. //'~Br

~ C 4

NHTs

MeOH,N a i l 55 ~ 5 h" pd(PPh3)4

~OMe "~__._/N--Ts 5

Parallel liquid synthesis has been applied to the synthesis of a range of N,N'-disubstituted 3-aminoazepin-2-ones 7 (e.g. R I = m-BrC6H4) starting from 6. These compounds were required for SAR studies as specific famesyl transferase inhibitors <03BMC3193>.

~

.,N ~N

CN

:

6

7

The synthesis of the reduced 2H-azepin-2-imine 9, which is an inhibitor of inducible nitric oxide synthase, from 8 has also been described <03BMC689>. Me

Pr~oEt 8

Me

Pr~H 9

N

Seven-MemberedRings

433

An alternative and surprising transformation to the 2H-azepin-2-one system has been noted on reaction of DBU, normally regarded as non-nucleophilic, with saccharin derivatives <03SC1937>. Mechanistic aspects of the formation of 2-methoxy-2H-azepine derivatives l l a - d from 3H-azepines 10a-d on reaction with bromine have been reported by Satake et al. Unlike the case with cycloheptatrienes, delocalised azatropylium salts were not formed on reaction of the 3H-azepines with bromine in the absence of an alcoholic solvent. Thus reaction of 12 with bromine gave 13 plus the bis-ether 14 (and MeBr). The latter product 14 was also obtained from the reaction of 12 with NBS (0.5 equivalents); with an equivalent of NBS, 12 afforded 15 which on base-induced elimination gave the 2H-azepine 16 < 03H(60)2211 >.

RI

R2 ~ R -N

1. Br 2 (1.0 equiv). 2. Me OH },3. aq. K2CO 3

1 "R 3

R

1

R2 ~

MeO"

10

a: R 1 = tBu, R2 = a 3 = H R1

-N-

b: R 1 = H, R 2 = R3 = tgu c: R 1 = H, R 2 = tBu, R3 = OMe

"R 3

d: R 1 = H, R 2 = Me, R3 = OMe

11

tBu

tB u

tBu

tBu

1. Br2 (0.5 equiv). ,....._

OMe

12

2. aq. K2CO 3

~

Br

OMe

13

1. NBS (0.5 equiv.) 2. aq. K2CO 3

NBS (1.0 equiv.) tBu

Br

tBu Et3N

O

-HBr

~ O

~. O OMe

OMe

15

16

The bacterial translocase 1 inhibitor, A-500359C, 17 (and a methoxy analogue A-500359A), isolated from Streptomyces griseus SANK 60196, has been shown to incorporate a tetrahydro azepin-2-one unit <03JAN243>.

434

J.B. Bremner

OH o

H

#..r

.

H(~

"OH

17 7.2.2

Fused azepines and derivatives

A combination of ruthenium-mediated isomerisation and ring closing metathesis has been applied to the synthesis of the benz[c]azepine derivative 21 in moderate yield from 20 via 18 and 19 <03SL1859>. H/~O

/ ~ C MeO" ~ .

v

-,~

.-,,, ,.,Ts

(0' (ii) ~".v- ~ MeO

O~Pr

O~Pr

18

20

/--q

19

Ts

O~Pr

0i0' ('v)-' '~

/Ts

Catalyst 1:

MesINyN'Mes CI..... ~ Ph Cl~ u PCY3

Catalyst 2:

[RuCIH(CO)(PPh3)3]

O~Pr 21

Reagents: (i) TsNH2, toluene, 110 ~ 4 d, 8 20% and recovered 3 78%; (ii) catalyst 2 (1%), toluene, 80 ~ quantitative; (iii) NaBH4, MeOH, 0 ~ 30 min, 98%; (iv) allyl bromide, Nail, THF, 6 h, r.t., 64%; (v) 5% catalyst 1, toluene, 60 ~ 2 h, quantitative.

A ring interconversion strategy has been used to access the functionalised benz[c]azepinones 23 from 22. The key ring expansion is initiated by lithium-bromine exchange in 22 followed by internal carbanion attack on the lactam carbonyl group; trapping of the ring expanded lactam intermediate by various electrophilic species then gave 23 in moderate to good yields <03SL2025>. None of the isomeric benz[c]azepinones 24 expected from the lithium enolate intermediate were observed.

Seven-Membered Rings

435

,GH3

CH3

EI-X

- 78 ~ to r.t. CH3 ~ . ~ - l r "

H''-

o

tert-BuLi

23

THF,-45 ~

CH3

Br

, CH3

EI-X

~-OLi

22

H3C 24

CH3

EI-X = CH31 (74%) EI-X = CH2=CH-CH2Br (50%) EI-X = PhCHO (64%)

Silver ion-promoted ring enlargement of the 1-tribromomethyl-dihydroisoquinoline 26, from 25, provides a concise approach to [3]benzazepinones 27 <03TL4203>.

~ N

(i) =

~ N

O,., | bn Br

25

(ii)= [ ~ N

(iii) = "Bn CBr3

26

[

~

O

N-Bn

RO

27a:R = Me b:R=H

Reagents: (i) PhCH2Br (1.1 equiv.), MeOH, reflux for 2 weeks (quant.); (ii) 25 dissolved in CH3CN/H20 (1/1) then HCBr3 (1.3 equiv.) and aq. KOH (1.2 equiv.), r.t., 45 min (89%); (iii) 26 in MeOH at-40 ~ then aq. AgNO3 (3 equiv.), up to r.t., 16 h (44%).

A key step in the asymmetric synthesis of the angiotensin converting enzyme inhibitor, benazepril HC1 32, was the reduction of the ketoester 28 with baker's yeast to afford the chiral a-hydroxy ester 29 in high chemical yield and ee. Formation of the benz[b]azepinone 31 directly from 29 proceeded in 42% yield (without racemization at C-3) or in 74% yield in two steps via 30, again with no racemization <03TA2239>.

436

J.B. Bremner O ~NO2

O (i) =

O

(ii)

~ C O 2 E t --.7 -NO 2

O

@

28

OH

C02Et

29

(iv)

OH OH

.HCI ....

~

(v)

~ N O ~ cO2Et

C02Et Et

32

30

31

Reagents: (i) diethyl oxalate, NaOEt, THF, 0 ~ (99%); (ii) baker's yeast, phenacyl chloride, Et20/H20, 30 ~ (85%); (iii) H2, Pd-C, HCI, MeOH, then HOAc/toluene, 80 ~ (42%); (iv) NaBH(OAc)3, THF, 0 ~ (v) H2, Pd-C, HCI, MeOH, then HOAc/toluene, 80 ~ (74%, two steps).

Lactim ether formation from 2,3,4,5-tetrahydrobenz[b]azepin-2-one on reaction with dimethyl sulfate and triethyloxonium tetrafluoroborate has been described, and its reaction with a variety of primary amines assessed <03CHE344>. Dibenzazepine systems also received some attention in 2003. Treatment of the Nmethoxyamide 33 with phenyliodine(III)bis(trifluoroacetate) (PIFA) afforded the dibenzazepinone 34 in high yield (84%) in hexafluoroisopropanol (HFIP) as solvent; ipso cyclisation of the nitrenium ion intermediate to afford a spirocyclic system is suppressed in this case without the stabilising para-methoxy group in the aryl ring in 33. When trifluoroethanol (TFEA) was used as the solvent both benz-annulation and spiro-cyclisation was observed <03H(59)149>. Similarly, when TFEA was used as a solvent in the case of 35, benzannulation was observed with the benz[b]azepinone 36 being isolated in 50% yield, together with the spiro-cyclized product 37 in 48% yield.

PIFA HFIP 1 min

H3CO

33

34 P,F

O OCH 3 35

TFEA 15 min

H3CO 36

H

,

H3CO 37

\, O

Seven-Membered Rings

437

Ring closing methodology was also used to access the axially chiral dibenz-fused lactams 39 and 4t1 from the unsymmetrically substituted biphenyls 38 and (R)-phenylglycinol; high yields and diastereselectivities were obtained. The relative stereochemistry of the minor diastereomer 40 was established via a NOESY experiment <03JOC9517>. hoe H

Ph/,.~/~'- 0 hi ,l,~Me

COOR

38

Ph/,.

N--~ Me

39

40

Reagents: (i) (R)-phenylglycinol, toluene, reflux 18 h (R = H) or 38 h (R = Et). A new Stemona alkaloid sessilifoliamide C, 41 (from Stemona sessilifolia) has been described with a fused azepine skeleton; a butanolide analogue (sessilifoliamide B) was also isolated <03T7779>.

0 O H

0 41

7.2.3

Oxepines and derivatives

Ring-closing olefin metathesis has been extended to vinyl chloride precursors, resulting, for example, in the preparation of the chloro-substituted oxepine derivative 43 from 42 in high yield (88%) <03OL2505>.

Phil, 65 ~ Grubbs' catalyst* 42

*Catalyst:

Ph(H2C)2~ 43

/--1

M e s ~ N y N--Mes CI~ R ~ P h CI~ i u

PCY3

CI

438

J.B. Bremner

RCM methodology was also at the heart of the synthesis of the dihydro-7H-oxepin-4-one 45 from the Boc-protected D-phenylalanine derivative 44 <03TL5511>. H2C---CH---CH2---O

O

ph~JJ~~~CH2

tBu-- O--C-- ~H II 0

tBu--

O----C-- NH II

O

O

44

45

A new and efficient approach to oxepine derivatives based on singlet oxygen oxidation of a furan ring has been described <03TL4467>. Synthetic interest continues in the 7-membered oxaheterocyclic systems of marine natural products, and Crimmins and DeBaillie have published a chiral synthesis of rogioloxepane A, 46 <03OL3009>.

6r

#

Cl 46

7.2.4

Fused oxepines and derivatives

The benzoxepine 49 was accessed in 18% overall yield from the diene 47 via a base induced isomerisation to 48 and a subsequent RCM reaction <03SL 1859>.

MeO

~

"~. O~Pr

(28~

MeO-

'~ ",,,~ -~ O~Pr I

47

9

48 (ii)

r (64%)

Ru catalyst: MeO

O~Pr

M e s I N y N-Mes CI\-.Ph C i / iRu ~ / PCY3

49 Reagents: (i) t-BuOK, DMF, r.t., 18 h, quantitative; (ii) 5 mol% Ru catalyst, toluene, 2 h at 60 ~ h at 80 ~

then 2

The spirocyclic benzoxepines 50 (R = Ph, p-MeC6H4, t-butyl) were obtained unexpectedly by isomerisation of the vinyl carbonyl ylide intermediates obtained from reaction of indanetrione with vinyl diazo compounds, and subsequent cyclisation and a 1,5-hydrogen shift.

Seven-Membered Rings

439

This reaction sequence was not observed however with six-membered cyclic tricarbonyl compounds <03TL4339>.

o

HO~ R

='-

Me

o o

CN 50

Me~8~,Me Me'Me

51

52

An elegant enantiocontrolled, five-step, total synthesis of the sesquiterpenoid plant product (+)-heliannuol D 51 has now been realised starting from (-)-xanthorrhizol and utilising a palladium-catalysed cyclisation to form the seven-membered ring . A racemic synthesis of 51 was also reported <03T1679>. The reaction of Meldrum's acid with 3,4-bis(chloromethyl)-2,5-dimethylthiophene (or the bromomethyl analogue) proceeds under kinetic control to afford the bis-fused oxepine 52 <03JOC7455>. A novel quinolone-ring fused oxepine 56 (n = 1), reported by Joseph et al., was accessed by a ring-closing metathesis reaction on the precursor 55, which was made in turn from 53 via 54, and a Claisen rearrangement on the last compound. An aza analogue of 56 (n = 1) was made in a similar direct approach <03SL2089>.

J.B. Bremner

440

OH O . ~ / O C H 3 CH30/[~

1) Nail (2 equiv) DMF, 0 ~ 2) allyl bromide (2 equiv) Nal, 90 ~

CH3

71%

Of O

/OCH3

2 h

CN3 54

53

xylene, 200 ~ 24 h sealed tube OCH3

CH~30 -

i;~ OH3

. PCY3 CI/,.~ ~,I-<.u~'~ CI I ~ , . , , PCY3 L'6n5 (10 mol%) CH2CI2,r.t., 2 h 81%

OCH3

~CH30_ -

I;~ OH3 55

56

1) Nail (2 equiv) DMF, 0 ~ 2) RBr (2 equiv) Nal, 90 ~

~___,,.~= H 80% = CH2-CH=CH2 55%

7.3

SEVEN-MEMBERED SYSTEMS CONTAINING TWO HETROATOMS

7.3.1

Diazepines and fused derivatives

The liposidomycins are a family of novel lipid-containing nucleoside antibiotics which inhibit bacterial peptidoglycan synthesis. A crucial component of their structures is a substituted 1,4-diazepan-3-one moiety. As part of work to assign stereochemistry in these antibiotics, analogues of this moiety have been synthesised using a reductive amination/ring cyclisation approach <03H(59)107>. The compounds synthesised were 57 and 58.

Me BzO,~/'~ N' ..OMOM HO H 0 57

OBz

OBz~~N"

Me

OMOM

p ,"" N OBz Me/

0

58

A 1,4-diazepan-2-one system is also incorporated in the new spermidine alkaloid dovyalicin D isolated from Dovyalis macrocalyx <03OL2793>. A solid phase synthesis of peptidomimetics based on a 3,6-disubstituted-l,4-diazepan-2,5-dione skeleton has also been described <03JOC7893>.

441

Seven-Membered Rings

An interesting new approach to 1,3-diazepin-2-ones 61 via a palladium-catalysed highly regioselective, cyclisation of 2-vinylpyrrolidines 59 with aryl isocyanates 60 has been developed by Zhou and Alper <03JOC3439>. This reaction has considerable potential for further applications in heterocyclic synthesis. a1

10mo1% dppp, THF, 5 psi

59

60 R1 = H, R 2 = n-Bu

61 X = H, Br, CI, NO2, MeO

R 1 = H, R 2 = Cy R 1 = Me, R 2 = n-Bu

The synthesis and single crystal X-ray structural analysis of some new 1,5-benzodiazonium picrates has been described by Schmidt and co-workers <03H(60)2645>. In the single crystal, layers of the benzodiazepinium molecules are formed with a head-to-tail arrangement of the overlapped seven-membered rings. The pyrimidine-fused 1,4-diazepinol 62 has been converted to the pteridinedione derivative 63 by tosylation and a thermally induced ring contraction <03H(60)2511 >. o

MeN ,N O - ' ~ N I/L,N ~ ' O H Me Ts

H

i rsc,,Py

N

i,) Alacetonitril'~e

"-

62

O"~N I~ N Me Ts 63

Y = OTs (70%) Y = O H (47%)

An intriguing enantioselective preparation of substituted quaternary 1,4-benzodiazepin-2-one scaffolds has been reported by Carlier et al. <03JA11482>. Enantioselective alkylation is used to prepare chiral products 64 (e.g. R = H; R 1 = Me, PhCH2; R 2 = MezCH) from nonracemic glycine-derived 1,4-benzodiazepinones. If the N1 substituent is sufficiently large (e.g. an isopropyl group) then the stereochemistry at the 3-position of the 3-substituted 1,4benzodiazepinones is transmitted to the product despite the loss of chirality at C-3 on intermediate enolate anion formation. a2

N

CI

O

' R1 Ph 64

442

J.B. Bremner

The tautomerism of other pyrimidine-ring fused 1,4-diazepines has been investigated by NMR spectroscopy, X-ray structural analysis, and by quantum chemical calculations. In the case of 65 the enamine tautomer is more stable than the diimine tautomer, while in 66 the latter form is preferred. Rationalisation of these findings is given on the basis of the electronwithdrawing effect of the 4-hydroxypyrimidine ring and intermolecular hydrogen bonding in the case of 65 <03JHC25>.

OH Ar ~N~ N~A N N H r1 65

O Me..N.~,., N~----~AAr O~lj~NL N r~ Me

,COOEt ~/~_~ ~O Me OMe

66

67

Alanine was the starting point for the synthesis of new fused 1,4-diazepine-2-ones (e.g. 67), using N-acylnitrenium ion formation and intramolecular trapping by the thiophene moiety in the key cyclisation step <03T7103>.

7.3.2

Dioxepines, dithepines and fused derivatives

The enzyme mediated Baeyer-Villiger reaction of the ketones 68 (R = Me, Et) gave high yields (and high ee values) of the seven-membered ring products 69. Recombinant E s c h e r i c h i a coli producing cyclohexanone monooxygenase was used in this work. Significantly though, as the size of the R groups increased, the yield of product decreased, and with R = n-Bu there was no conversion <03SL 1973>.

0 J~ R'...... R 68

0 BL21(DE3)(pMM4) ..._ ,,,~-O~~,, R 9 "R 69

An efficient route to 1,4-dithiepine derivatives has been established based on the deprotection of 1,3-dithioacetals of enolizable ketones with 2,4,6-trichloro-l,3,5-triazine and DMSO <03S2547>. Dibenzothiepines 71 can also be accessed readily from thianthrene 70 by lithiation and subsequent reaction with electrophiles, hydrolysis and acid-catalysed cyclisation <03T2083>.

443

Seven-Membered Rings

1=.~= v

R

OH

HS ~

70

72 RI=H R2 = tBu, Ph

7.3.3

Miscellaneous

derivatives

with two heteroatoms

Ring-closing metathesis methodology has been applied to the synthesis of 1,2-oxazepine derivatives. Thus 75 and 76 were prepared in good yields from the respective diene precursors 74 and 73, both accessed in turn from 72 <03SL1043>.

o ~ I

Boc~NH

Nail THF ,

//-...../Br

72

~

Et3N

CH2 CI2

I

NH

BOC/

Boc/

CH2CI2 45~ 24h. 84%

73

CI

76

O

O, ~ Boc ~ N . . . r ] ~

Ru cat.

10 mol.%

CH2CI2 45 ~

O 74

Similarly the <03SL2017>.

_

o/"'/~

CI.. PCy3 CI"*RI u - ~"~ PCY3 Ph

?N~ ,. Boc

11 h. 84%

1,2-oxazepines

O 75

78 were prepared

from N-alkynyl

analogues

77

Cl/, PCY3

I:; 'Su----"Ph

C PCy3 BocN\

R= H, 87%, R= CH3, 90% n=2 77

9 BocN R 78

The unsaturated sultones 82 were also formed from 81 (prepared in turn by esterification of the alcohol 80 with the sulfonyl chloride 79) using Grubbs' imidazolidine - based ruthenium catalyst <03SL667>.

444

J.B. Bremner

O%_//0 m~"~(~S'-Ci

O

Et3N

79

O

Phil 70 ~ '

THF -15~

+

R

~.~

%//O

S-O

Ru cat.

R

n 82

81

R = (CH2)3OBn

80

m=l,n=l

An intramolecular Ugi-four component condensation between the acids 83, amines, and cyclohexyl isocyanide gave the hexahydro-l,4-thiazepin-5-ones 84 in generally good yields <03JOC3315>. The 1,4-thiazepin-5-one nucleus has also been identified in the natural product A-500359M-2, 85, from Streptomyces griseus SANK 60196 <03JAN259>, while a 1,4-oxazepinone alkaloid 86, from ladybird beetles in the genus Calvia, was noted in <03H(60)1284>, although published earlier <99EJO1749>; a synthesis of 86 has also been published <00EJO2057>.

"O ~

" ~ CO2H

,.

a4

83

O

H

,-,1

.~:~

84

0 _OH OH -~ r ~ ' " ' CONH2 H~

.~'~-- ?

Me(~ "~OH 85

86

A new synthesis of optically active 3-substituted 1,4-oxazepin-7-ones 88 (e.g. R F = CF3, R 1= H) from 87 has been reported by Richard et al. <03HCA726>.

R1 RF CO2C2H5 87

aF 2.1 equiv. Nail toluene, 80 ~ 4 h

RI,'L-..,./-O 88

445

Seven-Membered Rings

A new method of synthesis of the cyano-substituted fused 1,4-oxazepine derivative 91 has been outlined by Abramov et al. <03H(60)1611>, based on nucleophilic aromatic substitution reactions with 89 and 90.

NC ~]~

NO2 +

NC

Br

Ph :...N ~ ;N K2CO~ N C ' ~ " ~ N ' ~ , k

N-N ph--~ NH ~

NC" ~

89

~

"O~X\ ~

90

91

Fused 1,4-oxazepines 92a have also formed the basis for a ring destruction approach to the eleven-membered ring systems 93 <03H(60)887>.

c,.

R" ~

""y.~N

92

c,. o.E

OH31

-OH3

Na, liq. NH3 ~

R~.~~J'~ d.-CH3

a: R = H, X = O b:

93

R = OCH3,X = CH2

7.4

SEVEN-MEMBERED HETEROATOMS

SYSTEMS

7.4.1

Systems with N, S and/or O

CONTAINING

THREE

OR

MORE

The triazepine dione derivatives 94 (R 1, R 2, R 3, R 4 = H, alkyl groups) have neurotrophic activity and are potentially useful in the treatment and prevention of neuronal disorders including, for example, Parkinson's disease, Alzheimer's disease and multiple sclerosis <03WOP028734>.

R2 R1-N.~O

R 0 HO(H)NOC'~N..~3~..~ Ar

Ra

H 94

95

A series of benzothiadiazepines, for example 95 (R = (CH2)4NHSO2Me, X = OCH2, Ar = 3,5-dimethoxyphenyl) have been reported by Cherney and co-workers <03JMC 1811 >. These hydroxamate derivatives were designed and evaluated as selective tumour necrosis factor-or converting enzyme inhibitors. New approaches to cyclic sulfamide analogues (e.g. 98, 99) of HIV protease inhibitors have been described, with ring-closing metathesis from 96 to 97 a key step <03T8901 >.

446

J.B. Bremner

a1

R o,,0 R2OOC..~ N.. S.. N,Me

_ _ o,,,o R2OOC..--JL,.N)S/.. N. i e

96

97

RI = M e , R 2=Et

RI = M e , R 2=Et

Ri = CH2CH(CH3)2, R2= Me

R1 = CH2CH(CH3)2, R2= Me

Reagents: (i) 6 mol% (PCY3)a(CI)2Ru=CHPh, CH2CI2, 45 ~ 97% R1

97

(ii)

o,,,o R2OOCI%N"S" N"Me

R1 _ _ o,,o R2OOCI~'N)S~ N"Me

HO

HO

OH 98

OH 99

Reagents: (ii) OsO4, NMO, 3:1 acetone/H20 97% (dr~1.3:1.0). In a detailed experimental and computational study, more information on the role of amines in pentathiepine biological activity has been elucidated. The work suggests that the amine group present in the natural products varacin 100 (R - Me) and lissoclinotoxin A 100 (R = H) may enhance their reactivity; if so, then this would assist with the design of new biocides <03JA396>. The reaction of thiols with 7-methylbenzopentathiepine has also been described, and the reaction resulted in complex mixtures of polysulfides which then decomposed further <03 BMCL 1349>. OMe s

100

A novel fused germanium/sulfur containing seven-membered system 103 has been synthesised (17% yield) by reaction of the germabenzene derivative 101 (Tbt = 2,4,6tris[bis(trimethylsilyl)methyl]phenyl) with elemental sulfur. A 1,2,3,4-trithiagermolane, 102 was also produced in this reaction as the major product (53%) <03JOM66>.

447

Seven-Membered Rings

Tbt

Phil, r.t.

Tb

S Tb S~S_S~S

_

101

102

103

The dibenzotrithiepine antitumour active compound lissoclinotoxin F, 104, isolated from a Philippine didemnid ascidian, has been described <03T2855>.

MeO MeO@~

S-S OMe ~ "~J~OMe

MeS/~ Me2N~

"S" ~ - ~ S M e '~..-- NMe2 104

Other marine natural products with potent antitumour and antiviral activities, the eudistomins, continue to attract attention. As part of a new synthetic approach to the eudistomins, the stereoselective formation of the D-lactam fused oxathiazepine 110 has been reported <03SL738>; C-N bond formation from 106 (via 105) was used to complete the seven-membered ring, and then this product 107 was converted into 110 via 108 and 109. Unfortunately, after ring opening the ]3-1actam in 110 and setting up the substituents for indole ring formation, this crucial indolisation was not successful. Other pathways are being explored but the [3-1actamprecursor concept is a clever one. PhthN'O--~S

(i), ( i i )

PhthN'O--~S

(iii)

OAS

(iv) v

O'~--N~Ar

r

105

O~S

(v),(vi)

INk ,~NA 108

~ r

0"

106

O~S Ac,~N..x,_~.

(vii)-(ix)

. . . . . ~:Hr . HO~__

~

109

\Ar 107

O~S

H '. ~x ~Is" AoN O Boc 110

Ar= I ~ ~ - - O M O M Reagents:(i) NH4.HF, CH3CN, 78%; (ii) (COCI)2,DMSO, CH2CI,-78 ~ Et3N, - 78 ~ to r.t.; (iii) NH2NH2.H20, THF; (iv) POCI3, pyridine, CH2CI2, 88% (3 steps); (v) LiBH4,THF, 79%; (vi) AcCI, Et3N,CH2CI2,(vii) TMSCI, Nal, CH3CN, 88% (2 steps); (viii) (NH4)2Ce(NO2)6,CH3CN-H20,67%; (ix) Boc20, DMAP cat., CH3CN,60%.

448

7.5

J.B. Bremner

S E V E N - M E M B E R E D SYSTEMS OF P H A R M A C O L O G I C A L S I G N I F I C A N C E

Seven-membered ring systems, including those fused with other rings, have continued to attract attention because of the pharmacological activities displayed. Examples include a range of novel azepane derivatives with N-based substituents in the 3- and 4- positions as antitumor agents <03WOP076429>, the conformationally restricted benz[c]azepine derivative 111, which is a dual inhibitor of acetycholinesterase (IC50 = 14 nM) and the serotonin transporter (IC50 = 6 nM), as a potential agent for the treatment of Alzheimer's disease <03BMC4389>, pyrazolo[3",4":6,7]azepino[5,4,3-cd]indoles as dopamine receptor sub-type ligands <03H(60)1339>, 1,4-diazepine derivatives as novel 5-HT3 and O2 receptor antagonists <03JMC702>, a 1,4-benzodioxepin-3-yl-5-fluorouracil derivative as an antiproliferative agent and apoptosis inducer in breast cancer cells <03T5457>, antibacterial and antifungal 3,9-disubstituted 1,2,4-triazolo [3,4-b] [ 1,3,4] quinolinothiadiazepines <03IJC(B)211>, potent benzodiazepine •-secretase inhibitors <03JMC2275>, benzo[b][1,4]thiazepines as selective V2 arginine vasopressin receptor antagonists <03BMCL4031>, diazepan-2-one based selective inhibitors of the coagulation cascade serine protease, Factor XA <03BMC3379), cytotoxic analogues of the pyrrolo[ 1 ",2": 1,2][ 1,4]diazepin[7,6-b]indol-5(6H)-one skeleton <03CL512>, and an efficient approach to the medicinally significant heterobenzazepine nucleus <03JOC644>.

Me2NCOO~ ~,NMe 111

7.6

' ~ NO2

FUTURE DIRECTIONS

The full potential of ring-closing metathesis methodology in the synthesis of sevenmembered heterocyclic systems is still to be realised, and there are many opportunities to investigate different substituents in the diene precursors. A combination of ring-closing metathesis with other reaction types in a cascade context is also likely to realise novel sevenmembered ring based systems. The use of seven-membered ring heterocycles in new medicinal agent design is likely to continue, especially in the context of the search for greater structural novelty from combinatorial synthetic methods. This promises to be a challenging area for the future.

7.7

REFERENCES

03BMC689 03BMC3193 03BMC3379

Y. Kawanaka, K. Kobayashi, S. Kusuda, T. Tatsumi, M. Murota, T. Nishiyama, K. Hisaichi, A. Fujii, K. Hirai, M. Nishizaki, M. Naka, M. Komeno, H. Nakai, M. Toda, Biorg. Med. Chem. 2003, 11,689. T. Le Diguarher, J-C. Ortuno, G. Dorey, D. Shanks, N. Guilbaud, A. Pierre, J-L. Fauchere, J.A. Hickman, G.C. Tucker, P.J. Casara, Biorg. Med. Chem. 2003, ! 1, 3193. J. Cui, D. Crich, D. Wink, M. Lam, A.L. Rheingold, D.A. Case, W.T. Fu, Y, Zhou, M. Rao, A.J. Olson, M.E. Johnson, Biorg. Med. Che, 2003, 11, 3379.

Seven-Membered Rings

03BMC4389

03BMCL1349 03BMCL4031 03CHE344 03CL512 99EJO1749 00EJO2057 03H(61)65 03H(59)107 03H(61)125 03H(59)149 03H(60)887 03H(60)1284 03H(60)1339 03H(60)1611 03H(60)2211 03H(60)2511 03H(60)2645 03HCA726 03IJC(B)211 03JA396 03JA11482 03JAN243 03JAN259 03JHC25 03JMC702 03 JMC 1811

03JMC2275

03JOC644 03JOC3315 03JOC3439 03JOC7455 03JOC7893 03JOC9136 03JOC9517 03JOM66 030L2505 03OL2793 03OL3009 03S2547 03SC1937 03SL202 03SL667

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N. Toda, M. Keiko, S. Marumoto, K. Takami, M. Ori, N. Yamada, K. Koyama, S. Naruto, K. Abe, R. Yamazaki, T. Hara, A. Aoyagi, Y. Yasuyuki, T. Kaneko, H. Kogen, Biorg. Med. Chem. 2003, 11, 4389. T. Chatterji, K.S. Gates, Biorg. Med. Chem. Lett. 2003, 13, 1349. M.J. Urbanski, R.H. Chen, K. T. Demarest, J. Funnet, R. Look, E. Ericson, W.V. Murray, P.J. Rybczynski, X. Zhang, Biorg. Med. Chem. Lett. 2003, 13, 4031. T.V. Golovko, N.P. Solov'eva, O.S. Anisimova, V.G. Granik, Chem. Heterocycl. Compd. (Engl. Transl.) 2003, 39, 344. A. Tsotinis, M. Vlachou, K. Kiakos, J.A. Hartley, D.E. Thurston, Chem. Lett. 2003, 32, 512. J.-C. Braekman, A. Charlier, D. Daloze, S. Heilpom, J. Pasteels, V. Plasman, S. Wang, Eur. J. Org. Chem. 1999, 1749. P. Laurent, J.-C. Braekman, D.Daloze, Eur. J. Org. Chem. 2000, 2057. H. Ohno, H. Hamaguchi, M. Ohata, S. Kosada, T. Tanaka, Heterocycles 2003, 61, 65. N. Nakajima, T. Isobe, S. Irisa, M. Ubukata, Heterocycles 2003, 59, 107. H. Kishuku, T. Yoshimura, T. Kakehashi, M. Shindo, K. Shishido, Heterocycles 2003, 61, 125. E. Miyazawa, T. Sakamoto, Y. Kikugawa, Heterocycles 2003, 59, 149. T.W. Wittig, C. Enzensperger, J. Lehmann, Heterocycles 2003, 60, 887. Heterocycles 2003, 60, 1284. P. Gmeiner, H. Htibner, K. A.A. Safieh, I. I. Fasous, M.M. E1-Abadelah, S.S. Sabri, W. Voelter, Heterocycles 2003, 60, 1339. I.G. Abramov, A.V. Smirnov, L.S.A.N. Sakharov, V.V. Plakhtiniskii, Heterocycles 2003, 60, 1611. K. Satake, C. Cordonier, Y. Kubota, Y. Jin, M. Kimura, Heterocycles 2003, 60, 2211. M. Tada, T. Shimamura, T. Suzuki, Heterocycles 2003, 60, 2511. A. Schmidt, A.G. Shilabin, M. Nieger, Heterocycles 2003, 60, 2645. S. Richard, G. Pri6, A. Guignard, J. Thibonnet, J.-L. Parrain, A. Duch~ne, M. Abarbri, Helv. Chim. Acta 2003, 86, 726. B. Kalluraya, R. Gururaja, G. Rai, Indian J. Chem., Sect. B. 2003, 42B, 211. E.M. Brzostowska, A. Greer, J. Am. Chem. Soc. 2003, 125, 396. P. Carlier, H. Zhao, J. DeGuzman, P.C.-H. Lam, J. Am. Chem. Soc. 2003, 125, 11482. Y. Muramatsu, A. Muramatsu, T. Ohnuki, M.M. Ishii, M. Kizuka, R. Enokita, S. Tsutsumi, M. Arai, Y. Ogawa, T. Suzuki, T.Takatsu, M. Inukai, J. Antibiot. 2003, 56, 243. Y. Muramatsu, S. Miyakoshi, Y. Ogawa, T. Ohnuki, M.M. Ishii, M. Arai, T. Takatsu, M. Inukai, J. Antibiot. 2003, 56, 259. V.A. Chebanov, S.M. Desenko, A.V. Shishkin, N. Nadezhda, S.A. Komykhov, V.D. Orlov, H. Meier, J. Heterocycl. Chem. 2003, 40, 25. Y. Hirokawa, I. Fujiwara, K. Suzuki, H. Harada, T. Yoshikawa, N. Yoshida, S. Kato, J. Med. Chem. 2003, 46, 702. R.J. Cherney, J.J.-W. Duan, M.E. Chen, L. Wang, D.T. Meyer, Z.R.Wasserman, K.D. Hardman, R.-Q. Liu, M.B. Covington, M. Qian, S. Mandlekar, D.D. Christ, J.M. Trzaskos, R.C. Newton, R.L. Magolda, R.R. Wexler, C.P. Decicco, J. Med. Chem. 2003, 46, 1811. I. Churcher, S. Williams, S. Kerrad, T. Harrison, J.L. Castro, M.S. Shearman, H.D. Lewis, E.E. Clarke, J.D. Wrigley, D.J. Johnathan, D. Beher, Y.S. Tang, W. Liu, J. Med. Chem. 2003, 46, 2275. B.J. Margolis, J.J. Swidorski, B.N. Rogers, J. Org. Chem. 2003, 68, 644. S. Marcaccini, D. Miguel, T. Torroba, M. Garcia-Valverde, J. Org. Chem. 2003, 68, 3315. H.-B. Zhou, H. Alper, J. Org. Chem. 2003, 68, 3439. C.A. Snyder, J.P. Selegue, E. Dosunmu, N.C. Tice, S. Parkin, J. Org. Chem. 2003, 68, 7455. L.R. Lampariello, D. Piras, M. Rodriquez, M. Taddei, J. Org. Chem. 2003, 68, 7893. S. Garbacia, B. Desai, O. Levastre, O. Kappe, J. Org. Chem. 2003, 68, 9136. M. Penhoat, V. Levacher, G. Dupas, J. Org. Chem. 2003, 68, 9517. N. Nakata, N. Takeda, N. Tokitoh, J. Organomet. Chem. 2003, 672, 66. W. Chao, S.M. Weinreb, Org. Lett. 2003, 5, 2505. D. St~erk, M. Witt, H.A. Oketch-Rabah, J.M. Jaroszewski, Org. Lett. 2003, 5, 2793. M.T. Crimmins, A.C. DeBaillie, Org. Lett. 2003, 5, 3009. B. Karimi, H. Hazarkhani, Synthesis 2003, 2547. P.C.B. Page, H. Vahedi, D. Bethell, J.V. Barkley, Synth. Commun. 2003, 33, 1937. M. Valacchi, W. Cabri, A. Mordini, A. De Philippis, G. Reginato, Synlett 2003, 13, 2025. A. Le Flohic, C. Meyer, J. Cossy, J.-R. Desmurs, J.-C. Galland, Synlett 2003, 667.

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T. Yamashita, H. Tokuyama, T. Fukuyama, Synlett 2003, 738. Y.-K. Yang, J. Tae, Synlett 2003, 1043. W.A.L. van Otterlo, R. Pathak, C.B. de Koning, Synlett 2003, 1859. M.D. Mihovilovic, F. Rudroff, W. Kandioller, B. Gr6tzl, P. Stanetty, H. Spreitzer, Synlett 2003, 1973. 03SL2017 Y.-K. Yang, J. Tae, Synlett 2003, 2017. M. Valacchi, W. Cabri, A. Mordini, A. De Philippis, G. Reginato, Synlett 2003, 2025. 03SL2025 C. Pain, S. C61anire, G. Guillaumet, B. Joseph, Synlett 2003, 2089. 03SL2089 F.A. Macias, D. Chinchilla, J.M.G. Molinillo, D. Matin, R.M. Varela, A. Torres, Tetrahedron 03T1679 2003, 59, 1679. M. Yus, F. Foubelo, J.V. Ferrandez, Tetrahedron 2003, 59, 2083. 03T2083 03T2855 R.A. Davis, I.T. Sandoval, G.P. Concepcion, R.M. da Rocha, C.M. Ireland, Tetrahedron 2003, 59, 2855. E. Saniger, J.M. Campos, A. Entrena, J.A. Marchal, I. Suarez, A. Aranega, D. Choquesillo, J. 03T5457 Niclos, M.A. Gallo, A. Espinosa, Tetrahedron 2003, 59, 5457. A. Correa, M.T. Herrero, I. Tellitu, E. Dominguez, I. Moreno, R. SanMartin, Tetrahedron 03T7103 2003, 59, 7103. D. Kakuta, Y. Hitotsuyanagi, N. Matsuura, H. Fukaya, K. Takeya, Tetrahedron 2003, 59, 03T7779 7779. J.H. Jun, J.M. Dougherty, M. del Sol Jim6nez, P.R. Hanson, Tetrahedron 2003, 59, 8901. 03T8901 03TA2239 C-Y. Chang, T-K. Yang, Tetrahedron: Asymmetry 2003, 14, 2239. 03TL4203 M. Pauvert, S. Collet, A. Guingant, Tetrahedron Lett. 2003, 44, 4203. 03TL4339 M. Hamaguchi, K. Takahashi, T. Takumi, H. Tamura, Tetrahedron Lett. 2003, 44, 4339. 03TL4467 Y. Fall, B. Vidal, D.Alonso, G.Gomez, Tetrahedron Lett. 2003, 44, 4467. A. Kulesza, F.H.Ebetino, A.W. Mazur, Tetrahedron Lett. 2003, 44, 5511. 03TL5511 03WOP028734 Z. Sui, S.P. Walsh, (Ortho McNeil Pharmaceutical, Inc., USA) WO 2003028734. 03WOP076429 W.-G. Friebe, B. Masjost, R. Schumacher, (R. Hoffmann-La Roche, A.-G., Switz.) WO 2003076429. 03SL738 03SL1043 03SL1859 03SL1973

451

Chapter 8

Eight-Membered and Larger Rings George R. Newkome

The University of Akron, Akron, Ohio USA newkome@uakron, edu

8.1

INTRODUCTION

In the twenty-first century, there will continue to be a noticeable trend from studies of classical "crown ethers" towards directed polyazamacromolecules for metal atom complexation and the introduction of multiple heteroatoms for tuned directed self-assembly, including most recently metal atom centers, as the heteroatom. Numerous reviews and perspectives have appeared throughout 2003 that are of interest to the heteromacrocyclic scientist and those delving into supramolecular chemistry at the molecular level, as well as those studying supermolecules (nanoconstructs) and probing the rationale for tuning the power of crystal engineering: polyvalent iodine macromolecules <03JOC2997>; peptide- and glycocalixarenes <03ACR246>; perhalogenated heteromacro-molecules <03 CEJ 1465>; macrobicyclic and macrotricyclic hetero-clathrochelate complexes <02CCR255>; photochromic crown ethers <03BCSJ225>; supramolecular systems, as luminescent anion chemosensors <02CCR171>; functionalized calix[4]arenes <02CCR289>; laterally non-symmetric azacryptands <03CCR1B>; supramolecular solid-state architectures, using bis(4-pyridyl)- and bis(4-pyridyl-N-oxide) tectons <03CCR91>; molecular tectonics and molecular recognition of anions to molecular networks <03CCR157>; selenoethers and telluroethers <02CCR159>; anionic triazacyclononanes <03CC1025>; chalcogen inter-actions affording tubular structures <03CEJ2676>; artificial muscles at the nanometric level <03CC1613>; templation/encapsulation <03CC1617>; core-modified expanded porphyrins <03ACR676>; resorcinarenes, as templates <03CEJ5180>; trimeric perfluoro-orthophenylenemercury <03CEJ5188>; laterally non-symmetric azacryptands <03CCRI>; topologically constrained azamacrocycles <03CCR27>; ammonium-based anion receptors <03CCR57>; macrocyclic anion receptors <03CCR101>; mercura-carborands <03CCRlll>; highlights of anion and ion-pair receptors <03CCR191>; N-confused porphyrins <03CCR1A>; inverted metal-organic frameworks <03CCR169>; thiacalixarenes <03RJOCI> polycatenation, polythreading, and polyknotting in coordination networks <03CCR247>; crown ethereal cyclic polycarbenes <03HC540>; twenty years of annulenes <02JCSP 11601>; chiral 2,2'-bipyridines <02JCSP(1)1831>; asymmetric catalysis with lanthanide complexes <02ACIE3554>; oxathiacrown ethers <02CHC261>; cavitands <02CHC646>; selenophenes and tellerophenes <02CHC763>; cavitands and related container molecules <02H2179>; heterogeneous and solid supported dendritic catalysts <02JCSP(1)2209>; supramolecular crown ether adducts in the gas phase <03AG(E)1896>; 4'-substituted 2,2':6',2"-terpyridines <03S155>; imprinted polymers

G.R. Newkome

452

<03T2025>; porphyrins <03MI01>; molecular recognition and dynamics in receptor-substrate complexes <03ACR919>; thia-, seleno-, and tellero-ether ligands <02HC550>; and transitionmetal-templated synthesis of rotaxanes and catenanes <03JPSA3470>. One of the cutest publications of 2003 describes the synthesis of 2 nm tall anthropomorphic molecules in monomeric, dimeric, and polymeric forms, which include several macrocyclic "NanoPutians", thus their inclusion. This article demonstrates that the synthetic cleverness and imagination in the minds of chemists are alive and flourishing <03JOC8750>. As always, because of space limitations, only meso- and macrocycles possessing heteroatoms and/or subheterocyclic rings are reviewed; in general, lactones, lactams, and cyclic imides have been excluded. In view of the delayed availability of some articles appearing in previous years, several have been incorporated, where appropriate. 8.2

CARBON-OXYGEN RINGS

Crown ethers possessing appended substituents have continued to probe new amphiphilic and utilitarian purposes. Simple crown ethers possessing different subunits, such as 2,7-dioxy-9Hfluoren-9-one <03TL7373>, biphenyl <03TL2665>, 2,2'-diphenylacetylene <03OL3951>, aminomethylbenzo- <03TL4251>, and 5-substituted 2,6-phenol <03TL1549> have appeared. Dibenzocrowns, possessing appended cholesterol moieties, as chiral aggregate-forming sites, have been synthesized and shown to gelatinize in organic solvents; sol-gel polycondensation of tetraethoxysilane was conducted with these materials, as templates in the gel phase, affording a rare example of transcription of gel superstructures into inorganic silica materials <03CEJ5307, 03CC1352>. The one-step construction of bis-pyrrolidine functionalized fullerenedibenzo[18]crown-6 conjugate and its metal complexation at the crown ether site have been demonstrated <03CC1754>. The first supramolecular poly(taco complex) was formed in the solid state from bis(m-phenylene)-32-crown-lO and appropriately bis-substituted 4,4'bipyridinium urethane derivatives <03CC 1480>; related studies of cryptands and paraquat have also appeared <03JA9272, 03JA9367>. The related electron-rich bis(phenylene)-34-crown-lO, possessing a half of a Meijer's AADD quadruply H-bonding homodimer, was reacted with the H-bonding counterpart, possessing either electron-deficient pyrometallitic diimide or naphthalene diimide, to generate the self-assembled heterodimer 1 <03CEJ2904>. Host[2]rotaxanes, containing a diarginine-derivatized dibenzo-24-crown-8, as ring, and aromatic cleft, as one blocking group, were shown to be cell transport agents <03JA8290>. The construction of amino acid-[2]rotaxanes possessing phenylalanine and 3,5-di-tert-butylbenzene, as blocking groups, and dibenzo-24-crown-8, derivatized with either N-acetylargininyl or a carboxylic acid moiety has appeared <03JOC2547>. A thermodynamically controlled selfassembly of a neutral donor-acceptor rotaxane 2, capped by porphyrins coordination and bound to polystyrene beads has been described <03CC 1396>. Isocyanatobenzo-18-crown-6 was polymerized in the presence of MeLi in THF to afford 3, which in the presence of L-phenylalanine perchlorate induced macromolecular helicity <03M3709>. The ditopic complex formation of 2-styrylbenzothiazole containing a 15-crown-5 ether moiety has been shown <03NJC280>. An oligophenylene-vinylene benzo-crown ether conjugate has been synthesized and its binding selectivity has been ascertained by electrospray mass spectrometry <03TL3039>. The 18-crown-6 possessing an appended triarylphosphine was synthesized from 2-aminomethyl-18-crown-6 with triphenylphosphine carboxylic acid; the tagged ether was successfully applied to the Mitsunobu and Heck reactions <03TL1305>. An

453

Eight-Membered and Larger Rings

18-membered chiral crown ether, prepared from a chiro-inositol, was evaluated as a catalysis in the Michael reaction with glycine imine and several Michael acceptors <03CC1734>. The

?~0~

nC4H9"N ~ N"Lx~N"~O

IH IH i ;

;

~~

~/N'H"O

~C8H17

o O?o o

~ O~/'~ ...... ~ ~-../0 :NO---~ 0 ~'J

i

o.~/.~.~o

1

o

o

(: o

( 2

o

~0/..... ]

o%o ;

|

~

o

o~ o

preparation of novel cyclopolymers bearing oligoethylene glycol substituents in the form of malonate crown ethers embedded within a rigid polymer backbone has been reported <03M8894>. Mono-4 <03TL8265>, di- <03TL5397>, and multiple 5 <03TL805, 03TL993> bridged calix[n]arenes continue to offer a rigid polyfunctional cores for capping and functionalization <03TL29>; conversion to a calix[4]semitubes has offered entrance to a new class of ionophore <03OBC1232, 03CEJ2439> and isomers of p-tert-butylcalix[4]-crown-6 derivatives were shown to form self-assembled monolayers on gold electrodes <03TL9079>. A fluorogenic ionophore has been prepared by conjugating calix[4]crown-5 with boron-dipyrromethene fluorophore <03TL8265>. Introducing two aromatic aldehyde groups onto the lower rim of calix[4]arene afforded access to 6 via the McMurry reaction <03TL4519>. Biscalix[4]arenes 7 have been synthesized by either a one-pot coupling procedure in a pressurize container or step-wise approach <03TL33>. The extraction of Francium by a representative member of the cesiumselective calix[4]arenecrown family has recently been reported <03JA1126>.

454

G.R. Newkome

n

~

n

T

~ 0

0-'(\

~

/}

~

~,

",,

. m ~_

o--_/

n

Is

OH

H

R

4 6

7

Bu

0

0

H•O R

10

Since there is a dearth of fully aromatic crown ethers, the use of a resorcinarenes template was cleverly adapted to generate (87 %) the 32-crown-8 ether 8 or in 50 % conversion from the starting resorcinol and bridging 3,5-dibromobenzal bromide <03JA650>. Furan-containing oligoaryl cyclophane 9 has been synthesized from propargylic dithioacetal <03OL4381>. 4 , 1 5 -

Eight-Membered and Larger Rings

455

Dioxaoctadeca-l,6,17-triyne, when treated with [RhCl(cod)]2 and the trisodium salt of tris(msulfonatophenyl)phosphine in water at 75 ~ furnished (32 %) the 12-membered metacyclophane 10 along with the normal (ortho) cyclized product (57 %); related ethereal analogues also underwent similar macrocyclization <03JA7784, 03OL4537>. Ring-closing metathesis reactions of para-dialkenoxy aromatics produced the macrocyclic [n,n]- and [n,n,n]paracyclophanes via dimerization and trimerization reactions <03OL741>. 8.3

CARBON-NITROGEN RINGS

Azobenzenophanes, possessing 2, 3 or 4-azobenzene moieties connected at the metapositions by methylene linkers, have been constructed; the effects of photochemical and thermal isomerizations of the azo-linkages were investigated <03JOC8291>. Treatment of a DMSO solution of 1,4-dibenzyl- 1,4-diazacyclododec-8-ene-6,10-diyne 11 in the presence of 100-fold

excess of 1,4-cyclohexadiene for 12 h at 170 ~ gave (70 %) the Bergman cyclized product 12 <03CC1156>. The formation of hexa- and heptaazamacrocycles, possessing a single N-(2aminoethyl) appendage, was accomplished from 3-benzoyl-N1,NS-ditosyl-3-aza-pentane-l,5- or tetraamine with diamine and the appropriate fully N-tosylated N~,N~ Cs2CO3 <03OBC854>. A convenient synthesis of mono-N-alkylated 1,4-bis(tertbutoxycarbonylmethyl)tetraazacyclododecane (cyclen) has been reported <03JOC2956>. An exceptionally high yield route to triprotected cyclam and cyclen using ethyl trifluoroacetate has

456

G.R. Newkome

been described <03TL2481>. The treatment of tris(2-aminoethyl)amine with formalin in the presence of HCIO4, KI, and CdI2 gave the slightly deformed Ta symmetrical cubic capsule 13 containing 16-nitrogen donors derived from the self-assembly of 20 components <03CC1836>. Amination of 1,2- or 1,3-dihalobenzenes by linear polyamines in the presence of Pd(dba)2/B1NAP afforded a simple one-pot procedure for the assembly of benzopolyazamacrocycles <03TL1433>. The step-wise construction of a novel, rigid, functionalized macrocycle 14 based on triazene and phenylene linkers has appeared <03TL1359>. Macrocyclic cyclophanes 15, possessing tetraexometallic sites, were easily prepared by 1,4-addition of diamines to a,13-unsaturated Fischer bis-carbene templates <03OL1237>. Although structures of rotaxanes are becoming more complicated in order to probe their unique shuttling behavior <03JOC2704, 03CEJ2982, 03CEJ2649>, they are generally based on bis(4,4'-bipyridinium)cyclophane as one of the key components; recently, its functionalization has started to address its limited solubility <03TL2307, 03CEJ543>. Condensation of 2,4-bis(phenylhydroxymethyl)furan with pyrrole and p-toluylaldehyde formed the intermediary 5,20-diphenyl- 10,15-di(p-tolyl)-2-oxa-21 -carba-porphyrin, which under further addition of pyrrole to generate (10 %) the unexpected 16 <03CEJ4650>. Treatment of tetraaryl-m-benziporphyrin with pyridine and AgBF4 initially afforded the 22-pyridiniumyl-mbenziporphyrin, which rearranged to a fused m-benziphlorin containing a 4a-azafluorene fragment <03OL3379>. The unexpected pyrrole-containing cryptand 17 with a sp 2 hybridized apical bridging centers was prepared (15 %) from tripyrranes and its diformyl analogue under acidic conditions <03CC1646>. meso-Aryl-expanded porphyrins were prepared in a ring-size selective manner from methanesulfonic acid-catalysis of dipyrromethene and tripyrromethane

17

18

16 Ar

AF

19

"1=0-3

Ar

with aryl aldehydes <03TL2505>. The newly coined "imidacene" 18 was prepared by reductive coupling of a diformyl-substituted 2,2'-biimidazole using low-valent titanium, followed by DDQ oxidation <03CEJ3065>. The structurally related ~-tetrakis(trifluoromethyl)porphycene has been synthesized and reported to be the first fluorine-containing porphycene <03OL2845>.

Eight-Memberedand LargerRings

457

Oxidation of 5,15-bis(3,5-di-tert-butylphenyl) Nin-porphyrin with Sc(OTf)3 and DDQ gave a series of interesting meso-~ doubly linked NiILporphyrin tapes, e.g. 19 <03CC 1096>. The inner C-cyanide addition and subsequent addition of a methoxy were reported when Ni n N-confused tetrakis(p-tolyl)porphyrin was treated with NaOMe and DDQ <03CC1062>. N-Confused porphyrin, possessing meso-pentafluorophenyl moieties, was formed (20 %) from N-confused dipyrro-methene <03OL 1293>; whereas, N-confused 5,20-diphenylporphyrin was synthesized (7 %) by a [3+ 1] condensation, followed by oxidation <03OL 1427>. When N-confused tripyrranes were treated with pentafluorobenzaldehyde in the presence of p-TSA followed by oxidation, meso-hexakis(pentafluorophenyl)-substituted doubly N-confused hexaphyrins were generated <03JA878>. Benzocarbaporphyrins were found to undergo regioselective oxidations with FeCI3 alcoholic solvents to afford benzo[ 18]annulenes ketals in excellent yields <03JOC8558>. A series of 4-substituted pyridine-capped 5,12-dioxocyclams has been synthesized and characterized <03JOC7661 >, but to further MRI studies with gadolinium complexes, a lipophilic moiety was attached to 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),ll,13-triene-3,6,9triacetic acid <03OBC644> to modify its water solubility. The formation and coordination of bipyridinophane 20 and its 4,4'-isomeric analogue with Cu n and Ni n have been reported <03DT1299>. Facile removal of 2-oxazolidinone and 2-hydroxyethylamine auxiliaries in methoxide-carbonate leads to the synthesis of an enantiomerically pure nicotinate possessing a planar-chiral [10]para-pyridinophane <03TL3625, 03TL3599>; this mild procedure has many useful applications. Azaarenecyclynes 21 containing geometrically-controlled and shapepersistent azamacrocycles have been synthesized; the SbV complex has very strong light-emitting properties <03TL 1469>. The selective linking of 2,6-bis(dec-9-enyloxy)pyridine units by alkene metathesis generated a specific, preorganized 69-membered tris(pyridinyl) macrocycle; this very novel approach using shape-persistent templating offers a simple route to very large tailored macromolecules with precise connectivity patterns <03AG(E)228>. Recently, members of the macrocyclic [n.m.1]-(2,6)-pyridinophane family have also been created by a Chichibabin-type macrocyclization procedure <03JOC4806, 03NJC665, 03CC358>; other than some derivatives, the parent [ 1.1.1 ]pyridinophane has yet to be realized. H ~

(N H-N

N

I:! 2O 21 8.4

CARBON-SULFUR RINGS

The oxidation ofp-tert-butylthiacalix[4]arene or its tetra-O-benzyl ethers generated all four stereoisomers of p-tert-butylsulfinylcalix[4]arenes based on the orientations of the sulfonyl moieties relative the mean plane of the four bridging sulfur centers <03JOC2324>. Alkenes, when treated with N-bromosuccinimide and dimercaptoethane, gave the corresponding fl,fl'-

458

G.R. Newkome

dibromodithioethers, which with Cs2CO3 in DMF in the presence of dimercaptoethane afforded a disubstituted 12-thiacrown-4 <03TL5263>. Attempted bis-quaternization of 22 with 1,2dibromoethane failed under normal conditions; however, in the DMF at 10 kbar pressure at 25 ~ for 3 days the desired TTF-diquat cyclophane cis-23 <03TL2979> was realized. 8.5

CARBON-BORON RINGS

The polyhomologation of 1-boraadamantane'THF by dimethylsulfoxonium methylide formed a series of new macrocyclic trialkylboranes 24, oxidation generated a three-armed star polymethylenic polymer, based on a cis, cis-l,3,5-trisubstituted cyclohexane core <03JA12179>.

RS" i S~=~SI~SR s,~S St\ s |

~._._/ | 23

22

B m

24 8.6

CARBON-IODONIUM RINGS

The high yield macrocyclization of iodonium containing macrocycles with rhomboid, square, and pentagonal shapes has been reported; for example, bisiodonium triflate 25 with the diaryliodonium trifluoroacetate 26 gave rise (70 %) to the desired molecular square 27 <03JOC9209>. 8.7

CARBON-SELENIUM RINGS

Treatment of cis-dichloroethene with sodium selenide (Na2Se) generated (Z,Z,Z,Z,Z)1,4,7,10,13-pentaselenacyclopentadeca-2,5,8,11,14-pentaene 28 as well as its all cis, hexahomologue; X-ray data indicated that the Se atoms were located on one side of the ring-plane, their oxidation indicated that they oxidize more easily than the S-analogues, and they both form silver(I) complexes <03OL1443>. The reaction of 2,4,6-triisopropylphenyl-ethynyllithum with Se(0) afforded (67 %) the lithium 2,4,6-triisopropylphenylalkynyl-selenolate, which is stable in the solid-state but disproportionates to form (55 %) the Se-macrocycle 29 along with Se-free byproducts <03OL 1867>.

459

Eight-Membered and Larger Rings

| II

~

Me3Si

I | 2OTf|

1

| lI ~ ~ ~ ~ ~ - - i I | 4OTfO

0

Me3Si

25

o

§ 27

(F3CCO2)21~I(O2CCF3)2 26

8.8

C A R B O N - N I T R O G E N - O X Y G E N RINGS

The C,N, O-macrocycles continue to be of synthetic interest, in that the N-appendage can be so readily modified e.g., guanidinium receptors <03JA8270> and lariat ethers <03CC2536>, as well as there is diminished strain relative to C-bonded counter-parts. Spironaphthoxazines

se/Se.~~ I / [ ~ ~ ~ S e ~ S e I~ Se

Se

~Se~ n 28 n=3,4

I se~Se

/

29

conjugated with aza-15(18)-crown-5(6)-ether moieties 30 have been synthesized and complexed with Li + as well as several alkaline earth metals; hypsochromic shifts occur with the spiro-form, whereas bathochromic shifts are demonstrated with the merocyanine-form <02NJCl137>. Amino acid binding was realized using a novel stereoregular poly(phenylacetylene) bearing a azacrown ether moiety, as the host pendent 31 <03JA1278, 03M6599>. m- or pPhenylenediamine and chlorophenyl-substituted azacrown ethers were synthesized by sequential nucleophilic substitution of [(r/5-cyclopentadienyl)(r/6-(m- or p-dichlorobenzene))]iron hexafluorophosphate by azacrown ethers and cyclohexa-amines <03JOC2161 >.

460

G.R. Newkome

Me Me

--N

m

n=12

H

30

(/~O

O ~O ~

O~]

O nO~

n

C~/~~t~no

O/~-~o~O~n31

/NR r

RN

MOO"j ~~r~ / OMe ~eu__ O OMeOI

33 H The theme of double-bridged calix[4]arenes has been further shown by the three-step conversion of 25,27-bis(5-chloro-3-oxapentyloxy)calix[4]arene to 1,3-alternate 25,27-[4-(10cyano-9-anthrylmethyl)- 1,2-phenylene-bis(5-dioxy-3-oxa- 1-pentyloxy)]calix[4]-aza-crown-5 32, which was demonstrated to be a fluorescent sensor <03JOC597>. The first C3v-symmetrical calix[6](aza)crown 33 has been synthesized in five-steps from a 1,3,5-tristosylate calix[6]arene precursor <03JOC3416>. Macrocyclization under high dilution conditions has been used to prepare different liquid crystals composed of 2-phenylpyrimidine or 5-phenylpyrimidine connected by PEG units <03JOC597>. Treatment of polyoxypropylenediamine (Jeffamine) with 1,4-benzoquinones afforded low but variable yields of the 2,5-bridged quinoid(aza)crown ethers not utilizing high dilution conditions <03TL5531 >. The use of 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane has been shown to be an ideal core to either bis-substitute with one or two appendages [e.g., 6-methyl-2,2'-dipyridine <03CM656>] or bridge thus generating novel macrobicyclic ligands <03JA1468, 03OBC27, 03CC1330, 03NJC1251> capable of metal ion encapsulation or cryptate formation. The efficient syntheses of substituted poly(ethylene glycol)-capped dioxocyclams and bridged bis-dioxocyclams have also been presented <03JOC8409>. Dihydroxylation with OsO4 of mesotetraaryldithiaporphyrins generated the corresponding meso-tetraaryldithia-7,8dihydroxychlorins and -7,8,17,18-tetrahydroxybacteriochlorins; these dihydroxychlorins are readily susceptible to oxidative ring-openings to form dithiaporpholactones <03TL7793>, also see <03OL 19>.

Eight-Memberedand Larger Rings 8.9

461

CARBON-SULFUR-OXYGEN RINGS

Crown-annulated quater- and sexithiophenes with oligooxyethylenes connected at the terminal 3-positions of the thiophene rings have been synthesized by treatment of 3,3'"-bis[(2cyanoethyl)sulfonyl]-2,2':5',2":5",2"'-quaterthiophene with diiodooligooxy-ethylenes under high dilution with CsOH-H20 <03JA1363>; see the related structure 34 below. The selective ring-closure of tert-butylthiacalix[4]arene with oligoethylene glycols were successful using DEAD/TPP (Mitsunobu procedure) <03TL4681 >. Similarly, 1,3-alternating thiacalix[4]monocrowns were prepared by the reaction of hydroxylthiacalix[4]arene with the appropriate poly(ethylene glycol)ditosylate and Cs2CO3 then the addition of 1-iodopropane or additional ditosylate to generate the thiacalix[4]biscrowns <03JOC6720>. A series of dithia[n.3.3](1,3,5)crownophanes were prepared (10-31%) by the use of a Cs2CO3-assisted intramolecular macrocyclization <03OL2781 >. 8.10

CARBON-NITROGEN-SULFUR RINGS

The tricyclotetramerization of isoindolinediimine possessing cryptand functionality gave rise to metal-free phthalocyanines bearing four peripheral tetraazadithiahexaoxa-cylindrical or spherical macrotricycles <03TL6973>. The synthesis and structural characterization of aromatic core-modified (N4S2 and N4Se2) 26 7t hexaphyrin analogues have appeared <03OL3531>.

S --S

S

_N

LLsLY

34

36 35

An acid-catalyzed or,a-coupling of tetrapyrranes containing thiophene (or furan/selenophane) rings resulted in the generation of meso-substituted 347t core-modified octaphyrins <03CEJ2282>. Treatment of the deprotected thiolate groups of bis-cyanoethylsulfanyl quaterthiophene with bis-p-bromomethyl-azobenzene gave the switchable azo-C,N,S macrocycle 34 <03JA2888>. The 9,21,22-triaza-2,11-dithia[3.3](2,6)pyridino-(2,9)phenanthrolinophane 35 was prepared by the macrocyclization of 2,6-bis(mercapto-methyl)pyridine and 2,9bis(bromomethyl)phenanthrolines; the barrier of interconversion between the two syn isomers was estimated (NMR) to be 36.5 kJ mol 1 <03TL3527>. The first example of a NS4 pyridinecontaining quinquedentate macrocycle, specifically 2,5,14,17-tetrathia[6](1,2)benzo[6](2,6)pyridinophane, has been synthesized and complexed with selected metal ions <03DT295>. Treatment of 2,9-dichlorophenanthroline with H2S at 170 ~ afforded (80 %) the S-bridged bisphenanthrolines macrocycle 36 <03TL7099>. Calix[2]bipyrrole-[2]thiophene (and the related [2]furan) have been synthesized and shown to exhibit a preference for carboxylate anions <03JA13646>.

462

G.R. Newkome

8.11

CARBON-METAL RINGS

Chiral molecular squares 37 were synthesized via a step-wise procedure from monoprotected enantiopure bis(alkynes) with cis-PtCl2(PEt3)2 in the presence of CuCI catalyst in EtzNH at 25 ~ giving a PtL2 intermediate, which after deprotection was subjected to the same reagents affording the directed assembly <02JA12948>; the products exhibited interesting dual luminescence at 25 ~ thus giving entr6e to proposed chiral sensory applications <03CC2124>. 8.12

CARBON-SULFUR-METAL RINGS

The reaction of c/s-Pt(dppp)Cl2 with terthiophene-diyne in the presence of 10 mol% CuI and 2-eq. of NEt3 at 25 ~ gave (91%) the stable bisplatinomacrocycle 38, which with iodine, followed by NazS afforded the stable, red, microcrystalline octabutylcyclo[8]-thiophene in 19 % yield <03CC948>.

Cl

CI

P-P,t ~

~

CI OR Cl

B

u

Bu ~

B

u

RO

OR OR

vP-~ I~ .t_``I/j`~~~ CI

,
RO~

OR

Bu

P,t-P,~

3"/

iI/~c'

F :~ I-PS . ~-C -'~ .~., CI

p

i~ph )

Bu

Bu 38

463

Eight-Membered and Larger Rings

jpd

iPd pd

//N~,,,~ N . .

24+

% N/._~N

] 24OTf-

2OTf| '

/

-

pd7

f It o . N%.iN/r~, `

N\

" x x

Pd

p d ~ ' - - N ~ pd ~j~ 39

O II

Pt.~p

6+ 6NO 3 -

"RH(//,~Pit(, ~ ~ ' ~ ~ I"~ ,\_

40 8.13

C A R B O N - N I T R O G E N - M E T A L RINGS

Treatment of 2,9-dibromophenanthrene with Pt~ followed by bromine-nitrate exchange gave the desired 60 ~ tecton, 2,9-bis[trans-Pt(PEta)2(NO3)]phenanthrene, which with different linear connectors afforded a series of self-assembled supramolecular triangles <03JA5193>. A series of related binuclear metallomacrocycles [Cd(NO3)2L]2,where L is an angular exo-bidentate, such as 4-(4'-pyridinyl)(2-pyridinylethynyl) benzene, have been reported

464

G.R. Newkome

<03JA6753>. The amazing self-assembly of 12 Pd centers and 6 ligand [1,4-bis(3,5pyrimidyl)benzene] connectors gave (>90 %) the tetrahedral coordination cage 39 in 5 h at 25 ~ <03JA9260>. Dendritic molecular squares with 16 ferrocene groups on the bridging ligands derived from perylene bispyridinyl imides and with [[Pt(dppp)][(OTf)2]] corners have been self-assembled in high (68 - 77 %) yields <03JA9716>. A series of enantiomerically pure multinuclear metallacalixarenes has been constructed with Pd comers and 1,2-diamino-cyclohexane and substituted 2-hydroxypyrimidine components <03CEJ4414>. The magnetism of related tetranuclear complexes of the [FeUnLn](Xs) [2x2]-grid-type [L = 4,6-bis(2',2"-bipyridin-6'yl)-2(substituted)pyrimidine] was shown to possess spin translation behavior; the phenomenon depends directly on the substituent at the 2-position on the central pyrimidine <03CEJ4422>. Chirally twisted porphyrin-based molecular capsule and polymeric capsule have been synthesized from chiral cis-Pd[(R)-(+)-2,2'-bis(Ph2P)-l,l'-binaphthyl] with porphyrins bearing either four (for a capsule) or eight (for the polymeric counterpart) pyridinyl moieties <03JOC1059>. 8.14

C A R B O N - P H O S P H O R U S - M E T A L RINGS

The self-assembly of two tripodal caps, such as tris[4-(trans-Pt(PEt3)2(NO3))phenyl]phosphine oxide, with three 1,8-bis(4-pyridinylethynyl)anthracene connectors afforded a nanoscopic prism 40 in an incredible 98 %; the C- and Si- capped analogous were also reported <03JA9647>. 8.15

CARBON-OXYGEN-NITROGEN-METAL

RINGS

The b/s-mono-dentate ligands, constructed from a PEG moieties (n = 3 or 4) with pyrazolyl end groups, afforded either mono or binuclear silver metallomacrocycles; X-ray diffraction of single crystals confirmed their structures <03TL1457>. Bowl-shaped, water-soluble, C2v symmetric superstructures have been assembled by intra-clipping of resorcin[4]arene, capped with (pyridinylOCH2) moieties, upon treatment with (en)Pd(NO3)2 <03CC998>. Treatment of cis-l,8-bis(pyridin-8-oxy)oct-4-ene-2,6-diyne (cis-bpod) with either Cu(ll) or Zn(ll) in a 2.1:1 ratio gave the corresponding [Metal(bpod)2] complexes; the photo-Bergman cyclization of the [Cu(bpod)2] afforded (87 %) a ring-contacted 1,2-bis(2'-pyridinyloxymethyl)benzene <03JA6434, 03CC2876>. 8.16

REFERENCES

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02CHC763

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466 03CEJ1465 03CEJ2282 03CEJ2439 03CEJ2649 03CEJ2676 03CEJ2904 03CEJ2982

03CEJ3065 03CEJ4422 03CEJ4650 03CEJ5180 03CEJ5188 03CEJ5307 03CM656 03DT295 03DT1299 03HC540 03JA650 03JA878 03JA 1126 03JA1278 03JA1363 03JA1468 03JA2888 03JA5193 03JA6434 03JA6753 03JA7784 03JA8270 03JA8290 03JA9260 03JA9272 03JA9367 03JA9647

G.R. Newkome

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Eight-Membered and Larger Rings

03JA9716 03JA12179 03JA13646 03JOC597 03JOC1059 03JOC2161 03JOC2324 03JOC2547 03JOC2704 03JOC2956 03JOC2997 03JOC3416 03JOC4806 03JOC6720 03JOC7661 03JOC8291 03JOC8409 03JOC8558 03JOC8750 03JOC9209 03JPSA3470 03M3709 03M6599 03M8894 03MI01 03NJC280 03NJC665 03NJC 1251 03OBC27 03OBC644 03OBC854 03OBC1232 03OL19 03OL741 03OL1237 03OL1293 03OL1427 03OL1443 03OL1867 03OL2781 03OL2845 03OL3379

467

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468

03OL3531 03OL3951 03OL4381 03OL4537 03RJOC1 03S155 03T2025 03TL29 03TL33 03TL805 03TL993 03TL1359 03TL1433 03TL1457 03TL1469 03TL 1549 03TL2307 03TL2481 03TL2505 03TL2665 03TL2979 03TL3039 03TL3527 03TL3599 03TL3625 03TL4251 03TL4519 03TL4681 03TL5263 03TL5397 03TL5531 03TL6973 03TL7099 03TL7373 03TL7793 03TL8265 03TL9079

G.R. Newkome

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469

INDEX 2,5-bis-Acetylenic furans, 170 N-Acyl oxazolidin-2-ones, 300 N-Acyl-5,5-dimethyloxazolidin-2-one, 304 2-Alkylidene-l,3-dioxolanes, 273 3-Alkylidene-4-alkenyltetrahydrofurans, 177 2-Alkylidenetetrahydrofurans, 176 3-Alkylidenetetrahydrofurans, 177 2-Alkyl-substituted benzo[b]furans, 180 2-Alkynylchromanones, 419 3-Alkynylflavones, 418 3-Alkynyltetrazines, 390 2- Amidofurans, 168 3-Amidofurans, 168 3-Amino- 1,2,4-triazines, 386 3-Aminoisochroman-5,8-diol, 413 3-Am inomethylenedihydrofuran-2-ones, 165 5-Aminooxazoles, 293 Anthocyanins, 414 Artemisinin, 423 3-Aryl- 1,2,4-triazines, 388 2-Arylbenzo[b]furans, 180 4-Arylideneoxazolones, 295 6-Aryl sul fanyl-3,4-dihydro-2H-pyrans, 408 6-Aza-(2'-deoxy)isocytidine, 388 6-Aza-5-methyl-(2'-deoxy)isocytidine, 388 2-Azabicyclo[2,2,0]hex-5-enes, 83 Azabicyclo[2,2,1 ]heptane, 88 Azacoumarins, 45 Aza-Diels-Alder, 7 Azazirconacyclobutanes, 92 2H-Azepin-2-imine, 432 2H-Azepin-2-one, 433 2H-Azepine, 433 Azetidines, 83,84 3-Azetidinones, 82 2-Azetidinones, 84-91,292 Aziridines,86,289,298 Azocino[ 1,2-a:6,5-b ]indoles, 150 Azomethine ylides, 289 Azuleno[4,5-c]furan, 187 Azuleno[ 5,6-c] furan, 187 Benz[4,5]imidazo[1,2-c]pyrido[3',2':4,5]thieno[2,3e]pyrimidine, 363 Benz[b]azepinones, 435,436 Benz[c]azepine, 434 Benz[c]azepinones, 434 Benz[f]indenone, 165 [3]Benzazepinones, 435 Benzimidazo[2,1 -f][ 1,2,4]triazine, 397 Benzimidazole[ 1,2-c] [ 1,2,3]thiadiazoles, 254 Benzo[ 1,2,4]triazine 1,4-dioxides, 395 Benzo[1,2-b:4,3-bqdithiophenes, 108 Benzo[ 1,2-b:4,5-b ]dithiophenes, 110

Benzo[ 1,2-b:5,4-b ~]dithiophenes, 102 Benzo[ 1,2-c:4,5-c']dithiophenes, 103 Benzo[4,5]thieno[2,3-d]pyrimidines, 362 5H-Benzo[6,7]cyclohepta[ 1,2-d]pyrimidines, 359 Benzo[b]furan natural products, 158,159 Benzo[b]furan-3-carboxylate, 185 Benzo[b]furans, 2-substituted,182 Benzo[b]phenanthro[9,10-d]furan, 183 tris-(2-Benzo[b]thienyl)methane, 421 Benzo[b]thiophenes, 98, 99, 112 Benzo[c]phenanthridines, 40 Benzo[c]pyrylium salt, 414 Benzo[c]selenophenes, 102 Benzo[d]azepin-3-ones, 333 Benzo[d]isothiazoles, 246, 250, 252 Benzo[/]isoquinolines, 45 Benzo[h]isoquinolines, 39, 43, 44, 331 1,4-Benzodiazepin-2-one, 441 2,3-Benzodiazepine, 397 Benzodiazepinium, 441 1,4-Benzodioxanes, 422 1,4-Benzodioxepin-3-yl-5-fluorouracil, 448 1,4-Benzodioxins, 410,422 Benzodioxoles, 273,274 Benzofurans, 2,5-disubstituted, 182 Benzofurans, Diels-Alder reaction, 167 [ 1]Benzofuro[2,3-e] [ 1,2,4]triazine, 398 2,1-Benzoisothiazoles, 248 1,2-Benzoisothiazolin-3-ones, 246 Benzonitrile oxides, 284 1H-2-Benzopyran-5,8-diones, 413 2,1,3-Benzothiadiazoles, 257 Benzothiazoles, 230,213,232, 250 Benzothiazolines, 241 Benzothieno[2,3-d]pyrimidines, 368 [ 1]Benzothieno[3,2-b]pyrans, 98 [ 1]Benzothienol[3,2-d]pyrimidin-4-ones, 370 Benzothiopyano[2,3-b]indol- 11-ones, 144 1H-2-Benzothiopyrans, 421 2-Benzothiopyrylium salts, 421 1,2,4-Benzotriazines, 231 Benzotriazoles, 146 Benzotrithioles, 279 [ 1,4]Benzoxathiin-2-ones, 426 4//- 1,2-Benzoxazines, 412 S-Benzoxazolyl (SBox) glycosides, 295 Benzoxepine, 438 2,2'-Biindoles, 142 Bithiazoles, 228, 229 Bithiophenes, 117, 121 2,6-Bridged pyran-4-ones, 415 5-Bromofuran-2-carbaldehyde, 173 4-Bromopyran-2-ones, 416

470

Index

Bromopyrroles, 21 ),-Butenolides, 160 2,5-bis(Butyltelluro)furan, 170 C60, 276 C60, 391 C60F18, 276 Calix[2]bipyrrole[2]thiophenes, 107 Calix[4]arenes, 121 Camptothecin, 38 Carba-2-oxacephem, 88 Carbacephams, 89 4a-Carbafuranoses, 160 Carbapenam, 87,88 Carbazoles, 148 B-Carbolines, 142, 146, 147, 363 y-Carbolines, 146, 148 Carbon suboxide, 415 Cephalosporins, 87,88 Chalcones, 419 ot-Chloroglycinates, 296 6-Chloropyran-2-ones, 416 2H-Chromen-4-yl enol phosphates, 410 2H-Chromenes, 110 Chromone-3-carboxaldehydes, 418 Coumarins, 164 1-Cyanocyclopropancarboxamides, 165 Cyanuric chloride, 389 Cycloalka[b]pyrans, 406 Cycloalkanonaphthofurans, 185 Cyciobuta[b]pyran-4-one, 415 Cyclobuta[b]pyrano[2,3-d]pyran-2,5-diones, 415 Cyclobuta[b]thieno[2,3-J][ 1]benzothiophenes, 110 Cyclopent[b]indoles, 147, 150 Cyclopenta[b]pyranones, 409 Cytotoxicity, 4 8-Deazapteridines, 387 3- Deazapuri nes, 387 9-Deazaxanthines, 392 Dendrilla sp,, 1 3-Deoxyanthocyanidins, 414 2,5-Dialkylfurans, oxidation, 161 4,6-Diamino- 1,2-dihydro- 1,3,5-triazines, 387 2,6-Diaminoimidazo[3,4-a][ 1,3,5]triazine, 392 2,5-Diarylfurans, 169 3,4-Diarylpyran-2-ones, 415 [1,3,2,4]Diazadiboretidine, 92 1,4-Diazepan-3-one, 440 1,4-Diazepin-2-ones, 442 1,4-Diazepinol, 44 I 1,3-Diazetidin-2-ones, 92 1,2-Diazetidine, 92 Dibenzo[b,d]pyran, 411 3,5-Dibromopyran-2-one, 416 Didemnum sp,, 1 Difluoro-2,3-dihydrobenzofuran, 168

2,5-Diformylfuran, 169 1,4-Dihydro- 1,2,4,5-tetrazines, 390 1,6-Dihydro- 1,2,4,5-tetrazines, 391 4,5-Dihydro- 1,2,4-triazin-6-one, 388 4,5-Dihydro- 1,3-oxazin-6-ones, 299 1,2-Dihydro-4(3H)-carbazolones, 142 6,7-Dihydro-5 H-imidazo[2,1 -c][ 1,2,4]thiadiazole-3thiones, 256 Dihydrobenzo[b]furan natural products, 158,159 Dihydrobenzo[c]furan natural products, 158,159 Dihydrobenzo[c] furans, 18 Dihydrobenzoxanthenes, 420 Dihydrodibenzo[b,d]furans, 184 Dihydrofuran natural products, 156,157 2,3-Dihydrofuran Patem6-Biichi rection, 166 2,3-Dihydrofuran, Heck coupling, 165,166 2,3-Dihydrofuran-2,3-diones, 415 Dihydrofurocoumarins, 181 3,4-Dihydroisoquinolines, 1l 3,4-Dihydroisoquinoliniums, 22 3,4-Dihydroisoxazolo[4,3-d][ 1,2,3]triazin-4-ones, 391 5,6-Dihydropyrano[2,3-c]pyrazol-4-ones, 205 tris(Dihydropyranyl)indium, 408 1,2-Dihydropyridine, 83 Dihydrotetrazolo[ 1,5-a]pyrimidines, 392 5It, 10H-Diimidazo[ 1,5-a; l ',5'-d]pyrazine-5,10-dione, 374 1,3-Dioxanes, 422 Dioxetanes, 91 1,3-Dioxoi-2-ones, 273 ! ,3-Dioxolan-2-ones, 272 1,3-Dioxolan-4-ones, 273 1,3-Dioxolium salts, 272 N-(Diphenylphosphinoyl) imines, 297 2,2'-bis(5,6-Diphenyl- 1,2,4-triazin-3-yl)-4,4'-bipyridine), 385 1,3-Diphosphacyclobutane, 93 1,3-Diphosphacyclobutane-2,4-diyl, 93 Dipyranone, 162 2,4,6-(Dipyridin-2-ylamino)- 1,3,5-triazine, 3 85 1,3-Diselenole-2-thione, 275 3A-1,2,3,4-Disiladigermetene, 93 Disilagermirenes, 93 Distannoxanes, 93 1,3-Ditelluretane, 93 1,3-Dithianylium triflate, 424 1,3-Dithiaphosphetane-2,4-disulfide, 93 Dithiatricyclo[4,2, I, 1]deca-3,7-dienes, 114 1,2,3-Dithiazoliums, 248 1,4-Dithiepines, 442 1,3-Dithietanones, 92 [ 1,2]Dithiete- l, 1-dioxides, 92 1,2-Dithiins, 424 Dithiolane sulfoxides, 274 1,3-Dithiolanes, 274 1,3-Dithiolium salts, 274

Index

1,2-Dithiolium salts, 278 DNA binder, 4 3-Ethoxycarbonylcoumarin, 181 Fluoropyran, 167 3-Formyl-5-hydroxy-2,3-dihydrofurans, 178 Furan natural products, 157,158 3(2H)-Furanones, 285 Furanophane, 187 Furans from allenes, 171,172 Furans, [4+3] cycloadditions, 163 Furans, cyclopropanation, 161 Furans, Diels-Alder reactions, 162 Furazano[3,4-b]pyrazines, 347 Furo[2,3-b]pyridones, 173 Furo[2,3-d]pyrido [ 1,2-a] pyrimidines, 357 Furo[2,3-d]pyrimidines, 347 Furo[2,3-d]thiazolidines, 236 2H-Furo[2,3-h]-l-benzopyran-2-ones, 181 Furo[3,2-b]pyridines, 314 Furo[3,2-b]pyrroles, 133,160,173 Furo[3,4-c] isoxazole, 284 Furo[3,4-c]pyridines, 187 Furobenzopyrandione, 420 Furyl sulfonamides, 168 Furyl-ot-pyrone, 169 2-Furylcarbenes, 170 1,6-bisFuryltriene, 169 Gelsemoxonine, 83 2-Geranylfuran, 160 Germabenzene, 447 Heptathiocanes, 101 Hexahydrobenzofuran-3a-ol, 166 Hexahydrocyclonona[ 1,2-b:4,5-b'qtriindoles, 149 3-Hydrazino- 1,2,4-triazin-5(2H)-one, 388 3-Hydrazino- 1,2,4-triazin-5-ones, 387 2-Hydroxychromanone, 419 3-Hydroxychromanone, 419 4-Hydroxycoumarin, 418 Hydroxycoumarins, 295 (R)-2-Hydroxyethyl- 1,3,5-triazine, 386 Imidazo[ 1,2-a][ 1,3,5]triazine-4-thione, 392 Imidazo[ 1,2-a]pyrazin-3 (7H)-ones, 372, 374 Imidazo[ 1,2-a]pyridines, 212, 213,216, 311-313,349 Imidazo[1,2-a]pyrimidines, 213,356-358 Imidazo[ 1,2-b][ 1,2,4]triazine, 391 Imidazo[ 1,2-b]pyridazinones, 352 Imidazo[ 1,2-b]pyridazines, 350 Imidazo[ 1,2-c]pyrimidines, 353, 357 6H-Imidazo[ 1,2-c]quinazolines, 213 5H-Imidazo[ 1,5-a]pyrazin-8-ones, 372 Imidazo[2,1 -b]thiazoles, 235 Imidazo[4,5-b]pyridines, 391 Imidazo[4,5-c]pyridines, 387 Imidazo[4,5-d]pyridazin-7-ones, 210, 350 Imidazo[ 4,5-d] pyri dazin- 7-ones, 392

471

Imidazo[4,5-f]pyridazines, 3 74 Imidazo[5,1 -b]thiazoles, 235 Imidazolines, 206 3-Imino- 1,2-dithioles, 278 2-Iminobenzoxathioles, 277 Imino-sugars, 162 Indazoles, 201 5H-Indeno[ 1,2-c]pyridazin-5-ones, 352 Indenopyrrolocarbazoles, 147 Indol-2-yl- 1H-quinolin-2-ones, 142 Indol-2-yl-2-pyridones, 142 3H-Indol-3-ones, 144 Indole-2,3-diones, 148 Indolizidines, 41, 150 Indolo[2,1-c]benzo[ 1,2,4]triazine, 397 Indolo[2,3-a]carbazoles, 142, 150 Indolo[3,2-b]benzo[b]thiophenes, 103 Indolo[3,2-b]carbazoles, 149 Indolo[3,2-b]quinolin-6-ones, 148 Indolo[3,2-e] [ 1,2,3 ]triazolo [ 1,5-a] pyrimidines, 214, 357 2-Indolones, 91 Integrase inhibitors, 4 o-Iodoacetoxycoumarins, 181 3-Iodoflavones, 418 lsatins, 148 Isobenzopyrylium, 162 Isobenzothiazoles, 231 Isochromans, 412 Isochromenoquinone, 413 Isocyanoacetamides, 293 Isomunchnones, 234 Isopropenyldihydrobenzofuran, 167 Isoquinolines, 9,15, 49 Isothiazolo[3,4-d]pyrimidines, 361 3-Isoxazole carbaldehydes, 286 Isoxazole-benzisoxazole rearrangement, 177, 284 Isoxazoles, 5,75, 88 Isoxazolidines, 89 5-Isoxazolidinones, 291 Isoxazolines, 16 Isoxazolo[3,4-d]pyrimidines, 286 Isoxazolo[4,5-b]pyridine N-oxides, 393 Isoxazolo[4,5-b]pyridines, 310 Isoxazolo[4,5-c]pyridine, 285 Isoxazolo[4,5-c]quinolines, 285 Iso xazolo [5,4-b ]pyri dine, 285 13-Lactams, 83-87,89-91 13-Lactones, 91 Lamellaria sp,, 1 Lamellarins, bioactivity, 4 Lamellarins, biogenesis, 3 Lamellarins, structures, 2,3 2-Lithio-2,3-dihydrofuran, 165 3-Lithiofuran, 168

472

Index

Loracarbef, 88 Lukianols, 3 Melamine, dendrimers, 389 (Menthyloxy)(3-furyl)carbene, 160 Merocyanine dyes, 411 2-Methoxyfuran, 162 2-Methoxyfurans, with Grignards, 170 3-Methoxyisoxazoline, 288 Methylazetidin-3-ones, 84 Methylenedioxolanes, 273 3-Methylenetetrahydrofurans, 177 Multi-drug resistance, 4 M~inchnones, 208,295 Naphth[3,2,1-cd]indoles, 147 Naphtho[ 1,2-b] furan, 414 Naphtho[ 1,2-b]pyran-4-one, 419 2H-Naphtho[ 1,2-b]pyrans, 411 Naphtho[ 1,2-c:5,6-c]difuran, 187 Naphtho[2,3-c]chromenes, 41 l 1,8-Naphthyridinyl-3 (2H)-pyridazinones, 350 Ningalines, 3,14 8-Nitro-2-dimethylam ino- 1,2,3,4-tetrahydro2-dibenzofuran, 182 2-Nitro-3-substituted-2,3-dihydrofurans, 178 3-Nitro-4-nitromethylchromans, 412 Nitrocoumarins, 184,417 Nitrones, 289-293 Oligothiophenes, 115, I 16, I 17 10-Oxa-3-aza-tricyclo[5,2, 1,01'5]dec-8-en-4-ones, 162 Oxabenzonorbornadienes, 164 1,3,4-Oxadiazoles, 205 1,2,4-Oxadiazoles, 304 1,3,4-Oxadiazolo [3,2-a] [ 1,3,5 ]triazi ne-5,7-dithiones, 393 [ 1,2,3]Oxadigermetanes, 93 [ 1,2]Oxaphosphetane 2-oxides, 93 1,2-Oxaphosphetanes, 93 1-Oxaspiro[4,5]deca-6,9-dien-8-one, 186 1,2-Oxastibetanes, 93 Oxathianes, 425 Oxathiins, 425 Oxathiolanes, 278 Oxathiolanones, 278 1,3-Oxathiolium salts, 277 1,2-Oxathiolium salts, 279 Oxazaphospholes, 75 1,4-Oxazepin-7-ones, 445 1,2-Oxazepines, 442,443 1,2-Oxazetidines, 92 Oxazole amino acids, 296 Oxazole C-nucleosides, 294 Oxazoles, 90 Oxazolidin-2-ones, 293,302,304 Oxazolidin-2-ones, 302 Oxazolidin-4-ones, 301 Oxazolidin-5-ones, 302 2-Oxazolidinethiones, 300

Oxazolidinones, 74, 300 Oxazolidinyl[ 1,2]oxazetidine, 291 2-Oxazolidinyloxirane, 29 l bis-Oxazoline ligands, 298 Oxazolines, 68 Oxazolo[ 3,2-a] pyrazin- 5-ones, 373 [ 1,3]Oxazolo[3,2-a]pyrimidinones, 363 Oxazolo[4,5-b]pyridines, 294 Oxazolo [4,5-c] quinoline-4(5//)-ones, 294 Oxazolo[4,5-c]quinoline-4-ones, 323 Oxazolones, 208 5(4H)-Oxazolones, 295 Oxazoloquinolines, 326 7H-Oxepin-4-ones, 438 Oxetanes, 90,91 4-Oxoazetidines, 89 Paclitaxel, 83,161 Papaverine, I l, 13 Pentathiepine, 446 Pentathiophenes, I 15 5,5'-bis-Perfluoroalkyl-2,2'-bisoxazoles, 294 Perhydrofuro[2,3-b]oxepine, 164 Phenanthrolines, 59 N-Phenyitriazolinedione, 92 Piperidine-2-thiones, 420 Platina[1,2]diphosphetane 1-oxide, 93 Platinaoxetanes, 93 Polycitones, 3 Polyketides from isoxazoles, 284 Polythiophenes, 119 Porphyrins, 85, 105,276,451,452, 456 Pteridines, 396,44 l Purine Grignard reagent, 394 Purines, 392-395 (2H-Pyran-6-yl)-3-phenylpropenones, 408 Pyrano[2,3-d]pyrimidines, 356 Pyrano[ 3,2-c]pyranones, 408 Pyrano[3,4-c]isoxazole, 284 Pyranoanthocyanins, 414 bis-Pyranone, 410 Pyranophane, 406 Pyrazino[ 1,2-a] indole- 1,4-diones, 375 Pyrazino[ 1,2-a]indoles, 146, 147, 216 Pyrazino[2,1 -b]quinazoline-3,6-diones, 347 Pyrazino[2,3-c][ 1,2,6]thiadiazine 2,2-dioxides, 396 l H-Pyrazino[2,3-c][ 1,2,6]thiadiazine, 374 Pyrazino[2,3-fl][ I, 10]phenanthrolines, 374 Pyrazolines, 201 Pyrazolo[ 1,3,5]triazines, 392 Pyrazolo[ 1,5-a][ 1,3,5]triazines, 392,393 Pyrazolo[ 1,5-a]pyrimidin-7-ones, 369 Pyrazolo[ 1,5-fl]phenanthridines, 202 Pyrazo Io[3 ',4':6,7] azepi no[ 5,4,3-cd] indoles, 205 Pyrazolo[3,4-b]pyridazines, 353,391 Pyrazolo[3,4-b] pyridines, 391

Index

Pyrazolo[3,4-b]pyrimidines, 391 1H-Pyrazolo[3,4-b]quinoxalines, 205 Pyrazolo [3,4- d]- 1,3-thiazolino [2,3-J] pyrim id in e s, 236, 362 Pyrazolo[3,4-d]pyrimidines, 353,363,368-370 Pyrazolo[ 3,4-d] pyrimidines, 395 Pyrazolo[4",3":5,6][4',3'-e]pyrido[3,2-c]pyridazines, 350 2H-Pyrazolo[4,3-c]isoquinoliniums, 333 6H-Pyrazolo [4,3-d]isoxazoles, 205 Pyrazolo[4,3-d] pyrimidin-7(6H)-ones, 358 Pyrazolo[4,3-d] pyrimidin-7-ones, 362 Pyrazolo[4,3-d]pyrimidines, 369 Pyrazolo[4,3-e]- 1,2,4-triazolo[ 1,5-c]pyrimidines, 369 Pyrazolo[ 5,1 -c][ 1,2,4]triazine, 392 Pyrazolopyridines, 42 tris(Pyrazolyl)- 1,3,5-triazine gold(I), 385 tris(Pyrazolyl)- 1,3,5-triazine palladium(II), 385 Pyridazines, 8 Pyridazino[3,4-h]psoralens, 349 Pyridazino[3,4-j]angelicins, 349 Pyridazino[ 4',3 ':4,5]thieno[ 3,2-d][ 1,2,3]triazines, 349 Pyridazino[ 4,3-h]psoralens, 350 Pyridazino[4,5-b][ 1,4]oxazine-3,8-diones, 350 Pyridinium salts, 415 Pyridino[2,3-d]pyrimidin-4-ones, 363 Pyridino[2,3-d]triazolino[4,5-a]pyrimidin-5-ones, 363 Pyrido[ 1',2': 1,2]imidazo[4,5-d]pyridazines, 349 Pyrido[ 1,2-a]pyrimidin-2-ones, 361 Pyrido[ 1,2-a]pyrimidines, 357, 364 1H,2H-Pyrido[ 1,2-c]pyrimidine- 1,3-diones, 353 Pyrido[2,3-b] [ 1,4]oxazin-2-ones, 310 Pyrido[2,3-d]pyrimidin-7-ones, 360, 369 Pyrido[2,3-d]pyrimidine oxides, 286, 358 Pyrido[2,3-d]pyrimidines, 356, 367, 368,370 Pyrido[ 2,3-d] pyrimidines-2,4(1H,3 H)diones, 365 Pyrido[3',2':4,5]pyrrolo[ 1,2-c]pyrimidines, 361 Pyrido[3',2':4,5]thieno[2,3-e]pyrrolo[1,2.a]pyrazines, 373 5H-Pyrido[3',2':5,6]thiopyrano[4,3-d]pyrimidines, 367 Pyrido[3,2-d] pyrimidin-4-ones, 387 Pyrido[3,2-d]pyrimidine-2,4-diones, 358, 362 Pyrido[3,4-b]pyrazines, 372, 375 Pyrido[4',3':4,5]thieno[2,3-d]pyrimidines, 357, 362 Pyridotriazines, 51 2-Pyridyl- 1,3-dioxolanes, 273 Pyrimido[ 1,2-b]- 1,2,4,5-tetrazin-6-ones, 396 2H,6H-Pyrimido[2,1-b][ 1,3]thiazines, 362 Pyrimido[4',5':4,5]thieno[2,3-c]pyridazines, 349 1H-Pyrimido[4,5-b][1,5]diazepine-2,4-diones, 354 Pyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones, 351 Pyrimido[4,5-c]pyridazines, 351

473

Pyrimido[4,5-d]pyrimidine-2,4( 1H,3H)-diones, 356 Pyrimido[4,5-d]pyrimidine-2,4-diones, 396 Pyrimido[ 5,4-e] [ 1,2,4]triazines, 396 Pyrroles, 3,5-14,17 Pyrrolidines, 83,88 Pyrroline N-oxide, 290 Pyrrolizidines, 150, 289 Pyrrolo[ 1,2-a]pyrazines, 375 Pyrrolo[ 1,2-a]quinoline- 1,4-diones, 324 Pyrrolo[ 1,2-c]pyrimidin- 1(5H)-ones, 364 Pyrrolo[2,1-a]isoquinolines, 11 Pyrrolo[2,1-b]thiazoles, 235 Pyrrolo[2, I-d][ 1,2,4,5]tetrazinones, 391 Pyrrolo[2,3-d]pyridazinones, 351 Pyrrolo[2,3-d]pyrimidine 5-oxides, 392 Pyrrolo[2,3-d]pyrimidines, 363,367, 369 1H-Pyrrolo [3,2-c] isothiazole-5 (4H)-ones, 247 Pyrrolo[3,2-c]pyridines, 136 1H-Pyrrolo[3,2-d]pyrimidines, 360 Pyrrolo[3,4-b]pyrazines, 373 Pyrrolo[3,4-c]quinolines, 328 6H-Pyrrolo[ 3,4-d]pyridazines, 348 Pyrylium salts, 414 Quadruple ring-closing metathesis, 179 Quarterthiophenes, 117 Quinazolinones, 210 Quinolizidines, 41 Radical bromo- and iodoetherizations, 175 1,2,3-Selenadiazoles, 261 1,3-Selenazoles, 260 Selenophenes, 451 Sexithiophenes, 108, 117, 461 5-Silabicyclo[3,2,0]heptatrienes, 93 Silacyclobutanes, 93 Silacyclobutenes, 93 4-Silatriafulvenes, 93 Siletanes, 93 2-Silyloxyfuran, 160,161 Solid-phase synthesis, 22,24 Solid-phase, in situ monitoring, 24 Spiro[ 1,3] oxazino[2,3-a]isoquinolines, 333 Steroidal [2,3-d]isoxazole, 284 3-Styrylchromones, 418 13-Sultams,92 T-Sultones, 279 Taxane, 91 Taxinine, 83 Taxol,90 Tellerophenes, 451 Tellurophenes, 102 Terthiophenes, 117, 121 Tetra(p-m elamin-2-ylphenyl)methane, 385 Tetraboranes, 93 4,4',6,6'-Tetracyano-2,2'-bis-triazine, 388 Tetrahydro- 1,2,4,5-tetrazines, 390

474

Index

Tet rahydro- 1H-imidazo[4,5-c] [ 1,2,5 ] -thiadiazol-5 ones, 257 Tetrahydrobenz[b]azepin-2-one, 436 Tetrahydrocarbazoles, 144 Tetrahydrofuran natural products, 156,157 Tetrahydrofuran radical, 166 Tetrahydrofuro[3,2-c]benzothiopyrans, 176,421 Tetrahydroimidazo[ 1,2-a] [ 1,3,5]triazine-4-thione, 392 Tetrahydropyrano[3,2-c]benzothiopyrans, 421 Tetrahydropyrrolo[3,2-e][ 1,2,4]triazines, 388 Tetraselenafulvalenes, 275 Tetrathiafulvalenes, 275,276, 277 1,2,4,5-Tetrazines, 7,8 Tetrazolo[ 1,5-a]pyridine, 395 Tetrazolo[ 1,5-b]pyridazines, 351 Tetrazolo[5,1 -a]-isoquinolines, 332 2-Thia- 1-phospha-bicyclo[3,2,0]heptane, 93 1,2,3-Thiadiazoles, 253 1,2,4-Thiadiazoles, 254 1,2,5-Thiadiazoles, 257 1,3,4-Thiadiazoles, 258,259, 368 bis([ 1,3,4]Thiadiazolo)[ ! ,3,5]triazinium halides, 398 [ 1,3,4]Thiadiazolothieno[3,2-e]pyrimidin-5(4H)ones, 368 Thianthrene, 442 1,2-Thiaphospholes, 93 1,4-Thiazepin-5-ones, 444 1,2-Thiazetidines, 92 1,3-Thiazin-4-ones, 249 Thiazole[4,5-c]quinolin-4(5 I/)-ones, 235 Thiazolidinethione, 82 1,3-Thiazolidinones, 230, 233 2H-A2-Thiazolines, 89 1,3-Thiazolium-4-olates, 85 Thiazolo[ 1,3,5]triazines, 392 Thiazolo[2,3-c][ 1,2,4]triazoles, 236 5H-Thiazolo[3,2-a]pyrimidin-3-ones, 353 Thiazolo[3,2-a]pyrimidines, 235,362 Thiazolo[3,2-a]triazines, 235 Thiazolo[3,2-b][ 1,2,4]triazoles, 235 Thiazolo[3,2-c]pyrimidines, 362 Thiazolo[4,5-b] pyridines, 236 Thiazolo[4,5-c]quinolines-4-ones, 323 Thiazolo[4,5-d]pyrim idine-7(6t/)-thiones, 235 Thiazolo[4,5-d]pyrimidines, 367 2(3H)-Thiazolones, 238 Thieno[2,3-b]carbazoles, 103 Thieno[2,3-b]pyrazines, 373 Thieno[2,3-b]pyridines, 101 Thieno[2,3-c][ 1,2,4]triazines, 393 Thieno[2,3-c]chromen-4-ones, I 01 Thieno[2,3-c]coumarins, 101 Thieno[2,3-c]pyridazines, 349 Thieno[2,3-d]pyrimidine-2,4-diones, 369

Thieno[2,3-d]pyrimidines, 101,362, 363 Th ieno[2,3-J] [ 1,2,4]triazolo[ 1,5-a] azepines, 220 Thieno[3,2-b]thiophenes, 119 Thieno[3,2-c]carbazoles, 103 Thieno[3,2-d] [ 1,3]oxazines, 104 Thieno[3,4-b]indolizines, 102 Thieno[3,4-b]thiophenes, 101 Thienocarbazoles, 141 Thienopentathiepins, 101 Thietanes, 92 Thietes, 92 o-Thiobenzoquinone methides, 421 Thiobutyrolactones, 92 2H-Thiochromen-4-yl enol phosphates, 410 Thiohydantoins, 92 Thioisomiinchones, 85 Thiophene- 1-imides, 92 3-Thio-substituted furans, 171 1,2,4,6-Thiotriazine 1, l-dioxide, 387 5-Thioxo-3,4-dihydro-2H- 1,2,4-triazin-3-one, 388 Topoisomerase I, 4 2,4,6-Triamino- 1,3,5-triazines, 387 2,3,5-Triarylfurans, 169 1,2,3-Triazin-5-ones, 386 1,2,4-Triazin-5-ones, 391,395 1,3,5-Triazine-2,4,6-trione, 385 2H- 1,2,4-Triazine-3,5-diones, 388 4H- 1,2,4-Triazine-5,6-di ones, 388 1,2,4-Triazines, 386 1,2,3-Triazinium salts, 387 1,3,5-Triazino[ 1,2-a]benzimidazoles, 213 [1,2,4]Triazino[4,3-a]benzimidazole, 397 1tl-[l,2,4]Triazino[4,5-a]quinoline-l,6(2H)-dione, 397 1,2,4-Triazoline-3,5-diones, 92 bis([l,2,4]Triazolo)[l,3,5]triazinium hal ides, 398 [ 1,2,4]Triazolo[ 1,3,4]thiadiazolo[ 1,3,5]triazinium halides, 398 Triazolo[ 1,3,5]triazines, 392 [ 1,2,3]Triazolo[ 1,5-a]pyrimidinium salts, 214, 365 [ 1,2,3]Triazolo[ 1,5-c]pyrimidinium salts, 214, 365 1,2,4-Triazolo[3,4-b] [ 1,3,4]quinolinothiadiazepines, 448 Triazolo[4,3-a]pyrimidines, 358 1,2,4-Triazolo[4,3-a]pyrimidines, 361 1,2,4-Tri azolo[4,3-b] [ 1,2,4]triazinones, 388 2H- 1,2,3-Triazolo [4,5-d] pyrim idine-5,7-d iones, 358 1,2,4-Triazolopyridines, 311 1,2,4-Triazolothiadiazine, 393 5-Tributylstannanyl isoxazoles, 286 4-Tributylstannanyl isoxazoles, 286 3-Trichioroacetyl-4,5-dihydrofuran, 165 Trichlorooxazolines, 299 2,4,6-Tricyano- 1,3,5-triazine, 388 6,5,5-Tricyclic cyclopenta[b]benzofuran, 181 N-Triisopropylsilylpyrrole, 17 5-Trimethylsilylthebaine, 167

Index

4H, 10H-6,8,9-Trioxa-2-thiabenz[/] azulen-5-ones, 104 1,3,5-Trioxanes, 32 1,2,4-Trioxanes, 423 1,2,4-Trioxolanes, 279 Tris(3',5'-dim ethylpyrazol- 1-yl)- 1,3,5-triazine, 385 1,2,3-Triselenagermolanes, 279 Tris-tetrahydropyran, 409 2,3,4-Trisubstituted furans, 17 l, 172

475 2,3,5-Trisubstituted furans, 172 1,2,3-Trithiagermolanes, 279 TTFs, 275,276,277 Uracil, 90 Uridine, 83 5-Vi nyloxazolidin-2-ones, 303 Zirconocene benz[t]indene complex, 165

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