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PROGRESS IN

HETEROCYCLIC CHEMISTRY Volume 17

Related Titles of Interest Books BRANDSMA: Best Synthetic Methods: 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 & AUBÉ: Principles of Asymmetric Synthesis GRONOWITZ & HÖRNFELDT: Best Synthetic Methods - Thiophenes HASSNER & STUMER: Organic Syntheses Based on Name Reactions KATRITZKY: Advances in Heterocyclic Chemistry KATRITZKY & POZHARSKII: Handbook of Heterocyclic Chemistry, 2 n d 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 BARTON, NAKANISHI, METH-COHN: Comprehensive Natural Products Chemistry BARTON & OLLIS: Comprehensive Organic Chemistry KATRITZKY & REES: Comprehensive Heterocyclic Chemistry I CD-Rom KATRITZKY, REES & SCRIVEN: Comprehensive Heterocyclic Chemistry II KATRITZKY & TAYLOR: Comprehensive Organic Functional Group Transformations I McCLEVERTY & MEYER: Comprehensive Coordination Chemistry II SAINSBURY: Rodd's Chemistry of Carbon Compounds TROST & FLEMING: Comprehensive Organic Synthesis Journals BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) PHYTOCHEMISTRY TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS Full details of all Elsevier Science publications, and a free specimen copy of any Elsevier Science journal, are available on request at www.elsevier.com or from your nearest Elsevier Science office.

PROGRESS IN

HETEROCYCLIC CHEMISTRY Volume 17 A critical review of the 2004 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 The School of Chemistry, The University of Manchester, Manchester, UK

Amsterdam - Boston - London - New York - Oxford - Paris San Diego - San Francisco - Singapore - Sydney - Tokyo

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ISBN: 0-08-044711-2 Hardcover ISBN: 0-08-044710-4 (ISHC members edition) ISSN: 0959-6380 @ The paper used in this publication meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper). Printed in The Netherlands.

Contents Foreword

vii

Editorial Advisory Board Members

viii

Chapter 1: Furans as versatile synthons for target-oriented and diversity-oriented synthesis

1

Dennis L. Wright, Department of Chemistry, Dartmouth College, Hanover, NH, USA. Chapter 2: Synthesis and photochromic properties of naphthopyrans John D. Hepworth, James Robinson Ltd., Huddersfleld, UK and B. Mark Heron, Department of Colour and Polymer Chemistry, University of Leeds, Leeds, UK.

53

Chapter 3:

63

Three-membered ring systems

Chapter 4: Four-membered ring systems Benito Alcaide, Departamento de Quimica Orgdnica I, Facultad de Quimica, Universidad Complutense de Madrid, Madrid, Spain and Pedro Almendros, Instituto de Quimica Orgdnica General, CS1C, Madrid, Spain.

64

Chapter 5: Five-Membered Ring Systems Parti.

Thiophenes and SE/TE Analogues

84

Tomasz Janosik and Jan Bergman, Department of Biosciences at Novum, Karolinska Institute, Novum Research Park, Huddinge, Sweden, and Sodertorn University College, Huddinge, Sweden Part 2. Pyrroles and Benzo Derivatives Erin T. Pelkey, Hobart and William Smith Colleges, Geneva, NY, USA.

109

Part 3. Furans and Benzofurans Xue-Long Hou, Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China, Zhen Yang, Key Laboratory ofBioorganic Chemistry and Molecular Engineering of the Ministry of Education, Department of Chemical Biology, College of Chemistry, Peking University, Beijing, 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.

142

VI

Part 4. With More than One N Atom Larry Yet, Albany Molecular Research, Inc., Albany, NY, USA.

172

Part 5. With N and S (Se) Atoms Yong-Jin Wu and Upender Velaparthi, Bristol Myers Squibb Company Wallingford, CT, USA and Bingwei V. Yang, Bristol Myers Squibb Company, Princeton, NJ, USA

197

Part 6. With O and S (Se, Te) Atoms R. Alan Aitken, University of St Andrews, UK.

227

Part 7. With O and N Atoms Franca M. Cordero and Donatella Giomi,

238

Universita degli Studi di Firenze, Italy.

Chapter 6: Six-Membered Ring Systems Part 1.

Pyridines and Benzo Derivatives

261

Heidi L. Fraser and M. Brawner Floyd, Chemical and Screening Sciences, Wyeth Research, Pearl River, NY, USA and Ana C. Barrios Sosa, Pharmaceutical Process Development, Roche Carolina Inc., Florence, SC, USA Part 2. Diazines and Benzo Derivatives Michael P. Groziak , California State University East Bay, Hayward, CA, USA.

304

Part 3. Triazines, Tetrazines and Fused Ring Polyaza Systems Carmen Ochoa, Pilar Goya and Cristina Gomez de la Oliva, Instituto de Quimica Medica (CSIC), Madrid, Spain.

337

Part 4. With O and/or S Atoms John D. Hepworth, James Robinson Ltd., Huddersfield, UK and B. Mark Heron, Department of Colour and Polymer Chemistry, University of Leeds, Leeds, UK.

362

Chapter 7: Seven-Membered Ring Systems

389

John D. Bremner, Institute for Biomolecular Science and Department of Chemistry, University of Wollongong, Wollongong, NSW, Australia.

Chapter 8: Eight-Membered and Larger Ring Systems

418

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

Index

438

Vll

Foreword This is the seventeenth annual volume of Progress in Heterocyclic Chemistry, which covers the literature published during 2004 on most of the important heterocyclic ring systems. References are incorporated into the text using the journal codes adopted by Comprehensive Heterocyclic Chemistry, and are listed in full at the end of each chapter. This volume opens with two specialized reviews. The first, by Dennis Wright covers Furans as Versatile Synthons for Target-Oriented and Diversity-Oriented Synthesis. The second, by John Hepworth and Mark Heron discusses 'The Synthesis and Photochromic Properties of Naphthopyrans'. The remaining chapters examine the recent literature on the common heterocycles in order of increasing ring size and the heteroatoms present. Unfortunately, the chapter on Three-Membered Rings does not appear in this volume. Again this year 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-fc]indoles' are mentioned an indexed entry under that name will be found; similarly 'aceanthrylenoll,2-e]|l,2,4]triazines', 'azirines', '2//-pyran-2-ones', '1,2,4-triazoles' etc. etc. are listed. But, subjects like '4-ethyl-5-methylpyrrole', '5-acylazirines', '6alkyl-2W-pyran-2-ones', '3-alkylamino-l,2,4-triazoles', are not listed as such in the Index. 'DielsAlder 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 modern heterocyclic chemistry. As always, we encourage both suggestions for improvements and ideas for review topics.

Gordon W. Gribble John A. Joule

Vlll

Editorial Advisory Board Members Progress in Heterocyclic Chemistry 2004 - 2005 PROFESSOR M. A. CIUFOLINI (CHAIRMAN)

University of British Columbia, Canada

PROFESSOR M. BRIMBLE

PROFESSOR D. W. C. MACMILLAN

University of Auckland New Zealand

California Institute of Technology USA

PROFESSOR T. FUKUYAMA

PROFESSOR M. SHIBASAKI

University of Tokyo Japan

University of Tokyo Japan

PROFESSOR A. FURSTNER

PROFESSOR L. TIETZE

Max Planck Institut Germany

University of Gottingen, Germany

R. GRIGG University of Leeds UK

Pennsylvania State University USA

PROFESSOR S. M. WEINREB PROFESSOR

PROFESSOR P. WIPF

H. HIEMSTRA University of Amsterdam The Netherlands

PROFESSOR

University of Pittsburgh USA

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

1

Chapter 1 Furans as versatile synthons for target-oriented and diversityoriented synthesis Dennis L. Wright Department of Chemistry, Dartmouth College, Hanover, NH, USA [email protected]

1.1

INTRODUCTION

Furan, more than any other aromatic heterocycle, has found considerable application as a distinct building block for alicyclic, heterocyclic and acyclic substructures in high complexity targets. Furans are commonly found as synthons in natural product synthesis, medicinal chemistry and diversity-oriented synthesis. The focus of this review article will be on processes that lead to an overall de-aromatization of the furan with special emphasis placed on the use of furans in the synthesis of complex targets such as natural products and combinatorial libraries. The review is non-comprehensive and surveys the literature from approximately 1995. Earlier examples of these and related strategies can be found in reviews from Padwa , Vogel and Wright . Synthesis and functionalization of furans are not covered but have been extensively reviewed elsewhere .

1.2

OVERVIEW OF THE CHEMISTRY OF FURAN

One of the main reasons that furan has become such an integral part of modern synthetic strategies relates to the ready availability of the parent heterocycle and many simple derivatives. Furan 1 is prepared by decarbonylation of 2-furfuraldehyde 2 which arises from acidic hydrolysis of the pentosan derivatives found in cornhusks and other agricultural products. A variety of simple furan-derived building blocks 1-10 are offered commercially, some of which are shown below (Figure 1).

OR 1 2

f\ 3

f \ f\ OH 4

5

f\ 6

Figure 1

f\(H°)2B>TVlYl 7

89

10

D.L. Wright However, the primary reason for the versatile role of furan relates to the ease with which it is transformed to a variety of non-aromatic structures. In many instances, furan behaves in a manner analogous to other aromatic ring systems, undergoing a full range of electrophilic aromatic substitution reactions, direct metallations and even nucleophilic aromatic substitution. However, it also shows behavior typical of non-aromatic alkenes and dienes, undergoing addition reactions and cycloadditions. In comparison to the sulfur and nitrogen analogs, furan only benefits from approximately 16 kcal/mol of resonance stabilization energy, making it the least aromatic of the series. From the viewpoint of a synthetic chemist, furan can be regarded as a highly flexible and versatile four-carbon building block. Many synthetic strategies involving furan center on exploitation of its aromatic-like reactivity to easily incorporate the heterocycle into a more complex system followed by conversion to a non-aromatic moiety. An overview of the major reaction pathways (Scheme 1) involving the de-aromatization of furan involves a variety of highly diverse transformations.

Scheme 1 Perhaps the most simple reaction is the direct opening of the heterocycle either through acidic hydrolysis or oxidative opening to produce saturated or unsaturated 1,4-dicarbonyl derivatives 11 and 12 respectively. Reduction and oxidation of the furan nucleus without ring-opening are also facile methods for de-aromatization. Oxidation can provide direct access to both 2- and 3furanones (13-14), hydropyrones 15 (when a hydroxymethyl group is placed in the 2-position), or maleic anhydrides 16. Likewise, partial reduction can lead to 2,3- or 3,4-dihydrofurans (1718) while full reduction of the heterocycle produces the tetrahydrofuran system 19. These

Furans as versatile synthons for target-oriented and diversity-oriented synthesis

3

oxidative and reductive processes are frequently coupled to C-C bond forming steps which increases the synthetic power of the overall transformation. Another powerful class of reactions is the cycloaddition processes. Furan readily participates in Diels-Alder reactions to produce oxabicyclo[2.2.1 |heptene products 20 and [4+3] cycloadditions to yield oxabicyclo[3.2. l]octene systems 21. The latter bicyclic compounds are also available from a [5+2] cycloaddition through the pyrilium ion available from hydropyrones 15. Much recent work has focused on asymmetric variants of both the [4+2] and [4+3] reactions . These bicyclic compounds have found wide application in synthetic chemistry as opening of one of the bridges can lead to five and six-membered oxacycles and six and seven-membered carbocycles 22-26. It is easy to appreciate the diversity of substructures that can be accessed from furan building blocks.

1.3

FURANS AS PRECURSORS TO 1,4-DICARBONYL DERIVATIVES

Furan rings are one of the best precursors to 1,4-dicarbonyl derivatives. Unlike 1,3dicarbonyl derivatives (aldol synthon) and 1,5-dicarbonyl derivatives (Michael synthon), the 1,4dicrbonyl group is not well suited to a general approach involving condensation reactions. The ability to easily functionalize the furan ring and then cleave the heterocycle either hydrolytically or oxidatively is frequently exploited for the incorporation of this unit. 1.3.1

Hydrolytic Ring Opening

Spur utilized the hydrolytic opening of a furan followed by a spontaneous aldol cyclization to synthesize new prostaglandins (Scheme 2).

The furyl carbonyl 26 was exposed to an aqueous solution of zinc chloride which presumably opens the furan to give the ketoaldehyde 27 that spontaneously cyclizes to 28. The cyclization is likely preceded by an acid promoted a-ketol rearrangement. Tanis and co-workers utilized a hydrolytic opening promoted by an initial electrophilic attack to synthesize the natural alkaloid epilupinine (Scheme 3).

4

D.L. Wright

Exposure of carbinolamide 29 to a biphasic mixture of formic acid and cyclohexane initially generates the corresponding acyl iminium ion that is trapped by the tethered furan to generate oxocarbenium ion 30. Rather than simply lose a proton to regenerate the furan, it is believed that a 1,5-hydrogen shift is followed by ring-opening to directly give the 1,4-diketone 31 in good overall yield. This intermediate is converted to epilupinine 32 in five additional transformations. 1.3.2 Oxidative Ring Opening Oxidation of the furan nucleus with concomitant ring opening appears to be a more popular transformation than direct hydrolysis and leads to diacylethylene units. A variety of oxidants can be used in the process including peracids, singlet oxygen and bromine. Depending on the substitution, several different 1,4-dicarbonyl compounds can be accessed. Ballini has used furan 33 as a precursor to a ketoaldehyde, Raczko used it as a diketone synthon in 36 and Miles as a ketoacid for Vitamin D analogs 41 (Scheme 4).


5

The simple alkylfuran 33 could be oxidatively opened with PCC to aldehyde 34 which was in turn oxidized to the acid 35, a natural product from a Streptomyces. Bromine oxidation of the 2,5-disubstituted furan 36 gave the diketone 37, a key fragment of the macrolide antibiotic tylonolide. Oxidation of the annulated furan 39 with buffered peracid directly gave the ketoacid 40 in very good yield, which is in equilibrium with the hydroxylactone 41. Kobayashi has used a furyl group as a Y-oxo-ct,[3-unsaturated carboxylic acid in the synthesis of several natural products including brefeldin 44 , aspicillin 48 and the macrosphelides 51 (Scheme 5). Highly substituted furans 42, 45 and 49 were prepared and oxidized under the Kobayashi conditions (NBS and pyridine) to the sensitive keto-aldehydes which were directly oxidized to the carboxylic acids 43, 47 and 50 by action of sodium chlorate. Macrolactonization of the seco-acids and additional peripheral modifications completed the syntheses of these complex natural products.

Extreme oxidation of the furan nucleus can effect C-C bond cleavage which allows furan to function as an equivalent of a carboxylic acid. A recent example was Demiri's route to conformationally restricted homophenylalanine analogs (Scheme 6).

6

D.L. Wright

Cyclopropanation of the cinnamate 52 followed by oximination gave rac-53. Asymmetric reduction of the oxime ether gave two diastereomers, one of which was taken on to 54 by oxidative cleavage of the furyl group.

1.4

FURANS AS PRECURSORS TO FIVE-MEMBERED OXACYCLES

Furan can give rise to a variety of five membered oxacycles. There are four main strategies: oxidation of the furan ring, reduction of the furan ring, addition reactions or cycloaddition followed by cleavage of a carbon-carbon bridge. 1.4.1 Oxidation of the Furan Ring Similar oxidants can be used as above for the preparation of open-chain compounds. The addition of singlet oxygen to the furan ring has found wide application in synthesis (Scheme 7).

Halcomb carried out the singlet oxygen oxidation of the 3,4-disubstituted furan 55 to give hydroxybutenolide 56, an intermediate in a formal total synthesis of zaragozic acid 57. Hall coupled the oxidation of 58 with an intermolecular addition reaction to produce fused oxacycles in high yield. Upon deprotection of 59, a spontaneous conjugate addition occurred to give pyran 60. Brominating agents such as bromine and NBS are also used in the oxidation of furans (Scheme 8).

Furans as versatile synthonsfor target-oriented and diversity-oriented synthesis

7

Scheme 8 Stockman used an NBS oxidation to trigger a domino spirocyclization event to yield the tricycle 62, as a model of the trioxadispiroketal unit found in a variety of marine natural products. Trost employed the simple dihydrofuran 63, prepared by bromine oxidation of furan, in a synthesis of showdowmycin 65. Use of a chiral ligand effected a desymmetrization of the meso compound during formation of the Jt-allyl complex. Interception of the complex with a modified succinimide gave intermediate 64 in good yield and high enantiomeric excess. Isobe developed a three step conversion of furan to a maleic anhydride during a synthesis of tautomycin. Model compound 66 was converted to anhydride 67 by initial oxidation to a dihydroxydihydrofuran with NBS, followed by Jones oxidation to the hydroxybutenolide stage and finally PCC oxidation to the anhydride. Peracids find frequent use in related transformations (Scheme 9).

8

D.L. Wright

Robertson developed a route to the spiroacetal portion of the lituarine natural products that involved a simultaneous furan oxidation/spirocyclization. Treatment of the furan 68 with mCPBA resulted in a direct conversion to a spiroacetal that was further oxidized to the butenolide 69. The use of a trimethylsilyl group at the 2-position of the heterocycle to control the regioselectivity of the oxidation is common. A somewhat different route to spirocyclic products was developed by Wong for the synthesis of sphydrofuran. Oxidation of 70 with peracetic acid led directly to the butenolide 71 in good yield. After removal of the acetonide, a base induced conjugate addition assembled the spirocyclic framework of the natural product. Although the cyclization occurred in good yield, a ratio of isomers was formed. The desired isomer 72 was formed as a 1:1 mixture with 73 although 72 could be separated and taken on to a synthesis of sphydrofuran. Tanis made use of this oxidation in the total synthesis of fastigilin C. Peracid oxidation of 74 gave the butenolide 75 which was reduced in a directed hydrogenation to give 76. Since 2-hydroxyfurans prefer the butenolide tautomer (as in 75), silyloxy or alkoxy furans can be seen as direct precursors to these structures that are already in a higher oxidation state than a furan. These compounds undergo ready addition of electrophiles such as protons or aldehydes which effect a vinylogous aldol condensation (Scheme 10).

Jacobi generated the methoxyfuran 77 via an oxazole Diels-Alder route and found that the primary adduct spontaneously hydrolyzed on work-up to yield the butenolide 78


9

which could be converted in a single step to the natural product stemoamide. An early example of an aldol-type reaction was shown in Boukouvalas' synthesis of the antibiotic patulin 82. Silyl triflate catalyzed condensation of siloxyfuran 80 with benzyloxyacetaldehyde gave 81 which was converted in five steps to the natural product. Diastereoselectivity is often observed in these reactions such as the preparation of 84 reported by Nielsen in the search for antagonists of quorum sensing bacteria. Casiraghi has made wide use of this reaction in an approach to acetogenins and sugars such as the condensation of threose derivative 87 with a siloxyfuran to give 88 as a single diastereomer. Martin has developed a Mannich type variant on this and applied it to the synthesis of ergot alkaloids. Reduction of nitrile 89 gave an imine that was immediately trapped by the tethered furan to produce 91 in good yield. Recent work has focused on the development of chiral variations involving a Michael-type additions (Scheme 11). Katsuki studied the addition of 83 to the crotonate 92 catalyzed by a copper bis-oxazoline ligand . These conditions produced the butenolide 93 in good yield and excellent ee. Brimble has developed a direct annulation based on the addition of silyloxyfurans to quinones which has been studied in an asymmetric version . Use of a copper-pybox complex gave 95 in good yield but only moderate ee.

In addition to 2-furanone structures, 3-furanones can be accessed if a silyloxy group is placed at the 3-position of the furan (Scheme 12).

10

D.L. Wright

Kraus developed a very short route to hyperalactone C based on a Claisen rearrangement to effect C-2 alkylation of the furan. Heating allyl ether 96 presumably generated 3-furanone 97 which spontaneously lactonized to give the natural product 98. Winkler recently reported the vinylogous aldol reaction of 3-silyloxy furans. High diastereoselectivity can be observed as in the reaction of furan 99 with isobutyraldehyde to produce furanone 103 as the major isomer. 1.4.2 Reduction of the Furan Ring Five-membered oxacycles are also available by reduction of the furan nucleus, the industrial procedure for the production of the solvent tetrahydrofuran. Recent work in this area has centered upon coupling a reduction step with the formation of a carbon-carbon bond. Donohoe has utilized this process elegantly in a number of studies (Scheme 13). Sodium/ammonia reduction of the furylamide 104 followed by addition of an alkylating agent gave high yields and high diastereomeric ratios of the dihydrofuran 105 which was used in a total synthesis of nemorensic acid 106. Interestingly, the 3-methyl group was required for high selectivities as the corresponding des-methyl derivative gave an almost equal mixture of the two diastereomers. Donohoe speculated that the group is critical in controlling the geometry of the intermediate enolate. They later developed a variant using a trimethylsilyl group as a proton equivalent which could be removed under acidic conditions to produce 109. This strategy was recently used in an asymmetric synthesis of secosyrin 111 featuring the use of an anisyl group as a carboxylic acid surrogate and an approach to medium ring oxacycles .


11

1.4.3 Addition to the Furan Nucleus In addition to reaction with traditional oxidants and reductants, furan readily undergoes analogous reactions that can be formally viewed as a net addition reaction across the re-system and as a conjugated diene, products of both 1,2- and 1,4 addition can be formed (Scheme 14).

Scheme 14 Moeller effected a formal 1,4 addition across an anulated furan during the synthesis of alliacol A 114. A silver-induced cyclization between the 2-position of the furan and the primary iodide in 112 gave an intermediate oxonium ion that was trapped at the 4position by methanol to give 113. A related process can be seen in the dehydrative isomerization of furyl carbinol 115 during Wu's study on analogs of the spiroketal tonghaosu . Exposure of the alcohol to camphorsulfonic acid promoted the formation of a C2-furylmethyl cation that is trapped at the 4-position by the pendant ephedrine alcohol to yield 116 as a single diastereomer after equilibration. Harman has developed an elegant strategy for dearomatization of furan by the use of an r|2-osmium complex 117. Coordination of the least substituted olefin in sylvan gives 117 where the un-complexed olefin behaves as a traditional enol ether. Protonation of this olefin with triflic acid occurs at C3 to give the oxonium ion 118 that can be trapped with a variety of latent nucleophiles such as a silyl enolether to give 119. It is noteworthy that this strategy reverses the normal reactivity of furan which is more likely to add electrophiles at C2. Other formal 1,2-addition products can be directly produced in a cycloaddition manifold (Scheme 15).

12

D.L. Wright

Furan reacts directly with carbenoids to produce cyclopropanes. Davies reported an intermolecular variant where decomposition of diazoketone 120 in the presence of a rhodium(II) catalyst effected cyclopropanation to produce 121 that underwent a spontaneous rearrangement to the interesting tricycle 122 in an overall 78% yield. Reiser has recently explored an asymmetric version of the intramolecular process en route to several natural products. Cyclopropanation of the more electron-rich olefin of 123 in the presence of a chiral copper catalyst gave the stable adduct 124. Ozonolysis of the remaining olefin led to highly substituted cyclopropanes that have been used in the synthesis of roccellaric acid and other terpenoid skeletons . A well-known furan cycloaddition leading to 2,3dihydrofurans in the Paterno-Buchi reaction which has been recently reviewed . A classic example of the power of this reaction is found in the Schreiber synthesis of asteltoxin . Photolysis of furan 126 and an aldehyde led to oxetane 127. Oxidation of the enol ether proceeded smoothly to give intermediate 128. Furans have also been shown to react effectively as a 2n-component with different 1,3-dipoles (Scheme 16).


13

Vogel and Jager described a novel route to analogs of nojirimycin based on the cycloaddition of a nitroalkane with furan . Reaction of furan with dipole 129 gave the isoxazoline 130 in good yield. The remaining olefin underwent a smooth dihydroxylation to give 131 as a mixture of anomers that could be taken on to the targets of interest. Later, Jager employed a nitrile oxide-furan cycloaddition process for the synthesis of furanomycin analogs. A chiral dipole was prepared from chlorooxime 132 by treatment with base and trapped regioselectively with sylvan 10 to give the furoisoxazoiine 133 in good overall yield but as a mixture of diastereomers. Padwa recently reported the ability of furan to function as a 2jt-component in a dipolar cycloaddition with a carbonyl ylide. Decomposition of 134 with a rhodium catalyst gave the ylide 135 that was trapped by the tethered furyl group, albeit in modest yield. Another popular strategy for the synthesis of five-membered oxacycles from furan is based on intermediate oxabicyclic compounds that can be ring opened to unveil a 2,5-disubstituted furan derivative. Oxidative opening of one of the bridges has been the most widely used method (Scheme 17). Cossy utilized the oxabicyclo[2.2.1 Jheptene derivative 137 in a synthesis of isoavenaciolide. This popular derivative is available through a Diels-Alder reaction between furan and a ketene equivalent. The ketone was converted into 138 by a brominepromoted rearrangement of the bis-propargyl ketal. The two-carbon bridge was efficiently opened by an initial Baeyer-Villiger oxidation followed by acidic methanolysis of the Iactone intermediate to yield tetrahydrofuran 139. A similar oxidative ring-expansion was employed by Jung in an approach to sclerophytin A. The oxabicyclo[3.2.1]octane derivative

14

D.L. Wright

140 was prepared from the reaction of furan and an oxyallyl cation followed by reduction and alkylation. Baeyer-Villiger oxidation produced the lactone 141 that was treated with the Tebbe reagent to give enol ether 142. There was a very high propensity for this enol ether to isomerize into the endocyclic position. If allowed to isomerize fully in the reaction, compound 143 could be obtained in excellent yield. Hydrolysis of the endocylic enol ether unveiled the highly substituted furan intermediate 144.

Some interesting alternatives to oxidative cleavage have recently appeared in the literature and provide a variety of interesting furanoid building blocks (Scheme 18).


15

Gilchrist has studied the cycloaddition reaction between furan and various azirines. It was found that condensation of furan and azirine 145 led to good yields of the adduct 146 (determined by X-ray) that was found to undergo rapid hydrolysis upon addition of water to produce the dihydrofuran 147 in excellent yield. Ring-opening metathesis has recently become a popular method for cleaving these oxabridged intermediates. Wright reported a route to spirofused furans by coupling the ring opening with a ring-closing metathesis. Furan 148 was converted in high yield to the adduct 149 by Diels-Alder reaction with Nphenylmaleimide. Exposure of this compound to the Grubbs' catalyst effected a domino metathesis process to produce 150 in very good yield. Rainier recently reported high regioselectivities in the opening of adduct 151 with electron-rich olefins to give compounds such as 152 in very good yields. 1.5

FURANS AS PRECURSORS TO SIX-MEMBERED OXACYCLES

Another major target for furan-based synthons are six-membered oxacyclic systems. Two major strategies have emerged for the transformation. One of the most common is the Achmatowicz reaction, the oxidative rearrangement of hydroxymethyl furans to 3-pyrones. The other involves the preparation of oxabicyclo[3.2.11octenes through a [4+31 cycloaddition reaction followed by cleavage of the unsaturated two-carbon bridge.

16 1.5.1

D.L. Wright Oxidative Rearrangement of Furylcarbinols

The oxidative ring expansion of furyl carbinols can be accomplished with many of the same oxidants discussed earlier for routine oxidation of the furan ring. As a pyran is formed in the reaction, an obvious application would be for the synthesis of pyranose sugars (Scheme 19). Voelter reported an approach to spiro-fused glycosides that involved addition of 2-lithiofuran to ketose 153 to give an equal mixture of diastereomeric alcohols 154. Peracid oxidation of the mixture led to the production of the isomeric spiropyrans in good yield. Sharma has adapted this strategy for a variety of carbohydrate scaffolds . Addition to the more biased furanose 156 proceeded with high diastereoselectivity to produce 157 which was oxidized with aqueous NBS to give 158 in high yield. Nelson reported an interesting variant on this process in a diversity-oriented manifold to generate novel C-(l—>6) disaccharide mimetics. The chiral bis-furan 159 was prepared by CBS reduction of the corresponding diketone and oxidized with a vanadium system to give the bispyran 160 after glycoside formation. O'Doherty has used a related strategy to access 2,3-dideoxyhexoses, a component of several aminoglycoside antibiotics. Sharpless asymmetric dihydroxyaltion of the sensitive 2-vinylfuran 161 followed by silylation of the primary alcohol was followed by NBS promoted oxidative expansion to give 3-pyrone 162. Protection of the hemiacetal and reduction of the ketone gave the glycai 163 in 47% yield from furfural. When diols are used as in the formation of 162, acid catalyzed ketalization can lead to useful bicyclic derivatives (Scheme 20).

Martin has made ample use of this strategy for the synthesis of various polyketide natural products. Furan 164, prepared by addition of lithiofuran to a lactaldehyde derivative, gave the bridged ketal 165 upon oxidation and acid catalyzed dehydration . The bicyclic architecture allowed highly diastereoselective reactions which led to 166, a key intermediate for

Furans as versatile synthonsfor target-oriented and diversity-oriented synthesis

17

the synthesis of herbimycin. Likewise, furan 167 was converted to 169, a key intermediate for the synthesis of ambruticin . Ogasawara utilized this type of ketalization in an asymmetric synthesis of frontalin 172. Furan 170, prepared by asymmetric dihydroxylation, gave 171 spontaneously upon peracid oxidation. Three additional steps were required for completion of the total synthesis. Since the AD reaction can be used to prepare either configuration in 170, both antipodes of frontalin are available. As the intermediate lactols can be easily oxidized, this oxidative expansion straegy has also found use in the synthesis of valerolactone derivatives (Scheme 21). Trivedi exposed furyl carbinol 173 to a Sharpless kinetic resolution to remove the undesired isomer followed by ring oxidation to give 3-pyrone 174 in high ee. Eventual oxidation of the lactol to the lactone along with installation of an allyl ether gave 175, a precursor for ring-closing metathesis. Reaction of the diene with the Grubbs' catalyst gave the bicyclic compound 176 in excellent yield. This intermediate is envisioned as a versatile building block for the synthesis of naturally occurring polyethers. O'Doherty used an oxidative ring expansion in the total synthesis of phomopsolide D. The furyl enone 177 was reduced in a diastereoselective manner using a Noyori ruthenium system to produce alcohol 178. NBS promotes the initial oxidation to the lactol which was oxidized to keto-ester 179 by action of the Jones reagent. Several steps followed to complete a synthesis of the natural product 180. The propensity of the electron-rich furan ring to undergo preferential reaction with electrophilic oxidants is even selective when a trisubstituted olefin is present (Scheme 22).

18

D.L. Wright

Scheme 22 Baldwin utilized the oxidation of furan 181 for the synthesis of fumagillin analogs. Treatment of 181 with mCPBA gave 182 in fair yield which was taken on to analogs such as 183. Other heterocycles can be prepared by modification of the above strategy. Danishefsky utilized this sequence en route to eleutherobin while Casiraghi used an aminomethyl furan to synthesize pipecolates (Scheme 23).

Scheme 23 Danishefsky prepared the furanophane 184 and converted it to hydropyrone 185 through a directed epoxidation with DMDO. Diastereoselective addition of methyllithium was followed by an acid catalyzed isomerization to the furanoside 186. Vinylogous aldol addition of a silyloxy furan to an imine gave 189 that was easily isomerized to the azacycle 190. Another general strategy to prepare pyran derivatives is a cycloaddition/fragmentation route involving an oxabicyclo|3.2. l]octane intermediate (Scheme 24).


19

Scheme 24 Hoffmann has disclosed several reports using the meso ketone 191 to prepare key pyran fragments of lasonolide , bryostatin and phoboxazole . Compound 192 was prepared in homochiral form by oxidative cleavage of the olefinic bridge . The diol was desymmetrized by virtue of the neighboring PMB group to give a key fragment for altohyrtin A. Wright has explore the use of ring-opening cross-metathesis reaction to prepare non-symmetric pyrans. Ketone 194 was opened in high yield with styrene and the Grubbs' catalyst to give diene 195. Recently, the homochiral 196, prepared from the condensation product of furan and tetrabromocyclopropene , was shown to undergo a highly regioselective opening to produce 197 in good yield. An intramolecular domino process has also been reported by Wright exemplified by the conversion of 199 to the spiropyran 200 in very good yield. An interesting conversion of a furan to a six-membered oxacycle was reported by Harman and McMills that involved a furyl osmium complex (Scheme 25).

The osmium complex 201, prepared directly from furan methanol, was treated with MVK to give the complexed 3-pyrone 203 in good overall yield. The suggested mechanism involves Michael addition of the furan at C3 to give 202 followed by rearrangement.

20 1.6

D.L. Wright FURANS AS PRECURSORS TO CARBOCYCLIC RING SYSTEMS

The other major class of compounds available from furan synthons are carbocyclic rings. Furans provide convenient access to both six and seven-membered alicyclic and aromatics. 1.6.1 Furans as Precursors to Six-Membered Rings The abundance of oxygenated cyclohexanes in natural products and medicinal agents suggests the use of furans through a Diels-Alder reaction followed by cleavage of the C-O bond. There are an abundance of such applications, some of which are shown (Scheme 26).

Hayashi has used the intermolecular Diels-Alder of Furan (IMDAF) reaction to synthesize the epoxyquinols through intermediate 204. Iodolactonization to give 205 was followed by saponfication/epoxidation and base-induced elimination of the oxobridge to give enoate 206. Steel used the adduct 207 derived from nitroacrylate to prepare novel cyclohexyl aminoacids. Again, enolate formation was used to effect opening of the oxabridge to yield 208. Arjon and Plumet have reported studies using IMDAF chemistry to prepare fragments for baconipyrones and taxol . Dimethylfuran was converted to the bicycle 210 which underwent elimination, presumably through generation of an ally! lithium. The use of annulated furans in IMDAF reactions has received much less attention (Scheme 27).


21

Wright utilized the IMDAF reaction of a 2,3-annulated furan 212 in an approach to the eunicellin diterpenes while Takadoi employed the IMDAF reaction of a 3,4-annulated furan 214 in a preparation of himbacine derivatives, giving the exoadducts in both cases. Heavily oxygenated cyclohexanes such as inositols, conduritals and others have been popular targets for the IMDAF/oxabridge cleavage strategy (Scheme 28).

Arjona and Plumet have used IMDAF adducts such as 216 to synthesize pinitol , rancinamycin III and deoxypancratistatin in homochiral form. For their synthesis of pancratastatin, conjugate addition of a lithioarene to the vinyl sulfone was used to effect cleavage of the oxabridge to give the key intermediate 217. Sutbeyaz synthesized bromocondurital 219 from the IMDAF adduct of furan and vinylene carbonate. Due to issues of solubility, the carbonate was converted into the bis-acetate 218 and the oxabridge cleaved by exposure to boron tribromide to give a bromoalcohol derivative which was ultimately taken on to 219. Close relatives of these natural products are the carbasugars, glycoside mimetics that replace the endocyclic acetal oxygen with a methylene group. These non-natural products have considerable biological activity and have been popular targets for this methodology (Scheme 29).

22

D.L. Wright

Bloch utilized the homchiral building block 220 to gain access to aminocarbasugars. This adduct can be prepared by a lipase mediate desymmetrization of the meso diester. A Curtius rearrangement was used to introduce an exocyclic nitrogen in 221 which was followed by a base-induced fragmentation of the ether bridge. Arjona and Plumet used adduct 223, available in eight steps from furan, to synthesize various deoxy-carbasugars such as 225. Again, base induced fragmentation was the method of choice for opening the bridging ether. Intramolecular furan Diels-Alder reactions have also been shown to be valuable for the preparation of polycyclic ring systems (Scheme 30).

Scheme 30 De Clercq utilized an intramolecular furan Diels-Alder reaction for model studies relating to ll-oxo-10a-steroids. Treating enone 226 with an aluminum catalyst at low termperatures induced a stereoselective cycloaddition to produce 227 in reasonable yield. Hudlicky studied the cyclodextrin-promoted Diels-Alder reaction of furyl oxazolidine 228 in an approach to morphinans. A transannular Diels-Alder of a furanophane has been studied by Deslongchamps in the context of a synthesis of anhydrochatancin. Heating furanophane 231, prepared by RCM reaction, gave the tricycle 232 in good yield and with high diastereoselectivity. Padwa has been very active in the development of aminofuran Diels-Alder reactions en route to several different alkaloids (Scheme 31).


23

Alkylation of amidofuran 233 with bromide 234 gave furan 235 which underwent an intramolecular [4+2] reaction upon heating. Because the oxabridge of the primary adduct is part of a labile aminal linkage, spontaneous opening occurred to give 236, an intermediate in the total synthesis of dendrobine . Padwa also developed a route to thioamido furans which are excellent dienes in the |4+2J reaction. Generation of a thionium ion from 237 triggers a ring closure to produce the annulated furan 238 that undergoes a spontaneous cycloaddition to produce 239 in excellent yield which was used for a synthesis of stenine. This method has been extended to a variety of different azapolycyclic systems . The cyclohexene products arising from IMDAF reaction can also ultimately serve as precursors to open-chain systems. The stereochemical bias created by the bridged bicyclic systems often allows for the controlled introduction of stereogenic centers prior to ring cleavage (Scheme 32). Arjona and Plumet have developed an elegant approach to all possible stereotetrads from IMDAF products which they have applied to the C1-C6 subunit of discodermolide . Use of the symmetry inherent on these molecules allows for a high level of control over the stereogenic centers. An illustrative example commences from IMDAF product 240, which is available in either enantiomeric form. Reduction of the acid and thioetherification delivered the tricycle 241 in very good yield. Metallation adjacent to the sulfide promoted elimination of the more strained bridge to give 242 after tosylation of the resultant alkoxide. Reduction of the tosylate to a methyl substituent and oxidation to the sulfone sets up for cleavage of the ether bridge. Stereoselective addition of methyllithium to the vinyl sulfone followed by epoxidation gave 244 in good yield. Baseinduced epoxide opening generated an enone which was stereoselectively reduced and protected to give cyclohexene 245. Oxidative cleavage of this compound under basic conditions led to the terminally differentiated acyclic system 246 with four contiguous stereogenic centers.

24

D.L. Wright

Keay has used an intramolecular furan [4+2] adduct to approach the C15-C23 segment of the vebturicidins. These types of reactions are also finding use in the synthesis of medicinal agents and diverse libraries for drug discovery (Scheme 33).

Scharf used the IMDAF reaction of furan and vinylpyridines to generate adducts such as 247, potential analogs of epibatidine. Paulvannan has made extensive use of furan in diversity-oriented synthesis a nice example being the solid phase preparation of tricyclic compounds such as 249 through reaction of a resin-bound furan with maleic anhydride. Lautens has developed an exciting route to polycyclic cage compounds such as 251 using a pincer cycloaddition reaction. Extensive dehydration of IMDAF products provides a direct route to aromatic compounds (Scheme 34). Moreno has reported a one-pot synthesis of phenols such as 253 by cyclocondensation of furan and an


25

activated acetylene under a mixture of Lewis acid and microwave catalysis. Padwa has extended their use of amino furan Diels-Alder reactions to prepare substituted anilines. Heating the morpholino furan 254 with N-phenyl maleimide gave 255 directly through opening of the intermediate oxabridged compound.

Scheme 34 Wright prepared acetylenic furans such as 256 through an Ugi condensation and found that heating these compounds in the presence of a ytterbium catalyst directly produced isoindolinone 257 in high yield. Benzyne adducts are also prone to aromatize such as in the conversion of 258 directly to 259 in Suzuki's synthesis of the angucyclines. Boger has reported an elegant strategy to anhydrocorinone using an oxadiazole to furan to arene transformation. An initial Diels-Alder reaction with the oxadiazole 260 produces an intermediate furan 261 after loss of nitrogen. Further heating promotes a second cycloaddition to produce arene 262. A few example using furans as precursors to six-membered rings by alternative strategies have appeared (Scheme 35).

26

D.L. Wright

Ducrot used the four carbons of furan to build a cyclohexyl unit by oxidation of 263 followed by a direct aldol cyclization to give 264. Casiraghi prepared the lactone portion of 265 from a silyloxy furan aldol reaction followed by another aldol process to produce 266 as a precursor to various carbasugars. Miyashita used furan in a non-traditional way in a Diels-Alder approach to zoanthamine . The pendant furan of 267 was oxidatively opened to produce a dienophile, ultimately leading to tricycle 269. 1.6.2 Furan as a Precursor to Seven-Membered Carbocycles Two key methods for the converison of furan to seven-membered carbocycles have emerged, [4+3] reaction with oxyallyl cations and [5+2] reactions of oxidopyrylium ions. The intermolecular [4+3] methodology has found considerable application (Scheme 36).

Cha has used this strategy for the synthesis of tropoloisoquinolines and colchicines with the conversion of 270 to 271 as the key step. Wright used an intermolecular addition to annulated furan 272 to give 273, an


27

intermediate for erinacine C. Annulations on the oxabicyclo[3.2. ljoctene nucleus have also been shown as in Lautens' conversion of 274 by an anionic addition and by Cha in their formal total synthesis of phorbol. Harmata has used the intramolecular variation to give model compounds for ingenol and widdrol (Scheme 37).

Generation of a cyclic oxyallyl from 278 is followed by trapping with the pendant furan to give the iso-ingenane skeleton 279. A thiol substituted oxyallyl was generated from 280 and trapped in an intramolecular fashion to give 281 along with an equal amount of a diastereomer. As with [2.2.1] products, [3.2.1] products have also been converted to a cycloalkane and then on to acyclic products as exemplified by Vogel's synthesis of polyketide spiroketals and Lautens' synthesis of callystatin A (Scheme 38).

Vogel used a double cycloaddition to the bis-furylmethane 282 to ultimately give 283, a meso compound. Desymmetrization by an asymmetric dihydroxylation was followed by glycol cleavage to give 284. Lautens opened bicyclooctene 285 with a cerate followed by ozonolysis to produce 287, a key propionate synthon. One of the earliest applications of a [5+2J pyrylium ion cycloaddition was Wender's landmark synthesis of phorbol, recently executed in asymmetric form . Magnus has also used this approach in a synthesis of the cyathin skeleton (Scheme 39). In both cases, a central furan is oxidized, as previously described, to a hydropyrone which serves as a direct precursor to pyrylium ions 289/292 which are poised to undergo addition to the tethered olefins to give 290/293.

D.L. Wright

28

1.7

CONCLUSIONS

The power of furan has long been appreciated in target-oriented synthesis and more recently in diversity-oriented synthesis. Schreiber has made elegant use of the embedded diversity in this heterocycle to build complex, natural product-like libraries (Scheme 40).

Scheme 40 A library of resin bound furans 294-296 with diverse appendages were prepared and oxidized. Those furans with appended diols gave bicyclic acetals 297, those with a single alcohols the hydropyrones 298 that underwent dehydration and those without a hydroxyl gave the open-chain compounds, thus generating three structural types from a common intermediate. This last diversity-oreiented example nicely illustrates the synthetic flexibility and power offered by the use of furans. It is certain that the role of furan in complex-molecule synthesis will continue to expand in many new directions.

Furans as versatile synthons for target-oriented and diversity-oriented synthesis 1.8

29

ACKNOWLEDGMENTS

The author would like to thank the National Science Foundation and the Petroleum Research Fund for support of our program on the use of furans in synthesis. Professors Gordon Gribble, and Amy Anderson, Jeff Sperry and Jasmine Constanzo are thanked for careful editing of the manuscript.

1.9

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Furans as versatile synthons for target-oriented and diversity-oriented synthesis 02AG(E)3192 02AG(E)4560 02BMCL3271 02CEJ4255 02EJO1051 02H209 02H479 02JOC2919 02JOC3412 02JOC7361 02OL1515 02OL1771 02S1993 02T3801 02T5441 02T10469 02TL943 02TL1705 02TL4381 02TL4753 02TL9155 03ARK43 03BMC3261 03COC1443 03JA36 03JOC6847 03OBC3592 03OL941 03SCI613 03SL735 03T6819 O3T10181 03TL1161 03TL4467 03TL7411 03TL8227 04HCA1493 04H583 04JA9106 04JA14095 04JNP1039 04JOC6931 04OL465 04OL2189 04OL3241

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M. Shoji, J. Yamaguchi, H. Kakeya, H. Osada, Y. Hayashi, Angew. Chem. Int. Ed. 2002,41, 3192. L.C. Usher, M. Estrella-Jimenez, I. Ghiviriga, D.L. Wright, Angew. Chem. Int. Ed. 2002, 41, 4560. M. Takadoi, K. Yamaguchi, S. Terashima, Bioorg. Med. Chem. Lett. 2002, 12, 327]. S. Akai, T. Naka, S. Omura, K. Tanimoto, M. Imanishi, Y. Takebe, M. Matsugi, Y. Kita, Chem. Eur. J. 2002, 8,4255. S. Claeys, D. Van Haver, P.J. De Clereq, M. Milanesio, D. Viterbo, Eur. J. Org. Chem. 2002, 1051. T. Takahashi, Y. Yamakoshi, K. Okayama, J. Yamada, W.Y. Ge, T. Koizumi, Heterocycles 2002, 56, 209. O. Arjona, M.L. Leon, R. Menchaca, J. Plumet, Heterocycles 2002, 56, 479. J.L.G. Ruano, C. Alemparte, F.R. Clemente, L.G. Gutierrez, R. Gordillo, A.MM. Castro, J.H.R. Ramos, J. Org. Chem. 2002, 67, 2919. A. Padwa, J.D. Ginn, S.K. Bur, C.K. Eidell, S.M. Lynch, J. Org. Chem. 2002, 67, 3412. S.E. Wolkenberg, D.L. Boger, J. Org. Chem. 2002, 67, 7361. J.D. Ginn, A. Padwa, Org. Lett. 2002,4, 1515. M.H. Haukaas, G.A. O'Doherty, Org. Lett. 2002,4, 1771. M. Lautens, T.A. Stammers, Synthesis 2002, 1993. G.V.M. Sharma, V.G. Reddy, P.R. Krishna, A.R. Sankar, A.C. Kunvvar, Tetrahedron 2002, 58, 3801. J.E. Baldwin, P.G. Bulger, R. Marquez, Tetrahedron 2002, 58, 5441. P. Gupta, S.K. Singh, A. Pathak, B. Kundu, Tetrahedron 2002, 58, 10469. D.L. Wright, C.V. Robotham, K. Aboud, Tetrahedron Lett. 2002, 43, 943. M. Sakai, M. Sasaki, K. Tanino, M. Miyashita, Tetrahedron Lett. 2002, 43, 1705. Y. Kobayashi, Y.G. Wang, Tetrahedron Lett. 2002, 43,4381. V.O. Rogatchov, H. Bernsmann, P. Schwab, R. Frohlich, B. Wibbeling, P. Metz, Tetrahedron Lett. 2 0 0 2 , « , 4753. M. Shoji, S. Kishida, M. Takeda, H. Kakeya, H. Osada, Y. Hayashi, Tetrahedron Lett. 2002, 43, 9155. M. Towers, P.D. Woodgate, M.A. Brimble, Arkivoc 2003,43. T. Hjelmgaard, T. Persson, T.B. Rasmussen, M. Givskov, J. Nielsen, Bioorg. Med. Chem. 2003, //,3261. M. D'Auria, L. Emanuele, R. Racioppi, G. Romaniello, Curr. Org. Chem. 2003, 7, 1443. J. Mihelcic, K.D. Moeller, J. Am. Chem. Soc. 2003,125, 36. A. Toro, P. Deslongchamps, J. Org. Chem. 2003, 68, 6847. R.A. Tromp, J. Brussee, A. van der Gen, Org. Biomol. Chem. 2003,1, 3592. B. Nosse, R.B. Chhor, W.B. Jeong, C. Bohm, O. Reiser, Org. Lett. 2003, 5, 941. M.D. Burke, E.M. Berger, S.L. Schreiber, Science 2003, 302, 613. I.B. Masesane, P.G. Steel, Synlett 2003,735. S.M. Berberich, R.J. Cherney, J. Colucci, C. Courillon, L.S. Geraci, T.A. Kirkland, M.A. Marx, M.F. Schneider, S.F. Martin, Tetrahedron 2003, 59, 6819. J. Raczko, Tetrahedron 2003, 59, 10181. W.H. Miles, K.B. Connell, Tetrahedron Lett. 2003,44, 1161. Y. Fall, B. Vidal, D. Alonso, G. Gomez, Tetrahedron Lett. 2003, 44, 4467. A.R. Rodriguez, B.W. Spur, Tetrahedron Lett. 2003, 44,7411. U.M. Krishna, G.S.C. Srikanth, G.K. Trivedi, Tetrahedron Lett. 2003, 44, 8227. K. Meilert, G.R. Pettit, P. Vogel, Helv. Chim. Ada 2004, 87, 1493. M. Harmata, M. Kahraman, G. Adenu, C.L. Barnes, Heterocycles 2004, 62, 583. J. Mihelcic, K.D. Moeller, J. Am. Chem. Soc. 2004, 726, 9106. M.D. Burke, E.M. Berger, S.L. Schreiber, J. Am. Chem. Soc. 2004, 126, 14095. G.A. Kraus, J.Q. Wei, J. Nat. Prod. 2004, 67, 1039. P.M. Pelphrey, E.A. Abboud, D.L. Wright, J. Org. Chem. 2004, 69, 6931. T.J. Donohoe, J.W. Fisher, P.J. Edwards, Org. Lett. 2004, 6,465. Q. Wang, A. Padwa, Org. Lett. 2004, 6, 2189. J.M. Mejia-Oneto, A. Padwa, Org. Lett. 2004, 6, 3241.

32 04OL3861 04SL1259 04T11655 04TL5007 04TL5207 04TL6407 05OL27 05OL131 05OL387 05TL2789

D.L. Wright J. Robertson, P. Meo, J.W.P. Dallimore, B.M. Doyle, C. Hoarau, Org. Lett. 2004, 6, 3861. A. Moreno, M.V. Gomez, E. Vazquez, A. de la Hoz, A. Diaz-Ortiz, P. Prieto, J.A. Mayoral, E. Pires, Synlett 2004, 1259. P.H. Liang, J.P. Liu, L.W. Hsin, C.Y. Cheng, Tetrahedron 2004, 60, 11655. I.B. Masesane, P.G. Steel, Tetrahedron Lett. 2004,45, 5007. M. Perez, P. Canoa, G. Gomez, C. Teran, Y. Fall, Tetrahedron Lett. 2004, 45, 5207. M.S. Li, G.A. O'Doherty, Tetrahedron Lett. 2004,45, 6407. P.J. McDermott, R.A. Stockman, Org. Lett. 2005, 7, 27. Z.Q. Liu, J.D. Rainier, Org. Lett. 2005, 7, 131. J.D. Winkler, K. Oh, S.M. Asselin, Org. Lett. 2005, 7, 387. J.B. Sperry, J.R. Constanzo, R.J. Butcher, D.L. Wright, Tetrahedron Lett. 2005, 46, 2789.

33

Chapter 2 Synthesis and photochromic properties of naphthopyrans

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: b.m.heron(cbleeds.ac.uk

2.1

INTRODUCTION

The ring-chain tautomerism of 2//-pyrans (Scheme 1) is markedly influenced by substituents; 2//-pyran itself has still to be synthesised and yet 2//-[l]benzopyrans abound in nature. The ratio of tautomers in the equilibrium mixture is also affected by the prevailing conditions of temperature, light and solvent . The tautomers not only have different geometries but also different absorption spectra and other physical and chemical properties.

Photochromism, a phenomenon that is well documented and the subject of a number of reviews , is defined simply as the light-induced reversible transformation of a chemical entity into an isomeric species that has different absorption characteristics. In the case of the benzo- and naphthopyrans, the heterocycle is the stable colourless ground state that upon UV-excitation rapidly generates the ring-opened species that absorbs at longer wavelength, possibly in the visible region (Figure 1). On cessation of irradiation, the unstable acyclic species reverts over time to its original state. The weak photochromic behaviour of 2i/-[l]benzopyrans 1 associated with the electrocyclic ring-opening process, first noted by Becker , is enhanced on annulation of an additional benzene ring, with the ring-opened tautomer exhibiting both a more intense colour and having an increased lifetime. These desirable features are further improved by geminal diaryl substitution adjacent to the heteroatom and such naphthopyrans are currently the system of choice for imparting photochromic properties to a variety of polymeric host materials. These host materials are utilised for a range of variable optical

34

J.D. Hepworth and B.M. Heron

transmission devices, e.g. sun and contact lenses (ophthalmic and fashion), glazing (aerospace, automotive and building), agrochemical films, UV protection screens and assorted cosmetic and ink formulations, including security applications. The intense competition for new molecules with superior properties such as improved stability, optimised rate of fade (ring closure) and a wide colour range, has resulted in a proliferation of papers and patents describing the synthesis and photochromic properties of derivatives of the diaryl substituted naphthopyrans.

Figure 1 UV-visible spectrum of a 3,3-diaryl-3//-naphtho[2,l-&]pyran Of the three isomeric naphthopyrans 2 4, the linear isomer 2//-naphtho[2,3-6]pyran 4 displays no significant photochromic response at ambient temperature, a feature which may be rationalised by considering the extensive 7t-system reorganisation which must accompany an electrocyclic ring opening and which would disrupt the aromaticity of both rings of the naphthalene unit.

The angular isomers, 2 and 3, have received much attention since they display good photochromic properties in solution under ambient conditions. Further structural diversity has been achieved by the fusion of aromatic and heterocyclic moieties onto 2//-[l]benzopyran and the isomeric naphthopyrans. This review discusses the consequences of the reversible opening of the pyran ring in such compounds under the influence of UV-irradiation and draws together the information reported in the scientific and patent literature concerning the synthesis and photochromic properties of these molecules. Particular attention is paid to the

Synthesis and photochromic properties of naphthopyrans

35

fusion of heterocyelic rings on to the various faces of the diaryl substituted benzopyran unit 1 and the angular 3//-naphtho[2,l-6]pyran 2 and 2//-naphtho[l,2-6]pyran 3 units.

2.2

DISCUSSION

2.2.1

Synthesis of the diaryl substituted pyran ring

Routes to 2//-[l]benzopyrans have been reviewed and in many cases these methods are readily adaptable to naphthopyran synthesis. However, the specific interest here lies with naphthopyrans containing a gem diaryl unit, a substitution pattern that imposes restrictions on the synthetic approach. The classical reaction of aryl Grignard reagents with coumarins suffers from moderate yields and by-product formation when applied to naphthopyranones (benzocoumarins) 5 .

Similarly, the widely used route to 2,2-dialkyl- and 2-alkyl-2-aryl- benzopyrans by reduction and dehydration of dihydrobenzopyran-4-ones 6, readily available from 2'-hydroxyacetophenones and ketones , is not appropriate for the diaryl derivatives because of low yields even when /-butoxide is used as the condensing reagent .

Reagents: (i) R2C=O, PhMe, pyrrolidine, reflux; (ii) NaBH4, EtOH, reflux; (iii) 4-TsOH, PhMe, reflux

The compatibility of substituents to the organolithium reagent is the only limitation to the formation of benzopyrans by reaction of cc,p-unsaturated aldehydes with dilithiated o-bromophenols . This methodology has been adapted for the synthesis of a 2,2-diaryl-2//-naphtho[l,2-6]pyran (Scheme 2) . In a reversal of roles, a metallated heterocycle reacts with 2-hydroxy-l-naphthaldehyde to give naphthopyrans e.g. 7 (Scheme 3) .

36


Reagents: (i) 2 n-BuLi, RT, Et2O then p-phenylcinnamaldehyde; (ii) 4-TsOH, PhMe, 60 °C Scheme 2

Scheme 3

The reaction of titanium phenolates, derived from phenols and titanium(IV) ethoxide, with p-phenylcinnamaldehydes 8 (R2 = Ph) can be successful where other strategies fail. The extra effort involved in the synthesis of the cinnamaldehyde, of which relatively few structurally diverse aryl substituted examples are readily available, may be justified, as for example in their reaction with electron-deficient hydroxy-substituted heterocycles (Scheme 4) .

Scheme 4

The most expeditious route to diaryl substituted naphthopyrans that offers good flexibility is based upon the thermal rearrangement of naphthyl propargyl ethers 9 , derived from the alkylation of a naphthol with a haloalkyne, to substituted naphthopyrans 10 (Scheme 5) reported by Iwai and Ide . Catalysis by Cu(I) or (II) has been noted for the synthesis of aryl dimethylpropargyl ethers and zeolites facilitate the reaction of naphthols with 2-phenylbut-3-yn-2-oK97JOC7024>.

Reagents: (i) anhyd. K2CO3, Me 2 CO, reflux; (ii) /V./V-diethylaniline. reflux, 40 min. Scheme 5


37

In a substantially modified version of this protocol that yields diarylnaphthopyrans in a single step and in good yield , readily available 1,1-diarylprop-2-yn-l-ols , are heated with a naphthol in toluene containing an acidic catalyst that promotes the in situ formation of the naphthyl propargyl ether (Scheme 6). This protocol is suitable for hydroxy-substituted heterocyclic systems e.g. and has recently been adapted for the solid-state synthesis of naphthopyrans . However, it should be noted that interception of the intermediate carbocation by a nucleophilic C-site in the naphthol may result in the formation of propenylidenenaphthalenones 11 along with, or to the exclusion of, the naphthopyran O3EJ01220, 03TL1903>. A further development of this route incorporates (MeO)3CH as a dehydrating agent .

1,1 -Diarylprop-2-yn-l-ols condense with enolisable ketones under acidic catalysis to afford merocyanine dyes. Dehydrogenation with concomitant electrocyclisation of dye 12 affords the nanhthopvran .

Reagents: (i) 4-TsOH, PhMe, reflux (46%); (ii) p-chloranil, PhMe, reflux (36%)

The Stobbe condensation is particularly valuable in the synthesis of 1-naphthol derivatives and has been much used in the production of photochromic naphthopyrans. Its use in the synthesis of phenanthropyrans is illustrative (Scheme 7). The half ester formed from the reaction of dimethyl succinate with either a naphthaldehyde or naphthyl ketone is cyclised to the phenanthroate and thence hydrolysed to the l-hydroxy-3-methoxycarbonylphenanthrene. Propargylation then leads to the phenanthropyrans, which on irradiation exhibit two absorption bands in the range 420 - 480 and 490 - 580 nm .

38


Reagents: (i) dimethyl succinate, NaH, PhMe, RT; (ii) NaOAc, Ac2O, reflux; (iii) MeOH, c. HCI; (iv) 1,1-diphenylprop-2-yn-1-ol, dodecylbenzenesulfonic acid, PhMe, 35 °C Scheme 7

2.2.2

Photochromic Properties

The photochromic characteristics of a compound are usually measured in terms of Xmax of the ring opened and closed forms and the induced optical density of the coloured (ring opened) species at its Xmax (colourability) achieved after irradiation to constant value and at a specified temperature. The speed of the backward reaction (ring closure) is measured by recording the loss of colour with time, reporting the data as tic, the time in seconds required for the sample to return to half the optical density of the equilibrium value . The ideal combination of photochromic properties required for variable optical transmission devices is intense colour generation with a reasonably rapid rate of fade (bleaching) at ambient temperatures. It is also important that the compound exhibits good fatigue resistance; the ring-opening - ring-closing cycle must be repeatable many times (> 106) without loss of performance. It should be noted that the medium in which the photochrome is dissolved or dispersed can exert a significant effect on these properties. Thus, some photochromic naphthopyrans exhibit solvatochromism . More significant is the influence of a polymer matrix, which in addition to causing minor shifts in X.max generally hinder ring closure, thereby increasing X\a . The thermal fading of naphthopyrans is also slowed down by more viscous solvents. It is suggested that the substituted ethenyl group changes its position in the solvent sphere while the naphthalene unit remains in the same position during cyclisation . The addition of epoxy compounds during the manufacture of photochromic ophthalmic lenses can have a beneficial effect on the kinetic performance of the photochromes . The photochromic process for the naphthopyrans involves initial photolytic cleavage of the O-C bond that leads to the generation of two coloured ring-opened structures, a cis-trans (CT) and a trans-trans (TT) merocyanine, of which the latter is the more stable (Scheme 8) . PPPMO calculations predict the absorption characteristics of 3//-naphtho[2,l-6]pyrans in better agreement with the experimental values when TT geometry is assumed . The trans -» cis conversion is slower than the thermal ring closure of the CT form but is accelerated by irradiation with visible light. Consequently, after a fast initial fade, some colour remains for an appreciable time with certain photochromes. The photochemical behaviour of a TT merocyanine has been described . The isomers of the ring-opened 3,3-bis(4fluorophenyl)-3//-naphtho[2,l-6]pyran have been studied by 19F NMR spectroscopy and comprehensive NMR data are available for a range of naphthopyrans . NMR studies indicate the involvement of an o-allenylnaphthol 13 derived by a 1,5-H shift from the dienone isomers in the photochemical and thermal


39

processes O20L3143, 03TL259>. The involvement of the CT and TT isomers in the solid state photochromism of some 3//-naphtho[2,l-6]pyrans has been observed .

A study of the racemisation of chiral 2-aryl-2-methylnaphthopyrans and hetero fused benzopyrans proceeding through thermal cleavage of the O-C2 bond has indicated that AG* decreases with the electron donating power of a 4-substituent in the pendant phenyl ring in naphtho[l,2-6]pyrans. Presumably the transition state for thermal ring opening is stabilised by the additional conjugation with the substituent. Similarly, fusion of an additional benzene ring, giving the phenanthropyran, has a stabilising influence such that AG* is reduced. Conversely, fusion of either a benzene or a pyridine ring on to 2//-[l]benzopyran has little effect on AG* irrespective of the site of fusion. There appears to be a correlation between AG* and the calculated 7t-bond order for the fusion bond between the pyran and benzene rings; the more electron-rich the bond, the lower is AG* . 2.2.2.1

3i/-Naphtho[2,l-6]pyrans

The photochromic response of the angular 3i/-naphtho[2,l-6]pyran isomer 2, is typically characterised by the production of a weak colour associated with the photochemically induced electrocyclic ring opening of the colourless pyran ring to a coloured quinoidal form on irradiation with UV light (Scheme 8). The photogenerated yellow colour rapidly fades giving the overall impression of a weakly colouring molecule, e.g. for 2 Ar = Ph, X.max = 432 run with ti/2~ 45 s [(diethyleneglycol bis(allyl carbonate)] . Through judicious choice of substituents, the performance of the 3//-naphtho[2,l-6]pyran system can be significantly improved. The data in Table 1 illustrate the effect of substitution in the phenyl rings at the 3-position. Generally, electron-releasing groups at the para positions bring about a red shift of the absorption band and this is accompanied by an increase in the fade rate. Electron-withdrawing groups cause a blue shift and slow the rate of fade to some extent. The major effect arises from substitution at the ortho positions, when a pronounced increase in tin is observed . The lifetime of the open form increases with increasing size of the ortho substituent . Table 2 shows the response to substitution around the periphery of the molecule. The data for the methoxy derivatives indicate the importance of a donor substituent at the 6- or 8-positions for manipulating ?vmax . Dramatic increases in colourability follow the introduction of a 6-MeO or, better, a 6-amino function and this combined with an appropriate choice of an amino group in the para position of the 3-aryl rings enables intensely coloured yellow, orange and red photochromes to be produced .

40


1

R H H p-MeO p-Y H p-MeO />-NMe2

Table 1 (R3 = H)+ R2 ^-max (nm) H 430 p-MeO 458 />-MeO 475 428 P-F 422 p-CFj 512 p-NMe2 544 »-NMe2

Table 2 (R1 = R2 = H) { R3 X.max (nm) 5-MeO 435 6-MeO 423 7-MeO 435 8-MeO 477 9-MeO 432 10-MeO -

Notes: +Data recorded for PhMe solutions ;{ Data recorded for aliphatic acrylic polymer

2.2.2.2

2i/-Naphtho[l,2-6]pyrans

In contrast to the [2,1-6] isomer, 2//-naphtho[l,2-6]pyran 3, develops an intense colour, with >^max bathochromically shifted by ca. 45 nm relative to 3//-naphtho[2,l-6]pyran, and which persists for a much longer period of time e.g. for 3 Ar = Ph, \ ma x ~ 476 nm; \m > 1800 s [(diethyleneglycol bis(allyl carbonate)] . The differing rates of fade of the photoisomers of 2 and 3 have been attributed to the more significant steric interactions between 1-H and 10-H in the photoisomer of 2 compared with those between 4-H and 5-H in the photoisomer of 3 (Scheme 9) .

In an attempt to mimic the steric interactions present in the photoisomer of 2, substituents were introduced at the 5- and 6-positions of 3. These structural changes reported in a Research Disclosure promoted a faster ring closure and represented a significant


41

breakthrough in the commercialisation of photochromic naphthopyrans. Thus intense colour generation combined with an optimum rate of fade was achieved with compounds of the type 14, which on irradiation in toluene has Twx = 492 nm and ti/2 = 66 s. Further examples are given in Table 3.

Table 3 R1 CO2Et CO2Me CO2Et CO2Me CO2Et CO2Me CO2Me

R2 H 6-MeO 7-MeO 8-MeO 9-MeO 10-MeO 6-Me

âxCnm)* 493 502 [510]* 508 480 505 485 [505]'

t (s) 3 73 [305]' 3 11 3 21 [217]'

Notes: fData recorded for PhMe solutions ; [ ]' Data recorded for polymethacrylate

The response to substituents in different positions of the naphthalene unit is shown in Table 3. A methoxy group can bring about either a bathochromic or hypsochromic shift in Xmax and slows the fade rate when in the 6-, 8- or 10-positions . These data also illustrate the effect of the matrix on the photochromism. Incorporation into a polymer has a small effect on Xm?lX but slows the rate of fade considerably as molecular movement is restricted, hindering the bond rotation necessary for ring closure. 2.3

FUSED AND LINKED HETEROCYCLIC DERIVATIVES

A variety of heterocyclic rings have been incorporated into the benzopyran system either as substituents at the critical sp3 hybridised centre adjacent to the O heteroatom or around the periphery of the molecule. In a different vein, heterocycles have been fused onto both benzoand naphthopyrans. Aspects of the synthesis of these compounds and the influences of the new heterocyclic moiety on the photochromic properties are discussed. 2.3.1

Naphthopyrans with heterocyclic substituents

The synthesis of l-heteroaryl-l-arylprop-2-yn-l-ols or the 1,1-diheteroaryl analogues is fundamental to the introduction of a heteroeyele into the gem diaryl unit of the naphthopyran isomers. The route is outlined in Scheme 10; small variations are encountered in the technique used for the nucleophilic attack of the alkyne unit on the carbonyl substrate . The data in Table 4 indicate that red shifts of ?>-max follow the introduction of furyl, thienyl and 2,2-bithienyl groups at C-3 of 3Hnaphtho[2,l -6]pyrans.

42


Reagents: (i) n-BuLi, TMS-acetylene, THF, 0 °C - RT, N2; (ii) either KOH, MeOH, THF, RT orTBAF, THF, RT; (iii) Na-acetylide, xylene, mineral oil, 30 °C, N2 Scheme 10

Application of Suzuki cross-coupling methodology to thiophene boronates and bromo- or triflate-functionalised naphthols or naphthopyrans affords (2-thienyl)n derivatives of 3,3-diphenyl-3//-naphtho[2,l-&]pyrans (Scheme 11) .

Ar1 4-MeOC6H4 4-MeOC6H4 4-MeOC6H4 2-thienyl 2-thienyl 4-MeOC6H4 2-furyl 2-furyl 2-(7V-methyl)pyrrolyl

Table 4 Amax (nm) PhMe Ar2 475 4-MeOC6H4 2-thienyl 476 511 2,2-bithienyl 472 2-thienyl 2,2-bithienyl 510 468 2-furyl 2-furyl 466 2-thienyl 464 2-naphthyl 486

Reference

Pd-catalysed cross coupling also effects the conversion of triflates of naphtho[2,l6]pyrans into the iV-methylpiperazino derivatives. A bathochromic shift of ca. 80 nm is observed for the 8-substituted compound but an amino function in the 9-position has little influence on Km!lx . Stille coupling of stannylthiophenes with 3-(4-methoxyphenyl)-3-(5-bromothien-2yl)naphtho[2,l-6]pyran has been used to form photochromic ter- and quaterthiophenes 15, the open forms of which show enhanced conductivity . Transition metal promoted coupling also features in the synthesis of naphtho[2,l-6]pyrans 16 linked to thiophene units through an alkyne function. Apart from a shift in the absorption maximum,


43

these compounds have similar photochromic properties to the simple 3,3-diphenyl derivative . However, when two naphthopyran units are connected at the 3-positions through a 5,5'-(2,2'-bithienyl) moiety the pyran rings are opened sequentially on irradiation at 366 nm. Initial ring opening generates an absorption band at 517 nm which dies away with time to be replaced by a new stronger band at 580 nm (Scheme 12) . When the two naphthopyran units are linked by an ethyne - thiophene - ethyne bridge, fluorescence and intersystem crossing are in competition with photochromism. Irradiation rapidly results in the opening of one pyran ring (Xmax 480 nm) and after prolonged irradiation at 228 K the second ring opens (K,^ 550 nm) .

Scheme 12

The reaction of 9-ethynyl-9//-thioxanthenol, obtained from thioxanthone, with 1 - and 2naphthols leads to spiro[naphthopyran-thioxanthenes] 17 and 18, respectively. Linking the gem phenyl groups with a sulfur bridge results in a significant red shift in Xmax and interestingly those compounds derived from 1-naphthol show only one absorption band unlike 2,2-diphenyl-3//-naphtho[l,2-6]pyran. Additionally, both naphthopyran series exhibit faster fading than the simple diphenyl analogues, but they do show good fatigue resistance . Spiro[fluorenopyran-thioxanthenes] 19 that result from the reaction of the 9-ethynyl-9//-thioxanthenol with fluorenols are not only weakly colouring but also degrade upon UV irradiation . Further elaboration of this system includes spiro[naphthopyran-thioxanthenes] 20 derived from indeno-fused naphthols, the photochromic properties of which support the view that the S bridge increases the participation of the gem diphenyl group in the it-system. These molecules are fast fading and only weakly colouring .

44


17 X max =510nm (PhMe)

18 ^max = 490 nm (PhWle)

2.3.2

Hetero-fused 2/J-[l]benzopyrans

2.3.2.1

5-Membered rings

(PhMe)

20 X max = 552 nm (PhMe)

The use of hydroxy derivatives of five-membered benzo-fused heterocycles in place of naphthols in both the Iwai-Ide and Ti(OEt)4 syntheses of benzopyrans leads to hetero-fused 2//-[l]benzopyrans. Initial details of the formation and properties of the furo-, thieno- and their benzologues and indolo-fused benzopyrans appeared in the patent literature . The major consequence of fusion of a 5-membered ring is the extensive broadening or splitting of the absorption into two bands, a feature not observed with naphtho[2,l-6]pyrans but seen in the [1,2-6] isomer. 2.3.2.1.1 5-Membered heterocyclic rings fused across the/-face Only the angular thienobenzopyrans 21 and 22 R = H were isolated on propargylation of 5- and 6-hydroxy-2,3-dimethylbenzothiophenes with l,l-diarylprop-2-yn-l-ols . The spectra of the ring-opened form arising from irradiation of the thieno[2,3-/][l]benzopyran 22 shows two absorption maxima (>^ ax 452 and 542 nm) of similar intensity. The sulfur atom causes a 20 nm red shift of the lower wavelength band relative to 3,3-diphenyl-3//-naphtho[2,1-6]pyran. In the case of the thieno[3,2/][l]benzopyran 21, there is no shift of the lower wavelength band on which a shoulder appears at ca. 519 nm. Both of the/-fused analogues show enhanced fading relative to the hfused isomers in keeping with the difference between the naphtho[2,l-6] and [l,2-6]pyrans. A 5-methyl group, introduced to direct the chromenylation reaction to give the angular thieno[2,3-/|[l]benzopyran 22, R = Me, brings about red shifts of the order of 10 nm of both absorption bands and a small increase in colourability . The/ 1 fused benzothienobenzopyrans show two absorption bands and these are red-shifted relative to the corresponding naphthopyrans. A greater red shift but poorer colourability and increased stability of the open form are shown by the [2,3-/] 23 than by the [3,2-/] 24 isomer which were synthesised from the hydroxydibenzothiophene by the Ti-promoted and propargylation routes, respectively .


45

Furobenzopyrans are derived from hydroxybenzofurans using the Iwai-Ide route. However, the cyclisation is not regiospecific unless a blocking substituent is employed, and generally a mixture of angular and linear products results that is not always readily separable . The two isomers are easily distinguished by NMR spectroscopy with the angular isomer displaying a pair of doublets associated with H-5 and H-6. The linear isomer shows two singlets assigned to H-5 and H-l 1 in the region 8 6.8 to 7.1. The approach using 3-phenylcinnamaldehyde and Ti(OEt)4 is regiospecific and is preferred in some cases . Both the angular and linear isomers show two absorption bands on irradiation, Xmstx ca. 420 and 520 - 550 nm, and as a result appear brown. The lower absorption is the stronger but is blue shifted relative to the corresponding naphtho[2,lfr]pyran, although Japanese work mentions only one band for a 3-naphthyl-3-phenyl derivative of both the/- and h-fused compounds . Annulation of a benzene ring on to the b-face of furo[3,2-/]benzopyran increases the colourability and the rate of fade. Interestingly, fusion of a cyclohexane and a cycloheptane ring has a similar effect on the colour intensity but bleaching occurs at a similar rate to the parent naphtho[2,l-6]pyran . 6 H 7.0, s

Hydroxydibenzofurans also yield a mixture of isomers on chromenylation in which the angular isomer predominates. The products show two broad absorption bands and incorporated into a polyurethane film they colour to various shades of brown and olive green on irradiation .

46


3-Aryl-3-heteroaryl derivatives have been obtained through reaction of hydroxydibenzofurans and -thiophenes with l-aryl-l-(benzofur-2-yl)prop-2-yn-l-ol and the analogous benzothienyl alkynol. The resulting mixtures of [l]benzofuro[2,3-g][l]benzopyrans and the [3,2-/| isomer exhibit two absorption bands, both of which are red-shifted relative to the 3,3-diphenyl derivative but are weakly colouring and slower to fade . The hydroxydibenzofurans and analogous thiophene derivatives are accessible from trihydroxybiphenyls through cyclisation with KOH or P4S10, respectively and the hydroxybenzo[6]naphtho[. The introduction of a N heteroatom into the 3//-naphtho[2,l-6]pyran system has been achieved by reaction of the appropriate heterocyclic phenol with 3-phenylpropenal in the presence of Ti(OEt)4. The heteroatom causes small red shifts of the merocyanine absorption band but more significant changes are observed in the colourability. Thus the photochromes derived formally from isoquinoline and quinazoline are more intense and it appears that a N atom at the 9-position of the naphthopyran plays a major role in colour development. It is also noteworthy that these two compounds exhibit faster fading than the other derivatives and enhanced fatigue resistance . In a more polar solvent, ethanol instead of toluene, all the compounds exhibit small red shifts of Xmax, suggesting a quinoidal rather than a zwitterionic structure for the open form, and fading is faster . Examples containing a 3-naphthyl-3-phenyl unit, prepared by the propargylation route, show similar photochromic behaviour with ti/2 of ca. 45 s .

2.3.2.2.2 6-Membered heterocyclic rings fused across the g-face. Fusion of a 2,2-diarylpyran ring onto a diarylbenzopyran presents a special type of structure in which both pyran rings have the potential to open under the influence of UV light. Reaction of 1,4-dihydroxybenzene with various l,l-diarylprop-2-yn-l-ols affords pyrano-[2,3-g][l]benzopyrans e.g. 39. These compounds absorb at 430 - 460 nm and 520 560 nm in chloroform, giving the solutions a grey colour, attributed by the authors to the presence of more than one isomer in the product. Half-lives are between 7 and 24 seconds . In contrast, naphthodipyrans e.g. 40 derived from 2,6-dihydroxynaphthalene exhibit only one absorption band which is red-shifted 10 - 20 nm relative to 8-methoxy-3,3-diphenylnaphtho[2,l-6]pyran and are weak colouring . The


51

isomeric naphthodipyran 41 derived from 1,5-dihydroxynaphthalene is slower to fade with Xmax 508 nm (ethyl cellulose) .

The linear pyrano[3,2-g][l]benzopyran-2-one 42 R = H is the major product from the reaction of 7-hydroxycoumarin with l,l-diphenylprop-2-yn-l-ol and surprisingly in view of the lack of photochromism in the comparable linear 2//-naphtho[3,2-6]pyran it becomes quite strongly coloured on irradiation at room temperature. Fading is moderately fast indicating reasonable stability for the open form. This molecule also exhibits good fluorescence with an emission band at 396 nm but this appears to have no influence on the photochromic properties . Significant red shifts, ca. 40 nm, and pronounced increases in intensity follow the incorporation of either an ester or a carboxyl group at the 3-position of the pyranobenzopyranones e.g. 42 R = CCÊt. The enhanced colourability is particularly interesting in view of the fast fading shown by these compounds . Another structural variation follows from the use of benzo[£,/]xanthen-3-ol as the propargylation substrate (Scheme 14). The resulting [l]benzopyrano[6,7,8-A:,Z]xanthenes fade faster than the analogous 5,6-dimethyl-2//-naphtho[l,2-6]pyran and absorb some 70 nm to the red; 43 is violet in THF .

Reagents: (i) ethyl cyanoacetate, NH4OAc, AcOH, PhMe, reflux; (ii) 200 °C; 43 (iii) NaOH, 210 °C, 30 bar; (iv) 1,1-bis(4-methoxyphenyl)prop-2-yn-1-ol, BrCH2CO2H, xylene, reflux. Scheme 14

2.3.2.2.3 6-Membered heterocyclic ring fused across the A-face. Fusion of a pyranone ring across the /2-face (7,8-bond) of 2,2-diphenylbenzopyran, achieved by propargylation of 5-hydroxycoumarin, modifies the photochromic properties relative to the corresponding 2//-naphtho[l,2-fr]pyran. The absorption bands, red shifted to 420 and 512 nm from 403 and 481 nm, are of lower intensity and bleaching to the closed form is significantly faster . The pyrano[3,2-c]xanthen-7-one exhibits the two absorption bands associated with a heteroatom at a peri position of the benzopyran nucleus. Pyrano[2,3-a]xanthen-12-one 44, in which the fusion of the chromone ring is reversed, shows an intense single band blue-shifted some 14 nm relative to 2,2-diphenyl-2//-naphtho[l,2-6]pyran [>wx 403, 482 nm (PhMe)]. Both isomers are readily degraded . It is noteworthy that 44 could not be

52


obtained directly from 1 -hydroxyxanthone by the preferred alkynol route and instead the 9Hxanthen-1-ol was employed with a subsequent oxidation step (Scheme 15). 2,2-Diphenyl-2//-pyrano[2,3-/|isoquinoline, derived from 5-hydroxyisoquinoline, exhibits very similar photochromism to 2//-naphtho[l,2-fe]pyran .

Reagents: (i) LiAIH4, PhH, Et2O, Ar, reflux (56%); (ii) 1,1-diphenylprop-2-yn-1-ol, PPTS, CHCI3, Ar, reflux (63%); (iii) CrO3, py, RT (58%) Scheme 15

2.3.3

Hetero-fused naphthopyrans

In both the naphtho[2,l-6]pyran and the [1,2-6] series there are three sites for fusion of a heterocyclic ring on the benzene ring remote from the pyran unit. However, because of the greater photochromic activity of naphthopyrans compared with benzopyrans, such fusion has a reduced influence on the photochromic properties than so far encountered. A further mode of ring fusion is also possible exemplified by structure 48. 2.3.3.1

5-Membered rings

Dihydrofuro[2,3-Z>]naphthols, derived from 3,7-dihydroxy-2-naphthoic acids are sources of hetero-fused naphtho[2,l-6]pyrans through reaction with propynols. The oxacyclic substituent is equivalent to an alkoxy group and in the only data provided, the /-fused dihydrofuran derivative 45 exhibits a 9 nm red shift to 481 run compared with the 8-methoxy analogue 46 .

Construction of a side-chain onto 6-bromo-2-naphthol allows the formation of naphtho[2,l-ft]furan-6-ols and hence furo[3,2-/]naphtho[2,l-6]pyrans 47. Compared with the analogous 8-methoxynaphthopyran, >âx for both the closed and open forms of these compounds are further to the red. The intense colouring molecules have half-lives of the order of 2 minutes . Fusion of a benzofuran ring across the 5,6-bond (/"face) of naphtho[l,2-£]pyrans to afford 48 brings about a red shift > 20 nm of the higher absorption band. The synthesis involves reaction of naphthoquinone with a methoxyphenol and subsequent propargylation of the resulting naphtho[l,2-6][l]benzofuran. The benzofuran is effectively acting as the bulky 5-


53

and 6-substituents necessary to speed up the fade rate of naphtho[l,2-6]pyrans. Nevertheless, red shifts are observed relative to the 5,6-dimethylnaphthopyran 14 with slightly slower fade kinetics . In like manner, reaction of naphthoquinone with naphthols affords dinaphthofurans from which two differently fused naphthofuronaphtho[l,2-&]pyrans have been obtained (Scheme 16) which have A.max at 512 nm and 583 nm but of only moderate intensity and with half-lives of 34 s and 125 s, respectively .

Reagents: (i) 1,3-dihydroxynaphthalene, AcOH, H2SO4, reflux; (ii) MeOH, H2SO4, reflux; (iii) 1,1-bis(4-methoxyphenyl)prop-2-yn-1-ol, 4-TsOH, PhMe; (iv) 2-naphthol, AcOH, H2SO4, reflux Scheme 16

Application of the Stobbe reaction to 2-benzoyldibenzofuran gives access to two substituted 1-naphthols 49 and 50 which after cyclisation and possible further manipulation are substrates for pyran formation with l,l-diphenylprop-2-yn-l-ol (Scheme 17). The resulting heptacyclic photochromes absorb in the range 570 - 600 nm with half-lives of 20 70 s .

Hydrolysis of the ester functions of dimethyl 2,2-bis(4-methoxyphenyl)-2//-naphtho[l,26]pyran-5,6-dicarboxylate and cyclisation of the resulting diearboxylic acid yields the cyclic anhydride 51. Reduction affords a mixture of two isomerie furano-fused naphthopyrans. Treatment of the anhydride with primary amines provides a route to the corresponding pyrrole derivatives. Both types of hetero-fused naphthopyrans show a red shift relative to the starting naphthopyran diester and reduced half-lives .

54


A 7-methylene-5-oxofuro[3,4-/]naphtho[l,2-6]pyran has been obtained via reaction of a 6-methoxy-5-methoxycarbonylnaphthopyran with a vinyl Grignard derivative and subsequent Pd-catalysed cyclisation .

Reagents: (i) CH 2 =CHMgBr, THF, RT; (ii) KOH, EtOH, reflux; (iii) Pd(OAc) 2 , NaOAc, DMSO, RT

More complex structures can be derived from 1-tetralone through its conversion to (tetrahydro-l-oxo-2-naphthyl)ethanoic acid and subsequent reaction with a heteroaryllithium. Sequential cyclisation to the dibenzofuran or thiophene and propargylation affords fast fading 3,4-dihydronaphtho[2,l-/|[l]benzofuro[2,3-/!]naphtho[l,2-6]pyrans and thiophene analogues .

The fast fade rate shown by 2-(4-trifluoromethyl)-2-phenyl-5-trifluorophenyl[l]benzofuran[2,3-/]naphtho[l,2-6]pyran is attributable to the bulky 5-substituent rather than to the fused benzofuran ring . Its synthesis follows from the preparation of 9-hydroxy-7-trifluoromethylbenzo[6]naphtho[fi?]furan from 4-chloromethyldibenzofuran (Scheme 18).

Reagents: (i) THF, 0 °C, N 2 then AcOH; (ii) KOH, EtOH, reflux; (iii) Ac 2 O, NaOAc, reflux then KOH, EtOH; (iv) dodecylsulfonic acid, 1,1-diarylprop-2-yn-1-ol, xylene, reflux Scheme 18

55


A variety of substituted dihydrofuro[2,3-fr]naphth-l-ols have been derived from 2,3-dihydrobenzofuran and converted into furo[3,2-j']naphtho[l,2-Z>]pyrans e.g. 52, the open forms of which absorb at 420 - 440 nm and 530 - 540 nm. The former band is the more intense and so these intensely colouring molecules appear brown . Ar

3 7

Th

Ar = 4-MeOC6H4 Xmax = 440, 540 nm (polyurethane) 52

Ar

Ari

Ar2

>=
]furan-12-ols from which dihydrofuro[2,3-6]indeno[3,2-/]naphtho[l,2-6]pyrans 53 have been obtained by propargylation. The consequence of incorporating the O atom in a ring relative to its presence in a methoxy group is a small red shift of both absorption bands . A number of naphtho[l,2-6]furan-6-ols, hetero-fused 1-naphthols, have been synthesised using the Stobbe condensation and converted into the furo[2,3-;']naphtho[l,2-6]pyran 54 by reaction with a propynol. Provided that an amino function is present in one of the 2,2-diaryl units, irradiation in toluene generates blue merocyanines, Xmax 480 - 490 nm and 575 - 590 nm, which are strongly coloured and have half-lives of 30 - 60 s . The 8,9-methylenedioxy- and 8,9-ethylenedioxy-naphtho[l,2-fr]pyrans have been obtained using the same methodology. They exhibit similar photochromic properties. The reaction of 3-aminoprop-2-enoates with 1,4-naphthoquinone affords 5-hydroxybenzo[g]indoles and hence offers access to pyrano[3,2-e]benzo[g]indoles that become strongly red coloured on irradiation with half-lives similar to the analogous 5,6-dimethylnaphtho-[l,2-6]pyran 14 (Scheme 19) . Ar Ar \y O ' I I

OH

9

CO Et

S^S\

if

CO+ H ^ X U

h

p

1

(i)

f^V^S

(ii)

/.

1

I

Wyco,a — OCX "-< Ph'

^max= 516 nm,

t1/2=40s(THF)

^^fyco2Et

\

N~^ Ph' \ Reagents: (i) MeNO2, 40 °C (56%); (ii) 1,1-bis(4-methoxyphenyl)prop-2-yn-1-ol, cat. BrCH2CO2H, xylene, reflux (70%) Scheme 19

The synthesis of a 2-hydroxybenzo[c]carbazole involves a Curtius reaction and carbazole formation by photolytic decomposition of an azide as shown in Scheme 20. Subsequent reaction with a propynol leads to an^fused indole derivative of naphtho[l,2-6]pyran which absorbs further to the red than both 14 and the pyrrole derivatives in Scheme 19 . Absorption bands are shifted to the red when amino substituents are

56


introduced into the diaryl unit of this and the isomeric/fused indole derivatives, but the halflives are between 2 and 3 minutes . OAc

OAc

r

OAc

f ^ Y i (i)'(ii,) ^ i f n (iii) ^NpCO2H Â^NH2

r

^ | f l (iV)"(Vii) ^ ^ J ^ J ^ M " N 3 OCX

Reagents: (i) (PhO)2P(O)N3, Et 3 N, PhMe, then f-BuOH, reflux; (ii) TFA, CH2CI2, PhMe; (iii) NaNO2, HCI, Me2CO then NaN3; (iv) irradiation (254 and 365 nm), THF, 4 days; (v) NaOH, THF; (vi) 1,1-bis(4-methoxyphenyl)prop-2-yn-1-ol, BrCH2CO2H, PhMe, reflux; (vii) NaH, Mel, THF Scheme 20

2.3.3.2

>/

^

_452 564 nm _ '36 s (polymethacrylate)

max

(

6-Membered rings

6-Bromo-2-naphthol is a source of 8-hydroxynaphtho[2,l-6]pyrans from which pyrano[3,2-z']naphtho[2,l-£]pyrans are formed on reaction with a l,l-diarylprop-2-yn-l-ol. These molecules absorb at ca. 390 nm in the UV and at ca. 490 nm following irradiation . The 4//-naphtho[2,l-c]pyran-4-one 55 obtained by reaction of methyl l-hydroxy-3naphthoate with a propynol readily undergoes a second propargylation to give, after further manipulation, pyranonaphtho[l,2-6]pyrans which absorb in the region 521 - 592 nm with moderate bleaching kinetics . Various benzopyran-fused derivatives and their [2,1-i] analogues have been obtained from hydroxy-substituted dibenzo-fused benzopyranones and these generate colours from yellow through to blue on irradiation with half-lives of a few seconds to several minutes . OAc

f^Tl

OAc

(i)

^V-CO2H

' ("I ^ ] T i

Af

OAc

(iii)

ÂA N H 2

, f**^|fi

(iv) (vii)

^Y^N

Reagents: (i) (PhO)2P(O)N3, Et 3 N, PhMe, then f-BuOH, reflux; (ii) TFA, CH2CI2, PhMe; (iii) NaNO2, HCI, Me2CO then NaN3; (iv) irradiation (254 and 365 nm), THF, 4 days; (v) NaOH, THF; (vi) 1,1-bis(4-methoxyphenyl)prop-2-yn-1-ol, BrCH2CO2H, PhMe, reflux; (vii) NaH, Mel, THF Scheme 20

'

^^Lj

r

3

>/r

OCX x

_452 564 nm , _ g6 s (Dolvmethacrvlate)

max

Methyl 10-hydroxybenzo[6]naphtho[2,3-e][l,4]dioxine-8-carboxylate, synthesised from the reaction of 1,2-dihydroxybenzene and 3,4-difluorobenzaldehyde and subsequent Stobbe condensation, is a source of [l,4]benzodioxinonaphtho[l,2-fr]pyrans. Similarly, using 2-benzoyl[l,4]benzodioxine in the Stobbe reaction enables indeno analogues to be obtained (Scheme 21) . With appropriate gem diaryl substitution in the pyran ring, these molecules show two absorption peaks between 440 - 610 nm and are fast fading.


57

Reagents: (i) KOf-Bu, dimethyl succinate, PhMe, reflux; (ii) Ac2O, KOAc, reflux; (iii) aq. NaOH, MeOH, reflux; (iv) 4-TsOH, PhMe, reflux; (v) 1,1-bis(4-methoxyphenyl)prop-2-yn-1-ol, 4-TsOH, PhMe, reflux; (vi) PhMgBr, THF S c h e m e 2 1

Incorporation of a 6-hydroxy or a 6-methoxy group together with a 5-ester function into the naphtho[l,2-6]pyran system allows elaboration to/-fused heterocyclic derivatives (Scheme 22). Thus reaction of 56 (R1 = Ph, R2 = H) with an aldehyde in the presence of a base leads to the dioxinone 57 and with benzimidine to give a l,3-oxazin-4one 58 . The structurally related oxazine 59 and pyrimidine 60 derivatives result from the reaction of 56 (R1 = Me, R2 = H) with an isocyanate and 56 (R1 = R2 = Me) with an imino Grignard reagent, respectively. The analogous pyrano-fused product 61 is obtained from reaction with a vinylic Grignard reagent and cyclisation of the enoate with TMSC1 . For a series of 2,2-diphenyl derivatives, the fused pyrimidine absorbs at the highest wavelength (512 nm) with the other heterocyclic analogues absorbing in the range 460 - 478 nm.

5-Methoxy-6-methoxycarbonylnaphthopyrans react with the THP-protected Grignard reagent to give benzopyranone-fused naphtho[l,2-6]pyrans 62 (Scheme 23). In a related

58


manner, both 7-methoxy-8-methoxycarbonyl- and 8-methoxy-9-methoxycarbonylnaphtho[2,l-6]pyrans yield benzopyranone-fused naphtho[2,l-&]pyrans. Propargylation of the naphthol derived from the reductive cyclisation of 2-(2-methoxycarbonylphenyl)-l,4naphthoquinone gives access to further examples of benzopyran-fused naphthopyrans . The complex spiro hetero-/-fused naphtho[l,2-6]pyrans e.g. 63 show two absorption bands (444 - 474 and 568 - 582 nm) and have half-lives of 2 - 3 minutes . The synthesis of 4-acetoxy-l-phenyl-2-naphthylamine from 4-hydroxy-lphenylnaphthalene-3-carboxylic acid allows annulation of an isoquinoline unit onto 1naphthol and subsequent reaction with a propynol yields the fused pyranophenanthridine 64, Xmax 550 nm, t, /2 = 12 s (polymethacrylate) .

3//-Naphtho[2,l-£>]pyrans with piperidine, pyrazine, oxazine and quinolizine fused across the i and/or j faces, e.g. 65, have been claimed but neither synthetic nor spectroscopic data were provided . Quinolizine fused naphthopyrans 66 absorb between 522 and 588 nm depending upon the aryl substituents and have tm of 2 - 3 minutes .

2.4

CONCLUSIONS

The angular diaryl substituted naphthopyrans 2 and 3 are firmly established as the dominant heterocyclic systems for imparting a photochromic effect into a host object. The ever increasing demands made upon the performance of these heterocyclic materials by, in the main, the ophthalmic lens industries, has maintained a healthy interest in the design and synthesis of new and more effective substitution patterns and ring fusions. The union of a heterocyclic unit to the benzo- and naphthopyrans often provides beneficial effects such as enhanced kinetics, improved fatigue resistance and perhaps most significantly, broadened or dual absorption bands that enable the popular grey and brown shades of ophthalmic sun lenses to be produced using a single photochromic compound.

Synthesis and photochromic properties of naphthopyrans 2.5

59

REFERENCES

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63 Chapter 3

Three-membered ring systems

Unfortunately, the chapter on three-membered rings does not appear in this volume. We anticipate that PHC 18 will cover this area for the years 2004 and 2005.

64

Chapter 4 Four-membered ring systems Benito Alcaide Departamento de Quimica Orgdnica I. Facultad de Quimica. Universidad Complutense de Madrid, 28040-Madrid. Spain [email protected] Pedro Almendros Institute) de Quimica Orgdnica General, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain [email protected]

4.1

INTRODUCTION

The increasing interest in the preparation and synthetic utility of strained fourmembered ring systems in organic chemistry is mainly due to their importance biologically and industrially. In particular, oxygen- and nitrogen-containing heterocycles dominate the field in terms of the number of publications. These articles amply illustrate the ongoing vitality of four-membered heterocyclic chemistry. Obviously, Chapter 4 cannot offer a comprehensive description of all the aspects of the chemistry emanating from research groups active in this area in a space of 20 pages, so we have concentrated our efforts on the more relevant aspects. 4.2

AZETIDINES, 2-AZETINONES AND 3-AZETIDINONES

A review on the role of 1-azaallylic anions in heterocyclic chemistry, including the synthesis of azetidines, has been published . A report reviewing synthetic methods for azaheterocyclic phosphonates, including the synthesis of azetidines, has appeared . Diphenylimidoylketene can cyclize to azetinone 1, which is observable by means of a peak at 1814 cm"1 in the matrix IR spectrum but only at the mildest flash vacuum thermolysis (FVT) temperatures, 325-400 °C . 2,4-Dialkyl-azetidin-3-ones 2 have been prepared as single stereoisomers from rhodium or copper carbenoid N—H insertion of a,a'-dialkyl-a-diazoketones .

Key: i) FVT up to 400 °C. ii) Rh2(OAc)4 or Cu(acac)2, CH2CI2 or C6H6, 20-80 °C; P = Boc, Ts.

The asymmetric synthesis of 2-mono- and 2,3-fran.y-disubstituted azetidines 3 has been described . Key steps are a diastereoselective oc-alkylation of aldehyde SAMP-hydrazones with benzyloxymethyl chloride as the electrophile, and a nucleophilic 1,2-

Four-membered ring systems

65

addition of various organocerium reagents to the hydrazone CN double bond. Removal of the auxiliary, iV-tosylation, and hydrogenolytic cleavage of the benzylic protecting group, followed by ring closure under Mitsunobu conditions afforded the corresponding Ntosylazetidines in good overall yields. The synthesis and structure-activity relationship of a class of electrophile-based dipeptidyl peptidase inhibitors, the ketoazetidines 4 have been discussed . The structures of two natural enantiomeric azetidine-type amino acids, monascumic acids, were established to be 2-isobutyl-4-methylazetidine-2,4dicarboxylic acid . A practical process for the preparation of azetidine-3carboxylic acid has been published . The crystal structure determination of (S)JV-nitrosoazetidine-2-carboxylic acid reveals that the azetidine N atom is slightly pyramidalized . The [2+2] photocycloaddition of some difluoro-[(methylaminoK-7V)-alkenonato- K-C]-boron complexes with fraws-stilbene gave azetidines 5 together with cyclobutane derivatives .

2-Cyanoazetidines prepared from p-amino alcohols, are converted into enantiopure azetidine-containing vicinal diamines 6 using a sequence of nucleophilic addition and reduction . It has been reported that reduction with diphenylsilane and catalytic amounts of tris(triphenylphosphine)rhodium(l) carbonyl hydrides resulted in an efficient, chemoselective method for the transformation of amino acid-derived |3-lactams into the corresponding azetidines 7 . It has been proved that 5-substituted derivatives of 6-halogeno-3-[(2-(S)-azetidinyl)methoxy]pyridine exhibit low picomolar affinity for an a4|32 nicotinic acetylcholine receptor and a wide range of lipophilicity . A new specific radiotracer for a4p2 nicotinic acetylcholine receptors, (5)-5-trimethylstannyl-3-(2azetidinylmethoxy)pyridine 8 has been synthesized in six steps and 62% overall yield starting from (S)-2-azetidinecarboxylic acid . It has been observed that 1-acylazetidines derived from phenylalanine have an anti-HMCV (human cytomegalovirus) activity comparable to that of the reference compound, ganciclovir .

Key: i) RLi, then MeOH. ii) (a) NaBH 4 ; (b) Boc 2 0. iii) Ph2SiH2, RhH(CO)(PPh3)3.

The synthesis of 2,3-disubstituted-azetidines has been achieved from y-amino alcohols using l,l'-carbonyldiimidazole as a dehydrating reagent . A synthesis of stereodefmed enantiomerically pure 2-alkenyl azetidines 9 has been described using Wittig olefination as the key step . The quaternary ammonium triflates of these heterocycles were prepared in a stereoselective way and treatment of these azetidinium salts with base induced a regioselective Stevens rearrangement leading to 3-alkenyl pyrrolidines. The azetidinium salt 10 has been prepared from a chloroamine through ring closure and

66

B. Alcaide and P. Almendros

subsequent quaternization with iodomethane . Treatment of bromo alcohol bicyclic azetidine 11 with Deoxo-Fluor led to the bridged 5-a«//-fluoro 6-functionalized-2azabicyclo[2.1.1]hexane 12 . It has been reported that in the diastereoselective additions of the chlorotitanium enolate of 7V-propionylthiazolidine-2-thione to nitriles via the corresponding jV-metalloaldimines (Al, B, Zr as metals), thiazolidine-2-thioneazetines are formed preferentially over the dihydropyrimidinones . A stereoselective synthesis of azeto[2,l-6]quinazolines 13 bearing three stereocenters has been achieved via intramolecular [2+2] cycloaddition between ketenimine and imine functions supported on an ortho-benzylic scaffold . A stepwise mechanism, via a zwitterionic intermediate, has been established by ab initio and DFT calculations for the intramolecular cyclization of iV-(3-azabut-3-enyl)ketenimine to its corresponding [2+2] cycloadduct .

Key: E = CO2Et; i) Deoxo-Fluor.

A new synthetic route to 2-aryl-jV-tosyl azetidines 14 has been developed starting from Af-tosylarylaldimines in two steps in an overall yield of 63-70%. A formal [4+2] cycloaddition of these 2-aryl-Af-tosylazetidines with nitriles in the presence of BF3.OEt2 has been described for the synthesis of substituted tetrahydropyrimidines 15. It is proposed that the reaction proceeds in a Ritter fashion .

4.3

MONOCYCLIC 2-AZETIDINONES (0-LACTAMS)

A review on the asymmetric synthesis of p-lactams through the Staudinger reaction has been published . A review on the catalytic asymmetric synthesis of |3lactams has appeared . The preparation of P-lactams using the Kinugasa reaction has been reviewed . A report reviewing synthetic methods for azaheterocyclic phosphonates including the synthesis of P-lactams has appeared . A review on the formation of lactams via rhodium-carbenoids , as well as a review on the Pummerer reaction , both of them including p-lactam formation, deserve to be mentioned as well. Strategies for the formation of oxygen analogues of penicillins and cephalosporins have been reviewed . The use of P-lactams as intermediates for the synthesis of organic molecules has been reviewed . A review on penicillin- and cephalosporin-derived P-lactam inhibitors has been published . A review on p-lactam cholesterol absorption inhibitors has been published . An overview of the discovery of ezetimibe 16 has appeared . It has been observed that the new nonhydrolyzable glycoside 17, prepared using the scaffold of ezetimibe, is a potent inhibitor of cholesterol absorption


67

. The synthesis and anti-HMCV (human cytomegalovirus) activity of 1-acylP-lactams derived from phenylalanine has been studied .

Staudinger-like cycloaddition between proline-derived formaldehyde hydrazones and functionalized ketenes constitutes an efficient methodology for the stereoselective construction of 4-unsubstituted [3-lactams 18 (yield: 80-96 %, d.r. up to 99:1) O4CEJ6111>. Enantiopure yV,7V-dialkylhydrazones react with ./V-benzyloxycarbonyl-TV-benzyl glycine as an aminoketene precursor to afford fr-arc.s-3-amino-4-alkylazetidin-2-ones 19 as single diastereomers . N-N Bond cleavage in cycloadducts 18 and 19 afforded free azetidinones in high yields . It has been reported that the achiral bis(trimethylsilyl)methyl group acts as an efficient stereochemical determinant of the ccalkylation reaction in |3-branched a-phenyloxazolidinyl-|3-lactams and provides stereocontrolled access to syra-a-amino-a,|3-dialkyl(aryl)-|3-lactains 20, which are readily transformed into type II |3-tum mimetic surrogates .

The stereoselective synthesis of l,3-disubstituted-4-trichloromethyl azetidin-2-ones by the [2+2] cycloaddition of ketenes with imines derived from chloral has been described . The preparation of |3-lactams via ring closures of unsaturated carbamoyl radicals derived from 1 -carbamoyl-l-methylcyclohexa-2,5-dienes or from carbamoyl radicals drived from oxime oxalate amides has been accomplished . The reactivity of a new class of radicals, the |3-lactamido iV-sulfonyl radicals 21, has been studied . The creation of the |3-lactam ring by Ugi reaction with |3-keto-acids is unknown in organic solvents, but this reaction proceeds well in water to give 2-azetidinones 22 . The preparation of P-lactam 23 bearing an N - 0 bond has been achieved . Allyl halides of different structures, under CO pressure, undergo a [2+2] cycloaddition in the presence of Pd(OAc)2, PPI13, and Et3N to afford 2-azetidinones 24 .

68


Various iV-cinnamyl azetidin-2-ones have been synthesised starting from cinnamyl azide . 2,2'-Dibenzothiazolyl disulfide has been found to be a versatile reagent that provides a route for the synthesis of p-lactams from Schiff s bases and alkoxy acetic acids . It has been reported that rhodium-complexed dendrimers on a resin show high activity for the carbonylative ring expansion reaction of a variety of aziridines with carbon monoxide to give P-lactams 25 in good yields . 3-exo-Methylene Plactams 26 have been obtained in a single step via Cu(l)-mediated cycloaddition between propargyl alcohol and nitrones (Kinugasa reaction) in the presence of L-proline . P-Lactams 27 have been synthesized by acidic thermal rearrangement of spiro[cyclopropanel,5'-isoxazolidines], which can be obtained by 1,3-cycloaddition starting from methylenecyclopropanes and acyclic nitrones .

Key: i) 400 psi of CO, catalyst, C 6 H 6 , 90 °C. ii) Cul, L-proline, DMSO. iii) (a) 60 °C; (b) PTSA, MeCN, 50 °C.

Reformatsky reactions of an imine, an cc-bromoester, zinc dust and a catalytic amount of iodine in dioxane under high intensity ultrasound irradiation have been evaluated as a route for the synthesis of P-lactams . P-Lactam-forming photochemical reactions ofNtrimethylsilylmethyl- and jV-tributylstannylmethyl-substituted (3-ketoamides have been reported as have simple and fast protocols for the asymmetric synthesis of the potentially bioactive 3-substituted 3-hydroxy-|3-lactam moiety. The reaction of various activated vinyl systems with enantiopure azetidine-2,3-diones was promoted by DABCO to afford the corresponding optically pure Baylis-Hillman adducts 28 without detectable epimerization, while Sn-HfCU-mediated bromoallylation reaction between 2,3dibromopropene and azetidine-2,3-diones proceeded efficiently in aqueous media to achieve bromohomoallyl alcohols 29 as single diastereomers . A 3-phenyl 3-hydroxy-Plactam has been prepared by LHMDS-induced cyclization of an aminodioxolanone . The reactions of menthyl isobutyrate with imines were influenced by a catalytic amount of a chiral tridentate aminodiether ligand to give the corresponding |3lactams with high enantioselectivities . It has been reported that application of a new dimeric cyclophane ligand enhances diastereo- and enantioselectivity in the catalytic synthesis of P-lactams . The stereoselective synthesis of derivatives of azetidinone 30, a key intermediate to 1-P-methylcarbapenem, has been achieved .

Key: i) DABCO, activated olefin, MeCN. ii) 2,3-Dibromopropene, Sn, HfCI4, THF-H2O.

An efficient and selective solid-phase synthesis of trans 3-alkyl-4-aryl-P-lactams from nonactivated acid chlorides has been accomplished . The [2+2] cycloaddition between an aldehyde-derived resin-bound imine and a solution-generated ketene has been used to generate a variety of stereochemically pure cw-P-lactams . A new polymer-supported reagent has been used for the preparation of P-


69

lactams using the Staudinger reaction under sonication . A concise and high yielding synthesis of (-)-tabtoxinine-P-lactam 31, the cause of tobacco wildfire disease, has been achieved from L-serine using a zinc-mediated coupling reaction, Sharpless asymmetric dihydroxylation and lactamization of an 7V-OBn amide as the key steps . The synthesis and conformational stability of the cyclic peptidomimetic 32 and analogs containing a (S/J^S^-configured p-lactam moiety have been described . Contrary to this, the (3S,47?)-configured isomers did not cyclize but gave polymeric material. The stability of the P-lactam ring under reductive conditions was examined in order to find a selective method for the synthesis of (4-oxo-azetidin-2-yl)acetonitrile derivatives . An ab initio study has been performed to investigate intramolecular hydrogen-bonding in the following model monocyclic P-lactam antibiotics: oxamazins, thiamazins, JV-oxomethoxy and iV-thiomethoxy lactams .

A novel approach to enantiopure spirocyclic |3-lactams 33 has been developed by using different intramolecular metal-catalyzed cyclization reactions in monocyclic unsaturated alcohols, which were regiospecifically prepared through metal-mediated Barbiertype carbonyl-addition reactions of a-keto lactams in aqueous media . Preparation of proline-derived spiro p-lactams 34 can be achieved by the [2+2] cycloaddition of unsymmetrical cyclic ketenes with imines . It has been reported that the treatment of bis-spirocyclopropanated isoxazolidines with trifluoroacetic acid in acetonitrile furnishes 3-spirocyclopropanated P-lactams 35 in 75-96 % yields . The Mannich reaction of protected a-imino ethyl glyoxylate with a,adisubstituted aldehydes affords quaternary |3-formyl a-amino acid derivatives, which are further converted to spirocyclic P-lactams . The spiro P-lactam framework has been prepared by reaction of imines with ketenes generated from JV-acyl-thiazolidine-2carboxylic acids . 2-Azetidinones 36 bearing the indole spiro-p-lactam moiety of the chartellines were synthesized .

Key: i) allyl bromide, In. ii) (a) CMuctionalization; (b) Grubbs' carbene.

The use of P-lactams 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 analogues of siastatin B , alicyclic P-amino acids , Ppeptides , bridged cispentacin , l,4-diazabicyclo[4,4,0]decanes and

70


l,4-diazabicyclo[4,3,0]nonanes , carbo- and heterocyclic nucleoside analogues , pateamine A , y-alkylaminopentenoates , and y-lactams . The synthesis of a collection of bicyclic fused azepinones 37 via an intramolecular p-lactam ring-opening strategy has been reported . Addition of 2-(trimethylsilyl)thiazole (TMST) to cis- or fra«5-4-formyl-|3-lactams gave enantiopure aalkoxy-y-keto acid derivatives 38 via a novel N1-C4 bond breakage of the P-lactam nucleus . The synthesis of medium ring nitrogen heterocycles can be achieved via a tandem copper-catalyzed C-N bond formation-P-lactam ring expansion process .

Key: i) 4 N HCI, dioxane, RT. ii) DMF, 200 °C, nwave. iii) TMST, CH2CI2, 0 °C.

4.4

FUSED POLYCYCLIC P-LACTAMS

The development of a cephalosporin-based dual-release prodrug as well as a study on penicillins as p-lactamase-dependent prodrugs have been described . The X-ray crystal structure of an acylated p-lactam sensor domain has been reported . The reaction mechanism of hydrolysis of a common |3-lactam substrate (cefotaxime) by monozinc |3-lactamase has been investigated . The unusual bifunctional catalysis of epimerisation and desaturation by carbapenem synthase has been analyzed . The Mossbauer spectra of isopenicillin N synthase has been studied . The inhibition of a bacterial DD-peptidase by the newly prepared peptidoglycan-mimetic P-lactam 39 has been described . A sensitive and reagentless biosensor for p-lactam antibiotics such as cefuroxime 40 has been constructed from a modified class A |3-lactamase . Two penicillin derivatives, the active penamecillin and the inactive penamecillin-ip-sulfoxide, were used to study the relationship between their charge density and their activity . Mixed ab initio quantum mechanical/molecular mechanical calculations have been used to study the hydrolysis of the acyl-enzyme intermediate formed between cephalothin and a class C P-lactamase . The kinetics and mechanism of hydrolysis of A^-acyloxymethyl derivatives of azetidin-2-one have been studied . A kinetic analysis has been reported of the hvdroxvaminolvsis of 6-lactam antibiotics .

A method has been established to synthesize 6-methylidene penem compounds, which involves an aldol-type condensation on 6-bromopenem with aldehydes . SAlkyl dithioformates, generated by a cycloreversion process, react as 1,3-dipolarophiles with


71

P-lactam-based azomethine ylides to provide, after elimination of MeSH, C2-unsubstituted penems 41 . It has been reported that selenapenams and selenacephems can be prepared by nucleophilic and radical chemistry involving benzyl selenides . The synthesis of bicyclic P-lactam 42 has been accomplished by radical cyclization . Two polymorphs of/ra»5-13-azabicyclo[10.2.0]tetradecan-14-one display a unique example of isostructurality, differing only in the orientation of a given hydrogen bond with respect to the p-lactam bond .

I Key: i) Microwave, PhMe, 200 W. ii) (a) MCPBA; (b) Et3N. iii) n-Bu3SnH, AIBN.

SiMe,

The formation of P-lactam derivatives 43 through the reaction of dibenzoylacetylene and aryl isocyanates in the presence of trivalent phosphorus nucleophiles has been documented . It has been reported that the carbamoyl radical cyclization reaction through dithiocarbamate group transfer is a useful tool for the preparation of p-lactams such as 44 . Via the Ugi 4-centre 3-component reaction, bicyclic cis-2azetidinone derivatives have been synthesized from cyclic p-amino acids , and a synthesis of strained ring-fused p-lactams 45 by Ugi reaction of P-keto acids in aqueous solution has been described . The synthesis and rearrangement of 7V-organyloxy P-lactams 46 derived from a (4+2)/(3+2) sequential cycloaddition reaction involving enol ethers and nitro alkenes has been reported . Using ring closing metathesis as the key operation, a rapid access to P-lactams 47 fused to a sultam moiety of variable ring size has been developed .

The synthesis of 4/5/6, 4/6/6 and 4/7/6 tri- and tetracyclic P-lactams 48 has been carried out via one-pot enyne metathesis and Diels-Alder reactions . The synthesis of unprecedented inner-outer-ring 2-[tertbutyldimethylsilyloxy]dienes with a carbacepham structure in optically pure form and their totally it-facial endo selective Diels-Alder reactions to structurally novel polycyclic Plactams 49 has been reported .

Key: i) Grubbs' carbene, dienophile. ii) W-methylmaleimide, toluene, 145°C.

72


A stereoselective and substrate-controlled synthesis of polycyclic P-lactams 50 from a D-glucose-derived chiral template via intramolecular radical cyclization has been described . The [2+2]-cycloaddition of chlorosulfonyl isocyanate to polymerbound vinyl ethers followed by intramolecular alkylation of the (3-lactam nitrogen led to the formation of mixtures of the corresponding diastereomeric oxacephams or clavams with a low stereoselectivity. In the case of Merrifield and MPP resins, the [3-lactams were accompanied by the corresponding oxetanes or oxiranes . Novel tricyclic scaffolds 51 that incorporate a |3-lactam ring fused to the d bond of a 1,4-benzodiazepine seven-membered ring have been synthesized in a process that constitutes one of the few examples of Staudinger-type reactions involving ketimines described so far. In addition, the creation of an asymmetric quaternary center has been achieved . The [2+2] Staudinger cycloaddition between the C=N double bond of 2,3-dihydrobenzoxazepines and a series of acetyl chlorides gave azetidino[4,l-. Synthesis from D-xylose of oxetane 52, a scaffold for a range of methyl and hydroxymethyl analogues of the antibiotic oxetin, a naturally occurring oxetane acid, has been reported . Pseudoenantiomeric analogues of the


73

antibiotic oxetin have been prepared from L-rhamnose by efficient SN2 reactions in oxetane rings . A series of oxetane 8-amino acid scaffolds derived from L-rhamnose and D-xylose provide a new class of templated sugar amino acids, which can be considered as D/L-alanine-D-serine and glycine-L-serine dipeptide isosteres . The UV irradiation of alkoxy-substituted TV-alkenylmaleimides induces a sequence involving a [5+2] cycloaddition followed by a Norrish-Yang cyclization to form in good yield and with high diastereoselectivities highly strained alkylidene oxetanol-fused azepines 53 .

Key: i) (a) Br2; (b) PhCHO; (c) Tf 2 O, py; (d) K 2 CO 3 . ii) (a) Et 3 SiH; (b) Tf 2 O, py; (c) NaN 3 .

A new isotactic, perfectly alternating polymer of (S)-lactic acid and oxetane has been synthesized by the entropically driven ring-opening polymerization of a 14-membered cyclic diester . A novel cytotoxic oxetane diterpenoid as well as three new 14-P-benzoyloxy taxoids containing an oxetane ring have been isolated from plants . A steroidal oxetanyl ester was synthesized in eight steps as a biomimetic model of taxol oxetane . It has been reported that the solid-state photocycloaddition reactions of 2-pyrones with benzophenone derivatives afford highly siteand regioselective oxetanes . Photoinduced reactions of 7V-methyl-4,5,6,7tetrachlorophthalimide with styrene, jo-methylstyrene, a-methylstyrene and indene follow the Paterno-Biichi reaction pathway to give the corresponding diastereoisomeric spirooxetanes as main products . A report on the mechanism of stereo- and regioselectivity in the Paterno-Buchi reaction of furan derivatives with aromatic carbonyl compounds has established the importance of the conformational distribution in the intermediary triplet 1,4diradicals . The Paterno-Buchi reaction between benzoin derivatives and furans has also been examined . The photocycloaddition of methyl pyruvate and methyl phenylglyoxylate to 5-methoxyoxazoles bearing additional substituents at C-2 and C4 has been reported to lead with high to moderate (exo) diastereoselectivity to bicyclic oxetanes 54, that can be easily ring-opened to give bis-quaternary aspartic acid diester derivatives 55 .

Photoreactions of 1-acetylisatin with oxazoles initially give a [4+4] product with the O=C-C=O functionality in isatin and the 2-azadiene moiety in oxazole as 4n addends, which undergoes further [2+2] reactions with another isatin to furnish the spirocyclic oxetane 56 . The regioselectivity in the oxidative electron-transfer cycloreversion of 2,3diaryloxetanes depends on the substitution of the aryl groups and on the nature of the electron-transfer photosensitizer . Synthetic routes for the preparation of paclitaxel analogues with a thiol group in place of the hydroxyl group on the C-13 side-chain

74


have been developed . The 1:1 molecular complex between oxetane and water has been investigated using free-jet milimeter-wave spectroscopy . The one-step synthesis of Y-hydroxy-a,a-difluoromethylphosphonates 57 by an oxetane ringopening reaction has been accomplished . [3-Glycosides result from the reaction of per-O-benzylated glucosyl(galactosyl) iodides with oxetane .

Key: i) hv. ii) (a) (/-PrOyOJPCFjSMe, f-BuLi; (b) BF 3 .Et 2 0.

A dioxetane is a postulated intermediate in the photooxygenation of di- and trisubstituted indolizines . A 1,2-dioxetane has been used in a chemiluminescence enzyme immunoassay for determination of human chorionic gonadotropin . The synthesis of a thermally stable dioxetane 58 bearing a 3-(lcyanoethenyl)phenyl group has been reported. This compound exhibits a chemiluminescent decomposition induced by Michael addition of malonate anion . A theoretical study on oxete formation via ketene-acetylene [2+2] cycloaddition has been published . The olefmation of ketones via ynolates involves an initial cycloaddition to give p-lactone enolates . Hyperconjugative effects have been found to be responsible for the stereoselective ring-opening reactions of oxetenoxides 59 . It has been demonstrated that a planar-chiral azaferrocene derivative of 4-(pyrrolidino)pyridine 60 is an excellent catalyst for the enantioselective [2+2] cycloaddition of disubstituted ketenes to aldehydes, providing |3-lactones 61 with very good stereoselection and yield . The catalytic asymmetric acyl halide-aldehyde cyclocondensation reaction of substituted ketenes as well as the enantioselective ketene-aldehyde cycloaddition catalyzed by a cinchona alkaloid-Lewis acid system have been reported as entries to enantioenriched |3-lactones.

Key: i) 5% 60, THF, -78 °C.

The configuration of a |3-hydroxy ester, a key intermediate in the total synthesis of (-)-virantmycin, has been assigned on the basis of NOE experiments conducted on the corresponding (5-lactone . It has been reported that the selenium-catalyzed bromolactonization of |3,Y-unsaturated carboxylic acids yields a mixture of the y- and the |3lactone, the four-membered ring being the minor component . Catalytic carbonylation of epoxides to |3-lactones 62 has been effected by a highly active and selective bimetallic catalyst 63 comprised of a chromium(Ill) porphyrin cation and a cobalt


75

tetracarbonyl anion. Carbonylation of numerous linear epoxides, as well as bicyclic epoxides derived from 8- and 12-membered hydrocarbons, proceeded with high activity, selectivity, and yield . The synthesis and ring opening polymerization of the a-methyl-(3pentyl-p-propiolactone (MPP) 64 have been detailed .

Studies directed towards the synthesis of ebelactone A 65 have been carried out . Enantioselective total synthesis of belactosin A 66 and its homoanalogue belactosin C have been achieved . The first enantiospecific total synthesis of salinosporamide A 67 has been reported . A stereocontrolled synthesis of racemic lactacystin P-lactone 68 has been achieved . The crystal structure of 6a,7P-acetoxyvouacapan-17p-lactone, which is a natural furan diterpene, has been published .

The P-lactone nucleus has been used as a versatile intermediate in organic synthesis. Knoevenagel reaction products can be obtained from methylene |3-lactones . Dipropionate equivalents have been generated from P-lactones and used for the synthesis of the C1-C27 portion of the aplyronines . The catalytic carbonylation of P-lactones to give succinic anhydrides has been accomplished . Total syntheses of amphidinolide P, goniothalamin 69 and massoialactone 70 have been reported using a p-lactone-ring expansion by a translactonization process .

76 4.6

B. Alcaide and P. Almendros THIETANES, P-SULTAMS, p-SULTONES, AND RELATED SYSTEMS

The mechanism of reactions involving |3-sultams and their use as inhibitors of serine proteases have been reviewed . The preparation of the tricyclic thietanes 71 through the irradiation of Af-butenyl-5-thioxopyrrolidin-2-(thi)ones has been described . A facile Rh(II)-catalyzed reaction of thietanes with diethyl diazomalonate leading to highly substituted tetrahydrothiophenes along with allyl thioethers has been described . It has been reported that when irradiated, the doubly unsaturated bridgehead sultam 72 is isomerized via a two-photon process to the structurally novel spiro heterocycle 73 constituted of a cyclobutene, a thietane dioxide, and a pyrrolidine . It has been reported that N2S2 is essentially a 2jt-electron aromatic fourmembered-ring system with a formal N-S bond order of 1.25 even though it has 6JT electrons .

The hydrolysis of JV-acyl (3-sultams 74 as well as of 3-oxo-P-sultams 75, which are both |3-lactams and |3-sultams, is a sulfonyl transfer reaction that occurs with S-N fission and opening of the four-membered ring . Preparation of hybrid organic-inorganic MCM-41 and SBA-15 silicas functionalized with perfluoroalkylsulfonic acid groups has been achieved in a single step by reacting the mesoporous silicas with l,2,2-trifluoro-2-hydroxy-ltrifluoromethylethane sulfonic acid |3-sultone 76 . Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins 77, in which the p-lactam carbonyl oxygen of the cephalosporins has been replaced by sulfur, have been investigated .

4.7

SILICON AND PHOSPHORUS HETEROCYCLES. MISCELLANEOUS

(S,S)-l,\'-Di-tert-bvAy 1-2,2'-dibenzophosphetenyl 78 and its enantiomer, highly strained P-stereogenic diphosphine ligands which exhibited excellent enantioselectivity in the rhodium-catalyzed asymmetric hydrogenation of methyl a-acetylamidocinnamate, have been prepared from 2-bromobenzyl chloride and ferf-butyldichlorophosphine . Trapping the transient benzyne complex Cp2Zr(r|2-C6H4) with diacetylenic phosphanes resulted in the formation of fused benzo-zirconacyclohexadiene-phosphacyclobutene rings 79 . The treatment of tert-alkyl phenyl thioketones with Lawesson's reagent gave two diastereomeric 1,3,2-dithiaphosphetane 2-sulfides 80 and 81 in high yields .


11

Preparation of the first stable four-membered ring diaminocarbene 83 as well as the carbene dimer 84 from the heterocyclic iminium salts 82, has been reported. The starting iminium salts were prepared from a silylamidine .

Key: i) (a) R 2 NPCI 2 ; (b) TMSOTf. ii) MesLi or KHMDS.

A bis(thiophosphinoyl)methanediide palladium complex has been fully characterized . A phosphacyclometallated Pt(ll) compound has been detected . It has been shown that given the right set of substituents, the l,3-dibora-2,4diphosphoniocyclobutane-l,3-diyl diradicals 85 are indefinitely stable . The reactivity of diradicals 85 has also been reported . The synthesis and structure of the 1,3-diphosphacyclobutadienediide 86 have been achieved . Four-membred phosphairidium metalacycles have been generated . Oxaphosphetanes have been postulated as intermediates in condensation reactions . It has been reported that the thermal decomposition of the fluoroanalogue of Wilkinson's catalyst occurred to produce a phospharhodium metalacycle . The synthesis and X-ray analysis of the four-membered ring 2,3dihydro-l,3-phosphasiletes 87 have been reported . The formation of the stable, lattice-framework disilene 88 has been described . Stable cubic phosphorus-containing radicals have been obtained .

The synthesis of ;?-(l-methylsilacyclobutyl)styrene has been recorded . Single crystals of ferrous siloxanes have been obtained . A zirconacyclobutene-silacyclobutene has been obtained and reacted with nitriles to give pyrrolo[3,2-c]pyridines . Some diradicals with four-membered rings, 2,4disilacyclobutane-l,3-diyls, have been designed and shown to have singlet ground states and

78


to be more stable than the a-bonded isomers, 2,4-disilabicyclo[1.1.0]butanes . The synthesis of the digermadisilene 89 has been published . The isolation of a radical anion of a cyclotetrasilane has been achieved . The isolation and ring-opening of new l-sila-3-metallacyclobutanes leading to a new class of organometallic polymer have been reported . The insertion of alkynes into the Pt-Si bond of silylplatinum complexes leading to the formation of 4-sila-3-platinacyclobutenes 90 has been developed . The reduction of the four-membered 1,2,3,4-disilagermetenes with alkaline-earth metals to give bicyclo[1.1.0]butane 2,4-dianion skeletons has been detailed . The synthesis and ring opening reactions of the 2-silabicyclo[2.1.0]pentane 91 have been described . The azatantalacyclobutene complex 92 has been fully characterized . Carboamination reactions have been catalyzed by cyclic imidozirconocenes .

The preparation of the cycloaminoboranes 93 has been described . The synthesis and structural characterization of an azatitanacyclobutene has appeared . The synthesis and characterization of the biradicaloids l,3-diaza-2,4distannacyclobutanediide 94 and l,3-diaza-2,4-digermacyclobutanediide 95 have been reported . The bicyclic diazetidine 96 has been prepared through the rearrangement of a mesoionic compound .

The synthesis of the tetracoordinate 1,2-iodoxetane 1-oxide 97 and its application as an oxidizing reagent have been achieved . A four-membered tetranuclear alumoxane and the gallium congener have been prepared and characterized . The isolation, dynamic NMR study and X-ray characterization of the bis-sulfonium zirconocene-ate dimer 98 has been reported . The formation of the 1titanacyclopent-3-yne and a 2,5-dititanabicyclo[2.2.0]hex-l-ene 99 has been described . The isolation of the stable 1,2-digermacyclobutadienes 100 has been published .

Four-membered ring systems 4.8

79

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82 04MI1921 04MI1951 04MM5274 04OBC195 04OBC421 04OBC651 04OBC716 04OBC1051 04OBC1113 04OBC1274 04OBC2612 04OBC3518 04OL201 04OL373 04OL921 04OL973 04OL1313 04OL1481 04OL1653 04OL1669 04OL1765 04OL2153 04OL2507 04OL2519 04OL2749 04OL2781 04OL3361 04OL3747 04OL3945 04OL4053 04OL4239 04OL4443 04OL4829 04OL4893 04S237 04S543 04S1471 04S1696 04S2517 04S2665 04S2965 04SC3347 04SL979 04SL1249 04SL1425 04SL1637 04SL2025 04SL2751 04SL2776 04SL2824 04T93

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Four-membered ring systems 04T867 04T1317 04T1659 04T2035 04T3599 04T4133 04T5273 04T6777 04T6895 04T7177 04T7197 04TA489 04TA573 04TA2213 04TA2555 04TA2667 04TA2681 04TA2875 04TA3263 04TA3841 04TL1331 04TL2193 04TL3355 04TL3589 04TL3607 04TL3779 04TL3877 04TL4085 04TL4657 04TL4847 04TL5759 04TL6429 04TL6563 04TL7255 04TL7525 04TL8173 04TL8191

83

Y.-S. Lee , W.-K. Choung , K.H. Kim , T.W. Kang, D.-C. Ha, Tetrahedron 2004, 60, 867. N. Pirio, S. Bredeau, L. Dupuis, P. Schiitz, B. Donnadieu, A. Igau, J.-P. Majoral, J.-C. Guillemin, P. Meunier, Tetrahedron 2004, 60, 1317. L. Fournier, P. Kocienski, J.-M. Pons, Tetrahedron 2004, 60, 1659. N.A. Ross, R.R. MacGregor, R.A. Bartsch, Tetrahedron 2004, 60,2035. X. Qi, S.-H. Lee, J. Yoon, Y.-S. Lee, Tetrahedron 2004, 60, 3599. X. Qi, S.-H. Lee, J. Yoon, Y.-S. Lee, Tetrahedron 2004, 60, 4133. S. Ranganathan, K.M. Muraleedharan, N.K. Vaish, N. Jayaraman, Tetrahedron 2004, 60, 5273. M. Hayashi, N. Nakamura, K. Yamashita, Tetrahedron 2004, 60, 6111. L. Troisi, L. De Vitis, C. Granito, T. Pilati, E. Epifani, Tetrahedron 2004, 60, 6895. K.M. Schreck, M.A. Hillmyer, Tetrahedron 2004, 60, 7177. K. Matsumoto, H. Hasegawa, H. Matsuoka, Tetrahedron 2004, 60, 7197. M. Alajarin, A. Vidal, F. Tovar, M.C. Ramirez de Arellano, Tetrahedron: Asymmetry 2004, 15, 489. E. Forro, F. Fulop, Tetrahedron: Asymmetry 2004, 15, 573. T. Imamoto, K.V.L. Crepy, K. Katagiri, Tetrahedron: Asymmetry2004, 15, 2213. P. Del Buttero, G. Molteni, A. Papagni, L. Miozzo, Tetrahedron: Asymmetry 2004, 15, 2555. S.F. Jenkinson (nee Barker), T. Harris, G.W. J. Fleet, Tetrahedron: Asymmetry 2004, 15, 2667. S.W. Johnson, S.F. Jenkinson (nee Barker), D. Angus, J.H. Jones, G.W. J. Fleet, C. Taillefumier, Tetrahedron: Asymmetry 2004, 75,2681. E. Forro, F. Fulop, Tetrahedron: Asymmetry 2004,15, 2875. S.W. Johnson, S.F. Jenkinson (nee Barker), D. Angus, J.H. Jones, D.J. Watkin, G.W.J. Fleet, Tetrahedron: Asymmetry 2004, 15, 3263. E. Cesarotti, I. Rimoldi, Tetrahedron: Asymmetry 2004, 15, 3841. H. Oshida, A. Ishii, J. Nakayama, Tetrahedron Lett. 2004, 45, 1331. G. Gerona-Navarro, M.A. Bonache, M. Alias, M.J. Perez de Vega, M.T. Garcia-Lopez, P. Lopez, C. Cativiela, R. Gonzalez-Muniz, Tetrahedron Lett. 2004, 45, 2193. A.C.B. Burtoloso, C.R.D. Correia, Tetrahedron Lett. 2004, 45, 3355. D. Freitag, P. Schwab, P. Metz, Tetrahedron Lett. 2004, 45, 3589. E. Brenner, R.M. Baldwin, G. Tamagnan, Tetrahedron Lett. 2004, 45, 3607. M. Matsumoto, T. Mizuno, N. Watanabe, Tetrahedron Lett. 2004, 45, 3779. M. D'Auria, L. Emanuele, R. Racioppi, Tetrahedron Lett. 2004, 45, 3877. C.M.L. Delpiccolo, E.G. Mata, Tetrahedron Lett. 2004, 45, 4085. A. Macias, E. Alonso, C. del Pozo, J. Gonzalez, Tetrahedron Lett. 2004, 45, 4657. M.A. Calter, J. Zhou, Tetrahedron Lett. 2004, 45, 4847. V. Nair, S.M. Nair, S. Mathai, J. Liebscher, B. Ziemer, K. Narsimulu, Tetrahedron Lett. 2004, 45, 5759. B. Alcaide, P. Almendros, R. Rodriguez-Acebes, T. Martinez-del Campo, Tetrahedron Lett. 2004, 45, 6429. V.V. Govande, A.R.A.S. Deshmukh, Tetrahedron Lett. 2004, 45, 6563. B. Alcaide, R.M. de Murga, C. Pardo, C. Rodriguez-Ranera, Tetrahedron Lett. 2004, 45, 7255. F. Coury, F. Durrat, G. Evano, D. Prim, Tetrahedron Lett. 2004, 45, 7525. N. Kano, M. Ohashi, K. Hoshiba, T. Kawashima, Tetrahedron Lett. 2004, 45, 8173. H. Kiyota, T. Takai, M. Saitoh, O. Nakayama, T. Oritani, S. Kuwahara, Tetrahedron Lett. 2004,45,8191.

84

Chapter 5.1

Five-membered ring systems: thiophenes and Se/Te analogues 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.), [email protected] (J. B.)

5.1.1

INTRODUCTION

This chapter aims at summarizing the developments in thiophene chemistry, including some aspects on selenophenes and tellurophenes, reported during the period of January to December 2004. The emphasis is put on the synthesis and reactivity of basic thiophene systems. Much new chemistry in this area is currently focussing on thiophene containing oligomeric or polymeric organic materials. Even though coverage of these developments are beyond the scope of this chapter, there are short sections devoted to these types of structures included, as well as to the applications of thiophenes in medicinal chemistry. Several specialized reviews on thiophene containing compounds have appeared during the year. An account on single-crystalline photochromism of thienyl- or benzo[6]thienyl containing ethenes has been published , while the synthesis, properties and applications of bis(ethylenethio)tetrathiafulvalenes have been reviewed in detail . Thiophene- and selenophene-based materials have also been included in a review on the recent progress in semiconductor performance of devices based on such ring systems . An account on the role of single-site catalysts in the hydrodesulfurization of thiophenes has been provided . Fused thiophene systems, for example thienopyridazines , and thienopyrimidines have also been covered. A review concerning the chemistry and properties of benzo[6]tellurophene, dibenzo[6,]pyridine derivatives . OTMS

Ar

Y^r S

SMe +

NHR 22

A^

COzEt

Hg(OAc)o

CH2Ch

jj2

/

N2

' . A/co2Et A r

38.91o/o

^ S ^

23

21

The TV-protected 2-aminothiophenes 24 (R1 = Ac or Boc) have been prepared by initial alkylation of the thioamides 25, and subsequent base induced cyclization of the intermediate iminium salts 26 with concomitant elimination of HX and dimethylamine. The corresponding 2-aminothiophenes were thereafter obtained after removal of the acetyl or Boc groups .

S

S^R

L 25

2

X"

J 26

61 82%

"

24

Five-membered ring systems: thiophenes and Se/Te analogues

87

Several new routes to thieno-fused thiophenes have been disclosed, among others an interesting approach to various thieno[2,3-6]thiophenes. For example, treatment of 27 with tBuLi, followed by ethyl ./V.Af'-dimethylcarbamate gave the 8-membered ring intermediate 28, which was converted to the thiophene annulated thieno[2,3-6]thiophene system 29 upon exposure to ?-BuLi. Subsequent elimination of water from 29 gave the desired tetracyclic system 30 .

The related system 31 has been prepared by thionation of the diketone 32 with P4S10 or Lawesson's reagent. Furthermore, dithieno[2,3-6:2',3'-of]thiophene 31 was also submitted to electrochemical polymerisation . Lawesson's reagent has also been used to effect conversion of several 1,4-diketones to thiophenes employing a new reusable catalytic system consisting of Bi(OTf)3 and the ionic liquid [bmim]BF4 (l-butyl-3-methylimidazolium tetrafluoroborate) .

The fused thiophene 33, which belongs to the very interesting class of heterohelicenes, has been obtained as a minor product in a low yield by cyclization of the diethynylsulfide 34 .

A synthesis of the fused system 35 was achieved by conversion of the aryl bromide 36 to the sulfide 37, which in turn was brominated to 38, followed by metalation and a final oxidative intramolecular coupling. A study of the crystal structure of 35, as well as its electronic properties, has also been conducted . The structurally similar tetra?ert-butyldicyclopenta[6:(f]thieno[l,2,3-cfi?:5,6,7-c yjdiphenalene system has also been prepared, and its redox properties were studied .

88

T. Janosik and J. Bergman

The [l,2]dithiin 39 has been shown to undergo ring-contraction to the corresponding fused thiophene 40 upon treatment with Pt(COD)2 followed by heating, or simply by irradiation in benzene solution .

Ring contraction of the 3,6-dihydro-2//-thiopyrans 41, which are readily available in two steps from dimethyl malonate, was shown to give the tetrahydrothiophenes 42 upon treatment with jV-iodosuccinimide (NIS) in the presence of a carboxylic acid. The reaction was suggested to proceed via a bicyclic thiiranium ion intermediate. Moreover, base induced elimination of HI from 42 (with for example R = Bn) gave the partially unsaturated system 43 .

a CO2Me CO2Me

NIS

,

RCO2H(3equiv.)

CHCI3 35-98%

41

\

DBU

_ RO2Cs/3rCO2Me ^ ^ s CO2Me 42

r-y

CHCI3

J ô C 2

^CO2Me C 2 M e ° 43 S

In an interesting application of aluminacyclopentanes 44, the tetrahydrothiophenes 45 were synthesized employing a reaction with thionyl chloride. The starting compounds were readily prepared from the alkenes 46 and ethylaluminium dichloride in the presence of a zirconium catalyst. A mechanistic rationale for the formation of 45 was also provided . EtAlCl2 Mg, Cp 2 ZrCI 2 (cat.)

^R -^ 46

R

R

%

- ^

55

R

R '•-.—/

O - ^* 0 Al

Et

80%

S

45

44

Access to a number of fused thiophene based structures has been gained via intramolecular C-H insertions adjacent to sulfur with control of diastereoselectivity. Thus for instance,

Five-membered ring systems: thiophenes and Se/Te analogues

89

treatment of the diazofuranone 47 with Rli2(OAc)4 gave the interesting tricyclic system 48, via the strained intermediate 49 .

A series of thioanhydroaldoses and thioanhydropentitols, for example 50, has been prepared via the electrophilic bis-cyclic thionocarbonate 51, which was in turn obtained by treatment of the monobenzyl pentitol 52 with diimidazolyl thione (In^CS) .

An intriguing new fused thiophene derivative, trithia-[3]-peristylane 53, has been prepared from bullvalene 54, which underwent initial ozonolysis, followed by acetalization, to provide the intermediate 55. This material was subsequently subjected to Lawesson's reagent (LR) to give the target molecule 53. A detailed structural study of this C3V symmetric structure was also conducted .

Other new developments in thiophene ring synthesis include for instance efficient preparation of 2-aminothiophenes by an adaptation of the Gewald thiophene synthesis in ionic liquids catalyzed by ethylenediammonium diacetate . The Gewald reaction has also been adapted to a soluble polymer support . Moreover, a solid phase synthesis of 2-substituted benzo[Z>]thiophenes using titanium(IV) benzylidenes (Schrock carbenes) has been reported . A series of 2,3-dihydrobenzo[6]thiophenes has been obtained by nickel catalyzed electrochemical cyclization of allyl 2-haloaryl sulfides . Several thiophene derivatives have also been identified as products originating from cyclization of alkenylthioimidoyl radicals , or rhodium catalyzed decomposition of a-diazoketones bearing a cyclic dithioacetal . In addition, a new practical 10-step synthesis of (+)-biotin in 34% overall yield from L-cysteine has been developed . Several routes involving thiophene ring synthesis towards more complex heterocycle fused thiophene systems should also be mentioned. Thus for example, the alkaloid thienodolin 56 has been prepared by reaction of l-(terf-butoxycarbonyi)-2,6-dichloroindole3-carboxaldehyde with 2-mercaptoacetamide , while a double cyclization of 2,6-dichloropyridine-3,5-dicarbonitrile or the corresponding pyrazine derivative with ethyl 2-

90

T. Janosik and J. Bergman

mercaptoacetate gave the systems 57 (X = CH or N) . Other interesting achievements in this area include routes to the quinolinedione fused thiophene 58 , and some thieno[2,3-6]benzothiopyran-4-one derivatives . Naphtho[6]cyclopropene has been shown to participate in a cycloaddition process with trithiocarbonates to afford naphtho[2,3-c]thiophene derivatives . Finally, routes to thieno[2,3-c]pyridines , thieno[2,3-6]pyridines , thieno[2,3-99% regioselective). A palladium-catalyzed heteroannulation reaction was employed in the preparation of 2- and 3-trifluoromethylindoles , while a related heteroannulation sequence was investigated that exploited Pd-NaY zeolite catalysts . Another related reaction sequence involving trifluoroacetamidoaryl triflates was used to prepare 2-substituted C5-, C6-, and C7-nitroindoles . A tandem palladium/copper-mediated coupling/cyclization of o-iodobenzenesulfonamide 128 with

124

E.T.Pelkey

propargyl alcohol provided indole-2-methanol 129 . A different heteroannulation reaction of 128 with methyl propiolate provided a novel synthesis of an indole-2-carboxylate building block used in the preparation of duocarmycin SA . A different type of onepot strategy involved a regioselective hydroamination/Heck reaction sequence that converted ochloroanilines into 3-aryl-2-alkylindoIes .

Another class of metal-mediated heteroannulation reactions leading to indoles involves the condensation/Heck reaction o-haloanilines with ketones. These reactions involve intramolecular Heck reactions of enamine intermediates. For example, treatment of o-chloroaniline 130 with ketones in the presence of a palladium catalyst provided highly functionalized indoles 131 . The mild conditions involved allowed for the direct preparation of indole 132 containing an acid-labile dioxolane moiety. Similar reaction sequences provided large-ring fused indoles , cyclopenta[fr]indol-l-ones , and carbazol-4-ones . An intramolecular Heck reaction of cyanoenamine 133 afforded 3-cyanoindole 134, a useful building block for the preparation of indole analogs of mycophenolic acid .

A copper-catalyzed tandem reaction between 2-alkynylarylideneanilines 135 and alcohols provided a novel route to 7V-(alkyloxybenzyl)indoles 136 . A stable tungsten carbene complex was isolated from a reaction involving 135 (R, = Me), f-butyl vinyl ether, and tungsten hexacarbonyl . 2,3-Disubstituted indoles were prepared by the cyclization of 2-

Five-membered ring systems: pyrroles and benzo derivatives

125

alkenylimidoyl selanide radicals . A tandem palladium-mediated cyclization/coupling reaction involving 1,1-dibromo-l-alkenes was reported . For example, treatment of dibromoalkene 137 with arylboronic acids in the presence of a palladium catalyst provided 2-arylindoles 138.

A novel intramolecular carboamination reaction across an alkyne was reported . Treatment of o-alkynyl amide 139 with a platinum catalyst provided 3-acetylindole 141 presumably via zwitterionic intermediate 140.

Another class of indole syntheses involve annelations of pyrroles. One new example of this type of indole synthesis involved the electrocyclization of a 2-alkenyl-3-allenylpyrrole intermediate . This was exploited for the synthesis of indole-4,7-quinones. An important sub-category of indole syntheses includes the preparation of carbazoles. Benzyne chemistry was a key step in the preparation of simple carbazoles . Trapping the benzyne generated from triflate 143 with o-iodoaniline 142 provided yV-arylaniline 144. An intramolecular Heck cyclization of 144 then provided carbazole 145. A tandem anionic cyclization of aniline enediynes 146 furnished 4-substituted carbazoles 147 (not 5-substituted carbazoles as indicated in the paper) . A new milder method for converting nitrobiaryls into carbazoles was reported . Treatment of o-nitrobiphenyl 148 with palladium acetate and 1,10-phenanthroline in the presence of 70 psi carbon monoxide produced carbazole 149 in good yield.

126

E.T.Pelkey

Much research interest in the synthesis of carbazoles is directed at the preparation of natural products. The total syntheses of murrayafoline A 153 and murrayanine have been reported . The key step included a regioselective cycloaddition between oxazolidinone 150 and acrolein which led to benzoxazol-2-one 151 after DDQ oxidation. Ring opening of the oxazol-2-one ring of 151 followed by methylation provided A'-phenylaniline 152. A palladiumcatalyzed intramolecular cyclization of the latter then produced the natural product 153. Finally, venerable iron-mediated chemistry has been utilized in the total synthesis of furoclausine A 154 and 6-chlorohyellazole 155 .

5.2.6 REACTIONS OF INDOLES As a it-excessive heterocycle, indole readily undergoes reactions with electrophiles at nitrogen or C-3. New methods continue to be developed that allow for the regiocontrolled iV-substitution of indoles. The A'-alkylation of indoles 156 with epoxides 157 leading to 2-(indol-l-yl)ethanols 158 utilized cesium carbonate as a base . The yV-acylation of 5-substituted indoles utilized a DCC coupling reaction of benzoic acid derivatives . Thioglycolate proved to be an effective reagent for the deprotection of /V-tosylindoles .


127

A regioselective Friedel-Crafts 3-acylation of indoles was reported that utilized diethyl aluminum chloride as a Lewis acid mediator . A facile, 3-cyanoacetylation of indoles has been reported . Treatment of indole substrates with cyanoacetic acid in acetic anhydride led to the formation of the corresponding 3-cyanoacetylindoles. This reaction was also investigated with pyrroles and anilines. Three different methods for the preparation of 3-sulfenylindoles have been reported. Treatment of indole-2-carboxylate 159a with arenethiols and phenyliodine(III)bis trifluoroacetate (PIFA) in the presence of 1,1,1,3,3,3-hexafluoroisopropanol gave 3arylthioindoles 160. A similar reaction of indole-2-carboxylate 159b with A'-chlorosuccinimide (NCS) and arenethiols produced 3-arylthioindoles 161 . An intramolecular variation of this reaction afforded thioazepine 162. A vanadium catalyst has also been utilized to prepare 3-sulfenylindoles . Treatment of indoles with ammonium thiocyanate and iodine led to the formation of 3-thiocyanoindoles .

Indoles undergo Michael additions in the presence of acid catalysts. Gold-catalyzed conjugate additions of indoles with enones led to the formation of indol-3-yl propanones . With 3-substituted indole substrates, the reactions proceeded to give the corresponding 2substituted indoles. Homotryptamines were formed in a one-pot sequence that involved a Michael addition by indole substrates to acrolein imine derivatives followed by a reductive amination of the indole propionaldehyde intermediates . Asymmetric Michael additions of indole has been investigated with a couple of different catalyst systems. The absolute configuration of the major enantiomer product of the conjugate addition of indoie with benzylidene malonate 163 in the presence of bis-oxazoline 164 and copper triflate was solvent dependent . This reaction run in J-butanol produced (R)-165 in 97% ee while the same reaction in methylene chloride afforded the opposite enantiomer, (5)-165, in 78% ee. Asymmetric Michael additions (up to 89% ee) of indoles to (£)arylcrotyl ketones leading to indol-3-yl propanones was investigated with a salen-based catalyst .

128

E.T.Pelkey

3-Substituted indoles can undergo electrophlic substitution reactions introducing new functionality to the indole 2-position. For example, treatment of tryptamine 166 with NCS in the presence of a 10:3 acetic/formic acid solution led regioselectively to 2-chloroindole 167 . Imine formation followed by treatment with TFA led to the formation of spirooxindoles 168 with good diastereoselectivity (90%+ de). This chemistry was utilized in the total syntheses of spirotryprostatin A , spirotryprostatin B , and elocamine . Treatment of 3-substituted indoles 169 with r-butylisocyanate in the presence of boron trifluoride etherate produced indole-2-carboxamide 170 . Dehydration with phosphorus oxychloride then afforded 2-cyanoindole 171. An alternate method for introducing cyano groups to the 2-position involved generation of a 2-lithioindole followed by quenching with tosyl cyanide . This method was utilized to prepare 2,3-dicyanoindole.

3-Methylindole was regioselectively acylated on the methyl group by treatment with acid chlorides and aluminum chloride in 1,2-dichloroethane . Due to the their biological activity, an impressive number of methods have been reported for the synthesis of bisindolylarylmethanes 172 and trisindolylarylmethanes 173. The former are prepared by treatment of indoles with aryl aldehydes in the presence of an acid catalyst. Catalyst systems, activators, and solvents that have been investigated recently for this transformation include: cerium trichloride , dypsprosium triflate in ionic liquids , iodine , iron(lll) in ionic liquids , potassium hydrogen sulfate , and trichloro-l,3,5-triazine . A solvent-free synthesis of trisindolylarylmethanes 173 utilized acid-washed montmorillonite clay . Bisindolylalkanetriol 176 was prepared by treatment of indole with cyclic hemiacetal 175 in the presence of a clay catalyst


129

. A new synthesis of indole-substituted tetrahydrocarbazoles involved a rearrangement reaction of bisindolylalkanols promoted by diethylamino sulfur trifluoride (DAST) . Bisindolylarylethanes were prepared by combining indole with phenylacetylene in the presence of gallium(III) catalyst . The Amerlyst 15catalyzed condensation of indoles with pyrazole-4-carboxaldehyde furnished bisindolylpyrazolylmethanes 174 .

Three separate methods were developed for the synthesis of 2,3'-bisindolylmethanes 177 . These compounds were converted into indolo[3,2-b]carbazoles by an acidcatalyzed annelation reaction with triethyl orthoformate. A new synthesis of the structurally related indolo[3,2-a]carbazoles involved the cyclocondensation of 2,3'-biindoles with dimethylaminoacetaldehyde diethyl acetal .

An electrophilic annelation reaction was the key step in a synthesis of azepino[3,4-b|indole1,5-dione 179 . Intramolecular cyclization reactions of oxazolone-substituted indoles led to the formation of either p-carbolines or cyclopenta[b]indolones depending on the reaction conditions .

A novel preparation of fused indoles involved the platinum-catalzyed addition of indole to tethered alkenes . For example, treatment of 2-(4-pentenyl)indole 180 with platinum chloride produced tetrahydrocarbazole 181 via a regioselective 6-endo-trig cyclization. The mechanism of the reaction was investigated with a deuterated cycloalkene derivative. A

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similar palladium-catalyzed carboalkoxylation was also reported from the same research group . A palladium-catalyzed allylation of indoles with allyl carbonates furnished 3-alkylated indoles . An intramolecular variation with indolyl carbonates provided a novel synthesis of tetrahydro-p-carbolines and pyrazino|l,2-a]indoles. Due to their wide range of biological activity, many new synthetic routes to the p-carboline family of heterocycles starting from indole substrates have been reported. An intramolecular cyclization reaction of an A'-acyliminium tryptophan (Pictet-Spengler reaction) afforded a short synthesis of the tetrahydro-(?-carboline drug Cialis . A Pictet-Spengler-based four component MCR sequence involving tryptamines, alkynes, acid chlorides, and acryloyl chloride provided rapid access to complex indolo[2,3-a]quinolizin-4-ones 182 . The synthesis of the p-carbolin-1-one analog 183 of pancratistain has been reported . A traceless solid-phase synthesis of carbolin-1-ones has been developed . The key step involved a Bischler-Napieralski type cyclization that cyclized and cleaved the products from the resin.

Three reports of stereoselective Pictet-Spengler reactions leading to tetrahydro-p-carbolines have appeared. Treatment of tryptamine 166 successively with aldehydes, acetyl chloride, and the thiourea-based catalyst 185 furnished tetrahydro-p-carbolines 184 in high enantioselectivity . The acid-catalyzed cyclization of oxazolo[3,2-aJpyridin-5-one 186 (mixture of diastereomers) produced indolo[2,3-a]quinolizin-4-one 187 as a single diastereomer . The preparation of cis- 1,3-disubstituted tetrahydro-p-carbolines has been achieved utilizing a m-specific Pictet-Spengler reaction .

The generation and reactivity of 2-indolylacyl radicals has been studied . For example, irradiation of selenoester 188 and hexabutylditin produced


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benzo[£>|carbazole-6,l 1-dione 190 as the major product via the intramolecular cyclization of intermediate radical 189 followed by oxidation.

An intramolecular addition-elimination reaction of 3-chloro-2-acylindole substrate provided the central tropinone ring in a total synthesis of marine alkaloid caulersin 191 . A zirconium-catalyzed oxidative coupling reaction between /V-methylindole 192 and Nmethylpyrrolidinone furnished 5-substituted pyrrolidinone 193 . The regioselective preference for 3-substitution of the indole ring suggests that an /V-acyliminium cation intermediate might be involved.

An oxidative heterocoupling reaction between indoles and ketones was reported that provided a facile route into a-indolylketones . Treatment of indole and carvone 194 with lithium hexamethyldisilazane (LiHMDS) and the oxidant, copper 2-ethylhexanoate, produced 3substituted indole 195. The latter was converted into hapalindole Q 196.

LiHMDS, THF

A novel 2-arylation of A'-substituted indoles has been reported . Treatment of indole substrates with palladium acetate, triphenylphosphine, cesium acetate and aryl iodides led to the formation of 2-arylindoles. Lithiation of 1-substituted indoles at the 2-position provides a powerful strategy for the synthesis of 2-substituted indoles. Lithiation of A'-Boc-indole 197 and quenching with isopropyl borate gave indole-2-boronic acid 198 . Oxidation of 198 with a complex mixture of reagents including oxone then afforded yV-Boc-oxindoles 199. Lithiation of 3-vinylindoles followed by quenching with MTV-dimethylacetamide provided 2-acetyl-3-vinylindoles, building blocks utilized in a short synthesis of (3-carbolines . Directed lithiation of indole-3-

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carboxamide 200 followed by quenching with trimethyl borate provided indole-2-boronic acid 201, a Suzuki coupling substrate utilized in the synthesis of indolo[2,3-a]carbazole derivative 202 .

Another method for the regioselective functionalization of indoles is the halogen-metal reaction. The regioselective iodine-copper exchange reaction of 2,3-diiodoindole 203 with dineophylcuprate (neophil = nphyl) provided cuprate 204 which underwent reactions with electrophiles to produce 2-substituted indoles 205 . A second iodine-copper exchange then afforded a synthesis of 2,3-disubstituted indoles.

Organometallic cross-coupling reactions provide a regiocontrolled method for the introduction of substituents to the indole ring. Palladium-catalzyed cross-coupling of 2indolyldimethylsilanols have been utilized in the synthesis of 2-arylindoles . For example, treatment of indole-2-silanol 206 and aryl iodides 207 with a palladium catalyst, copper iodide, and sodium /-butoxide provided 2-arylindoles 208.

A detailed study of the Suzuki reaction of benzene-ring substituted bromoindoles was published . The highest yields were obtained with indole substrates containing a tosyl nitrogen protecting group. Palladium-catalyzed carbonylation reactions of unprotected bromoindoles allowed for the synthesis of indolecarboxamides. For example, treatment of 5-


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bromoindole 209 and piperidine with a palladium catalyst in the presence of CO gave indole-5carboxamide 210. A Suzuki reaction of an indole-4-boronic acid was utilized in a total synthesis of lysergic acid .

A regioselective palladium-catalyzed hydrodebromination of 4,6-dibromoindoles produced the corresponding 4-bromoindoIes . This chemistry was utilized in a key step in the preparation of the antihypertensive agent, U86192A 211. Intramolecular cycloaddition reactions of push-pull dipoles were utilized in synthesis of complex indole heterocycles . For example, treatment of diazoketoester 212 with rhodium acetate led to the formation of dipole 213 which underwent a cycloaddition followed by ring opening to give pentacyclic indole 214. The intramolecular cycloadditons of indole-tethered amidofurans provided another route to tetracyclic indoles . The Diels-Alder reaction of ortho-carbazolequinones led to the formation of the corresponding benzo-fused carbazolequinones . A synthesis of benzothiopyrano[2,3-/?]indoles was accomplished by the cycloaddition of l,3-dihydroindole-2-thiones with benzyne dienophiles .

Pummerer-like cyclization reactions were utilized to prepare spirocyclic oxindole derivatives . For example, treatment of 2-sulfenylindole 215 with an iodonium reagent in the presence of 2,6-lutidine produced thioimidate 216. Oxidation of the latter with cerium ammonium nitrate (CAN) gave spirooxindole 217.

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An enantioselective hydrogenation of 3-substituted indoles with a rhodium catalyst system led to the corresponding chiral 3-substituted indolines . 5.2.7 INDOLE NATURAL PRODUCTS AND MATERIALS A large number of structurally diverse indole natural products have been isolated during the past year. Non-fused indole natural products that have recently been identified include the pityriabins (bisindolylspiran alkaloids) and the plakohypaphorines (iodinated tryptophan derivatives) . New photoprotective pigments related to scytonemin have been isolated from cyanobacteria . Novel examples of familiar indole natural product classes that have been isolated include: an unnamed yohimbine alkaloid , conodusarine (vobasine-iboga bisindole) , macrodasine A (spirocyclic macroline alkaloid) , and manzamine-related alkaloids . New oxindole natural products that have been identified include citrinadin A and javaniside . The latter demonstrated DNA cleavage activity. A number of novel 2,3-fused indole natural products have been isolated including lundurine D (cyclopropyl-fused indoline) , mersicarpine 218 (azepine-fused indoline) , jusbetonin (indolo[2,3fejquinoline) , kopsifolines (methano-bridged hexacyclic monoterpene indoles) , and angustilodine (oxepane-bridge pentacyclic indole) . In an attempt to enhance the productivity of NGF-inhibitory carbazostatins, two new indolocarbazole alkaloids were produced and isolated, indolocarbazostatin C and D 219 .

The indole nucleus is commonly found in biologically active lead compounds and designed analogs, and just a few selected examples out of the many published will be mentioned here. The natural occurring meridianins (i.e., 220) were shown to be protein kinase inhibitors . Novel bridged bis-7-azaindolylmaleimides proved to be selective glycogen synthase kinase-3p inhibitors . Simplified manzamine analogs demonstrated anti-cancer and anti-malarial activity . A series of 2,5,6-trichloroindole nucleoside derivatives were investigated as antiviral agents . The total synthesis of complex indole natural products continues to be a thriving area of investigation. A few examples appear in the previous sections. Novel strategies directed towards familiar indole natural product targets that have been communicated include total syntheses of lysergic acid , ergocryptine (lysergic acid derivative) , phenserine (physostigmine congener) , yatakemycin (structurally related to CC-1065) , and strychnine . Halogenated indole natural products that have prepared include been prepared include arborescidine B 221 , dragmadicin F


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, and perophoramidine 222 . An early step in the synthesis of the latter included a cycloaddition between indol-2-one diene and 3-alkylindole. Additional examples of indole natural product total syntheses include: sauveoline (Rauwolfia alkaloid) , dehydrovoachalotine (sarpagine alkaloid) , fuchsiaefoline (sarpagine alkaloid) , gilbertine (uleine alkaloid) , clavicipitic acid (ergot alkaloid) , vallesamidine , vincamajinine (ajmaline bisindole) , and lapidilectine B 223 .

Finally, fused indole natural products that have been synthesized include: thienodolin (thieno|2,3-6]indole) and rutaecarpine (indoloquinazoline) . And lastly, in addition to previously mentioned examples, carbazole natural products that have been prepared include: hyellazole , carbazomycin B , and carbazoquinocin C .

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Five-membered ring systems: pyrroles and benzo derivatives 04OL329 04OL389 04OL533 04OL711 04OL759 04OL819 04OL1037 04OL1057 04OL1151 04OL1665 04OL1869 04OL2213 04OL2293 04OL2369 04OL2465 04OL2615 04OL2825 04OL2849 04OL2857 04OL2897 04OL2953 04OL2957 04OL3087 04OL3199 04OL3241 04OL3649 04OL3739 04OL3881 04OL3981 04OL4129 04OL4249 04OL4957 04OPP289 04PHC1 04PAC365 04SL137 04SL287 04SL439 04SL528 04SL883 04SL907 04SL944 04SL1428 04SL1767 04SL1905 04SL1965 04SL2239 04SL2374 04SL2394 04SL2705

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140 04SL2806 04SC1801 04S610 04S895 04S989 04S1187 04S1951 04S2277 04S2499 04S2574 04S2653 04S2760 04S3043 04T347 04T1505 04T1513 04T1625 04T2051 04T2147 04T2267 04T2517 04T3273 04T3957 04T5315 04T7141 04T8659 04T10739 04T10787 04T10983 04T11283 04T11435 04TL35 04TL539 04TL599 04TL693 04TL769 04TL907 04TL997 04TL1299 04TL1857 04TL2431 04TL2809 04TL2951 04TL3123 04TL3417 04TL3673 04TL3803 04TL3937 04TL4567 04TL5057 04TL5099 04TL5411 04TL5461

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Five-membered ring systems: pyrroles and benzo derivatives 04TL5605 04TL5873 04TL5995 04TL6471 04TL6513 04TL6549 04TL6787 04TL7103 04TL7197 04TL7273 04TL7491 04TL7577 04TL7729 04TL8087 04TL8409 04TL8631 04TL8995 04TL9245 04TL9315 04TL9541 04TL9573 04TL9627

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Chapter 5.3 Five-membered ring systems: furans and benzofurans Xue-Long Hou Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China. [email protected] 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. [email protected] Kap-Sun Yeung Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, P.O.Box 5100, Wallingford, Connecticut 06492, USA. [email protected] Henry N.C. Wong Department of Chemistry, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis,^ The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. hncwong® 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. [email protected] t An Area of Excellence of the University Grants Committee (Hong Kong).

5.3.1 INTRODUCTION We aim to review articles that were published in 2004 on applications and syntheses of furans, benzofurans and their derivatives. Like previous years, many new naturally occurring molecules containing tetrahydrofuran and dihydrofuran rings were identified in 2004. References on compounds whose biological activities were not mentioned are: , , , , , , , , , , , , and. References on those naturally occurring compounds containing tetrahydrofuran or dihydrofuran skeletons whose biological activities were assessed are: , , , , , , , , , , , , ,

Five-membered ring systems: furans and benzofurans

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, , , , , , , , and , References on those furan-containing compounds whose biological activities were not mentioned are: , , , , , , , , , , , , , , and . References of those naturally occurring compounds containing furan skeletons whose biological activities were assessed are: , , , , , , , , , and . References of those benzo|6|furan- or dihydrobenzo[b]furan-containing compounds whose biological activities were not mentioned are: , , , , , , , , , , , , , , , and . References on those naturally occurring compounds containing benzo|&Jfuran or dihydrobenzo[b]furan skeletons whose biological activities were assessed are: and . 5.3.2 REACTIONS 5.3.2.1 Furans Numerous furan cycloadditions and their applications to the synthesis of natural products were published in 2004. The diastereoselectivity as well as the mechanism of stereo- and regioselectivity of the Paterno-Buchi photochemical |2+2| cycloaddition of furan and carbonyl compounds were studied. Furan undergoes [4+21 cycloaddition with a range of benzynes, generated from 2-iodoaryl sulfonates with isopropylmagnesium chloride, to provide oxabenzonorbornadienes . As shown below, the furan 2,3-double bond of the furyl-benzocyclobutene participated in an efficient 6it-disrotatory electrocyclization with the intermediate quinone dimethide to form the fused tetracyclic ring system of the furanosteroid viridin . A related investigation using a cyano-substituted benzocyclobutene was also reported .

A furan-containing chiral alcohol reacted with p-chloroethanesulfonyl chloride, through an intramolecular Diels-Alder cyclization, to form the endo sultone isomer after thermal equilibration, as shown in the following scheme. The sultone was further converted into a substituted cyclohexene, which was a key intermediate in the total synthesis of 1,10seco-eudesmanolides eriolanin and eriolangin .

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The chemistry of intramolecular [4+3J cycloaddition of nitrogen-stabilized oxyallyl cations derived from chiral allenamides, originally reported in 2003, was extended to the use of a furan tethered to either the a- or p-position of the allene. As demonstrated below, polycyclic compounds were synthesized in good yields and with a high diastereomeric ratio (d.r.).

A related intermolecular [4+3] cycloaddition of a furan with 2-aminoallyl cations, generated from methyleneaziridines under Lewis acid conditions, was also developed. A representative example is shown below .

A novel photochemical cycloaddition between 2-cyanofuran and 2-alkoxy-3cyanopyridines gave the [4+4] product as the major isomer. The regioselectivity and stereoselectivity of this singlet photoaddition process was explained by frontier molecular orbital theory .

New Au(III)-pyridine-2-carboxylate complexes were developed to catalyze the intramolecular reaction between furan and acetylene to form phenols . These pre-catalysts provide higher reaction conversion than AuCl3. The Lewis acid catalyzed vinylogous Mukaiyama-Mannich addition of trimethylsilyloxyfuran to aldimines, that generates S-amino-y-butenolide intermediates, was applied to the synthesis of piperidines


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, and carba-/3-L-mannopyranose derivatives . Vinylogous Mukaiyama-Michael addition of trimethylsilyloxyfuran to 3-alkenoyI-2-oxazolidinones, as catalyzed by a chiral l,l'-binaphthyl-2,2'-diamine-Ni(II) complex, provided y-butenolides with high diastereo- and enantioselectivity (up to 97% ee) . As depicted by the following example, the triphenylphosphine-catalyzed addition of trimethylsilyloxyfuran to Morita-Baylis-Hillman acetates proceeded regio- and stereoselectively, providing interesting Y-butenolides with high diastereoselectivity and in high yields .

A notable application of the photosensitized oxidation of furan, reported in 2004, is the construction of the ABC ring system of the marine alkaloid norzoanthamine. As illustrated below, the furan moiety was oxidized to a Z-y-keto-a.p-unsaturated silyl ester intermediate, which was then converted to the stable methyl ester. This key intermediate was elaborated to the tricyclic compound via an intramolecular Diels-Alder reaction .

In a formal total synthesis of (-)-secosyrin 1, Birch reduction and subsequent alkylation of the chiral furylamide provided the dihydrofuran with high diastereoselectivity .

5.3.2.2 Di- and Tetrahydrofurans Dihydrofuran was used as an aldehyde equivalent in a reaction with an aryl hydrazine under strongly acidic conditions to give the 3-substituted indole in high yield. The isolation of the 2-methylindole derivative depicted below as a single regioisomer by this method is noteworthy .

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Indium trichloride in water catalyzed the conversion of dihydrofuran to the corresponding lactol, which was an intermediate in an indium-promoted allylation with various allylic bromides to provide 1,4-diols. The reaction with allyl bromide is shown in the following scheme .

Coupling of dihydrofuran with an alkene-zirconocene complex and subsequent addition of an electrophile, provided the ew-disubstituted homoallylic alcohol, as shown in the example below. An insertion/p-elimination pathway involving the formation of an oxazirconacyclooctene intermediate was proposed .

3-methoxy-substituted 2,5-dihydrofurans were oxidized using DDQ to form <x,punsaturated y-keto aldehydes, which are useful intermediates for the synthesis of tetronic acids and pyridazines . A hetero-Diels-Alder cycloaddition between 2,3dihydrofuran and an o-quinone methide intermediate, generated from o-methyleneacetoxy phenol derivatives, was a key step in the synthesis of alboatrin . Platinumcatalyzed cyclization of 2,3-dihydrofuran with the tethered alkynes provided the fused cyclopropane product, as illustrated below. Oxidative cleavage of the cyclopropane ring and subsequent trapping with water gave the interesting bisketal .


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The first example of an enantioselective dipolar cycloaddition of ethyl diazopyruvate to 2,3-dihydrofuran, catalyzed by the ruthenium-PyBox complex, to provide dihydrofurofuran of up to 74% ee, as shown below, was reported. The absolute configuration of the adduct was not determined .

Synthetic applications of 8-oxabicycloL3.2.1Joct-6-en-3-one were reviewed . Ruthenium-catalyzed [2+2] cycloaddition of oxabicyclic alkenes with a chiral acetylenic acyl sultam provided the cycloadduct with excellent diastereoselectivity and enantioselectivity. An example is shown in the scheme below .

A tandem ring opening/cross metathesis of 2-tosyl-7-oxanorbomene with vinyl acetate provided a 2,5-divinyl substituted tetrahydrofuran as a single regioisomer. The high regioselectivity of the reaction was derived from the apparent directing effect of the sulfone group .

An additional example of tandem ring opening/cross metathesis is shown in the scheme below . Formation of new six-, seven- and eight-membered rings in the polycyclic product was achieved in one single step, although the product was obtained in only 10% yield and stoichiometric amount of Grubbs' second generation reagent was used. Another interesting example of a one-pot ring opening/cross metathesis/ring closing metathesis to construct the 9-oxabicyclo[4.2.1]nona-2,4-diene of (+)-mycoepoxydiene from 7-oxabicyclo[2.2.1 |hept-2-ene and 1,3-butadiene was also reported .

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A rhodium-(PPF-P-r-Bu2) complex-catalyzed enantioselective addition of aliphatic and aryl thiols to 7-oxabenzonorbornadiene to provide 1,2-trans isomers in high yields and enantiomeric excess was developed . The scope of enantioselective palladiumcatalyzed alkylative ring opening of oxabicyclic alkenes using organozinc reagents was reported . Enantioselective ring opening of 7-oxabenzonorbornadiene by dimethylzinc was also catalyzed by a chiral palladium Fesulphos complex to provide 1,2-cis products in 97% ee . A related palladium-catalyzed ring opening with organozinc halides in the presence of the chiral ligand (S)-j-Pr-PHOX, to provide the cisisomer with up to 96% ee, is illustrated below .

A dimethylzinc/air-generated tetrahydrofuran radical reacted with aldehyde to give the a-hydroxylated p-addition product, which was isolated as the keto-lactone after Jones oxidation. It was proposed that the initial THF a-radical that was generated was able to react with molecular oxygen to generate an a-peroxygenated THF p-radical as the key intermediate .

Protection of hydroxyl groups as a 2-tetrahydrofuran ether can be performed by the reaction of an alcohol with THF using (diacetoxyiodo)benzene under microwave irradiation as shown below . A similar reaction using carbon tetrachloride and a catalytic amount of fer/-butylperoxy-Y3-indane was also reported .

Tetrahydrofuran was coupled to a variety of aromatic and aliphatic terminal alkynes under microwave irradiation to provide a mixture of cis- and rram-2-vinyltetrahydrofuran. A representative example is shown below .


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The [3+2] cycloreversion of the transient bicyclo[m.3.0]alkan-3-on-2-yl-l-oxonium ylide that was genenrated by the rhodium-catalyzed intramolecular reaction of a tetrahydrofuran substituted diazoketone was found to be stereospecific as illustrated below. The result supports a concerted mechanism .

2-Ethynyl-substituted tetrahydrofurans can be ring-opened via transfer hydrogenation using 10 mol% of TpRuPPh3(MeCN)2PF6 (Tp = tris(l-pyrazolyl)borate) to provide the dienyl ketone in high yield. An example is illustrated below .

5.3.3 SYNTHESIS 5.3.3.1 Furans An epothilone analog, fuano-epothilone C was synthesized using 5-allyl-2-furfural as an intermediate, which, in turn, was prepared from furan by allylation followed by a Vilsmeier-Haack reaction . The first total synthesis of racemic viridine, the parent member in the family of furanosteroids, was reported. Thus, the furan ring as a subunit was introduced by the reaction between 2-trimethylsilyl-3-vinyl furan and ra-BuLi, and was followed by treatment with a carbonyl compound . An asymmetric total synthesis of the trisubstituted furan-containing natural product, (-)-nakadomarin A was reported, in which the furan ring was formed by treatment of an endoperoxide with ?-BuOK, followed by HC1 . A modified synthesis of a chiral furan diol from D-glucal in 82% yield employing HC1O4 supported on silica gel was reported . Chiral furan amino acids were synthesized by the traditional cyclization of cw-2-butene-1,4-diol in the presence of PCC. Cyclic trimers were obtained using these furan amino acid building blocks . In an enantioselective synthesis of ricciocarpins, better diastereoselectivity in the reaction of chiral aldehyde with furyl organometallic was provided when the furyltitanium reagent, furan-3-Ti(OPr')3, was used instead of the corresponding Li-, Mg- and Zn-furyl reagents . An acid-catalyzed synthesis of 2,3,4-trisubstituted furans using substituted 1,4-diketones under microwave irradiation was recorded . Furan-3-carboxylic acid derivatives were prepared via aromatization of 3trichloroacetyl-4,5-dihydrofuran followed by nucleophilic displacement by hydroxide, alcohols and amines as can be seen below .

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Siphonodicidine, a natural sesquiterpene containing a 2,4-disubstituted furan as a substructure, was synthesized in a regioselectivity-controlled manner. The key intermediate was prepared by the coupling of a silyloxyfuran with a bromogeranyl acetate in the presence of silver trifluoroacetate followed by reduction and hydrolysis as depicted in the following scheme .

Furyldifluoromethyl aryl ketones were formed when furan was allowed to react with difluoroenolsilyl ethers in the presence of Cu(OTf)2. If 2-furylcarboxylate was used, the corresponding substituted furan was also provided .

Mercury triflate was an effective catalyst for the transformation of l-alkyne-5-ones to 2-methyl-5-substituted furans. The reaction involves a protodemercuration of a vinylmercury intermediate generated in situ. When other substituents are present at the a-position of the carbonyl group, corresponding 2-methyl-4,5-disubstituted furans were provided. A plausible reaction path was provided .

2,4-Furanophanes were synthesized from the palladium-catalyzed cyclization of 1 ,ndiallenyl diketones although the yields were low .


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An example of palladium-catalyzed furan synthesis utilizing allenes as starting materials was reported, in which 2,4-disubstituted-2,3-butadienoic acids and 1,2-propadienyl ketones were used and 2,4-disubstituted furans were produced. The reaction may proceed via a matched double oxypalladation-reductive elimination process . In a similar cycloisomerization of substituted allenes to tri- and tetrasubstituted furans with regioselectivity, the allenes were produced in situ from acyloxy-, phosphatyloxy- and sulfonyloxy-substituted alkynylketones via a 1,2-migration of such substituents catalyzed by CuCI or AgBF4 .

l,l-Bisfuryl-l-[5-(tri-2-furylmethyl)Jfurylmethane was serendipitously formed in an attempt to synthesize a tricarboxaldehyde via the reaction of tri-2-furylmethane and DMF and n-BuLi. The same product was also formed when the reaction was carried out using 2 equivalents of r-BuOK in THF. Presumably the reaction proceeds via a radical intermediate .

Several tetraoxaquaterenes were prepared in relatively good yields from the reaction of 2,2-difurylpropane and ketones. The key point of the reaction is that highly concentrated sulfuric acid (88-91%) was used as a reaction media .

A one-pot synthesis of furan 2-substituted-3-carboxylic and 2-substituted-3,4dicarboxylic esters was reported. Thus, reaction of an acyl isocyanate with trimethylsilyldiazomethane, a safe replacement for hazardous diazomethane, gave 2substituted oxazoles, which were treated with dimethyl acetylenedicarboxylate or ethyl propiolate to afford the corresponding di- and trisubstituted furans in good yields .

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A nucleophilic substitution reaction of sulfinylfurans with an allyltin reagent via a Pummerer-type reaction afforded 2,3-disubstituted and 2,3,5-trisubstituted furans with high regioselectivity. An example is shown below .

Reaction of a naphthalene derivative with chloroacetone gave rise to the natural product named neotanshinlactone, whose biological activity as an anti-tumor agent was evaluated .

An unexpected bridged bicyclic furan was formed by rearrangement of a tetrahydroxydecalinone, as illustrated below. Presumably the reaction proceeds via a basepromoted retro-aldol process .

The naturally occurring furanoeremophilane sesquiterpenoid, 6p-hydroxyeuryopsin, was synthesized via an intramolecular cyclization of the trisubstituted furan, which in turn was prepared by a Stille-coupling of the corresponding 2-furylstannane and cyclohexylmethyl bromide, followed by a suitable transformation of the protected hydroxymethyl to a formyl group .


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An efficient and atom-economical Au-catalyzed poly substituted furan synthesis was reported . As can be seen, Au-catalyzed cyclization of 2-(l-aIkynyl)-2-alken-lones in the presence of MeOH as a nucleophile afforded 2,3,5-trisubstituted furans with high regioselectivity and high yields. A variety of alcohols, 1,3-diketones, some indoles, and amines can serve as nucleophiles.

A novel organophosphine-mediated protocol for the construction of substituted furans with different substitution patterns was disclosed, in which a variety of y-aroyloxy butynoates were converted to 2,3- and 2,4-disubstituted furans as well as 2,3,5-trisubstituted furans as shown below . Another phosphine-initiated reaction leading to the formation of vinylfurans with substituents on the furan ring using 2-penten-4-ynones and a various aldehydes was also published .

2-Alkenyl 1,3-diketones were reported as useful starting materials for the preparation of 2,3,5-trisubstituted furans via a palladium-catalyzed oxidative alkoxylation process. The alkenyl group can be allyl, homoallyl and 4-pentenyl .

A highly regioselectivity-controlled transformation of alkylidenecyclopropyl ketones, easily prepared by the regioselective cyclopropanation of allenes or the reaction of alkylidenecyclopropanyllithium with yV,./V-dimethyl carboxylic acid amides, to 2,3,4trisubstituted and 2,3,4,5-tetrasubstituted furans using Nal (or PdCl2(MeCN)2 or Pd(PPh3)4) as catalyst, is depicted in the following scheme .

A previously reported palladium-catalyzed preparation of 2,3,5-trisubstituted furans from epoxyalkynyl esters was extended successfully to the synthesis of 2,3,4,5-

154


tetrasubstituted furans as well as 2,3,4-trisubstituted furans when aryl halides and triflate were used .

A novel one-pot, three-component reaction using an aminopentanoate, aldehydes and isocyanoacetamide as starting materials gave tetrahydrofuro[2,3-c]pyridines in high yields .

Another three-component reaction between aldehydes, dimethyl acetylenedicarboxylate and cyclohexyl isocyanide in ionic liquid under mild conditions afforded tetrasubstituted furans in high yields as illustrated below . A similar reaction using 2-furyl-2-oxoacetamide derivatives instead of aldehydes produced substituted furylfurans .

An efficient formation of substituted furans under solvent-free, microwave irradiation conditions was reported . Under these conditions, many alkylidenecyclopropanes were converted to ring fused furans in good yields.

A detailed description of the synthesis of furylcyclopropanes from the reaction of alkenes and previously reported 2-furylcarbenoids by a metal-catalyzed cyclization of enyne ketones also appeared as shown in the following scheme . This protocol was expanded by the same authors to the synthesis of furylcyclopropane-containing polymers as well as furfurylidene-containing polymers when phenyl enynones with a vinyl and formyl group at the ortho position of a benzene ring were used .


155

5.3.3.2 Di- and Tetrahydrofurans Extensive efforts have been given to the synthesis of di- and tetrahydrofurans in 2004. A review on the syntheses of furofuran lignans has appeared . Like before, Williamson cycloetherization continues to be one of the most popular and practical methods for preparing tetrahydrofurans , , , , . An interesting example in this category involved the formation of substituted tetrahydrofuran derivatives upon treatment of oligomers of to-alkenyl iodoacetates with Grignard reagents . The intramolecular opening of epoxides by hydroxy groups is also a very popular method to realize tetrahydrofurans , , , , , , , , . Another way in which tetrahydrofuran rings can be obtained is by electrophile-promoted cyclization of 4-pentenol derivatives. The electrophile can be mercuric salts , ; halogenating reagents , , , , , ; phenylselenium reagents , , , , or a platinum catalyst . A one-pot synthesis of 2,3,5-trisubstituted tetrahydrofurans by a double SakuraiHosomi reaction was reported and an example is shown below . Another procedure featuring the pivotal use of an O-alkylation route is also known .

Radical-mediated cyclization has also been employed in the synthesis of tetrahydrofurans , , , , , , , , , , . An application of the radical strategy was recently utilized in the synthesis towards entnocardione A .

Permanganate- and perruthenate-promoted oxidative cyclization of hexa-l,5-dienes are usually key steps in the total synthesis of naturally occurring molecules containing tetrahydrofuran rings , , . Cycloaddition reactions of oxygen-tethered compounds were also used to construct oxygen-bridged heterocycles, in particular tetrahydrofurans. These methodologies include intramolecular nitronate cyclization , ; intramolecular Diels-Alder cycloaddition , , ; intermolecular [4+3]

156


oxocarbenium cycloaddition ; intermolecular [5+2] oxidopyrylium cycloaddition ; intermolecular carbonyl ylide cycloaddition , and intermolecular |3+2| carbonyl ylide cycloaddition , . With appropriate transformations, heterocycles such as acetals , , , , ; y-lactones ; 2,3dihydrofuran and 2,5-dihydrofuran were all converted to substituted tetrahydrofurans. Organometallic reagents are also useful in the construction of tetrahydrofuran skeletons. These procedures include a microwave-assisted group-transfer cyclization of organotellurium compounds ; rhodium-catalyzed carbonylative | 2 + 2 + l | cycloaddition of 1,3-dienes, alkenes and CO , ; palladium-catalyzed 1,2,7-triene cyclization/arylation cascade reactions ; intramolecular cyclization involving a copper carbenoid and a one-pot three-component 1,3-dipolar procedure involving carbonyl ylides, aldehydes and dipolarophiles . The following scheme shows the reaction of a zirconacyclopentene with an aldehyde in the synthesis of a tetrahydrofuran derivative .

Aldehydes were utilized to react with a number of reagents, e.g., cyclic allylsiloxanes , dicobalthexacarbonyl complex of dimethyl 2-ethynylcyclopropane-l,ldicarboxylate and an acylated bromooxazolidinone to form complex tetrahydrofuran frameworks. The scheme below is an example to demonstrate the versatility of this approach .

An O-alkylation procedure generated 2-methylenetetrahydrofuran skeletons in good yields, and an example is shown in the following scheme .

In the presence of I ^ ' E t j O , methylenecyclopropanes reacted with aldehydes to afford 3-methylenetetrahydrofurans . Using a catalytic amount of Zn(OTf)2 in EtjN, various alkylidene malonates react with propargyl alcohol to give 3methylenetetrahydrofurans . Oxygen-tethered bromodienes were shown to provide 3-methylenetetrahydrofurans via a cascade palladium-catalyzed cyclizationcarbonylation reaction . On the other hand, propargyl allyl ethers underwent a cycloisomerization reaction catalyzed by palladium reagents , ;


157

rhodium reagents , , , , and nickel reagents to form 3-methylenetetrahydrofurans. Similarly, rhodium-catalyzed cycloisomerization of bis(propargyl) ethers also led to 3,4bis(methylene)tetrahydrofuran frameworks as shown below.

When acyclic and cyclicl-alkenyi aminosulfoxonium salts were allowed to react with a base, p-silyloxy alkylidene carbenes were generated, which underwent a l,5-O,Si-bond insertion and 1,2-silyl migration to form 2,3-dihydrofurans . As can be seen in the scheme below, 2,3-dihydrofurans could also be formed from various 2,2-dimethyl-5methoxy-carbonyloxy-3-pentyn-l-ols in the presence of p-methoxy phenol via a palladiumcatalyzed cyclization reaction .

Naturally occurring molecules including a 2,3-dihydrofuran ring named CJ-16,169 and CJ-16,170 were synthesized employing a hydroxypyridinone as a precursor as illustrated in the following scheme .

epACJ-16,169 (40%)

ep/-CJ-16,170 (11 %)

Formation of dihydrofurocoumarins through palladium-catalyzed cascades and subsequent acid-catalyzed cyclization was also recorded . An unexpected formation of tetrasubstituted 2,3-dihydrofurans was reported through reactions between pketo polyfluoroalkanesulfones and aldehydes . Photochemically-induced rearrangement of 3-azabicyclo[3.3.1]nonane skeletons also led to novel compounds fused with 2,3-dihydrofurans rings as shown below .

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2,5-Dihydrofurans can most conveniently be synthesized via ring-closing metathesis of bis(allyl) ethers , , , , . Substituted 2,3-butadienols were also utilized to form 2,5-dihydrofurans , . The latter synthesis is shown in the following scheme.

Ring contraction of 3,6-dihydro-l,2-dioxines with PPh3 also led to the formation of 2,5-dihydrofurans as depicted below .

5.3.3.3 Benzo[6]furans and Related Compounds 3(S),17-Dihydroxytanshinone was obtained by the ultrasound-promoted Diels-Alder reaction between a benzofurandione and a vinylcyclohexene, followed by oxidation and desilylation as illustrated in the following scheme . A fully functionalized benzofuran was also utilized as a major building block in the total synthesis of kendomycin . Benzofuran-based tetraols were also employed as key fragments in the synthesis of some helical molecules .

Two new classes of voltage-gated potassium channel Kvl.3 blockers were obtained by transformations of naturally occurring khellinone .


159

Two model p-quinone methide ring systems of kendomycin were obtained by oxidation with 2,2-dimethyldioxirane (DMDO) and NaIO4, respectively. The demonstrated chemistry paves the way for the total synthesis of kendomycin . Anodic oxidation of 2,3-dihydrobenzol61furan derivatives was also utilized to synthesize 2-fluoroand 2,3-difluoro-2,3-dihydrobenzo[6]furan derivatives .

Dibenzofurans can be constructed using benzyne chemistry, by nucleophilic addition of o-iodophenols to benzyne (generated by treatment of silylaryl triflate with CsF), followed by the Pd-catalyzed intramolecular arylation .

The intramolecular Fujiwara-Moritani/oxidative Heck reaction was applied to the synthesis of functionalized benzo[bjfurans and dihydrobenzoL£>]furans in 50-80% yields, and 15 examples are given in the article . Ionic liquid (fbmimJBF4) was found to be an effective solvent for the PdCl2-catalyzed intramolecular Heck reaction to realize benzofurans . Another palladium-catalyzed intramolecular Heck reaction between vinyl triflate and benzo[£>]furan was utilized to construct the seven-membered ring based (-)-frondosin B .

Palladium-catalyzed annulation to make the biologically interesting dihydrofuroflavonoids was realized by coupling 1,3-dienes with o-iodoacetoxyflavonoids as shown in the following scheme. This reaction is quite general and regioselective, and a wide variety of terminal, cyclic, and internal 1,3-dienes can be used .

160

X.-L. Hou, Z. Yang, K.-S. Yeung andH.N.C. Wong 0 Pd(dba)2 (5 mol%) dppe(5mol%)

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In connection with a total synthesis of frondosin B, the key intermediate shown below was synthesized by a sequential reaction of the phenol, the enyne and the bromide in a onepot operation as shown . The palladium-catalyzed intramolecular C-0 bond formation between aryl halides and enolates was employed to make 2,3-disubstituted benzo|b|furans . 1. MeMgBr THF

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I—v

80 °C, 9 h ( 61%

\

)=O

l

ifV-/

^^-O

/ \

\=/

BrJ 3-Fluoromethylated benzo[i]furans were made by palladium-catalyzed coupling of fluorine-containing internal alkynes with various 2-iodophenols in the presence of P('Bu)3 as an essential ligand . Pd2(dba)3 (20 mol%) P*Bu3 (80 mol%)

ff—\

F3C

r^N^'

K2CO3 (5 equiv)

— { Vci + r £

CF 3

]furan was also made by the olefin metathesis approach .

The first total and biomimetic synthesis of violet-quinone illustrated below was accomplished by utilizing an oxidative dimerization of the substituted 4-methoxy-l-naphthol with a ZrO2/O2 system, the initially formed dimer eventually led to the target molecule . The same research group later published the SnCl4-mediated oxidative biaryl coupling reaction to build up the dinaphthanofuran framework . Silver(I) acetate was found to be an efficient agent to make the dimer of resveratrol in a high yield . Oxidation of phenol with PIFA was also applied to construct the framework of (-)-galanthamine .

A new family of benzo[£>lfurans was made by an anodic oxidation of an aqueous solution of 3-substituted catechols, and then coupled with dimedone as depicted below .

162


As shown in the scheme below, an efficient construction of optically active dihydrobenzo[i)]furan-ring via a C-H insertion reaction led to the total synthesis of (-)ephedradine A . A radical initiated benzo[fc]furan formation was applied to the synthesis of spiro[chroman-3,3'-(2'//)-benzofurans] with n-Bu3SnCl and Na(CN)BH3 as reagents . A similar approach was also demonstrated by the same group to make spiro[pyrimidine-6,3'-2',3'-tetrahydrobenzofuran]-2,4-diones . On the other hand, w-Bu3GeH was reported to be an effective agent as compared to «-Bu3SnH in the synthesis of 3-substituted-2,3-dihydrobenzo|6|furans . Moreover, a photoinduced fast tin-free reductive radical dehalogenation was found to be useful for the synthesis of 2,3-dihydrobenzo[>]furans.

3-Cyano- or 3-ethoxycarbonyl-2-methylbenzo[b]furans were prepared in a one-step synthesis by microwave induced Claisen rearrangements without solvent as illustrated in the following scheme . The Fries rearrangement was employed in the synthesis of benzo[£>lnaphtha[2,3-]furans from 2-stannane substituted benzol |furans .

2-Arylbenzo[£>]furans were synthesized by the [3,3]-sigmatropic rearrangement of oxime ethers .

In the synthesis of furoclausine A, the acid-catalyzed furan formation was used to make the framework of furo[3,2-a]carbazole from the ketal as depicted in the scheme below . An acid-catalyzed intramolecular cyclization to form the framework of furoquinoline alkaloids was also achieved from 3-oxiranylquinolines . Furanoeremophilane sesquiterpenes were synthesized by acid-mediated furan ring formation from the corresponding phenolic a-ketone ethers . 3-Aryl-2,2-dialkyl-2,3dihydrobenzo[£>]furans were derived from phenols and 2-aryl-2,2-dialkylacetaldehydes in the presence of a catalytic amount of CF3SO3H . A ZnCl2-mediated benzo[6]furan formation was utilized to make benzo|&]furan-2-carboxylate from 3dimethylaminopropenoates .


163

The fra«.s-5,6-ring system existing in phenylmorphans was constructed by the displacement of nitro-activated aromatic fluorine with a hydroxyl group .

The synthetic strategy involving an intramolecular hydroxyl epoxide opening was applied to build up the cyclopenta[b]benzofuran ring for the total synthesis of the naturally occurring rocaglaol .

Coumestrol was synthesized by the condensation of a phenyl acetate with a benzoyl chloride, followed by demethylation and cyclization .

5.3.3.4 Benzo[c]furans and Related Compounds The common alkyne trapping reagent 1,3-diphenylisobenzofuran was used as a precursor towards the synthesis of new analogs of famesyltransferase inhibitor RPR 130401 . A rhenium isobenzofuryl carbene complex was also synthesized recently . As depicted below, thermal rearrangement of the ri2-(o-ethynylbenzoyl)rhenium complex produced the benzo[c]furyl rhenium carbene complex, presumably via a nucleophilic attack of the carbonyl oxygen on the rhenium-bound alkyne. The alkyne rhenium complex and the rhenium carbene complex were both observed at equilibrium. Like all other benzo[c]furans, the rhenium isobenzofuryl carbene species reacted smoothly with

164


dimethyl acetylenedicarboxylate .

to

form

the

corresponding

Diels-Alder

adducts.

Cyclotrimerization of 'oxabenzonorbornadiene' utilizing copper(I) thiophene-2carboxylate as a catalyst generated the potentially ionophoric syn- and anri-isomers of 5,6,1 l,12,17,18-hexahydro-5,18:6,1 l:12,17-triepoxytrinaphthylene . Bis(propargyl) ethers were converted to dihydrobenzo|c]furans through either a palladiumcatalyzed tandem reaction with arylboronic acids or an iridium-catalyzed [2+2+2] cycloaddition reaction with alkynes.

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 04AG(E)610 04AG(E)615 04AG(E)1417 04AG(E)1857 04AG(E)1860 04AG(E)1935 04AG(E)1998 04AG(E)2020 04AG(E)2280 04AG(E)2661 04AG(E)3175 04AG(E)3932 04AG(E)3944

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168 04JOC5302 04JOC5322

04JOC5770 04JOC6486 04JOC6715 04JOC6874 04JOC7220 04JOC7989 04JOC8789 04JOC8796 04OBC585 04OBC806 04OBC965 04OBC1145 04OBC2131 04OL79 04OL115 04OL389 04OL457 04OL465 04OL893 04OL961 04OL1123 04OL1175 04OL1405 04OL1593 04OL1625 04OL1661 04OL1749 04OL1761 04OL1773 04OL1841 04OL1895 04OL1943 04OL2015 04OL2027 04OL2063 04OL2229 04OL2733 04OL2833

X.-L. Hou, Z. Yang, K.-S. Yeung andH.N.C. Wong K.M. Dawood, T. Fuchigami, J. Org. Chem. 2004, 69, 5302. A. Hashimoto, A.K. Przybyl, J.T.M. Linders, S. Kodato, X. Tian, J.R. Deschamps, C. George, J. L. Flippen-Anderson, A.E. Jacobson, K.C. Rice, J. Org. Chem. 2004, 69, 5322. G. Prestat, C. Baylon, M.-P. Heck, G.A. Grasa, S.P. Nolan, C. Mioskowski, J. Org. Chem. 2004, 69, 5770. C.-H. Xing, S.-Z. Zhu, J. Org. Chem. 2004, 69, 6486. J. Montalt, F. Linker, F. Ratel, M. Miesch, J. Org. Chem. 2004, 69, 6715. S.M. Miles, S.P. Marsden, R.J. Leatherbarrow, W.J. Coates, J. Org. Chem. 2004, 69, 6874. N. Pichon, A. Harrison-Marchand, P. Mailliet, J. Maddaluno, J. Org. Chem. 2004, 69, 7220. Y. Matsuya, K. Sasaki, M. Nagoaki, H. Kakuda, N. Yoyooka, N. Imanishi, H. Ochiai, H Nemoto, J. Org. Chem. 2004, 69, 7989. K.-i. Takao, H. Yasui, S. Yamanato, D. Sasaki, S. Kawasaki, G. Watanabe, K.-i. Tadano, J. Org. Chem. 2004, 69, 8789. D.M. Hodgson, F. Le Strat, T.D. Avery, A.C. Donohue, T. Briickl, J. Org. Chem. 2004, 69, 8796. W.R. Bowman, S.L. Krintel, M.B. Schilling, Org. Biomol. Chem. 2004, 2, 585. CM. Williams, R. Heim, DJ. Brecknell, P.V. Bernhardt, Org. Biomol. Chem. 2004, 2, 806. D.G. Hulcoop, H.M. Sheldrake, J.W. Burton, Org. Biomol. Chem. 2004, 2, 965. M.F. Buffet, D.J. Dixon, S.V. Ley, D.J. Reynolds, R.I. Storer, Org. Biomol. Chem. 2004,2, 1145. T. Yamada, M. Iritani, K. Minoura, K. Kawai, A. Numata, Org. Biomol. Chem. 2004, 2, 2131. K.R. Campos, J.C.S. Woo, S. Lee, R.D. Tillyer, Org. Lett. 2004, 6, 79. A. Fayol, J. Zhu, Org. Lett. 2004, 6, 115. G. Minetto, L.F. Raveglia, M. Taddei, Org. Lett. 2004, 6, 389. D.J. Kerr, A.C. Willis, B.L. Flynn, Org. Lett. 2004, 6, 457. T.J. Donohoe, J.W. Fisher, P.J. Edwards, Org. Lett. 2004, 6, 465. G. Nguyen, P. Perlmutter, M.L. Rose, F. Vounatsos, Org. Lett. 2004, 6, 893. H. Hioki, S. Yoshio, M. Motosue, Y. Oshita, Y. Nakamura, D. Mishima, Y. Fukuyama, M. Kodama, K. Ueda, T. Katsu, Org. Lett. 2004, 6, 961. R.D. White, G.F. Keaney, CD. Slown, J.L. Wood, Org. Lett. 2004, 6, 1123. M. Shi, B. Xu, J.-W. Huang, Org. Lett. 2004, 6, 1175. P. Cironi, J. Tulla-Puche, G. Barany, F. Albericio, M. Alvarez, Org. Lett. 2004, 6, 1405. Y.-H. Shen, S.-H. Li, R.-T. Li, Q.-B. Han, Q.-S. Zhao, L. Liang, H.-D. Sun, Y. Lu, P. Cao, Q.-T. Zheng, Org. Lett. 2004, 6, 1593. G.M. Weeresakare, Z. Liu, J.D. Rainier, Org. Lett. 2004, 6, 1625. J. Marrero, A.D. Rodriguez, P. Baran, R.G. Raptis, J.A. Sanchez, E. Ortega-Barria, T.L. Capson, Org. Lett. 2004, 6, 1661. M.P. Sibi, L. He, Org. Lett. 2004, 6, 1749. O. Miyata, N. Takeda, T. Naito, Org. Lett. 2004, 6, 1761. J.S. Clark, T.C. Fessard, C. Wilson, Org. Lett. 2004, 6, 1773. J. Wu, Q. Xiao, J.-S. Huang, Z.-H. Xiao, S.-H. Qi, Q.-X. Li, S. Zhang, Org. Lett. 2004, 6, 1841. G. Keum, S.B. Kang, Y. Kim, E. Lee, Org. Lett. 2004, 6, 1895. D.M. Howells, S.M. Barker, F.C. Watson, M.E. Light, M.B. Hursthouse, J.D. Kilburn, Org. Lett. 2004, 6, 1943. M. Nakamura, C.-G. Liang, E. Nakamura, Org. Lett. 2004, 6, 2015. P.-Y. Roger, A.-C. Durand, J. Rodriquez, J.-P. Dulcere, Org. Lett. 2004, 6, 2027. D.M. Smith, K.A. Woerpel, Org. Lett. 2004, 6, 2063. E. Dorta, A.-R. Diaz-Marrero, M. Cueto, L. D'Croz, J.L. Mate, J. Darias, Org. Lett. 2004, 6, 2229. K. Uneyama, H. Tanaka, S. Kobayashi, M. Shioyama, H. Amii, Org. Lett. 2004, 6, 2733. M. Li, X.-X. Yan, W. Hong, X.-Z. Zhu, B.-X. Cao, J. Sun, X.-L. Hou, Org. Lett. 2004, 6, 2833.

Five-membered ring systems: furans and benzofurans 04OL2877 04OL3059 04OL3131 04OL3191 04OL3513 04OL3617 04OL3679 04OL3793 04OL3699 04OL3739 04OL3793 04OL3821 04OL3865 04OL4041 04OL4595 04OL4755 04OM4121 04P127 04P207 04P221 04P377 04P387 04P427 04P439 04P921 04P969 04P1095 04P2031 04P2051 04P2057 04P2101 04P2499 04P2533 04P2833 04P2929 04P3021 04P3075 04P3083 04P3113 04S811 04S865 04S1262

169

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170 04S1359 04S1864 04S2376 04SL65 04SCI495 04SL528 04SL655 04SL829 04SL1207 04SL1375 04SL1434 04SL1437 04SL1933 04SL2291 04SL2484 04SL2573 04T115 04T1229 04T1417 04T1637 04T1665 04T1913 04T2843 04T3359 04T3941 04T4139 04T4475 04T4781 04T6015 04T6295 04T9283 04T9615 04T9675 04T9963 04T9991 04T10619 04T10651 04T10921 04T11695 04T12231 04TA405 04TA1949 04TL257 04TL303 04TL351

X.-L. Hou, Z. Yang, K.-S. Yeung andH.N.C. Wong Y. Hari, T. Iguchi, T. Aoyama, Synthesis 2004, 1359. K.C. Majumdar, P.P. Mukhopadhyaya, Synthesis 2004, 1864. J.S. Yadav, B.V.S. Reddy, S. Shubashree, K. Sadashiv, J.J. Naidu, Synthesis 2004, 2376. T. Gottwald, M. Greb, J. Hartung, Synlett 2004, 65. M. Miyashita, M. Sasaki, I. Hattori, M. Sakai, K. Tanino, Science 2004, 305, 495. H.J. Knolker, M.P. Krahl, Synlett 2004, 528. C.J. Kressierer, T.J.J. Miiller, Synlett 2004, 655. S. Juan, Z.-H. Hua, S. Qi, S.-J. Ji, T.-P. Loh, Synlett 2004, 829. U. Jahn, D. Rudakov, Synlett 2004, 1207. D. Schinzer, O.M. Bohm, K.-H. Altmann, M. Wartmann, Synlett 2004, 1375. J.E.P. Davidson, R. Gilmour, S. Ducki, J.E. Davies, R. Green, J.W. Burton, A.B. Holmes, Synlett 2004, 1434. G.D. Head, W.G. Whittingham, R.C.D. Brown, Synlett 2004, 1437. M.A. Chovvdhury, H. Senboku, M. Tokuda, Synlett 2004, 1933. A.N. French, J. Cole, T. Wirth, Synlett 2004, 2291. T.K. Chakraborty, S. Tapadar, T.V. Raju, J. Annapurna, H. Singh, Synlett 2004, 2484. S. Chappellet, P. Muller, Synlett 2004, 2573. A. Ricci, E. Fasani, M. Mella, A. Albini, Tetrahedron 2004, 60, 115. M. Horikawa, T. Noguchi, S. Takaoka, M. Kavvase, M. Sato, T. Tsunoda, Tetrahedron 2004, 60, 1229. C.-J. Zhao, J. Lu, Z.-P. Li, Z.-F. Xi, Tetrahedron 2004, 60, 1417. N. Al-Maharik, N.P. Botting, Tetrahedron 2004, 60, 1637. J. Zhang, W. Duan, J. Cai, Tetrahedron 2004, 60, 1665. H. Kuroda, E. Hanaki, H. Izawa, M. Kano, H. Itahashi, Tetrahedron 2004, 60, 1913. M. Yamashita, Y. Ono, H. Tawada, Tetrahedron 2004, 60, 2843. R. Grigg, M. Nurnabi, M.R.A. Sarkar, Tetrahedron 2004, 60, 3359. T. Ogata, I, Okamoto, E. Kotani, T. Takeya, Tetrahedron 2004, 60, 3941. J.M. Aurrecoechea, E. Perez, Tetrahedron 2004, 60, 4139. K. Mikami, Y. Yusa, M. Hatano, K. Wakabayashi, K. Aikawa, Tetrahedron 2004, 60, 4475. T. Rezanka, J. Spfzek, V. Prikrylova, A. Prell, V.M. Dembitsky, Tetrahedron 2004, 60, 4781. H. Wei, T. Itoh, M. Kinoshita, Y. Nakai, M. Kurotaki, M. Kobayashi, Tetrahedron 2004, 60, 6015. T. Takeya, H. Doi, T. Ogata, T. Otsuka, I. Okamoto, E. Kotani, Tetrahedron 2004, 60, 6295. P. Shanmugam, P. Rajasingh, Tetrahedron 2004, 60, 9283. W. Kurosawa, H. Kobayashi, T. Kan, T. Fukuyama, Tetrahedron 2004, 60, 9615. C.C. Hughes, D. Trauner, Tetrahedron 2004, 60, 9657. E. Tang, X. Huang, W.-M. Xu, Tetrahedron 2004, 60, 9963. V.S.P. Chaturvedula, Z.-J. Gao, S.H. Thomas, S.M. Hecht, D.G.I. Kingston, Tetrahedron 2004,60, 9991. L. Chill, A. Rudi, M. Aknin, S. Loya, A. Hizi, Y. Kashman, Tetrahedron 2004, 60, 10619. H. Makabe, Y. Hattori, Y. Kimura, H. Konno, M. Abe, H. Miyoshi, A. Tanaka, T. Oritani, Tetrahedron 2004, 60, 10651. P.A. Caruana, A.J. Frontier, Tetrahedron 2004, 60, 10921. T. Konno, J. Chae, T. Ishihara, H. Yamanaka, Tetrahedron 2004, 60, 11695. V.V.V.N.S. RamaRao, G.. Venkat Reddy, D. Maitraie, S. Ravikanth, R. Yadla, B. Narsaiah, P. Shanthan Rao, Tetrahedron 2004, 60, 12231. M. Tiecco, L. Testaferri, L. Bagnoli, V. Purgatorio, A. Tempering F. Marini, C. Santi, Tetrahedron: Asymmetry 2004, 15, 405. M. Tiecco, L. Testaferri, L. Bagnoli, R. Terlizzi, A. Temperini, F. Marini, C. Santi, C. Scarponi, Tetrahedron: Asymmetry 2004,15, 1949. U.M. Krishna, G.K. Trivedi, Tetrahedron Lett. 2004,45, 257. V. Piccialli, T. Caserta, Tetrahedron Lett. 2004, 45, 303. Y. Ishikawa, S. Nishiyama, Tetrahedron Lett. 2004,45, 351.

Five-membered ring systems: furans and benzofurans 04TL441 04TL591 04TL795 04TL911 04TL1079 04TL1599 04TL1717 04TL1861 04TL2017 04TL2125 04TL2155 04TL2223 04TL2331 04TL2377 04TL2805 04TL2989 04TL3557 04TL3877 04TL4193 04TL4437 04TL4457 04TL5023 04TL5163 04TL5211 04TL5689 04TL6235 04TL6753 04TL6871 04TL6891 04TL6997 04TL7099 04TL7581 04TL7935 04TL9483

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W. Adterman, N. Giubellina, E. Stanoeva, K. De Geyter, N. De Kimpe, Tetrahedron Lett. 2004,45, 441. J. Wu, S. Zhang, Q. Xiao, Q.-X. Li, J.-S. Huang, L.-J. Long, L.-M. Huang, Tetrahedron Lett. 2004, 45, 591. Y. Yamamoto, K.-i. Yamada, K. Tomioka, Tetrahedron Lett. 2004, 45, 795. R.V. Rozhkov, R.C. Larock, Tetrahedron Lett. 2004, 45, 911. H. Takao, A. Wakabayashi, K. Takahashi, H. Imagawa, T. Sugihara, M. Nishizawa, Tetrahedron Lett. 2004, 45, 1079. H. Yoda, Y. Suzuki, K. Takabe, Tetrahedron Lett. 2004, 45, 1599. F. Alonso, J. Melendez, M. Yus, Tetrahedron Lett. 2004, 45, 1717. M. Yoshida, Y. Morishita, M. Fujita, M. Ihara, Tetrahedron Lett. 2004, 45, 1861. B.-L. Yin, T.-S. Hu, Y.-L. Wu, Tetrahedron Lett. 2004, 45, 2017. P. Phuwapraisirisan, S. Matsunaga, R.W.M. van Soest, N. Fusetani, Tetrahedron Lett. 2004,45, 2125. C.J. Kressierer, T.J.J. Miiller, Tetrahedron Lett. 2004, 45, 2155. J.J. Underwood, G.J. Hollingworth, P.N. Horton, M.B. Hursthouse, J.D. Kilburn, Tetrahedron Lett. 2004, 45, 2223. R. Yanada, S. Obika, N. Nishimori, M. Yamauchi, Y. Takemoto, Tetrahedron Lett. 2004, 45, 2331. M. del Carmen Cruz, J. Tamariz, Tetrahedron Lett. 2004, 45, 2377. J.M. Kim, K.Y. Lee, S. Lee, J.N. Kim, Tetrahedron Lett. 2004, 45, 2805. X.-M. Niu, M.-H. Qiu, Z.-R. Li, Y. Lu, P. Cao, Q.-T. Zheng, Tetrahedron Lett. 2004, 45, 2989. M. Ochiai, T. Sueda, Tetrahedron Lett. 2004, 45, 3557. M. D'Auria, L. Emanuele, R. Racioppi, Tetrahedron Lett. 2004, 45, 3877. J.D. Ha, E.Y. Shin, S.K. Kang, J.H. Ahn, J.-K. Choi, Tetrahedron Lett. 2004, 45, 4193. M. Sakamoto, T. Yagi, S. Kobaru, T. Mino, T. Fujita, Tetrahedron Lett. 2004, 45, 4437. R. Wittenberg, C. Beier, G. Drager, G. Jas, C. Jasper, H. Monenschein, A. Kirschning, Tetrahedron Lett. 2004, 45, 4457. M. V. Spanedda, M. Ourevitch, B. Crousse, J.-P. Begue, D. Bonnet-Delpon, Tetrahedron Lett. 2004, 45, 5023. P. Liu, X.-X. Xu, Tetrahedron Lett. 2004, 45, 5163. T. Honda, H. Namiki, M. Watanabe, H. Mizutani, Tetrahedron Lett. 2004, 45, 5211. N. Zanatta, D. Faoro, S.C. Silva, H. G. Bonacorso, M.A.P. Martins, Tetrahedron Lett. 2004, 45, 5689. X. Xie, B. Chen, J. Lu, J. Han, X. She, X. Pan, Tetrahedron Lett. 2004, 45, 6235. M.E. Jung, S.-J. Min, Tetrahedron Lett. 2004, 45, 6753. K.C. Majumdar, S.K. Chattopadhyay, Tetrahedron Lett. 2004, 45, 6871. Y.-S. Che, J.B. Gloer, J.A. Scott, D. Malloch, Tetrahedron Lett. 2004, 45, 6891. P. Tane, S. Tatsimo, J.D. Connolly, Tetrahedron Lett. 2004, 45, 6997. I. Yavari, F. Nasiri, L. Moradi, H. Djahaniani, Tetrahedron Lett. 2004, 45, 7099. Y. Zhang, C.-J. Li, Tetrahedron Lett. 2004, 45, 7581. E. Dunach, A.P. Esteves, M.J. Medeiros, S. Olivero, Tetrahedron Lett. 2004, 45, 7935. U. Bhoga, R.S. Mali, S.R. Adapa, Tetrahedron Lett. 2004, 45, 9483.

172

Chapter 5.4

Five-membered ring systems: with more than one N atom

Larry Yet Albany Molecular Research, Inc., Albany, NY, USA Larrv.Yetffialbmolecular.com

5.4.1

INTRODUCTION

The synthesis and chemistry of pyrazoles, imidazoles, and 1,2,3-triazoles were actively pursued in 2004. Publications relating to 1,2,4-triazole and tetrazole chemistry were not particularly well represented this year. The solid-phase and combinatorial chemistry of these ring systems except for imidazoles 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

PYRAZOLES AND RING-FUSED DERIVATIVES

A review on new trends in the chemistry of 5-aminopyrazoles has been published . 1,3-Difunctional compounds are useful substrates in the synthesis of pyrazoles. [3-Alkyl chalcones 1 reacted with hydrazines under microwave conditions followed by additions of isocyanates to yield l-acyl-3,5-diaryl-5-alkyl-4,5-dihydropyrazoles 2 . Highly regioselective syntheses of 1,3,5-trisubstituted pyrazoles were prepared from acetylenic ketones and hydrazines . Reactions of a-trifluoromethylated a-arylacetates 3 with excess hydrazines in refluxing dioxane afforded the corresponding 5-fluoropyrazolin-3-ones 4 . Electrochemical reaction of 2,2,2-trichloroethylideneacetophenones 5 yielded 2,2dichlorovinylacetophenones 6 which reacted with methyl hydrazine to give 3-aryl-5dichloromethyl-2-pyrazolines 7 .

173


o

K

V, Ar 1 "\ 1 R1"N^

1.NH2NH2-H2O BOH, microwave I « I T -^nrnin "" 150 C, 30 mm 2 2. R COCI

1

R2NHNH2 1,4-dioxane gg^ -

^ ^ T |l „_ „ %^Kf-CO2Me 3

\ _ . N' ) < R V Ar2 IR ° 2

I \ P ^^^\J{ K y NH

C 3

4

0 1 ^ Ar^^CCfe 5

Ar^= Ar? = Ph, 4-BrC6H4, 3-HOC6H4 R1 = Me, (CH2)2Ph, (CH2)2OH R* = H, Me, Et, Ph, n-Pr

electrochemical

R1 = H, 4-Et, 3-F, 4-CI, 2-Me, 3-OMe, 3-F R2 = H M e B n

R2

o II Ar^^-^CCI, 6

NHMeNH2 E t 0 H 80 "C '

- Me N-N ArA>-CHCI 2 7

Several methods of preparing different aminopyrazoles have been reported. Novel ketene •SVV-acetals 8 were reacted with hydrazine to give 3,4,5-trisubstituted pyrazoles 9 . 5-(Substituted-amino)pyrazoles 11 were synthesized from (3-ketoamides 10 with hydrazines and Lawesson's reagent . Diketooximes 12 reacted conveniently with excess hydrazine in ethanol to give 4-amino-3,5-disubstituted pyrazoles 13 . (3-Tosylethylhydrazine 16 was condensed with either |3-ketonitriles 14 or p-aminoacrylonitriles 15 to give 5aminopyrazoles 17, which were deprotected with sodium ethoxide to 3-aminopyrazoles 18 . ?N ArHN._X.NHPh O

O ArHN-^ NHPh «'n™-\,

MH MH NH NH 2 2

H2N^N-N

SMe

H

R 8

R2 R

R5NHNH2-HCI

R3

i^\Aw'R II if 0

0

10

9

4

Lawesson's Reagent THF/pyridine (95:5) 50-c

R3 Ri_

^ R2

R4

T~{, N' R5

„

R1= Et, Bn, Ph R2 = H ,Me,Et 3

R = H, Me, Ph R 4 =Me, Ph R==Ph,Bn

174

L. Yet

Several reports have been published on the synthesis of indazoles. [3+2]-Cycloaddition of lithium trimethylsilyldiazomethane with benzynes, generated from halobenzenes 19, gave the corresponding 3-trimethylsilylindazoles 20 and 21 in various ratios . These trimethylsilylindazoles could also react with aryl aldehydes in the presence of cesium fluoride to give 3-(arylhydroxymethyl)indazoles in good to moderate yields . 2Bromobenzaldehydes 22 reacted with arylhydrazines in toluene in the presence of catalytic amounts of palladium catalyst and phosphorus chelating ligands to afford 1-aryl-1//-indazoles 23 in good yields . Reductive cyclization of o-nitroketoximes 24 in the presence of catalytic iron dimer in dioxane under a carbon monoxide atmosphere furnished 1//-indazoles 25 . Cyclization of hydrazones 26 in polyphosphoric acid (PPA) gave substituted indazoles 27 . Efficient regiocontrolled synthesis of highly substituted and annulated indazoles from a-oxoketene dithioacetals has been reported .


175

Hydrazones have been employed as substrates in the synthesis of pyrazoles. Hydrazones 28 and 31, prepared from palladium-catalyzed heteroaryl halides with benzophenone hydrazone, reacted with 1,3-bifunctional substrates 29 and 32 under acidic conditions to yield pyrazoles 30 and 3 3 , respectively . Treatment of hydrazones 34 with 2,4,6trichloro[l,3,5]triazine and jV,iV-dimethylformamide gave iminium salts 35, which were converted to 3-aryl-4-formylpyrazoles 36 .

176

L. Yet

Rapid condensation of 2,3-dihydro-4//-pyran-4-ones 37 with various aryl hydrazines in the presence of montmorillonite KSF clay under mild conditions afforded enantiomerically pure 5substituted pyrazoles 38 . The same results were obtained when aryl hydrazines were reacted with 2-formyl glycals under microwave irradiation . Treatment of 3(3-aryl-3-oxopropenyl)chromen-4-ones with hydrazine yielded pyrazolyl-2-pyrazolines . Intermolecular 1,3-dipolar cycloaddition of a-diazoarylacetates with alkynes in the presence of indium(III) chloride in water gave 3,5-disubstituted pyrazoles . Optically active pyrazolidine derivatives have been synthesized by the copper- and palladiumcatalyzed asymmetric one-pot tandem addition-cyclization reaction of 2-(2',3'-dienyl)-(3ketoesters, organic halides, and dibenzyl azodicarboxylate .

Reaction of 5-trichloromethylpyrazoles 39 with various amines efficiently provided pyrazole-5-carboxamides 40 . |3-Hydroxyethylpyrazoles were efficiently prepared from the regioselective ring opening of propylene and styrene oxide with various substituted pyrazoles . Pyrazole-4-carboxaldehydes reacted with malonic acid to give 3-(4pyrazolyl)propenoic acids in high yields under microwave irradiation . Various nucleophilic aromatic substitutions on 5-chloropyrazoles 41 occurred readily to give 5substituted pyrazoles 42 in warm Af,./V*-dimethylformamide . The photochemistry of trifluoromethyl substituted 1-methylpyrazoles has been reported . Pyridine-4carbaldehyde reacted with ferrocenyl-4,5-dihydropyrazoles to yield ferrocenyl-l-[2-hydroxy-l,2bis(4-pyridyl)ethyl]pyrazoles and ferrocenyl-l-[4-pyridylmethyl]pyrazoles . The reaction of functionalized 3-iodoindazoles with a higher order cuprate provided polyfunctional 3cuprated indazoles which were readily acylated with various acid chlorides to provide 3ketoindazoles .


Me

CHO

y-/ N

Me

CHO

NuH, KOH

- N /~~CI

DMF, 120"C

177

" \ N

~N

Nu

R 41 42 R = H, Me, Ph, 2-pyridyl NuH = nitrogen heterocycles, (thio)phenol, secondary amines

Reactions of iV-phenylpyrazoles 43 with carbon monoxide and ethylene in the presence of catalytic ruthenium resulted in the site-selective carbonylation of the ortho C-H bond in the benzene ring to give the corresponding ethyl ketones 44 .

^

p=\ N

^Y ^N L I R

Ru3(CO)12, ethylene CO (20 atm), DMA, 160 °C 43

IT )>

(T X pj^^^rr^^ .. 0 44

Several aromatization methods have been published for the conversion of pyrazolines to pyrazoles. Silica-supported l,3-dibromo-5,5-dimethylhydantoin was a useful reagent for the microwave-assisted aromatization of 1,3,5-trisubstituted pyrazolines under solvent-free conditions . 1,3,5-Trisubstituted pyrazolines were aromatized to their corresponding pyrazoles with molecular oxygen in the presence of activated carbon or with trichloroisocyanuric acid as the oxidizing agent under solvent free conditions . Clay-supported copper(II) nitrate (claycop) under ultrasound activation was found to be an ecofriendly reagent for the aromatization of various pyrazolines to pyrazoles . Several papers have been published on mild conditions for the 7V-arylation of pyrazoles. A combination of copper(I) oxide and chelating oxime-type ligands in the presence of cesium carbonate in acetonitrile was found to be effective under very mild conditions for the A'-arylation of pyrazoles with aryl or heteroaryl bromides or iodides with great tolerance of functional groups . L-Proline was an additive used in the copper-catalyzed 7V-arylation of pyrazole with aryl iodides . Copper(II) acetate-mediated TV-arylation with aryl boronic acids proceeded to form the N-2 substituted derivatives of 3-dimethylaminopropyloxypyrazoles . Copper(I) iodide-catalyzed JV-arylations of various pyrazoles with aryl bromides and iodides were effectively performed in the presence of diamine ligands . Many interesting pyrazolo-fused systems have been published. Access to the \Hpyrazolo[4,3-c]pyridine core 45 was obtained from bis-acetylenic-/V-benzoylhydrazones with aqueous ammonia . l//-Pyrazolo[3,4-6]pyridines 46 were obtained from copper(I) iodide-catalyzed cyclizations of 2-chloro-3-cyanopyridines with hydrazines . Condensation of 2-pyrone with 3-aminopyrazolone led to a novel synthesis of pyrazolo[3,46]pyridines 47 . 1-Substituted 4,5-diaminopyrazoles were useful precursors for the synthesis of pyrazolo[3,4-Z>]pyrazines 48 . Intramolecular [3+2] nitrile oxide cycloadditions led to the synthesis of tetrahydroisoxazoloindazoles 49 .

178

L. Yet

Intramolecular nitrilimine cycloadditions gave new pyrazolo[4,3-c]pyrrolizines 50 . The syntheses of 5-substituted ethyl 3-oxo-2//-pyrazolo[4,3-c]pyridine-7carboxylates 51 and 5//-pyrazolo[4,3-c]quinolines 52 have been described. Ring-closure reactions of 3-arylhydrazonoalkyl-quinolin-2-ones gave rise to 1-arylpyrazolo[4,3-c]quinolin-2-ones.

A fully automated polymer-assisted synthesis of 1,5-biaryl pyrazoles has been reported . 1,3-Dipolar cycloaddition of resin-supported acrylic acid 53 with phenylhydrazones under microwave irradiation gave resin-bound adducts 54, which were converted to l-phenyl-3-substituted-2-pyrazolinyl-5-carboxylates 55 .

5.4.3

IMIDAZOLES AND RING-FUSED DERIVATIVES

Cyclocondensation of iV-aryl-TV-formylethylenediamines 5 6 with trimethylsilyl polyphosphate furnished l-aryl-l//-4,5-dihydroimidazoles 57 in good yields . 1,2Diaminoimidazoles 59 were obtained in good yields by reaction of l,2-diaza-l,3-butadienes 58 with cyanamide under solvent-free conditions . Thiazolium-catalyzed addition of the


179

acyl imine formed from 61 to aldehydes 60 gave the intermediate a-ketoamide 62 which reacted with various amines to give 1,2,4,5-substituted imidazoles 63 in a one-pot procedure . Reactions of a-amino nitriles 64 and isocyanates 65 provided 5-amino-2imidazolones 66 in moderate to good yields . Routes to 4- and 5-nitro-lvinylimidazole have been disclosed . iV-Malonylimidate 67 was activated with magnesium chloride in the presence of imine 68 to give imidazoline 69 . Flash vacuum pyrolysis of arylmethyl azides 70 gave 2,4-diazepentadienes 71 which upon further heating gave 2,4,5-triarylimidazoles 72 . Syn- and #«ri-l,2-imidazolylpropylamines were synthesized regio- and stereospecifically from the reaction of l,l'-carbonyldiimidazole with syn- and a«rt-l,2-amino alcohols .

180

L. Yet

Me

N

CO2Me

T \ OB CO2Me 67

^ Ar^N3

MqCI? 2 J

NBn

+

MeCN

II Ph^H

M CO2Me Me^Nv^ \ _/^CO2Me Ph Bn' 69

,

25 "C

68

Flash Vacuum Pyralysis 400-450 QC

Ar \ H

_

70

N

N =

/

A H Ar

Ar H

«

140-150 "C 0.01 Tom

». ,Ar )=< N . NH J Ar

A rr N

71

72

Reactions of arylthioamides 73 with ethylenediamine in solventless conditions led to 2arylimidazolines 74 . 2-Arylmethylimidazolines 76 were prepared from 2-aryl-l,1dibromoethenes 75 with ethylenediamine under mild conditions and was further converted smoothly to imidazoles 77 by Swern oxidation . J\^ Ar

ethylenediamine 120'C *"

NH2

Ar

& \ N"^ H

73

74

A r

^^,Br

ethylenediamine

X

2!Tc

75

H Ar^N^v

""

N^/ 76

oxalyl chloride ^

Ar

H ^s^-N

Et3N, DMSO -78 "C

f!j.J> 77

Reaction of bis(triphenyl) oxodiphosphonium trifluoromethanesulfonate salt with |3tosylamino-a-acylamino esters 78 led to a highly efficient enantiospecific synthesis of imidazolines 79 . ./V-Acylated a-aminonitriles 80 were reacted with triphenylphosphine and carbon tetrachloride to afford 2,4-disubstituted 5-chloro-l//-imidazoles 81, which could undergo Suzuki palladium-catalyzed reactions . O

"NHTS 78

R=Ar,Bn

Ts

'

79


181

2,4-Disubstituted l//-imidazolines 84 were synthesized from aziridine 82 and nitriles 83 in the presence of boron trifluoride etherate or triethyloxonium tetrafluoroborate via a [3+2] cycloaddition reaction . Ritter reaction of enantiopure 2-(l-aminoalkyl)azidirines 85 with various nitriles afforded enantiopure tetrasubstituted imidazolines 86 .

Microwave irradiation has been employed in several published syntheses of substituted imidazoles. Microwave irradiation of aldehydes 87 and TV-substituted a-amino acid amides 88 under solvent-free conditions led to substituted imidazolidin-4-ones 89 . A simple, high yielding synthesis of 2,4,5-trisubstituted imidazoles 91 have been prepared from diketone 90 with aromatic aldehydes in the presence of excess ammonium acetate in acetic acid under microwave irradiation . Condensation of benzoin 92, aromatic aldehydes, amines and ammonium acetate in the presence of silica gel under microwave irradiation and solvent-free conditions led to tetrasubstituted imidazoles 93 .

182

L. Yet

Rhodium-catalyzed N-H insertion reactions of diazocarbonyls 94 with primary ureas 95 gave urea compounds 96 which cyclized readily with trifluoroacetic acid to give the corresponding imidazolones 97 . Similarly, rhodium-catalyzed N-H insertion reactions of diazocarbonyls with primary amides followed by treatment with ammonia or methylamine provided a convenient route to imidazoles .

Several reports on the synthesis and chemistry of benzimidazoles have been published. Indium-mediated reductive intermolecular coupling of 2-nitroaniline 98 with aromatic aldehydes and 2-bromo-2-nitropropane 99 gave 2-arylbenzimidazoles 100 . Copper(I) chloride-promoted intramolecular cyclizations of ./V-(2-aminoaryl)thioureas 101 provided a practical synthesis of 2-(7V-substituted)aminobenzimidazoles 102 . A highly effective microwave-assisted fluorous Ugi and post-condensation reactions for benzimidazoles has been reported . 2-Substituted benzimidazoles 104 have been prepared in a onepot procedure from activated alcohols with 2-iV-methyamino aniline 103 using a new tandem oxidation process . Reactions of tetrahydrobenzimidazoles with dimethyldioxirane led to rearranged 5-imidazolone products . Multistep parallel synthesis of substituted 5-aminobenzimidazoles from l,5-difluoro-2,4-diaminobenzene in solution phase has been reported . Substituted benzimidazoles underwent intermolecular coupling to alkenes at the C-2 position via rhodium-catalyzed C-H bond activation . 2Substituted styryl benzimidazoles were prepared from 2-methyl(or ethyl)benzimidazole with aromatic aldehydes in the presence of acetic anhydride under microwave irradiation and solventfree conditions . 1,2-Phenylenediamine reacted with aldehydes in the presence of ytterbium(III) triflate under solvent-free conditions or in the presence of scandium triflate under an oxygen atmosphere to give substituted benzimidazoles .

183


a

NHMe

ff^Y'\_R

MnO2, sieves, RCH2OH HCI, PhMe, 105 "C

NH

*"

^ ^ N

2

103

Me

104

Dilithiation of 1-(w-butyl)imidazole (105) followed by addition of ^-butylisocyanate and Nbromosuccinimide gave 2,5-imidazoledicarboxamide 106 which participated in a variety of palladium-catalyzed Heck, Suzuki and Sonagashira couplings to give 107 . \Himidazole 108 is readily N-alkylated to 110 by a copper-catalyzed reaction with a-diazocarbonyl compounds 109 . An efficient method for the regioselective protection of 4-alkyl-, 4iodo- and 4-vinylimidazoles has been developed via an alkylation-isomerization sequence with various imidazole-protecting groups . A library of 2-guanidinomethyl-4(5)sulfamoylimidazoles was synthesized in a convergent manner by introducing a sulfonyl chloride group via a trianion electrophilic sulfinylation of suitably protected 2-guanidinomethyl imidazoles . l-(Alkyldithiocarbonyl)imidazoles 112 were prepared from imidazole 111 in the presence of carbon disulfide and alkyl halides . 1. n-BuLi (2.2 equiv), THF, -30 JC

/T^ N

Br

2. (-BuNCO Bu

"" 105

R

—/ ° 79a/b HN >\

HN

[

H

V

CI

1

yNH2

1

NH

Y - V^ -* O ^ ^ V ^ ° L ^ i Jh J [ P ^ O J )T 80

81

82

83

The hetero-Michael addition of O-alkylthiocarbamates 85 to l,2-diaza-l,3-butadienes 84 followed by cyclization of the adduct 86 provides a direct approach to 2alkyliminothiazolines 88 . Me

r R2

Me

°2CV^N^VR1

Rl +

H

NAO'R4

HO

•

R = NH-alkyl, O-alkyl R2 = Me,Et,/-Pr R3=Et,n-Bu

85 R2O2C W

i

w []

i

R 2 O 2 c f ) N ' ^COR1

H 84

1

S

L

R

>c!>R3 4 0 g6

J

Me

s' N, N H C O R i Y R3,N

;

R 0H

^ ^ 7 58 85/ - "

88

rR 2 O 2 C

Me

1

>=< s' N-NHCORi R4OXNHR3 87

5.5.2.4 Reactions of Thiazoles and Fused Derivatives The total synthesis of the antifungal agent cystothiazole B 96b involves a regioslective bromine-lithium exchange reaction of thiazoles and Stille cross-coupling reactions . 2,4-Dibromothiazole 89 undergoes the known regioselective bromine-lithium exchange to give 4-bromo-2-thiazolyl lithium, acetone is added, and the resulting tertiary alcohol is converted to the silyl-protected bromothiazole 90. The required 4-tributylstannylthiazole 91 is prepared from 90 through bromine-lithium exchange followed by quenching with tributyltin chloride. Stille cross-coupling reaction of 91 with ditriflate 92 proceeds regioselectively to give bis(thiazole) triflate 93. The Stille cross-coupling of the vinyltin 94 with triflate 93 generates 95, which is deprotected with TBAF to furnish

204

Y.-J. Wu, U. Velaparthi andB.V. Yang

cystothiazole B 96b. A similar strategy is used to synthesize cystothiazole A 96a . f-BuLi,acetone, 64%

V-N

lt* 89

B r

TBSOT,bfase,

\^N

f-BuLi, Bu,SnCI

Me

Bu

3Sn\^N

X ^ T ^ T ^

98%

Me

XM^ 91

90 Pd(PPh3)4, V

OMeoMe

?

f J r ^ \ Meo\ M S {j>

S^\,N Me .. I >-TR Pd(PPh3)4, LiCI, 72% (95) 95:R = OTBS ^ S 96a: R = H (cystothiazole A) 96b: R = OH (cystothiazole B)

O

LiCI 68%

S " \ ^ N Me T V-UM/

^

QTIPS

Ar

(/.pr)2N

R= Me^^^^^^X.

N

/

A r =

}—( V-OMe O N=
90/ »

R..I

Me.N ' J • "b 'V

Me

H=(*ph

116

An operationally simple halogenation of 4,5-dimethyl-2-arylthiazoles provides a regioselective approach to bromo- or chloro-methyl substituted thiazoles . Thus, treatment of 117 and its hydrochloride salt with NBS and NCS affords 4-bromothiazole 118 and 4-chlorothiazole 119, respectively, with >99% regioselectivity. The remarkable regioselectivity observed may arise from a Pummerer-type rearrangement mechanism via 120.

H

206


/ Me NBS NBS N-/ % A r ^ - g ^ M e 53-82% 117 r

NBS

or NCS

/~Br

e

® /Me Cl H N - / Ar-^ s /-~Me

N-/ A r-^- s -^-Me

1E

*3N 2. NCS t 57-89%

118 "^r-H

M

q

-i

^ K

~{ Ar^g^-Me 119

/C\ e i

r

// Y

[

Ar-^ c V^-Me 0 N J - Ar">Si Me X> O J L 120 J 5.5.2.5 Thiazole Intermediates in Synthesis I

rC[

N

-

• 118 or 119

The thiazole-aldehyde synthesis has been involved in several synthetic methodologies . For example, addition of the double protected methyl ester of D-allylglycine 121 with 2-lithiothiazole gives the amino alcohol 122, which undergoes alkylation and selective deprotection to provide 123. This compound is subjected to the thiazole deblocking protocol to give aldehyde 124 .

II S

n

/f~N II II V^r ^ N S BnBr.NaH, ^ k N 1 ? O C M D U NS JL 1 ? O C 90%: CAN, OMe PMB 89% 121

s-Si^N 67% OH PMB 122

MeOTf; II NaBH4; k CuCI2-2H2O, ° [

\ ^S^^f^m CuO ^ ^ OBn Boc 67% 123

H H OBn Boc 124

A highly diastereoselective acetate aldol reaction that uses an L-tert-leucine-derived Nacetyl thiazolidinethione auxiliary 125 and dichlorophenylborane has been reported . Thiazolidinethione reagent 127, pseudoenantiomeric to 125, is also found to be effective in diastereoselective asymmetric aldol reactions, thus obviating the expensive D?ert-leucine . Asymmetric aldol additions of iV-propionyl thiazolidinethione 129 with 1 equiv. titanium tetrachloride, 1 equiv. diisopropylethylamine and 1 equiv. 7Vmethyl-2-pyrrolidinone proceeds with high diastereoselectivity for the "Evans syn" product 130 . Thiazolidinethione auxiliaries can be cleaved under various conditions, but a recent protocol using benzyl alcohol and catalytic amount of DMAP deserves to be mentioned . For example, treatment of 131 with benzyl alcohol and DMAP (0.1 equiv.) in dichloromethane at 5°C for 13 h affords the benzyl ester 132 in high yield. S II

0

V

S^N^^Me N—( Bu-f 125 S

II S

0

RCHO 65-92%

TiCI4,

S

o V,

S

II

0

M Bn

S Tf

O H H

9

0

II

PhBCI2l s (-)-sparteine, U

S - ^ N - ^ - ^ R S^N^Me RCHO \—( M 63 . 92 o /o Bu-f /r-Me 126 TESO XMe 1 2 7 0 H

II /-Pr2NEt, II II N ^ ^ E t RCHOr S N ^ S r - — ' R

M 129

PhBCI2, (-)-sparteine,

^ Bn

130

S

o

II

0

O H

y

|

. S^NI^^^^R \—/ >r-Me TESO^ Me 128 O

O H

OH

II BnOH, n : N " ^ ^ (CH2)4 DIVIAP^ B n O ^ " v ^ ^ ( C H 2 ) 4

S

M

Me ê

Bn 131

93%

fê ê 132

207

Five-membered ring systems: with N and S (Se) atoms

The diastereoselective additions of chlorotitanium enolates of 7V-propionyl thiazolidinethione 133 to various metalloaldimines 134, available from hydrometallation of the corresponding nitriles, furnish a mixture of azetine 135 and tetrahydropyrimidinone 136 . Among the three hydrometallation methods evaluated, the hydrozirconation process proves to be the best in terms of the yield and selectivity. The a-amino nitrile 139, a key intermediate in the synthesis of (+)-biotin, is prepared through a highly diastereoselective Strecker reaction of the bisulfite adduct 138 . This bisulfite is derived from the a-amino aldehyde 137 upon treatment with sodium bisulfite.

E«A N A S \

R

/-Pr~ 133

*" Me x> v

\

Bn

NaHSO3,

H2O

°« N

L.HU

X\

/

\ / »-Pr' 136 (minor)

i.BnNH 2

Bn

s ^ N '

99%

—Vun

, \

'- p r' 135 (major)

(-)-sparteine

g/^N' N

A H ^ JXHXS

I

2. NaCN

—\^°H

95%

^ S

^-A^NHBn

138 Ô 3 Na

137

Bn

^N' | 139 CN

Thiazolyl thioglycosides such as 140 are used as glycosyl donors . Glycosylation of 141 with 140 using silver triflate as a promoter proceeds stereoselectively to give disaccharide 142. One advantage of using thiazolyl thioglycosides in glycosylation reactions is that the thiazolylthio moiety (S-Taz) is stable toward common protecting group manipulations involving strong bases. Interestingly, S-Taz can be temporarily deactivated by engaging the 5-Taz of the glycosyl acceptor into a stable palladium(II) complex such as 144 . After glycosylation with 140, the resulting disaccharide is then released from the complex by ligand exchange to give 145 as a glycosyl donor.

140

141

BnO

OH

OH

BzO-Ô OBz

Br

2Pd

PdBr^ / B Z O ^ I ^ O

BzO-^-vV S ^N

143

142 B n O O M e

OMe

r > --/

s

""

BZOX^TVSN^N

\

B Z

140,

\ MeOTt ^CN^

OBz r ) 63% 144 S ^ / 2

°~^BT

? B

R

z0^^0 BZO-^^^V'SN^N

OBz T > 145 S - - /

5.5.2.6 Thiazolium Catalyzed Reactions The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the conjugate addition of

208


acylsilanes (R'C(O)SiX3) to unsaturated esters and ketones 149 using thiazolium salt 146 (Sila-Stetter reaction) and a ROMP gel-supported thiazolium iodide 147 for parallel Stetter reactions . ROMP gel is a general class of high loading polymer-supported reagents, catalysts, or scavengers, derived from ring-opening metathesis polymerization (ROMP). Thiazolium salt 146 is also utilized in the intramolecular benzoinforming reactions of aldehydes and ketones . Under optimized conditions, five- and six-membered cyclic acyloins are obtained in good to excellent yields as exemplified by the conversion of keto-aldehyde 151, derived from cholesterol, to ketol 152. However, the analogous closure of seven-membered rings proves to be difficult. Thiazolium salt 148 is used to generate activated carboxylates from epoxyaldehydes, thus providing a stereoselective synthesis of P-hydroxyesters. For example, treatment of epoxyaldehyde 153 with 3 equiv. ethanol in the presence of 10 mol % 148 and 8 mol % diisopropylethylamine (DIPEA) gives a 13 : 1 mixture of 155 (anti) and 156 (syn), with the former being isolated in 89% yield. H

\ ~ ^ V s

Ph

^ Y > ^ ) *n W^

146

n

J

147 ^

e

149

148

Me Me I

^?pcxy I

\

O Ph^X^H Me

153

148,

EtOH,

150

Me I

Me 146D | BU

Me

65%

I

I HJ ^ O

r

\

, ^p^xy YMe

151

JO ]\

RUo T y

Me

y

IH EH

R1c(O)Six3, 146, DBU

H o V n

OH O

1

Bn

1

11 N®

PI PEA. ph^YyVMe 89% Me S - ^ (155) |_ Me J 154

Me

152 OH O

X X ^ Ph^VÔEt Me 155 (a/if/)

OH O +

X X Ph^^ÔEt Me 156 (syn)

5.5.2.7 Chiral Bis(thiazoline) Ligands for Asymmetric Reactions The oxazoline ligands have been widely used in asymmetric catalysis, but in contrast, the corresponding thiazolines are relatively unexplored. Recent efforts on thiazoline ligands have led to the identification of chiral bis(thiazole) 157 for the enantioselective Henry reaction and 158 and 159 for palladium-catalyzed asymmetric allylic alkylation . However, these ligands generally provide moderate enantioselectivity.

209


JIV-O y—9 HN f-Bu..,.^N >=\

< S TT S > N

y Et

158

° ' HO i ° 2

H O M e ^ X O Et 1 5 7 ' Et 3 N yJ 70% ee + 2 ~tf%—"" Me^^CO2Et MeN °2

f-Bu—^N

Me Me V

CU( Tf)2

I

ys^ y^ \\ \ \ F V ^ ~ ~ A )=N

T

Pr/

+

X

Êt C j r C X P • Et

^ - ^

i g g

s /

OAc ^ \ Jk Ph^^^^Ph

CH2(C 2Me)2

P r .,

°

[Pd(C3H5)CI]2, 158or159, (TMS)2NAc,

KOAC CH2C 2

'

MeO2C^CO2Me V

', Ph^^Ph

BB%ee(1S8) 56%ee(159)

5.5.2.8 Thiazole-Containing Drug Candidates Among many biologically important thiazole analogs disclosed in 2004, six compounds worth noting are: BILN 2061 , BMS-387032 , AG-7352 , (£)-9,10-dehydro-dEpoB , tetomilast , and BMS354825 O4JMC6658; 04SCI399>. BILN 2061 is a potent and specific inhibitor of the hepatitis C virus non-structural protease (HCV NS3) in both enzymatic and the cell-based replicon assays, and it was evaluated in clinical studies. BMS-387032 has been identified as an ATP-competitive, cyclin-dependent kinase 2 (CDK2)-selective inhibitor and will enter Phase I clinical trials as an antitumor agent. AG-7352 exhibits potent cytotoxic activity in both in vitro and in vivo assays and was advanced as a preclinical candidate. Deoxyepothilone B (dEpoB), a member of the first generation of epothilone antitumor drug candidates, is currently in Phase II clinical trials, and more recent efforts have culminated in the identification of (£)-9,10-dehydro-dEpoB with enhanced in vitro activity and improved metabolic stability and efficacy against xenograft tumors. Tetomilast (OPC-6535) is a pyridyl thiazole derivative that potentially inhibits both superoxide production by human neutrophils and phosphodiesterase type 4 (PDE4), and it is in phase II and III clinical trials for the treatment of inflammatory bowel disease and chronic obstructive pulmonary disease (COPD), respectively. Finally, BMS-354825, a picomolar inhibitor of Src and Bcr-Abl kinase, is especially noteworthy. This thiazole derivative demonstrates efficacy in mouse model of both wild type and Gleevec resistant chronic myelogenous leukaemia (CML), and it shows promising activity in Phase I clinical trials for the treatment of CML.


210

r

I

L

s />—NHPr-/

II J

^

n

^-

II H

Me0

°

^ ^

s

N

H ^ H

S^

°2C

tetomilast

r^ Me

^ S

Ji^J j HO^

BMS-354825

S^

T T .-0H F3C^f

/=\

T

L.NH

N^S

^^"^ AG-7352

I J

ci H

BMS-387032

H^ ^ ^ ^ J BILN 2061

o

\\

N

^ ^ f

°

^N tf

Me > M e

Me (£)-9,10-dehydro-dEpoB

J Me-f

L- 0H Me

^ ^

Me dEpoB

5.5.2.9 Synthesis of Thiazole-Containing Natural Products During the past year, synthetic studies on thiopeptide cyclothiazomycin , macrocyclic antibiotics thiocilline I and sulfomycin I , cytostatic peptide tubulysin D and thiopeptide antibiotic amythiamicin A have been disclosed. In addition, there have been several reports on the total synthesis of thiazole-containing natural products, including antifungal and cytotoxic antibiotic cystothiazole A O4T187; 04OL3083> and cystothiazole B , antitumor agent epothilone C , neurotoxin kalkitoxin O4T6859; 04OBC2092>, antihypertensive agent WS75624B , cytotoxic antibiotics tenuecyclamides AD , bistratamides E and J . Of special note is the total synthesis of thiostrepton, an extraordinarily complex natural product that has been used as a topical veterinary antibiotic and also exhibits promising antimalarial and antitumor activity . Thiostrepton contains 10 rings, 11 peptide bonds, and 17 chiral centers, and it is the most complex member of a family of thiopeptide antibiotics. One of the key steps in the synthesis is the construction of the dehydropiperidine ring through a biomimetic hetero-Diels-Alder dimerization. This landmark synthesis opens up the opportunity of structure-activity relationship and mode-of-action studies.


oA

°\NA,

iH

tenuecyclamides A: R1 = H, R2 = Me B: R1 = Me, R2 = H C: R1 = H, R2 = (CH2)2SMe D:Ri=H,R 2 =(CH 2 ) 2 S(O)Me

»V-

bistratamide E

,

211

bistratamide J

O

M e - N ^

V~MV^/NH 2 dehydropiperidine

v

S

n

I

U

Me°Y

H

HO-V

-S VAOAVN

1 H

Me

/

N-K

HO

5.5.3

\ ,,

Me M

0 H

V

Q

O

\SZN

, AN

R1

NC S

H

. '

^

R1 i

NC R

"^J

^Te? L ^ V o J e

_ ! ^ _

)=/ RAN.S

R = Me; R1 = alkyl, aryl, furyl, thienyl.alkyny,

56-82% 164

165

166

Sultams can be accessed by the intramolecular cyclization of compounds containing preformed C-S-N-C-C or C-C-C-S-N fragments, wherein the C-C bond or C-N bond formation is the ring closure step. A carbanion mediated sulfonamide intramolecular cyclization has been described for the synthesis of sultams 170 . Treatment of sulfonamidonitriles 169 with a base, cesium carbonate (when R = Me, Bn) or BuLi (when R = H), results in abstraction of the a-position proton of the sulfonamide to generate anions that readily react with the nitrile group leading to spiro-sultams 170. An intramolecular cyclization through formation of an imine (C=N) bond is demonstrated by the conversion of ortho-sicyl sulfonamide 171 to benzo-isothiazole-dioxide 172 in the presence of TMSCl-Nal as Lewis acid . OR1

C o ^ O Me Yj>-°VMe

"I. R 2 CH 2 SO 2 CI (168)

' DMAP.Py

.OR 1

N

V ^ - ° C 1 J X

R2/",sr O'b

H2N 167

Cs 2 CO 3 , Me MeCN r6flUX

>R 169

' (R = ê,Bn) THF,-10°C (R = H)

R1O-x H N

0

^ x \ )^ y ^ )-U AMe ^"b 17Q 1

^^SO2NH-Bu-f

TMSC|

^L^\ —

MeCN, reflux

Ô y*

MeÂr

Na|

62-94%

171

R = Bz, Bn, CPh3 R2 = H, Me, Ph, R = Me,Bn,H

O ^ J h f [| J, ^,N \s*^ r Me

Ar= substituted phenyl Ar

172

5.5.3.2 Reactions of Isothiazoles iV-alkynylsulfonamides 174 are useful intermediates for diastereoselective synthesis . An efficient copper-promoted alkynylation of sulfonamide 173 has been developed to afford 174 with completely retained enantiomeric purity. The acetylenetitanium complexes 175, obtained from 174 upon treatment with titanium(II) alkoxide, react with aldehydes 176 to give alcohol 178, after hydrolysis, with virtually complete regio- and ii/Z-diastereoselectivity and also with high 1,5-diastereoselectivity (up to de = 98:2). The N-

213


arylation of 1,3-propanesultam 180 is carried out by palladium-catalyzed cross coupling with a variety of aryl halides 179 using Xantphos as the ligand . This palladiumcatalyzed reaction appears to be superior to the analogous copper-catalyzed reaction based on product yields and reaction rates. Palladium-catalyzed cross-coupling reactions are also effective at introducing aryl and heteroaryl groups to the 5-position of 3-benzyloxyisothiazole 182 . Iodoisothiazole 183 is a key intermediate, allowing access to a wide variety of 5-substituted isothiazoles 184 under either Suzuki or Negishi coupling reaction conditions.

H

N

°2s; r

R^H

R

Cul, K3PO4p

]|

(CH2NHMe)2,

R 1 toluene1

110-c

)=< / \

"' sN

°2 ;V

" 71-94 %

\

/.PrMgCI,'

R1 Ft n

f

T J°

,

R2CHO(176), o s

175

10mol%Pd(OAc)2, 15 mol% Xantphos, 1.5equiv.Cs2CO3

/—i Ar-N^J

d5" N b dioxane, 85 or 90 'C 180 74-93% Ar = substituted phenyl; n = 1, 2 179

OBn. y

P N 182

OBn ?,

1.LDA

1

/

^ l^N

l i°

r

Negishi

C0UP ng

183

Ar = phenyl, thienyl, furyl, pyridyl

" .

v

D 1

177 yields: 52-94% 1,5-ds: 88:12 to 98:2

O* v b

H+

R2

181

R v

O2S-N uzuk

r~Ti(OPr-/')

2 > R 1 -5Q-C,4h /V f i T *" r**T

174

I—> ArX + H N ^ S ^

R.J.,

bn(OPr-i)2 '

2

,nr ° ?A

W /^\

173

f

R

Ti(OPr-;)4

OBn J

X>J 184

1 y '0H H

J

1

/4>^R -^1,5< ^ (

U ^

remote

178

control

R = TMS,C 6 H l3 ;R 1 = Me,f-Bu R2 = Ph, p-CI-Ph, alkyl, alkenyl

A novel approach involving sequential aza[4+2] cycloaddition-allylboration-retro-sulfinylene reaction provides an easy access to c/.s-2,6-disubstituted piperidines in a high regio- and diastereoselective fashion . This step-economical process has been elegantly applied to the synthesis of the palustrine degradation product (-)-methyl dihydropalustramate 1 9 1 . The [4+2] cycloaddition of boronate-substituted hydrazonobutadiene 185 with chiral sulfinimide dieneophile 186 in the presence of propanal 187 generates the bicyclic adduct 188 as a single regio- and diastereoisomer. The retrosulfinyl-ene fragmentation of 188 is achieved under hydrolytic conditions to afford piperidine 190, which is converted to 191.


214 M

\> ,? =o O

L

195

,?«o O

J

196

.?-o L O

J

197

sô A> °

198

5.5.3.3 Isothiazoles as Auxiliaries and Reagents in Organic Syntheses Oppolzer's camphor sultam is a well known chiral auxiliary. Recent applications in a number of diastereoselective reactions include nucleophilic addition to the carbonyl and the oxime ether groups , conjugate addition reactions , [2+2] cycloaddition , [4+2] cycloaddition , hydrogenation of alkenes , oxidative cyclization of 1,6dienes and electrochemical carboxylation of a-bromo carboxylic acid derivatives . Two elegant applications of camphor sultam in the asymmetric aldol addition have been disclosed. One example is shown with the stereoselective syntheses of enantiomerically pure endo and exo isomers of 3-deoxy-8-oxatropanes, 204 and 205 . The aldol reaction of to-alkenoyl (25')-bornane-sultam 199 with 3-butenal 200 has tunable diastereoselectivity: in the presence of 2 equiv. diethylboron triflate and 2.2 equiv. diisopropylethylamine (/-P^NEt), sjM-adduct 201 is obtained with high diastereoselectivity, whereas by slightly reducing the amount of /-P^NEt (from 2.2 to 1.9 equiv.), a«?f-aldol

215


adduct 203 is generated exclusively. Conversions of syn-adduct 201 to exo-isomer 205 and a«/z'-adduct 203 to e«rfo-isomer 204 have been accomplished in four steps: ring closing metathesis (RCM), oxymercuration, reductive demercuration and hydrolysis. In another application, glyoxyloyl-(27f)-nornane-sultam 206 is shown to be a highly efficient chiral inducer in a nitroaldol addition reaction (Henry reaction), and superior to other chiral auxiliary groups investigated in the study . Sultam 206 reacts with nitro compound 207 (optimal conditions: anhydrous tetrabutylammonium fluoride (TBAF) or TBAF-3H2O, -78 °C) to give diastereoisomeric nitroalcohols 208 in high stereoselectivity. In all cases, the major diastereoisomers 208 possess the absolute (25) configuration at the center bearing the hydroxyl group and the relative syn configuration of nitro and hydroxyl groups (except R = H). A highly diastereoselective 1,3-dipolar cycloaddition of a nitrone employing the sultam auxiliary has been used in the synthesis of 215, a major metabolite of nicotine . Z-gulose-derived nitrone 212, upon treatment with a, |3-unsaturated sultam (2S)-213, undergoes 1,3-dipolar cycloaddition to afford the isoxazolidine 214 with high endo stereoselectivity, which is further elaborated to hydroxycotinine (+)-215. Me ,Me° ~ jL-~SsO /-Ps^N

^v

3-butenal (200), Et2BOTf(2equiv.), > 4 ^

9 xs^S^-v^^.

/-Pr2NEt(2.2equiv.)

fy

P x s-4

T

-

RCM

—-

HO^^^

199

2

°1

°

° II 1

^^

4 steps

203

(^N-< '"SÔ 0

/-'°M

V' O

RCH2NO2 H

206 JV

(207)TBAF THF '"78 "C '• 42-80%

,_*

XR

NO2

5

R

+

S

^0

XR

=

209

(2S)-syn

j _ _ P

NO2 R

208:209:210:211 =

0 H

NO2

XR\^R

" ^BN-|

5

205 (exo)

O

0H 208

/V 2^°vl

^-^V

O

Me^Me

0

-\V

1. Hg(OCOCF3)2 2. Bu3SnH 3. LiOH, H2O2

I 200, Et2BOTf(2equiv.), I ;-Pr2NEt(1.9equiv.)

JJ

T^N

HO

JH 210 {2R)-syn

(2S)-anf;

O -

90 : 1 0 : 0 : 0 (R = C5H,,) >99 : 1 : 0 : 0 (R = (EtO)2CH) 93 : 7: 0: 0 (R = Ph)

NO2

X^-V^R

OH 211 (2R)-anti

2S:2R=98:2(R = H)


216

^ffip

(T^"0

MgBr2

1 ~^r-

N'

5 steps

CNJ A

212

[

^-"

V

N

R=

^ U Me

214

V-/V

oô'

215

Me

Me

A^-Bromosaccharin 217 is an efficient reagent for the oxidative cleavage of oxime 216 to the corresponding aldehydes and ketones 218 under microwave irradiation . The hydroxyl functional group is well tolerated under these conditions. 9 R2

)=NOH + l| [ \^-s' 216

acetone,

N-Br

O •

)=O

88-97%

+

R2

217

218

\\ [ NH \iS^s'^

R

= alky!.a^ R2 = alkyl, aryl, H

219

5.5.3.4 Pharmaceutically Interesting Isothiazoles Isothiazoles and their saturated and/or oxygenated analogs play an important role in pharmaceutical research. Isothiazoles have been incorporated into inhibitor of vascular endothelial growth factor (VEGF)-receptor KDR 220 and HIV replication inhibitors , benzoisothiazole into selective 5HTID antagonist/serotonin reuptake inhibitor 221 , and benzosultam into cyclooxygenase-2 (COX-2) inhibitor 222 . Sultam hydroxamate 223 has been identified as potent inhibitor of matrix metalloproteinase-2 (MMP-2) (IC50 = 3.8 nM) with >1000-fold selectivity over MMP1 .

P

V^> R Y^n

rV "OCX-*

X-S 220

5.5.4 5.5.4.1

\J 221 (R = C(O)NH2)

MeO'^

loQ CON(H)OH

222

223 (R = p-OMe-Ph)

THIADIAZOLES 1,2,3-Thiadiazoles

The chemistry of 1,2,3-thiadiazoles has been recently reviewed in "1,2,3-Thiadiazoles, Heterocyclic Compounds" and also in "Science of Synthesis" . The Hurd-Mori reaction is frequently used in the synthesis of 1,2,3-thiadiazoles. For example, condensation of methyl ester of cyclopentanonopimaric acid 224 with semicarbazide gives semicarbazone 225, which, upon exposure to thionyl chloride, generates 1,2,3-thidiazolo terpenoid 226 .

Five-membered ring systems: with N and S (Se) atoms /_Pr

9°2Me

^ I V T ) fl

i^xj

._pr

NH2CNHNH2 ^ ^ J O X /

SOCI2

CO 2 Me

/vJ]|X>S

70-0 / ' C X j * > H ~7^r C X J f l

°

Me

QO2Me

/ p r

217

fcO?Me

Me 'CO2Me

224

I O^NH2

225

VN

Me 'CO2Me 226

2-Aryl-l,2,3-thiadiazol-5(2//)-imines 229 are prepared from arylhydrazonothioacetamides 227 by means of oxidative cyclization using bromine in acetic acid .

Ar'%*VNH2

Br Ac0H

*

Ar

I

ZTVNH

-" .

t >NH

Ar'NTT . H B r

WSO

L

227

23 %

228

229

An unexpected ring enlargement is observed in the attempted reduction of 1,2,3thiadiazole-4-carboxylate 230 . Treatment of 230 with powdered samarium and iodine in methanol at 0 °C leads to a mixture of 1,2,5-trithiepanes 231 and 232. Presumably, the carbon-carbon bond of thiadiazole 230 is reduced, the resulting thiazoline 233 releases nitrogen to give S,C-biradical 234, which reacts with 233 via S-S bond formation with concomitant loss of nitrogen to produce a symmetrical C,C-biradical 235. Interception by a second molecule of 233 leads to the third biradical 236, which undergoes intramolecular cyclization to afford 231 and 232 after expulsion of methyl acrylate. .N S

,

Sm,l2, MeOH, 0 °C

°N CO2Me

230

r

[H] ' N

S'% \

( "

2

S-S J

MeO2C^S^'-CO2Me 231(9%)

[" -i

r•

T

1_ ^ S -N2 [

M

e O 2 C ^ ^ C O 2 M e *" 232(14%)

CO2Me ] /

L

r

•

CO2Me -, ^~^~^ ^CO2Me

/

233 ST CO2Me . N ' s v ^

234

-CH2=CHCO2Me

S

233 ^ -N2

V

L

CO2MeJ 233

S-S ( 2

+

^CO 2 MeJ 235

S^^S^^ S \ _ i ^ L

^CO 2 Me 236

The 1,2,3-thiadiazole ring system is found in several medicinally important compounds such as 237, a potent inhibitor of cytomegalovirus (CMV) , and 238, a potent and selective antagonist of adenosine A2a receptor . CF 3

NH 2

Et

S 237

S

S

\A^N,

J 238


218

5.5.4.2 1,2,4-ThiadiazoIes A review on the chemistry of the 1,2,4-thiadiazoles has appeared in a book . A novel method is reported to convert l,3,5-oxathiazine-S'-oxides 239 into 1,2,4-oxathiazoles 241 under thermal conditions. Lewis acid promoted reaction of 241 furnishes 1,2,4thiadiazoles 243 .

*X*J-_ Ml -Vb -R2CHO

K^° I, 239

N^ 1, 240

=

N^/ R2 241

[«i i

+H2O -R2CHO L

y

;v\

N

50-100%

NH 2 242

J

N

-f R1 243

A novel approach to 1,2,4-thiadiazoles 246 is based on the monocyclic and cascade rearrangement of l,2,5-oxadiazole-2-oxides 244 . Thus, TV-oxides 244, upon treatment with ethoxycarbonyl isothiocyanate, undergo cascade rearrangement to give 1,2,4thiadiazoles 246 via 245. Ar N=N' HzN

V^/

K^

r EtO2CNCS, EtOAc, reflux

H Et

[

r

°2C 7 N^NHNj,N^( ffi

244

Ar 1

T>^^j

52 60%

"

245

NHCO2Et I S^N

" N^NO, 246

N

^NHAr

l,2,4-Thiadiazolo[2,3-a]pyridine derivatives are frequently prepared via oxidative heterocyclization as exemplified by the formation of 248 from thioacetamide 247 using nitrosobenzene .

O

S 247

N ^

54%

o

S'INv^ 248

The 1,2,4-thiadiazole unit is found in several biologically interesting compounds O4BMC613; 04IJHC249; 04BMCL235; 04BMCL2871; 04PHA756; 04PS1497; 04EJM793>, such as cephalosporin antibacterial agents , selective allosteric modulators of human adenosine A3 receptors , and inhibitors of cysteine protease cathepsin K . 5.5.4.3 1,2,5-Thiadiazoles The synthesis of furazanobenzo-l,2,5-thiadiazole has been developed in the study of fused porphyrins . Amination of 249 under basic conditions followed by reduction of the nitro group gives phenylenediamine 251, which upon treatment with thionyl chloride and pyridine furnishes 1,2,5-thiadiazole 252.

219


^y^,

NH2OH

^y^l\l'

^-yf-N,

68%

92% HgN^^r^^N'

NO 2 249

^y^N,

Na2S2O4

!

N

H 2 N'^ K'^ '

NO 2 250

SOCI2, Py 100% '

NH2 251

r*^^ N . 1,3,4Thiadiazoles 273 are prepared by condensation of triazole 271 with various carboxylic acids 272 in the presence of phosphorus oxychloride . H

^

P^nK

RCHO(269), (

TMSCI

R

-v/Sx

TY-QH

JJ

268

RCO2H (272),

ô^

AANVSH

271 2 Ar = 3-CI-4-F-Ph

270

^

II

Ar

^

AN^ 273

5-Amino[l,3,4]thiadiazole derivative 277 is prepared (albeit in poor yield) from the condensation of /7-anisaldehyde 275 with thiosemicarbazide, followed by ferric chloride mediated cyclization of (benzylidene)thiosemicarbazide intermediate 276 . S

ArCHO(275),

H 2 N^ N - NH 2 £ ^ H 274

86%

S

FeCI3,

. H 2 N A N ' N ^ A r ™— H 276

Ar

6%

Af

JYHH2

Ar = p-OMe-Ph

N^ N X 277

The cyclization of thiosemicarbazides 278 with dimethyl acetylenedicarboxlate appears to be solvent dependent: In methanol thiazolidine 280 is obtained, while dioxane favors the formation of thiadiazole 281 .


Ar

rR

H

%^N

NHAr

>

?

R=

Z80

I NH

R 2 R3 =

R

dioxane

alky,

path b

^N-NxyNHAr

MeO 2 C-t~-S CH2CO2Me 281

^ N

N

279

O

R3_/~~T| \ A

RHN-N

\\> MeO2C

R2

*r

1

NHxa

MeO 2 C—^—CO 2 Me

221

^

Several interesting papers on the chemistry of 1,3,4-thiadiazole have been published in 2004 , including a general facile synthesis of 2,5diarylheteropentalenes via Suzuki coupling of bromo-1,3,4-thiadiazole , and an one-pot diastereoselective synthesis of new chiral spiro- 1,3,4-thiadiazole from (IR)thiocamphor . The 1,3,4-Thiadiazole moiety is incorporated into thiosugar nucleosides as anti-HIV and human cytomegallovirus (HCMV) agents , into crown ethers , and into macroheterocyclic compounds . The 1,2,3-thiadiazole unit is ubiquitous in several medicinally important compounds, such as selective inverse agonists for the orphan nuclear receptor estrogen-related receptor a (ERRa) , and selective PDE7 inhibitors . 5.5.5

SELENAZOLES AND SELENODIAZOLES

The chemistry of selenazoles is reviewed in a book . Addition of malonic dinitrile with phosphorus pentaselenide in aqueous ethanol affords selenomalonic diamide 282, which undergoes double cyclization with phenacyl bromide to furnish bis(selenazole) 283 . 2-Acyl-l,3-selenazoles 287 are prepared in two steps from bromomethyl ketones 284 and selenoamides 285. A facile preparation of l,3-selenazole-5-carboxylic acids 289 is based on the cyclization of selenazadienes 288 with chloroacetyl chloride .

282

D Ri ^

B r

^

- H2NA/ X R3

284

285

Ph

57%

Et H

°

—

R N

V xX ^

R

283

S?r2O7

XK ^ ^

286

R1, R 3 =aryl;R = H, phenyl r>

RlAM-^M.Me 288

||

H2O, reflux

R4V «

,Se^ 28g

CO H 2

R

V \ R3

R 287X

H

222


5-Spirocyclopropane-annulated selenaoline-4-carboxylates 293 are synthesized in good yields via Michael addition of selenoamide 291 to ethyl 2-bromo-2-cyclopropylideneacetate 290 followed by an intramolecular substitution under basic conditions .

[>=< B r CO2Et 290

+

NaHC

A

°3

R^NH 2

L -

HN

L

291 (R = aryl, Bn)

A-S?R

Se VcO 2 Etl 70-88% *s/Y R

I /)—R

" 292

J

FtO C" 2

293

Selenoxychloride is used to convert phenylenediamine 294 to bis(selenadiazole) 295 . An improved procedure for the nitration of benzo-2,l,3-selenadiazoles (e.g., 296 to 297) and their reduction to orfAo-phenylenediamines (e.g., 297 to 298) has been developed .

HzN^V^N NH 2

100%

294

5.5.6

N^k^N1 N Se -N 295

X I N v |T Se-N2 96

94%

I J 95% \ \ U CY H 2 N-Y Se-N 297

298 NH2

ACKNOWLEDGMENT

We thank Dr. Mark Saulnier for helpful discussions and critical reading of this review.

5.5.7

REFERENCES

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Z. Lai, X. Gan, L. Wei, K.R. Alliston, H. Yu, Y.H. Li, W.C. Groutas, Arch. Biochem. Biophysics 2004, 429, 191. C.C. Cutri, A. Garozzo, C. Pannecouque, A. Castro, F. Guerrera, E.De Clercq, Antiviral Chemistry & Chemotherapy 2004, 15,201 K. Villeneuve, W. Tarn, Angew. Chem. Int. Ed. 2004, 43, 610. B.B.Toure, D.G. Hall, Angew. Chem. Int. Ed. 2004, 43, 2001. A. Demchenko, P. Pornsuriyasak, C. Meo, N. Malysheva, Angew. Chem. Int. Ed. 2004, 43, 3069. K.C. Nicolaou, B. Safma, M. Zak, A. Estrada, S. Lee, Angew. Chem. Int. Ed. 2004, 43, 5087. K.C. Nicolaou, M. Zak, B. Safma, S. Lee, A. Estrada, Angew. Chem. Int. Ed. 2004, 43, 5092. Y. Hachisu, J. Bode, K. Suzuki, Adv. Synth. Catal. 2004, 346, 1097. Z. Amtul, M. Rasheed, M.I. Choudhary, S. Rosanna, K.M. Khan, A.U. Rahman, Biochem. Biophy. Res. Commun, 2004, 319, 1053. G. Poindexter, MA. Bruce, J.G. Breitenbucher, M.A. Higgins, S.Y. Sit, J.L. Romine, S.W. Martin, S.A. Ward, R.T. McGovern, W. Clarke, J. Russell, I.A. Zimanyi, Bioorg. Med. Chem. 2004,12, 507. J. Zhong, X. Gan, K.R. Alliston, W.C. Groutas, Bioorg. Med. Chem. 2004, 12, 589. K.Y. Jung, S.K. Kim, Z.G. Gao, A.S. Gross, N. Melman, K.A. Jacobson, Y.C. Kim. Bioorg. Med. Chem. 2004, 72,613. H. Yoshizawa, T. Kubota, H. Itani, K. Minami, H. Miwa, Y. Nishitani. Bioorg. Med. Chem. 2004, 72,4221. G.D. Francisco, Z. Li, J.D. Albright, N.H. Eudy, A.H. Katz, P.]. Petersen, P. Labthavikul, G. Singh, Y. Yang, B.A. Ramussen, Y.I. Lin, T.S. Mansour, Bioorg. Med. Chem. Lett. 2004, 14, 235. S.K. Singh, P.G. Reddy, P. K.S. Rao, B.B. Lohray, P. Misra, S.A. Rajjak, Y.K. Rao, A. Venkateswarlu, Bioorg. Med. Chem. Lett. 2004,14, 499.

Five-membered ring systems: with N and S (Se) atoms 04BMCL677 04BMCL909 04BMCL2469 04BMCL2871 04BMCL3401 04BMCL4607 04BMCL4615 04BMCL5599 04CC102 04CC446 04CEJ71 04CEJ2529 04CL72 04CL274 04CL814 04CPB634 04DF1003 04EJM793 04H(62) 197 04H(62)203 04H(62)217 04H(62)815 04H(63)259 04H(63)773 04H(63)1083 04H(63)1555 04H(63)1783 03H(63)2243 04H(63)2319 04HAC175 04IJHC69 04IJHC249 04JA10913 04JA12897 04JA2314 04JCO746 04JHC419

223

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224 04JHC517 04JHC723 04JHC731 04JHC955 04JHC1023 04JMC588 04JMC663 04JMC1605 04JMC1719

04JMC2097 04JMC2981 04JMC4291 04JMC5057 04JMC5593 04JMC6658

04JOC487 04JOC843 04JOC1401 04JOC1415 04JOC2381 04JOC5023 04JOC6141 04JOC7329 04JOC7371 04MI1 04MI274 04MI277 04MI405 04MI777 04NNN1739 04OBC749 04OBC2092 04OBC2870

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Five-membered ring systems: with N and S (Se) atoms 04OL23 04OL727 04OL893 04OL1313 04OL2627 04OL3083 04OL3139 04OL3377 04OL3401 04OL4057 04OL4515 04PAC1691 04PHA756 04PS1497 04RJGC1031 04RJOC99 04RJOC818 04RJOC1047 04S17 04S20 04S87 04S221 04S233 04S875 04S1067 04S1257 04S1585 04S1739 04S1929 04S2975 04SC471 04SC2681 04SCI399 04SL131 04SL329 04SL1371 04SL1643 04SL1711 04SL1963 04SL2200 04SL2681 04T187 04T1175 04T1293 04T3967 04T4315 04T4709 04T4807 04T6859

225

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226 04T8627 04T9263 04X9997 04T12139 04TA793 04TA3433 04TA3869 04TA3979 04TL7269 04TL69 04TL1907 04TL3305 04TL3629 04TL4449 04TL5441 04TL5747 04TL6579 04TL7125 04TL7157 04TL9373

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227

Chapter 5.6 Five-membered ring systems: with O & S (Se, Te) atoms

R. Alan Aitken University of St. Andrews, UK (e-mail: [email protected])

5.6.1

1,3-DIOXOLES AND DIOXOLANES

A new method for conversion of carbonyl compounds into 1,3-dioxolanes involves treatment with ethanediol, triethyl orthoformate and catalytic Me2SBr+ Br under solvent-free conditions . A large number of new catalyst systems for the reaction of epoxides 1 with CO2 under mild conditions to give dioxolanones 2 have been developed including CoCl2 in DMF , Nb2O5 or NbCl5 , Cr salen , Co(II) salen/DMAP , A1C1 salen complexes and either Co(III) or Sn(IV) porphyrins . Kinetic resolution occurs upon reaction of racemic epoxypropene with CO 2 mediated by a Co salen catalyst to give chiral dioxolanones . Formation of spiro orthoesters such as 4 is achieved in high yield by reaction of cyclic ketene monothioacetals such as 3 with ethanediol and camphorsulfonic acid . A variety of substituted epoxy ketones 5 rearrange to the benzodioxoles 6 upon treatment with Bu4N+ CN~ in CH2C12 or KI in acetone . Condensation of phenacyl carbonates 7 with aromatic aldehydes in the presence of Mg(C104)2, 2,2'-bipyridyl, N-methylmorpholine and molecular sieves gives the trans dioxolanones 8 .

R1

R

.O

O^P

.CL,SPh

°-\

1— 'V C J - c P o

R2

3

1 n

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CX— 5

4

2

n

R

r 6

Ar2cH0

II

°

Ar2

JL

*

^/* —-'» 7

8

b

Reaction of aryl bromides under Heck conditions with 2-vinyloxyethanol and a Pd phosphine catalyst gives products 9 while Ru-catalysed cyclisation of 2-allyloxyethanol gives 10 . Reaction of the corresponding substituted catechol with 1-

228

R.A. Aitken

methoxycyclopentene and cyclopentanone has been patented as a method of preparing spiro benzodioxoles such as 11 and a range of tricyclic compounds 12 have been prepared from the corresponding cyclohexanetriol . A new method for dioxolane synthesis involves Rh-catalysed reaction of a diazo compound with an electron-rich and an electron-poor aldehyde in one pot to give products such as 13 formed from methyl adiazophenylacetate, 4-methoxybenzaldehyde and 2,4-dinitrobenzaldehyde . This reaction involves in situ generation of a carbonyl ylide and intramolecular carbonyl ylide formation also allows reaction of 4-diazo-l,3-diketones 14 with aromatic aldehydes, ArCHO, to give bicyclic dioxolanes 15 .

There have again been many new developments involving chiral dioxolanes. Enzymatic kinetic resolution of 16 has been achieved using an amidohydrolase and an erroneous [a D ] value for 17 has been corrected . Convenient preparation of bis(dioxolanones) 18 from tartaric acid and aldehydes has been described and addition of mandelic acid-derived chiral dioxolanone anions to substituted [3-nitrostyrenes to give products 19 has been examined . A range of salts 20 have been evaluated as asymmetric phase-transfer catalysts for alkylation and Michael addition of a protected glycine anion equivalent and the difluorodioxole analogue of BINAP 21 has been prepared . Dioxolane-containing P/N ligands such as 22 have also been introduced for asymmetric catalysis .

Cyclopropanation of the corresponding vinyldioxolane has been used to prepare compound 23 useful for pyrethrin synthesis and addition of Ph 2 P-SiMe 3 to the corresponding dioxolane aldehyde gives 24 . The preparation and reactions of alkene-containing dioxolanes have been reported and a calorimetric and theoretical study of benzodioxoles has appeared . The X-ray structure of dioxolane 25 has been

Five-membered ring systems: with O & S (Se, Te) atoms

229

reported . The oxa-Pictet Spengler rearrangement of aryldioxolanes 26 gives products 27 . Protection of a-hydroxy acids with hexafluoroacetone to give 28 has been reported and carbonyl compounds can be protected as the fiuorous dioxolanes 29 . The hydrolysis of 2,2-disubstituted dioxolanes can be accomplished under mild conditions using erbium triflate in wet acetonitrile . The hydrolysis of compounds 30 with K2CO3 in MeOH gives 31 when R1 and R2 are alkyl groups, but 32 when one or both of them are phenyl .

Ring-opening of dioxolanes with organoaluminium compounds has been examined and stereoselective TiCl4-promoted nucleophilic ring-opening of chiral dioxolanes has also been reported . A new anionic ring contraction of dioxolanes to give oxetanes is exemplified by conversion of 33 into 34 upon treatment with ?-BuLi . Stereoselective side-chain fluorination of sulfur-containing dioxolanes has been reported and functionalisation of 2,2-dimethyl-l,3-dioxolane to give products 35 is

230

R.A. Aitken

achieved by treatment with Me2Zn/air to give the dioxolanyl radical followed by addition to RCH=NTs . There have been various studies on the preparation and synthetic utility of 4-alkylidene-l,3-dioxolan-2-ones including their preparation from propargyl alcohols either using Na2CO3 as the CO2 source or by reaction with CO2 in an ionic liquid . Their reactivity with hydrazines has also been examined . The 1,2-migration of Br or I in lithiated benzodioxoles has been exploited synthetically and addition of diazomethane and methyl diazoacetate to the double bond of levoglucosenone 36 has been reported . Resolution of glycerol monoacetonide has been achieved using the inclusion complex with a TADDOL derivative and the cyclohexadienyltitanium TADDOL compound 37 reacts with aldehydes to give products 38 in good d.e. and e.e. . TADDOL promoted asymmetric Michael addition of diethyl malonate has been used in amino acid synthesis and a further report on bicyclic amino acid derivatives such as 39 has appeared . Bis(dioxolanes) such as 40 have been used as components of liquid crystal displays and benzodioxoles such as 41 have been evaluated as cannabinoid receptor antagonists to tackle obesity . 5.6.2

1,3-DITHIOLES AND DITHIOLANES

The reaction of carbonyl compounds with ethanedithiol to give 1,3-dithiolanes can be achieved using catalytic Me2SBr+ Br" , AIC13 supported on silica , aqueous HBr , scandium chloride , praseodymium triflate or silica-supported polyphosphoric acid and compound 42 can be used as an odourless equivalent of ethanedithiol in such reactions . Rapid deprotection of 2,2-disubstituted 1,3-dithiolanes to give carbonyl compounds occurs upon treatment with ammonium persulfate and wet montmorillonite K10 clay under microwave conditions . Theoretical and experimental studies on the cycloaddition of thiocarbonyl ylides to thiocarbonyl compounds to give 1,3-dithiolanes have appeared . Enzymatic oxidation of benzodithioles to give chiral monosulfoxides has been examined and ferrocene-containing benzodithioles 43 have been prepared . Treatment of the sulfoxide 44 with Fe2(CO)9 results in a remarkable insertion process to afford 45 the structure of which was confirmed by X-ray diffraction . A novel


231

metal templating effect allows the coupling process in complex 46 to give 47 upon treatment with Ar3NSbCl6 followed by Na2S2O4 . A two-step method for conversion of iminooxathiolium salts 48 (Ad = 1-adamantyl) into iminodithiolanes 49 has been reported and electrophilic aromatic substitution using the sulfenyl chlorides 50 has been described . Naphthocyclopropene 51 reacts with the dithiolethione 52 in an apparent 2JI + 2a process to give the spiro product 53 and the formation and structure of benzotris(dithioles) 54 have been reported .

An improved synthesis of l,3-diselenole-2-thione and its coupling to form tetraselenafulvalenes have been patented . There have been a large number of reviews in the tetrathiafulvalene area including a special journal issue covering the state of the art in almost all aspects of this chemistry. Specific topics include 1,3- and 1,2tetrachalcogenafulvalenes , TTF-based organic conductors , organic conductors with unusual band fillings , new trends in Jt-electron donors , synthesis of non-symmetrically substituted TTFs , highly functionalised TTFs , conducting organic radical salts with organic and organometallic anions , single-component molecular metals with extended TTF dithiolate ligands , materials based on bis(ethylenedithio)tetraselenafulvalene and bis(ethylenedithio)tetrathiafulvalene and its trihalide derivatives , hydrogen bonding in TTF-based conductors and magnetic TTF-based charge transfer complexes . Studies on new substituted TTFs include fluoroaryl TTFs , pyridine and pyrazine-containing TTFs , silicon substituted TTFs in a silica-based hybrid organic/inorganic material , 1,3,4-oxadiazole functionalised TTFs as electrochromic materials and TTF cation radical dimers within the cavity of curcurbit[8]uril . TTF oxazoline phosphines such as 55 have been used as redox-

232

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active chiral ligands and TTFs such as 56 with long alkylthiol substituents have been designed to form self-assembled monolayers on a gold surface . The diamide 57 has been found to form "microwires" , amide derivatives 58 have been prepared and the amide 59 undergoes an unusual 2+2 cycloaddition in the crystal . The synthesis and properties of compound 60 have been reported . A purely organic molecular metal has been formed from 2-imidazolyl-TTF and pchloranil and a variety of push-pull donor-acceptor alkenes have been evaluated as non-linear optical materials . Fluorescence switching of a dianthryl-TTF has been observed and a variety of new radical salts of BEDTTTF 61 as well as its dimethyl analogue and dehydro derivative have been investigated. Metallic conductivity down to 2 K has been observed for a salt of formula (62)6K2(BW12O40) and the metalinsulator phase transition for (63)2 PF6 has been examined . An important new donor 64 has been prepared . The complex (65)4Hg3 8 3 9I8 is an ambient pressure superconductor with Tc 8.1 K and new conductors based on lanthanide complexes of this donor have also been investigated .

The properties of the dithieno-TTF 66 have been examined (04SM(146)265> and pyrrole-fused TTFs 67 and 68 have been prepared. The new furoand thieno-BEDT-TTF derivatives 69 have been prepared and a new synthesis of l,3-diselenole-2-thione avoiding the use of CSe2 has allowed synthesis of a wide range of new selenium-containing donors such as 70-72 . A number of new donors of structure 73 have been prepared and compounds 74 (n = 5-8) have been examined . The area of bi-TTF, bis (TTF) and oligomeric TTF compounds has been reviewed and new examples of this type include the 1,4-diphosphinine 75 , tris-fused TTFs , TTF-fused dehydroannulenes , extended dimeric and trimeric TTFs and acetylenic extended TTF analogues . Reviews of TTF-containing cyclophanes and cage molecules as well as TTF-functionalised cavitands have also appeared.

Five-membered ring systems: with O & S (Se, Te) atoms 5.6.3

233

1,3-OXATHIOLES AND OXATHIOLANES

Ytterbium triflate in an ionic liquid is an efficient catalyst for reaction of aldehydes and ketones with mercaptoethanol to form 2-substituted 1,3-oxathiolanes and K-10 montmorillonite has been used for the same reaction where it shows selectivity for aldehydes over ketones . The compound 76 has been used to introduce a mercapto acid unit into peptide analogues and the diastereoselectivity of addition of the anion of 77 to carbonyl compounds has been examined .

5.6.4

1,2-DITHIOLES AND DITHIOLANES

The bis(l,2-dithiole-3-thione) 78 reacts with DMAD in a multiple cascade process to afford product 79 . 5.6.5

1,2-OXATHIOLES AND OXATHIOLANES

The 1,3-dipolar cycloaddition of 80 with nitrile oxides and nitrones to give products such as 81 has been reported . Diastereoselectuve hydrolysis of ysultones 82 to give products including homotaurine derivatives has been examined . The spiro-l,2-oxaselenolane 83 which has a key role in the glutathione peroxidaselike activity of (HOCH2CH2)2Se has been isolated and its structure determined by X-ray diffraction .

234 5.6.6

R.A. Aitken THREE HETEROATOMS

A series of spiro 1,2,4-trioxolanes 84 have been prepared and evaluated as antimalarials . The spiro 1,2,4-oxadithiolane 85 reacts with £-cyclooctene to afford the corresponding thiirane together with Ph2C=S and the cyclobutanedione . Treatment of sulfines with Lawesson's reagent has been used to obtain 1,2,4trithiolanes such as 86 and 87 and oxidation of the latter to the corresponding mono- and disulfoxide and sulfone has been investigated .

5.6.7

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Five-membered ring systems: with O & S (Se, Te) atoms 04T7637 04T7743 04T8341 04TA289 04TA803 04TL411 04TL2023 04TL5103 04TL6485 04TL6955 04USP186168 04WOP3001 04WOP5276 04WOP13120

237

A. Krief, A. Froidbise, Tetrahedron 2004, 60, 7637. T. Ohshima, T. Shibuguchi, Y. Fukuta, M. Shibasaki, Tetrahedron 2004, 60,1147,. Y. Huang, F.-L. Qing, Tetrahedron 2004, 60, 8341. M. Lombardo, S. Licciulli, C. Trombini, Tetrahedron: Asymmetry 2004, 15, 289. M. Markert, I. Buchem, H. Kriiger, R. Mahrwald, Tetrahedron: Asymmetry 2004,15, 803. D.A. Bianchi, F. Rua, T.S. Kaufman, Tetrahedron Lett. 2004, 45, 411. R.L. Paddock, Y. Hiyama, J.M. McKay, S.T. Nguyen, Tetrahedron Lett. 2004,45, 2023. R.J. Brown, G. Camarasa, J.-P. Griffiths, P. Day, J.D. Wallis, Tetrahedron Lett. 2004, 45, 5103. S. Muthusamy, J. Krishnamurthi, M. Nethaji, Tetrahedron Lett. 2004, 45, 6485. O.I. Kolodiazhnyi, I.V. Guliaiko, A.O. Kolodiazhna, Tetrahedron Lett. 2004, 45, 6955. J.L. Vennerstrom, Y. Dong, J. Chollet, H. Matile, M. Padmanilayam, Y. Tang, W.N. Charman, U.S. Pat. 186,168 (2004) [Chem. Abstr. 2004,141, 296022). J.J. Lalonde, Y. Yao, PCT Int. Appl. WO 3,001 (2004) [Chem. Abstr. 2004, 140, 77138]. T. Atsumi, A. Yanagisawa, I. Chujo, H. Tsumuki, S. Mohri, PCT Int. Appl. WO 5,276 (2004) [Chem. Abstr. 2004,140, 111406]. A. Alanine, K. Beieicher, W. Guba, W. Haap, D. Kuber, T. Lubbers, J.-M. Plancher, M. Rogers-Evans, G. Schneider, J. ZUgge, O. Roche, PCT Int. Appl. WO 13,120 (2004) [Chem. Abstr. 2004, 140, 163856].

238

Chapter 5.7

Five-membered ring systems: with O & N atoms

Franca M. Cordero and Donatella Giomi Universita degli Studi di Firenze, Italy [email protected]

5.7.1 ISOXAZOLES Substituted isoxazoles are of interest because they are versatile building blocks in organic synthesis and evince valuable pharmacological properties. The development of new methodologies for the synthesis and elaboration of isoxazole derivatives enhances more and more the appeal of these compounds. Copper(I) catalyzes the reaction between nitrile oxides and terminal alkenes providing 3,4disubstituted isoxazoles 3 with complete regioselectivity and good yields. The process is believed to go through a stepwise mechanism analogous to the copper(I)-catalyzed union of terminal alkynes and organic azides . Ar Ar r

H CuSO4.5H2O (2 mol%) Ar 11 sodium ascorbate (10 mol%) ^ i

c|

^f

+

%

+

*

1

O 0 R1^

KHCO3(4.3equiv) H2O/f-BuOH, 1:1, rt, 1-4h

H 2

AorB

k L

+

\—^N-0 Ri

^R2|1^DC ' 9\ . D2

RiNTr N-0 4

%-^R , 3

1 dimerization "• J

\

^ \ R

\\

A° °Vpi " \ ^ / ~ R 8* N_ , N ^ O °

p1 R

6

^

D2

R^SCVR N-0 5

R

Yield (%) 92

4-MeOC6H4

Ph

4

Ph CH2OH CO2H

NC H

-°2 e < 6 s 4-iyieOC6H4 c F

74 76 74

A : CAN(IV

> B: CAN(III)-HCO2H ; Reagent R1 Yield (%) 4 5 A Me 22-72 31-68 B Me 36-84 70-87

A

Ph 18-78 49-80

B

Ph

42-85 57-85

The reactions of several alkenes and alkynes with ammonium cerium(IV) nitrate [CAN(IV)] or ammonium cerium(III) nitrate tetrahydrate [CAN(III)]-formic acid in acetone under reflux gave 3-acetyl-4,5-dihydroisoxazoles 4 (R1 = Me) and 3-acetylisoxazoles 5 (R1 = Me), respectively through nitrile oxide 1,3-dipolar cycloaddition (1,3-DC). The

239


corresponding benzoyl derivatives were obtained in acetophenone. The existence of a nitrile oxide as an intermediate was proved by the formation of the dimer furoxan 6 when the reaction was carried out in the absence of any dipolarophile . Fused isoxazoles 9 were prepared by sequential Ugi/intramolecular nitrile oxide cycloadditions (INOC). Multicomponent reactions of carboxylic acids 7 bearing a nitro group with propargylamine and various isocyanides and aldehydes provided the Ugi adducts 8 that underwent INOC by treatment with POC13 and Et3N . Analogously, a fused isoxazoline was obtained by replacing the propargylamine with allylamine in the multicomponent step. ^

O N

H

2

CO H ^ \2 R1CHO

R2NC

ri U2 THF/H2O

66 64

2 Ph

50 27

Ph

Ar2 NH

^ 2

7 5

?9 63

"

R1

NOH

Ar1 H

^ O ^ ^ . 1^CO2Me

- ^ 51 53

Ph

1 n-Pr CH2Ph

NOH

T

Yield {%) S

VV

8

o

R2

R1

"'J 7

n R1

O R 1

R3

EDC ^115°C

~O^X°;N

/ \ y N = \ Ar' Ar 2 ^,' 0 A N ^13-R3 = O

. ._ r - 1 1 : R 2 = Me Ar = 2- and 4-CIC6H4, 2- and 4-MeOC6H4 A ^ = 4-MeC6H4, 4-CIC6H4, 4-MeOC6H4 1

An 18-member library of 5-isoxazol-4-yl-[l,2,4]oxadiazoles 14 was prepared on solidphase through nitrile oxide 1,3-DC to resin-bound alkynoate ester 10 . In a search for new isoxazole-based liquid crystalline compounds, the 22-member library of 3,5-diaryl isoxazoles 15 was prepared by parallel synthesis on solid phase (Rink resin). Supported phenylacetylene units were reacted with suitable aryl nitrile oxides generated in situ from hydroximinoyl chlorides. Then, the products were cleaved from the resin under acidic conditions with generation of the cyano moiety .

A r - ^ V ^ - ^

R2OBn Ri^^Ô

R = H,OCnH2n+1(n=1-10)

NHBoc ^s^v.«. ^fCO 2 Me

BnoVÂ-^=NOH NBS, then Et3N "

DMF,rt,6 h

Y2/0Bn , 1 ^ 0

N'O

Bno\^^JlLj>~~S B n 18

1

NHBoc )^

2

2

° R = H; R = OBn 66% R1 = OBn; R2 = H 72%

The C-glycosyl alanines 18 featuring an isoxazole ring between the sugar and amino acid residues were prepared by 1,3-DC of C-glycosyl nitrile oxides and an ethynyl functionalized

240

F.M. Cordero and D. Giomi

amino ester. In detail, the DMF solution of C-glycosyl oxime 16 and alkyne 17 (10.0 equiv) was treated sequentially with jV-bromosuccinimide (NBS) and Et3N. Chromatographic purification of the reaction mixture furnished the 3,5-disubstituted isoxazole cycloadducts 18 in good yield as the sole regioisomers, alongside small amounts of the corresponding furoxan . The thermodynamically more stable lithium enolate of phenylacetone, regioselectively prepared in situ with lithium diisopropylamide (LDA) at 0 °C, reacted with arylnitrile oxides giving 5-hydroxy-2-isoxazolines 19. The adducts were dehydrated under basic conditions to afford 3-aryl-5-methyl-4-phenylisoxazoles 20 in 38-73% overall yields. The phenyl and 5chloro-2-furyl derivatives 20 are selective cyclooxygenase-1 (COX-1) inhibitors . Ar Ph

-i

r

/ " LDA P V ArCNO A W P h Na2CO3 V T Vo X N \r°HUT^r N k. / °C L ^ ° - J ° ^ H2O ° 19

20

Yield 49%

2

^ ^ 73% 5-CI-2-furyl 40% 2,4,6-(MeO)3C6H2 38% 3-CI-2,4,6-(MeO)3C6H

45%

Pyrrolo[3,4-c]isoxazoles 21 were designed to act as non-polar scaffolds for elaboration to acyltetramic acids. In particular, hydrogenolytic N - 0 cleavage followed by hydrolysis of the resultant enaminone afforded the 3-(3-arylpropanoyl)tetramic acids 23, while N-0 reduction by molybdenum hexacarbonyl gave the corresponding 3-arylpropenoyl compounds 22 .

/~~^ V - f V-Ar

N

°A

R1^N"^°

,v ^ y * M[

Mo(CO)6

moist MeCN R 1 ^^ 0

H

H

22 83-97% R1 = Me, CHMe2, CH 2 CMe 2 Ar = Ph, 4-O 2 NC 6 H 4 , 4-MeOC 6 H 4

i)H2, Pd/C MeOH _

< \ ^—\ V / Âr

H)aqNaOH

R ^ N ^ O

H 55-69% 23 R1 = Me, CHMe2, CH2CMe2 Ar = Ph, 4-MeOC 6 H 4

21

3,5-Disubstituted isoxazoles 24 underwent reductive ring cleavage to (3-enaminoketones 26 by treatment with titanium(III) isopropoxide, generated from Ti(O;-Pr)4 with EtMgBr in diethyl ether. The reaction probably proceeds via titanium(III)-assisted homolytic cleavage of the nitrogen-oxygen bond with the intermediate formation of titanium(IV) derivative 25 . Under the same conditions, isoxazolines were smoothly reduced to p hydroxyketones (see § 5.7.2). P

/ - i l l

3

s_,

N

EtMgBr/Ti(O/-Pr)4

n

0

(2.2-2.5equiv)i

R

Et2O

C3H7^^^^R

Y^r

L(/-PrO) 3 Ti'

Ti(O/-Pr)3J

C 3 H 7 ^f^R

_H^

Y ^ Y

_ . R = C 4 H 9 95% R = Ph71%

Isoxazoles 27 were converted into bis(silyloxy) butadienes 28 by ring cleavage and subsequent silylation. In the case of the 4-acetyl compound 27a, C-3 deprotonation by LDA caused the isoxazole ring-opening with formation of a |3-cyanoenolate intermediate which was trapped with TMSC1. Under the reaction conditions, the acetyl group was changed into

241


the corresponding silyl enol ether with formation of 28a. Isoxazoles 27b and 27c underwent reductive cleavage by treatment with lithium in wet THF and then were silylated with an excess of triethylamine and trimethylsilyl triflate. The bis(silyloxy)butadienes 28 were used as dienes in Diels-Alder (DA) reactions with acetylene derivatives to achieve polysubstituted aromatic compounds such as 29 or were converted to different p-diketones by deprotonation and treatment with electrophiles such as Br2, Mel and EtBr .

^NyN

TMSO

27

OTMS

120 C

R3-^V^

28

29 OH

\_ Y

I

/

Ph

rt

\

30 27 a

Reaction Conditions

P

/^™ 31 67%

yield (%)

R1

R2

I)

R3

28

29

Ac

H

LDA, - 7 8 °C; TMSCI, ZnCI 2 (cat)

CN

93

75

b

H

Me

Li, w e t T H F , 0 °C; Et 3 N, TMSOTf

H

91

83

c

Me

Me

Li, wetTHF, 0 "C; Et 3 N, TMSOTf

Me

87

87

The reaction of a lithium acetylide with the electrophilic 3-methylisoxazol-5-carbonyl chloride 30 afforded the substituted isoxazole 31 in 67% yield . A DFT study of the Boulton-Katritzky rearrangement of (5/?)-4-nitrosobenz[c]isoxazole and its anion indicated that these reactions have a pseudopericyclic character . 5.7.2

ISOXAZOLINES

Sibi et al. have reported examples of highly regio- and enantioselective nitrile oxide cycloadditions to electron-deficient alkenes 32 using substoichiometric amounts (30 mol%) of the chiral Lewis acid derived from Mgk and 33. The achiral pyrazolidinone template Z which contain a fluxional nitrogen proved to be effective in the cycloadditions of various aromatic nitrile oxides providing adducts 34 in good yields (70-86%), and high regioselectivity (99%) and enantiomeric excess (86-99%) . To avoid potential problems involving coordination of the Lewis acid by amine bases, unstable nitrile oxides were generated by passing the corresponding hydroximinoyl chlorides through an external bed of Amberlyst 21 immediately prior to injection into the reaction mixture. The cycloadditons of aliphatic nitrile oxides also proceeded with good selectivity, although more slowly and in lower yields.

OJLQ

Rls^V.Z T O

^ ^

M 9'2 \J M C ^ A r u r - i rt MS 4 A, Ch^C^, rt 70-86%

°A

34 O 9 9 ; 1 86-99% ee

35

i'

°,

i

i '*

Z

! '

Ar

= 2,4,6-Me3C6H2; R1 = Me, Et, Ph, CO2Et Ar = Ph, 2-CIC6H4, 4-CIC6H4; R1 = Me

A library of 19 isoxazolinopyrroles 41 was prepared through a four-step solid-phase synthesis starting from 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene HL resin 36. Resinbound amines 37 were coupled with acids 38, which were synthesized in solution-phase by a

242

F.M. Cordero andD. Giomi

regioselective nitrile oxide 1,3-DC. The pyrrole annulation of 39 with various isocyano derivatives afforded the resin-bound products which were released from resin 40 by 10% TFA in moderate to excellent overall yields from 36 (14-100%) . The acidlabile resin 36 was found to give superior product yields and purity compared to the sulfinatefunctionalized resin used in the solid-phase synthesis of isoxazolinopyrrole derivatives.

Some polyfunctional isoxazolines of generic structure 44 were obtained in 78-91% yields by treatment of aryl aldoximes 42 with Baylis-Hillman adducts 43 in the presence of diacetoxy iodobenzene (DIB). The reaction is completely diastereoselective and involves the formation of nitrile oxides from aldoximes followed by 1,3-DC with the activated alkenes. Under the same conditions, ketoximes afforded only deoximation products .

The kinetic resolution (KR) of racemic isoxazoline 45 catalyzed by enzymes was studied. The best result was obtained with lipase B from Candida antarctica (CALB) that hydrolyzed the ethyl ester function of (-)-45 to the corresponding monoacid (-)-46. The reaction, which was run in 0.1 M phosphate buffer/acetone at rt, spontaneously stopped at 50% conversion to yield monoacid (-)-46 and the residual ester (+)-45 in ee's higher than 99% . The C-5 epimer of 45 underwent enantioselective hydrolysis (> 99% ee) of the methyl ester linked to C-5 in the presence of the protease proleather (Subtilisin Carlsberg) whereas CALB and other lipases were not able to resolve it.

Like isoxazoles 24 (see § 5.7.1), 3,5-disubstituted isoxazolidines 47 were reduced by lowvalent titanium isopropoxide reagent. The reaction afforded the corresponding |3hydroxyketones 48 in good isolated yields and was tolerant of various functional groups, including alkynyl and sulfide groups .

Five-membered ring systems: with O & N atoms 1) EtMgBr/Ti(O/-Pr)4 (2.2-3.2 equiv) C3H7^^\^R

C H 3

\—. N/uXR

Et2

° 2) H2O

47

..

O

OH 48

243

R = C 4 H 9 90%; R = CH2CH(OEt)2 50% R = CH2C=CPh78%; R =CH2CO2Et 70% R=CH 2 OH78%; R =CH2SC5H.,1 90% R= COC8H13 68%; R=CH 2 SO 2 C 5 H 11 73%

Enones 49 derived from disaccharides melibial and gentobial reacted with two equivalents of hydroxylamine to afford isoxazolines 50 as an inseparable epimeric mixture in 80-83% yield. By treatment with /?-toluenesulfonic acid, compounds 50 underwent dehydration to give isoxazole derivatives 51 in high yields . RO^S^S

BnO-'V O 49

NH2OH HCI R O ^ V * O H EWB0H

BHO'-SON

p-TsOH

9H

CH2CI2,rt

/^V
99% ee). In this reaction, the presence of molecular sieves 4 A (MS) was crucial as in their absence the nitrone decomposed and almost no cycloadduct was obtained . Sibi et al. found that square planar complexes derived from copper triflate and some chiral bisoxazolines favour the COZ-exo approach in the 1,3-DC of nitrone


245

67 with crotonate 69 in absence of MS. For example, the aminoindanol-derived ligand 33 provided the exo adduct 71 in high yield, and enantio- and exo-selectivity (96:4 dr, 98% ee). In this case, the addition of MS lead to a significant reduction in exo-endo selectivity (63:37 dr) . When the pyrazolidinone ring B in the dipolarophile was replaced by the oxazolidinone A, the reaction still proceeded in high yield (98%) and exo selectivity (dr 98:2), but with modest enantioselectivity (40% ee). This result suggested that the template B amplifies enantioselectivity working in concert with the chiral ligand, but is not the source of exo selectivity.

The complex of Co(II) with trisoxazoline 76 catalysed the 1,3-DC between a variety of nitrones and alkylidene malonates to give the corresponding isoxazolidines with both high enantio- and diastereoselectivity. The cycloaddition was reversibile and the endolexo selectivity could be effectively controlled by reaction temperature. For example, 66 and 73 reacted in the presence of catalytic amounts of Co(GC>4)2 6H2O (5 mol%) and 76 (3.3 mol%) at -40 °C under kinetic control affording mainly the cis isoxazolidine 74, but at 0 °C the thermodinamically more stable trans isomer 75 was the major product .

246


The enantioselective cycloadditions of nitrone 66 with a-alkyl- and a-arylacroleins catalyzed by bisoxazoline 79 complexes of Ni(II) and Mg(II) salts exclusively afforded isoxazolidine-5-carbaldehydes such as 77 in good yields . The chiral complexes 79/Zn(II) and {(r|5"C5Me5)Rh[(.K)-l,2-bis(diphenylphosphmo) propane](H2O)}(SbF6)2 80 catalysed the cycloaddition of 66 with methacrolein affording a mixture of 77 and its 4-formyl regioisomer in 55:45 and 37:63 ratio, respectively, with complete CHO-endo selectivity and good enantioselectivities. The Rh catalyst 80 could be recovered and reused up to four time without significant loss of either activity or selectivity. The reactions of acyclic nitrones with the electron-poor a-bromoacrolein were effectively catalysed by the Zn(II) complexes of 79 to give isoxazolidine-4-carbaldehydes such as 78 with high diastereo- and enantioselectivity. The halide counter anions of 79/Zn(II) complex catalysts strongly affected catalytic activity and selectivity. The best results were obtained with the catalyst prepared from equimolar amounts of 79, Znh, and AgC104 . The regioselectivity of 1,3-DC between N-benzyl C-(benzyloxy)methyl nitrone and 3acryloyl-l,3-oxazolidin-2-one was completely reversed in the presence of a Lewis acid such as Ti(O/-Pr)2Cl2 . Tetranitromethane (TNM) reacts with alkenes through the formation of an intermediate nitronic ester (1:1 adduct) which undergoes 1,3-DC with a second alkene molecule to afford 3,3-dinitroisoxazolidine derivatives (1:2 adduct). Zefirov et al. studied the three-component reaction of TNM with two different alkenes. When alkenes with different sterical and/or electronic requirements were used, 1:1:1 adducts were obtained with high selectivity. For example, an equimolar mixture of TNM, bicyclobutylidene 81 and methylenecyclobutane 83 afforded the isoxazolidine 84 as a 4:1 mixture of two diastereoisomers in 66% yield .

5-Spiro- and 4,5-bis(spiro)-cyclopropane isoxazolidines 85a and 85b prepared by 1,3-DC of acyclic nitrones with methylenecyclopropane (MCP), MCP derivatives or bicyclopropylidene (BCP) smoothly underwent fragmentation upon heating in the presence of a protic acid to yield monobactams 86a and spirocyclopropanated |3-lactams 86b in moderate to good yields (56-96%) . Under analogous reaction conditions, tricyclic isoxazolidines 85c afforded the |3homoprolines 87, probably by ring opening and #-acylation of the primary carbapenam intermediates 86c . The chemistry of spirocyclopropane isoxazolidines 85 as versatile precursors of different azaheterocycles has been reviewed .

247


Smi2 is a selective and mild reducing reagent and was used to prepare (5aminocyclopropanols and -cyclobutanols such as 89 and 91 by reductive ring opening of suitable 5-spiroisoxazolidines . f Bu0

-

H

Sml2

/ ^ \ .

-

(3.5equiv)

f-BuO.

H

/v.

/-4^-V/\

88

\

89 90%

Sml2

(""V^

^

(3.5 equiv) / ~ - p > - V

90

91 90%

Isoxazolidines 92 were converted into 3-nitro-4-hydroxymethyl tetrahydrofurans 94 by treatment with TBAF. The process is believed to occur through the formation of nitroso intermediates 93, that undergo a spontaneous aerobic oxidation. The two-step sequence of intramolecular silylnitronate olefin cycloaddition (ISOC) followed by oxidative ring cleavage was diastereoselective and allowed complete control of the relative configuration of the newly created stereocenters . i)f-BuOK

\

1

r

-,

H n

HP. i / S » - .ft S , ™ " ^ ) TBAF i "; =\ R - °- N 6P9 9— " R 'V-\ — R1"r"A R1 2 3 %- R2R i i r-\37—48% [ R Hj " -O - [Ôj R - Q I

R1 = Me, R 2 = C 5 H 1 -i; Ph; R 1 -R 2 =-(CH 2 ) 4 -

9 2

93

94

Polymer-supported isoxazolidines such as 96 and 99 were prepared by 1,3-DC of the polymer-bound nitrone 95 with alkenes. Reductive N-0 bond cleavage of 96 and 99 with Mo(CO)6 in wet acetonitrile afforded the 1,3-aminoalcohol 97 and the lactam 100, respectively. The piperazinone derivatives cleaved from the resin under basic conditions were generally of higher purity and produced in higher yields than the corresponding compounds obtained following an analogous synthetic sequence in solution phase .

Ar R OH

A>^> A o ^

o-/

o-

96 ^-OPh

95 Q - O H = Wang resin

o~^ 99

A>-R

y~i^

O OH p100:R=Q c) L*101: R = Me Reagents and conditions: (a) CH2=CHCH2OPh or CH2=CHCO2Me, THF, 65 °C; (b) Mo(CO)6, MeCN/H2O, 85 °C; (c) NaOMe, MeOH/THF, rt. C)

p97:R = Q l—98: R = Me

A P

CO2Me

5.7.4 OXAZOLES The great interest in the biological activity of oxazole-containing natural products, joined to the wide use of these heterocyclic rings as useful intermediates for chemical transformations, has stimulated intense research work summarized in review articles . Moreover, many studies are still focused on the synthetic strategies to access the antitumor marine natural product diazonamide A. In particular, a

248


series of synthetic methodologies have been developed to access the originally proposed molecular architecture, the most important being the identification of a powerful method to accomplish Robinson-Gabriel cyclodehydration in hindered keto amides using pyridinebuffered POC13, to close the oxazole A ring . The developed chemistry allowed two distinct successful total syntheses of the revised structure of diazonamide A O4JA12888; 04JA12897>. An elegant and straightforward one-pot reaction of propargylic alcohols 102, bearing a terminal alkyne moiety (R2 = H), with amides 103 gave substituted oxazoles 105 in good yields and complete regioselectivity by the sequential action of ruthenium and gold catalysts, through A'-propargyl amides 104 as likely intermediates . Conversion of propargyl amides into oxazoles via homogeneous catalysis by AuCb was also reported and 5methylene-4,5-dihydrooxazoles 106 were detected as intermediates via H NMR spectroscopy . Substituted oxazol-5-yl ketones and esters 105 (R2 = COPh, COr-Bu, COEt, COCH=CH2, CO2Et) were easily prepared in good yields by a mild SiO2mediated cycloisomerization .

R2

j t f

D1

U M H N

2

T OH

5

D

Y

R

° 102

H

m O l % C a t

R 1

10mol%NH4BF4

R 1 .

RJ

^PPhN2Y R ^ M ^ M ^ P P h 2

^

140

1

R

S^^N^^ 145

141

142

143

^^-r-OR 146

Et2N

E = CO2Me 147

/J 144

.-

^ 148 up to 86% ee

Novel chiral nitrogen-sulfur hybrid ligands 144, with a rigid cyclopenta[6]thiophene skeleton in which the sulfur atom is part of a strong n-donor structure, as well as the fused tricyclic derivatives 145, were synthesised and their activity tested in the Pd-allylic alkylation (up to 74% ee) and Cu-catalyzed conjugate addition of diethylzinc to enones (up to 74% ee), respectively . New chiral N-S 5-ferrocenyl-oxazolines have also been prepared from enantiomerically pure ferrocenyl cyanohydrins . N , 0 2-Ferrocenyl-oxazoline alcohols were found to be effective catalysts in the addition of alkynylzinc reagents to aldehydes with up to 93% ee of the propargyl alcohols , while N,P 1,1'-ferrocene ligands 146 allowed the creation for the first time of chiral quaternary carbon centers by Pd-catalyzed allylic alkylation of acetates 147 with dimethyl malonate affording 148 as predominant products in good to high regio- and enantioselectivities .

252


New chiral oxazolinylcarbene-rhodium complexes 149 proved to be efficient catalysts for asymmetric hydrosilylation of dialkyl ketones with diphenylsilane (77-95% ee) . Novel C2 symmetric chiral bis(oxazoline) ligands have been also synthesized. Derivatives 150, bearing a dibenzo[a,c]cycloheptadiene skeleton and a hydroxyalkyl group on the oxazoline rings, were applied in the catalytic asymmetric addition of diethylzinc to aromatic aldehydes (up to 96% ee) , while new xanthene (XaBOX) ligands 151 were evaluated in 1,3-DC reactions of nitrones with 3-crotonoyl-2-oxazolidinone in the presence of Mn(II) or Mg(II) perchlorate (92-98% de; 91-98% ee for the endo adduct) . A new class of substituted o-alkoxyaryl bis(oxazoline) ligands 152 have been introduced providing the highest enantioselectivities (up to 98% ee) yet reported for copper(II)-catalyzed asymmetric dienolsilane aldol addition to pyruvate and glyoxylate esters . A novel backbone l,8-bis(oxazolinyl)anthracene 153 (AnBOX) and CuOTf proved efficient to catalyse asymmetric aziridination of chalcones with up to 99% ee . New enantiopure fluorous bis(oxazolines) 154 (Rf = CsFn, C10F21) have been synthesized in 3470% yields by simple alkylation of nonfluorous bis(oxazolines). Their application in Pdcatalyzed allylic alkylation and Cu-catalyzed oxidation of cycloalkenes exhibited enantioselectivities up to 98 and 77% ee, respectively . The new spiro bis(oxazoline) 155 with seven stereogenic centers was prepared as a unique diastereoisomer and applied to Cu-catalyzed Henry reactions and carbonyl-ene reactions with good enantiocontrol . Novel tridentate ligands 156 with a diphenylamine backbone were also reported . Enantiopure Box and Pybox ligands continue to show interesting applications in many kinds of asymmetric reactions, such as Ir-catalyzed and Pd-catalyzed allylic alkylation , DA , hetero Diels-Alder (HAD) , 1,3-DC , and cyclopropanation in ionic liquids . The use of a Pybox-Cu(II) complex in catalytic asymmetric Passerini reactions with coupling of a bidentate coordinating carbonyl compound 158 and an isocyanide 159 with a carboxylic acid 157 allowed the synthesis of cc-acyloxyamides 160 in up to 98% yield and 98% ee .

253


R1

^° 2 H 157

R1^0

Cat.20mol%

2

3

Cat

2

R -CHO + CN-R CH2CI2, 0 °C 158 159 AW-300MS

=

H

R "^^

3

, V N ' V } ,

X/" Q

1 6 00

^

20Tf >J\ Qj

R1 = Ph, Bn; R2 = 2-furyl, BnOCH2, 2-thiophenecarboxyl; R3 = Bn, f-Bu, n-Bu, 4-MeOC6H4

Immobilized copper-zeolite Y (Cu-HY) bis(oxazolines) were employed as heterogeneous catalysts in carbonyl-ene and imino-ene reactions, allowing the synthesis of oc-hydroxy and a-amino carbonyl compounds 163 from 161 and 162 in satisfactory yields and high enantioselection . The use of a new, insoluble polystyrene-bound Box ligand (IPB-BOX) was also described with good activity (85-95% ee) . R

^ *

^

I

C

2 B

°

X

161

Cat

R

Cu-HY

162

R2R2

vK^vCO2Et

"

X = ONR'

XH

Cat.= / jf

163 23-94% ee 57-99%

Y R1

jf\ ~~\ R1

Novel alkenyloxazoline-titanium complexes 165, obtained by treatment of 164 with a Ti(II) alkoxide reagent formed from Ti(O;'-Pr)4 with two equivalents of i-PrMgCl, proved to be versatile templates for diastereoselective one-pot coupling reactions allowing the construction of acyclic carbon chains 168. Treatment of 165 with different alkynes gave titanacycles 166 where the carbon-titanium bond a to the oxazoline ring selectively reacted with aldehydes to give intermediates 167; hydrolytic workup led to compounds 168 as single regioisomers having exclusively an £-olefinic bond. Asymmetric reactions of chiral oxazolines were also reported . X^ Ti(O/-Pr)4/2/-PrMgCI

/ R

-N

'

— i ^

"

R i >'°'L

164

= ~ R2 ° N ^

»T*N Pr 2

»

^

R

J

165

^ U/Ti(O ( -Pr) 2

R1 = Ph, Ar, SiMe3; R2 = C6H13, SiMe3; R3 = C8H17, Ph, /-Pr r 3

R CHO -20 °C

i

~^N

R2

166

I—

R3

(^ jti i ° T

N

O^N

H^

0

Ti(O/-Pr)2

Ri*\s=^ R 167

J

T îfT^^^

3

OH R1 168 48-73%; de 76-92%

Reactions of a-chloroalkyloxazolines 169 with hexacarbonyltungsten and lithium amides allowed the preparation of a-oxazolinylalkanamides 170 . A new method for the preparation of 2-substituted oxazolines 173 by rhodium-catalyzed coupling of alkenes 172 with 4,4-dimethyl-2-oxazoline 171 has been reported. Compounds 173 were obtained in good yields and excellent selectivity for the linear product .

254


QV1 — OVV1 O~« ^ ^ ^ c V ^ * RI 169

THF -98 °C — rt

pji R2 1 7 0 46-88%

RCHO

\^NYE

MgCI25mol%

coe=c/s-cyclooctene 171

172

173 37-86% H OMe J.+

E

—#"{-£

OEt E

MeCN.rt

O^R

174

E=CO 2 Me

175 72-95%

^

"Yr

êOÔ'^90'2 L

176

Microwave irradiations of 2-amino-2-methyl-l-propanol with A^-acylbenzotriazoles in the presence of SOCl2 produced 2-substituted-2-oxazolines in 84-98% yields O4J0C811>. A^-Malonylimidates such as 174 gave catalyzed 1,3-DC reactions with aldehydes leading to oxazolines 175 in good yields. Reactions proceeded optimally at room temperature with the addition of 5 mol% of MgCk in MeCN, likely through a metal-coordinated azomethine ylide 176 coming from a 1,2-prototropic shift promoted by the Lewis acid .

5.7.6

OXAZOLIDINES

1,3-Oxazolidines, prepared from enantiomerically pure (3-amino alcohols, are widely employed as chiral inductors for the stereoselective transformation of adjacent prostereogenic C=C or C=O double bonds . Moreover, Evans' oxazolidinones are among the most efficient chiral auxiliaries in traditional solution-phase asymmetric synthesis. Their use in polymer-supported organic reactions in general, not only as chiral auxiliaries, but also as linkers for attaching the substrate to the polymer support, has been reviewed .

The Garner aldehyde 177, a synthetically important compound employed for instance to synthesize (25)-homopentafluorophenylalanine 179 in 57% overall yield through oxazolineolefin 178 , was incorporated in the oxazolidine linker for solid-phase chemistry 180. A stability and reactivity study was performed evidencing the compatibility of 180 with a wide range of reaction classes including nucleophilic, oxidizing, and reducing conditions . A new polymer-supported Evans-type chiral auxiliary 181, anchored to the Wang resin through the 5-position of the oxazolidinone ring and a piperidine4-carboxyl linker, has been synthesized; it proved to be a useful tool for solid-phase


255

asymmetric alkylation . Asymmetric iodolactamization reactions of unsaturated amides with oxazolidines as chiral auxiliaries were performed. With (45^)-4-[(2^)-2-butyl]-2,2-dimethyloxazolidine as chiral auxiliary and LiH as the base, unsaturated amides afforded smoothly y- and 8-lactams in 3098% yields and 59-97% de, as evidenced by the conversion of 182 into 183 . The indium-mediated allylation of chiral hydrazones 184 was investigated allowing the synthesis of derivatives 185 with essentially complete diastereoselectivity and quantitative yields for substrates coming from both aromatic and aliphatic aldehydes . The first asymmetric aminohalogenation of functionalised alkenes 186 has been established operating in an ionic liquid such as [Bmim][BF4]. By simply mixing the reactants, compounds 187 were obtained in satisfactory yields and diastereoselectivities .

Double asymmetric induction in the conjugate addition of (R)- and (5)-lithium iV-benzyl./V-a-methylbenzylamide 189 to (S)-3'-phenylprop-2'-enoyl-4-benzyloxazolidinone 188 was exploited as a mechanistic probe: the formation of compounds 190 and 191 respectively demonstrated that the reactive conformation of 188 was the anti-s-cis form . N-Acyliminium ion 193 generated by anodic oxidation of 192 reacted with alkenes and alkynes to give Y-aminoalcohols and P-amino carbonyl compounds, respectively, after treatment with H2O/NEt3. With vinyltrimethylsilane the reaction was highly diastereoselective affording enantiomerically pure a-silyl-y-amino alcohol 194 .

194

7V-Vinyl-2-oxazolidinones 195 proved to be efficient chiral dienophiles in Eu(fod)3 catalyzed inverse-electron demand HDA reactions with p\y-unsaturated a-ketoesters 196, leading to endo adducts 197a,b in high yields and with high facial diastereoselectivity. A unequivocal relationship between the inducing stereogenic center at C-4' of the oxazolidinyl ring and the two stereogenic centers created on the dihydropyranic ring was established .

256

F.M. Cordero andD. Giomi

An easy access to chiral oxazolidine-2-thione auxiliaries 198 using carbon disulfide and chiral amino alcohols in the presence of K2CO3 and H2O2 has been reported . Efficient removal of the 4-phenyloxazolidinethione auxiliary from ,/V-acyl derivatives was achieved by treatment with EtSH in the presence of a catalytic amount of DBU . fra«j--2,5-Disubstituted tetrahydrofurans 201 were obtained as major diastereoisomers when acetylated y-lactols 200 were treated with titanium enolates of iV-acetyl (TJ)-oxazolidin2-thiones 199. A simple transesterification allowed the isolation of the corresponding methyl esters and the recovery of the chiral auxiliary . f?

R

R

197a

R

195

197b

E = CO 2 Me; R = Ph, Of-Bu; R1, R2, R3 = H, Et, ;-Bu, Ph, Bn, Me n^M'Ac

U NH

°

<W? R

\

R

198 R=Ph, Bn,/-Pr

^ 199

+

I—\

1. TiCI 4 , DIPEA

ACO^X^R

n

200

1

6P

9

0--40°C

/

\s

e0A^/'-0AVR

M

2K 2 C0 3 ,Me0H

^

R = H, Ph; P = TBDMS, TBDPS; R1 = H, f-Bu

^ ^ O P

up to 100% de

Polyfunctionalized pyrrolidines were diastereoselectively synthesized via ring-closing metathesis of 3-allyl-4-vinyl-2-oxazolidinones. Compound 202 gave the bicyclic system 203, converted into 204 through cw-dihydroxylation and oxazolidinone ring-opening . A base-induced ring-opening imine isomerization/diastereoselective organometallic addition sequence on 4-substituted-2-perfluoroalkyl-l,3-oxazolidines 205 was developed for the asymmetric synthesis of perfluoroalkyl amino alcohols 207 via intermediates 206. Chiral compounds were obtained in good yields and high diastereoselectivity . / = ^

GrubbslM0% ^

I—( O

N ^ ^ ^

82%

O 202 R1^^

° Y

TMSCI

R2

N

1. K2OsO4.2H2O NMO, acetone/H2O,

T H F

'°^

R2^NAÔ™s

r t

206 2

1 T

ArLi

- ^ ^ H3O+

R = Et, /-Pr, /-Bu, f-Bu, Bn; R = CF 3 , CF 2 H, CF 2 CF 3

5.7.7

^'"

3. ion-exchange

Ri

1

•-—x / ^

rt

2. NaOH, MeOH, H2O reflux

°203

JTQO LiN(TMS)2 | 205

^-^ /—(^J

\\ ^

R2

n%

R1

ArANAÔH 2 07

" 60-97%

d r from 3 5 : 1 t o

="100:1

OXADIAZOLES

Several 5-substituted-2-amino-l,3,4-oxadiazoles 211 were prepared from acyl hydrazines and isothiocyanates through a one-pot reaction using commercially available supported reagents to induce cyclization and facilitate product isolation. In particular, a solution of 210

257


created in situ from 208 (1 equiv) and 209 (1.1 equiv) was treated with the resin-bound carbodiimide 212 (5 equiv) at 80 °C to form 211. Then, aminopropyl functionalized silica gel 213 (0.2 equiv) and resin 214 (0.2 equiv) were added to scavenge the unreacted 209 and 210, respectively. At the end, a simple filtration and evaporation of the reaction mixture afforded oxadiazole 211 in high purity (86-100% by LCMS) and good yield .

H2N R

R2NCS [

u

AO

DMF

208

fl R

A

fl S

2.213

O

rt, 20 h L

Ht R2

I 1.212 J

210

N^/°

214

R1 = Ph, 2,6-FCIC6H4CH2, 3,4-CI2C6H4CH2, 3-pyridylCH2, 3,4-(OCH 2 O)C 6 H 4 CH 2

R2 = Ph,/-Bu.Me

f

R1 2 11 64-82%

I Q ^ .

N,C6H11

j

k^Ô^N*

j

212

! ®K>-NH 2 ' ^^

i |

^

^Nf.Bu ,

Q^N'^N'' L J

L....213

; '

?. 1 . 4 .._.....J

Cyclohepta[c][l,2,5]oxadiazoles such as 216 were obtained from 3-(l,3-butadienyl)-4methyl-l,2,5-oxadiazole derivatives by treatment with LDA through an intramolecular cyclization of the C7-8jt-electron system .

1

LDA

V/

(

\

ITS^C" V Y

N',N

T H F

N

N

"

Ph^xO^Br

ArB(OH)2, Na2CO3

N-N

Pd(PPh3)4 (cat)

217

D M F

,H2O

85"C,3h

215

216 85/o

Ph-Ô-sÂr

I J 218

Ar = 4-MeOC6H4 85% Ar = 4-F3CC6H4 93%

The 2,5-diaryl 1,3,4-oxadiazoles 218 were prepared from the 5-bromooxadiazole 217 through Suzuki coupling with suitable boronic acids . The photochemical behaviour of some fluorinated 1,2,4-oxadiazoles has been investigated recently 04JOC4108; 04JFC165>.

5.7.8

REFERENCES

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T.G. Kilroy, P.G. Cozzi, N. End, P.J. Guiry, Synlett 2004, 5, 106. S. Chandrasekhar, B.N. Babu, M. Ahmed, M.V. Reddy, P. Srihari, B. Jagadeesh, A. Prabhakar, Synlett 2004, 1303. B. Dugovic, L. Fisera, C. Hametner, Synlett 2004, 1569. D.H. Churykau, V.G. Zinovich, O.G. Kulinkovich, Synlett 2004, 1949. R.C.F. Jones, T.A. Pillainayagam, Synlett 2004, 2815. K. Itoh, C.A. Horiuchi, Tetrahedron 2004, 60, 1671. A. Trifonova, K.E. Kallstrom, P.G. Andersson, Tetrahedron 2004, 60, 3393. H.A. McManus, S.M. Barry, P.G. Andersson, P.J. Guiry, Tetrahedron 2004, 60, 3405. J.R. Davies, P.D. Kane, C.J. Moody, Tetrahedron 2004, 60, 3967. G. Cuny,R. Gamez-Montano, J. Zhu, Tetrahedron 2004, 60, 4879. P. Passacantilli, S. Pepe, G. Piancatelli, D. Pigini, A. Squarcia, Tetrahedron 2004, 60, 6453. C.A. Zificsak, D.J. Hlasta, Tetrahedron 2004, 60, 8991. O. Tamura, A. Kanoh, M. Yamashita, H. Ishibashi, Tetrahedron 2004, 60, 9997. P. Carato, S. Yous, D. Sellier, J.H. Poupaert, N. Lebegue, P. Berthelot, Tetrahedron Lett. 2004,45, 10321. V.S.C. Yeh, Tetrahedron 2004, 60, 11995. D.L. Davies, S.K. Kandola, R.K. Patel, Tetrahedron: Asymmetry 2004, 15,11. B. Fu, D.-M. Du, J. Wang, Tetrahedron: Asymmetry 2004, 15, 119. M. Li, X.-Z. Zhu, K. Yuan, B.-X. Cao, X.-L- Hou, Tetrahedron: Asymmetry 2004,15, 219. C.W.Y. Chung, P.H. Toy, Tetrahedron: Asymmetry 2004, 75, 387. G. Jones, C.J. Richards, Tetrahedron: Asymmetry 2004, 75, 653. B.F. Bovini, L. Giordano, M. Fochi, M. Comes-Franchini, L. Bernardi, E. Capito. A. Ricci, Tetrahedron: Asymmetry 2004, 75, 1043. L. Bernardi, B.F. Bovini, M. Comes-Franchini, C. Femoni, M. Fochi, A. Ricci, Tetrahedron: Asymmetry 2004, 75, 1133. X.-L. Hou, D.X. Dong, K. Yuan, Tetrahedron: Asymmetry 2004, 75, 2189. N. End, C. Stoessel, U. Berens, P. di-Pietro, P.G. Cozzi, Tetrahedron: Asymmetry 2004, 75, 2235. G. Roda, P. Conti, M. De Amici, J.T. He, P.L. Polavarapu, C. De Micheli, Tetrahedron: Asymmetry 2004, 75, 3079. J. Bayardon, D. Sinou, M. Guala, G. Desimoni, Tetrahedron: Asymmetry 2004, 15, 3195. A. Mandoli, S. Orlandi, D. Pini, P. Salvatori, Tetrahedron: Asymmetry 2004, 75, 3233. S.-F. Lu, D.-M. Du, S.-W. Zhang, J. Xu, Tetrahedron: Asymmetry 2004, 75, 3433. T. Kato, K. Marubayashi, S. Takizawa, H. Sasai, Tetrahedron: Asymmetry 2004, 75, 3693. S. Paul, P. Nanda, R. Gupta, A. Loupy, Tetrahedron Lett. 2004, 45, 425. H. Danjo, M. Higuchi, M. Yada, T. Immoto, Tetrahedron Lett. 2004, 45, 603. C.C. Lindsey, B.M. O'-Boyle, S.J. Mercede, T.R.R. Pettus, Tetrahedron Lett. 2004, 45, 867. S. Iwasa, Y. Ishima, H.S. Widagdo, K. Aoki, H. Nishiyama, Tetrahedron Lett. 2004, 45, 2121. T. Haino, M. Tanaka, K. Ideta, K. Kubo, A. Mori, Y. Fukazawa, Tetrahedron Lett. 2004, 45, 2277. F.T. Coppo, K.A. Evans, T.L. Graybill, G. Burton, Tetrahedron Lett. 2004, 45, 3257. I. Akritopoulou-Zanze, V. Gracias, J.D. Moore, S.W. Djuric, Tetrahedron Lett. 2004, 45, 3421. T. Kotake, S. Rajesh, Y. Hayashi, Y. Mukai, M. Ueda, T. Rimura, Y. Kiso, Tetrahedron Lett. 2004, 45, 3651. G.L. Young, S.A. Smith, R.J.K. Taylor, Tetrahedron Lett. 2004, 45, 3191. M.M. Matsumoto, N. Hoshiya, R. Isobe, Y. Watanabe, N. Watanabe, Tetrahedron Lett. 2004, 45, 3895. M. Shirahase, S. Kanemasa, M. Hasegawa, Tetrahedron Lett. 2004, 45, 4061. X. Li, H. Takahashi, H. Ohtake, S. Ikegami, Tetrahedron Lett. 2004, 45, 4123. N.G. Argyropoulos, V.C. Sarli, Tetrahedron Lett. 2004, 45, 4237. E.B. Frolov, F.J. Lakner, A.V. Khvat, A.V. Ivachtchenko, Tetrahedron Lett. 2004, 45, 4693. P. Borrachero, F. Cabrera-Escribano, M. Gomez Guillen, M.I. Torres, Tetrahedron Lett. 2004, 45, 4835. M.A.P. Martins, D.J. Emmerich, CM.P. Pereira, W. Cunico, M. Rossato, N. Zanatta, H.G. Bonacorso, Tetrahedron Lett. 2004, 45, 4935. M. Ohba, I. Natsutani, T. Sakuma, Tetrahedron Lett. 2004, 45, 6471. P. Vachal, L.M. Toth, Tetrahedron Lett. 2004, 45, 7157. B. Das, H. Holla, G. Mahender, J. Banerjee, M.R. Reddy, Tetrahedron Lett. 2004, 45,1341.

260 04TL7715 04TL8027 04TL8375 04TL9581 04ZOR186 05JA210

F.M. Cordero andD. Giomi Y. Wu, Q. Hu, Y.-P. Sun, Y.-Q. Yang, Tetrahedron Lett. 2004, 45, 7715. S. Florio, F.M. Perna, V. Capriati, R. Luisi, C.F. Martina, J. Barluenga, F.J. Fananas, F. Rodriguez, Tetrahedron Lett. 2004, 45, 8027. J. Revuelta, S. Cicchi, A. Brandi, Tetrahedron Lett. 2004, 45, 8375. T. Saito, T. Yamada, S. Miyazaki, T. Otani, Tetrahedron Lett. 2004, 45, 9581. E.B. Averina, E.M. Budynina, O.A. Ivanova, Y.K. Grishin, S.M., Gerdov T.S. Kuznetsova, N.S. Zefirov, Russ. J. Org. Chem. 2004, 40, 162; Engl. Transl. from Zh. Org. Khim. 2004, 40, 186. F. Himo, T. Lovell, R. Hilgraf, V.V. Rostovtsev, L. Noodleman, K.B. Sharpless, V.V. Fokin, J. Am. Chem. Soc. 2005, 127,210.

261

Chapter 6.1

Six-membered ring systems: pyridines and benzo derivatives

Heidi L. Fraser and M. Brawner Floyd Chemical and Screening Sciences, Wyeth Research, Pearl River, NY, USA [email protected] and [email protected] Ana C. Barrios Sosa Pharmaceutical Process Development, Roche Carolina Inc., Florence, SC, USA ana.barrios [email protected]

6.1.1

INTRODUCTION

Pyridines and their benzo-derivatives have received considerable synthetic attention for a variety of reasons. They are key scaffolds in biologically active and naturally occurring substances; moreover, they have become important ligands for organometallic chemistry and material science. Two reviews published in 2004 illustrate the broad application of pyridines. The first focuses on 2,2'-bipyridines as functional nanomaterials and the second describes the use of chiral pyridine JV-oxides as ligands for asymmetric catalysis . Additional reviews on the chemistry of pyridines published in 2004 include Henry's review on de novo synthesis of pyridines and Lavilla's review on the chemistry of dihydropyridines and pyridinium salts . This review includes a summary of the methods developed for the syntheses and reactions of pyridines, quinolines, isoquinolines, and piperidines that were disclosed in the literature in 2004. This chapter covers selected advances in the field and will serve an update to the review published last year in this volume.

6.1.2

PYRIDINES

6.1.2.1 Preparation of Pyridines Asokan et al. has developed a practical synthesis of 4-chloropyridines 1 from carbonyl compounds having two enolizable carbons adjacent to the carbonyl such as compound 2 . Ketone 2 was subjected to Vilsmeier-Haack reaction conditions leading to the

262

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

formation of conjugated iminium salts 3, which upon reacting with ammonium acetate cyclized to form the 4-chloropyridines 1 after basic workup.

ReiBig and co-workers discovered a new synthesis of trifluoromethyl-substituted pyridines 4 from the reaction of lithiated methoxyallenes and nitriles in the presence of trifluoroacetic acid . The authors postulate that the reaction goes through initial protonation of iminoallene 5 followed by nucleophilic addition of the trifluoroacetate anion onto the iminoallene to give 6. Intermediate 6 then undergos intramolecular acyl transfer to give 7 and subsequent aldol condensation yields the pyridinol 4 as shown in Scheme 2. Kerwin et al. has shown that azaenyne allenes readily form the a,5-didehydro-3-picoline diradicals, which can then be trapped with 1,4-cyclohexadiene, chloroform-^, and methanol to produce various pyridine products .

Baldwin et al. examined an interesting pyridine cyclization in a new synthesis of pyrazolo[4,3-c]pyridine core 8 . This reaction proceeds through an initial iminohydrazone formation, followed by 9-endo-dig cyclization of the amidine moiety onto the terminal alkyne to give compound 9. Opening of the 9-membered ring of 9 by ammonia gives 10. Subsequent 5-endo-dig cyclization forming the pyrazole ring, followed by 6ite disrotory ring


263

closure and elimination of ammonia gave the pyrazolo[4,3-c]pyridine 8. A similar alkynyl imine moiety has been reported by Shimizu and co-workers to react with (3-keto esters to produce 5acetyl-2-pyridones in good yield . n

The [4+2] disconnection continues to be an approach of choice for the synthesis of pyridine rings. Guingant et al. reacted amidine-azadienes with 2-bromo-[l,4]-naphthoquinones as an efficient one-pot approach towards the 5-aza-angucyclinone-ring skeleton . Similarly, Delfourne and co-workers utilized a two step hetero-Diels-Alder reaction of quinoline5,8-diones with iV.Af-dimethylhydrazones to obtain a series of C and D-substituted phenanthrolin7-ones . Other synthetically useful aza-diene equivalents include oxazoles and 1,2,4-triazines. Ohba and co-workers exploited the intramolecular hetero-Diels-Alder reaction of an oxazole and tethered olefin in the synthesis of two Rauwolfia alkaloids . 1,2,4-Triazines were used by Branowska in reaction with cyclic enamines to prepare two new classes of 2,2'-bipyridines . Raw et al. has elaborated this reaction using a tethered imine-enamine, which facilitates direct conversion of the 1,2,4-triazine 11 to the substituted pyridine 12 without the need for a second and discrete aromatization step as shown in Scheme 4. Compound 13 is postulated to exist in equilibrium with compound 14, which undergoes in situ elimination directly to pyridine 12.


264

Stanforth and co-workers made additional improvements on the hetero-Diels-Alder approach. They accomplished a 'one-pot' synthesis of pyridines from a,,(3-diketoesters and amidrazones . Deniaud et al. has investigated diazadienium iodide 15 as an aza-diene moiety in the synthesis of pyridines . They have demonstrated that diazadienium iodide 15 reacts with ketenes, acetylenes and acrylic dienophiles to yield a variety of substituted pyridines as shown in Scheme 5. © e /

S

^

N

Y

C

°

2 R

,RO2C

ULOR ^

C

°2R

=-CO2R

'

S

^

N H 2

'

RHC=C=O

CH3CN,Et3N

L

CH3CN,Et3N

I8h,rt

^

18h,rt

R = Me, 62% R = Et, 66%

"" - ^ °

/S

N OH

XJL ^

R

R = CO2Me, 58% R = CO 2 B, 56% R = C6H5, 50%

1. (Boc) 2 0, Et3N, DMAP CH2CI2, 1h,rt90% 2. 60 °C, 18 h, = \ R R = COMe, 85% R = CHO, 65% R = CO2Me, 60% 3. TFA, CH2CI2,4 h, rt R = COMe, 70% R = CHO, 65% R = CO2Me, 53%

Scheme 5 Boruah et al. reported a facile and convenient synthesis of pyridines 16 from (5-formyl enamides 17 under microwave irradiation employing a Henry reaction . The author postulates that nitromethane reacts with the formyl group, followed by dehydration and subsequent cyclization and aromatization to yield the nitro-pyridine 16. R2 R

CHO ANA0

MeNO2 8-10 min

17

R

Y^yN02

Ri^N^Me 16

Scheme 6 Kappe and co-workers also utilized microwave irradiation to facilitate a three component onepot synthesis of a library of 3,5,6-substituted 2-pyridones 18 . This method utilizes a CH-acidic substrate 19, dimethylformamide dimethylacetal (DMF-DMA) and diverse active methylene nitriles 20 as building blocks.


I

R1Ô

+

I

MW

Ô^N^

I

*

I

I

100 °C, 5 min

R-S

19

R!

f

265

||

I

tfW

H

CN

18

20

Scheme 7 Various modifications have been made on the Bohlmann-Rahtz reaction for the preparation of pyridines. Bagley and co-workers have developed a three-component heteroannulation reaction that proceeds under mild non-acidic conditions . In this reaction, a 1,3-dicarbonyl compound, an alkynone and excess ammonium acetate are combined and presumably generate a Bohlmann-Rahtz intermediate similar to 21, which then cyclizes to yield the 2,3,6-trisubstituted pyridine. Other work done in this group accomplishes a bromocyclization of the BohlmannRahtz intermediate 21 to generate the 2,3,5,6-tetrasubstituted pyridine 22 in good yield O4SL811> as shown in Scheme 8.

A3 O

RO2 C

I)

jf R

NBS, EtOH

(orCH2CI2) NH

2

R°2C.^Br R 2

ANAR3

83-98%

21

22 Scheme 8

1,4-Dihydropyridines continue to be of interest to medicinal chemists due to their biological activity. The synthesis of choice is the Hantzsch dihydropyridine synthesis . Zolfigol et al. has developed a mild solvent free modification to this synthesis with improved yields . Tripathi and co-workers modified this method further through use of tetrabutylammonium hydrogen sulfate as a phase transfer catalyst and diethylene glycol as an eco-friendly solvent . Dondoni et al. utilized a one-pot thermal Hantzsch reaction for the synthesis of highly functionalized |3pyridylalanines 23 as shown in Scheme 9 . They simplified the purification process by incorporating polymer-supported scavengers to remove excess reagents. A mixed resin bed of strongly acidic resin and strongly basic resin was used to remove unreacted enamine and ketoester, respectively. The unreacted aldehyde and intermediate side products were scavenged with nucleophilic aminomethylated polystyrene.

266

H.L. Fraser, M.B. Floyd and A. C. Barrios Sosa f-BuO2C^

Ph

1

H^CO2f-Bu PhCHO + T II H2N^Me

| ° + J BnO2C '"NHBoc

1.4-AMS.MJuOH 70 °C, 24 h, A ' • (A-15) 2 Q -r S O 3 H ^ © e

a

f-Bu02CvJy502f-Bu 1 JL s -f^' Me J. H BnO2C NHBoc -

NMe3OH (Ambersep)

3. / - v _ {^J^HH2

(AM-resin)

"

Yield; 7 5 %

Purity: 92%

Scheme 9 6.1.2.2 Reactions of Pyridines Palladium couplings of pyridines, although not novel, continue to be used and elaborated. Suzuki couplings with 2-halopyridines , 3halopyridines and 4-halopyridines are used frequently by medicinal chemists in the preparation of innovative biologically active molecules. Likewise 3-pyridyl boronates have also been used in this manner. Delfourne and coworkers utilized a Stille aryl-aryl cross-coupling reaction as a key bond-forming step in the synthesis of subarine, a marine alkaloid, as shown in Scheme 10. O O o ^YÔ^ Pd(PPh3)4 f^yÔ^ ^Y^0^ ^ Jl^N 1,4-Dioxane U J\^N TFA, CH2CI2 l ^J L , N K24h

o I J

NHB0C

TT 0

Br

Me3Sn

-L

n 1J

rt 24

'

h

oil)

YJ O

Yl

HN

l^.NHBoc

\J\

Subarine

Scheme 10

Stille cross-coupling reactions have also been used in the synthesis of bipyridines and other biologically active compounds . Palladium catalyzed carbonylation reactions have been improved for chloropyridines and examined in cobalt-catalyzed cross-coupling reactions . Maes developed a unique elaboration of Buchwald chemistry . They accomplished the first tandem double palladium-catalyzed amination of 2-chloro-3-iodopyridine 24 with aminoazines 25 or aminodiazines, shown in Scheme 11, to prepare complex heterocycles such as compound 26. Munson also utilized Buchwald chemistry for the synthesis of 2-alkylamino-3-fluoropyridines .

a

1

Pd(OAc) 2

|^J*^

ci+ ^rANH2

BINAPorXANTPHOS %

CS2C 3

°

|/5V'N\V_

^r/VÂ

toluene, reflux, 17 h

24

25

\=~/

26

Scheme 11


267

interest in copper-catalyzed coupling reactions has resurged due to the economic attractiveness of copper. Two different groups described the use of copper as a catalyst for efficient arylation reactions. Cristau and Taillefer detailed a mild copper-catalyzed N- and Carylation with aryl bromides and iodides with various substrates . One reaction examined was JV-arylation of 2-pyridones. Li et al. has explored the copper-catalyzed coupling reaction of 2-pyridones 27 with aromatic halides 28 based on Buchwald's protocol to prepare JVaryl-2-pyridones 29 as shown in Scheme 12.

a Pj

°

-^jj.

(f 3 ~ R 2 if

20 mol% Cul 40 mol% Ligand

2 equiv. K3PO4 1,4-dioxane, 110 °C 16 24h

' 27

"

/^Ss

R 1 - £ "l H , ° R2jfS

R

28

l^jJ 29

Scheme 12 Metalation of pyridines is another powerful and well-studied way to elaborate pyridines. Specifically, the "halogen dance" has been used to prepare 2,3,4-trisubstituted pyridines and 2,4-disubstituted pyridines . Scheme 13 shows the conversion of 2fluoropyridine 30 to a 2,3,4-trisubstituted pyridine 31 via the "halogen dance", where iodine migrates to the 4-position and the subsequently added electrophile is incorporated at the 3position of the pyridine ring. I

f%

1.LDA>

rj^Y'

30

1. LDA ^

Af* 31

Scheme 13 Schlosser and co-workers have completed an exhaustive analysis of the metalation of halotrifluoromethylpyridines . This group has also examined the metalation of 2,6-difluoropyridine to incorporate fuctional groups at the 3position of the pyridine ring. Moreover, Mongin et al. examined the deprotonation of various chloro- and fluoropyridines with lithium magnesates . Song and coworkers used magnesium-halogen exchange in the preparation of 5-bromo-2-substituted pyridines 32 from 5-bromo-2-iodopyridine 33 because of the increased stability of the Grignard reagent as compared with the aryllithium and the decreased likelihood of magnesium migration as shown in Scheme 14 .

268


B

/-prMgci, B y ^

y^ %*N

°°

C

B r

_ ^

T l k

^N^MgCI

33

NAE

32

Scheme 14 Fort and Gros have discovered an unusual induction of ortto-lithiation versus halogen-lithium exchange with reaction of/-BuLi and 3-bromopyridines 34 . This reaction showed a strong dependence on addition order; when 7-BuLi was added to a solution of the 3bromopyridine 34, orr/zo-lithiation was exclusively observed to give 4-substituted-3bromopyridine 35. In the inverse addition order, the major product was that resulting from halogen-lithium exchange, which yielded 3-substituted pyridines 36. SiMe3

|j^Y

Br

^-N^

1. f-BuLi,THF

[j^YBr

-78 °C, 5min *" ^ N ^ 2. TMSCI,-78°C 35

34

134 THF

t-BuU

-

-78 °C, 5min 2. TMSCI, -78 °C

(J N 36

Scheme 15 In the last year, a lot of attention has been paid to the efficient directing effects of 2-pyridyl groups to facilitate a number of useful synthetic transformations. Mongin and co-workers have examined 2-pyridyl groups to direct metalation of 2-phenylpyridines 37 . Under the kinetic conditions studied no nucleophilic addition to the azine ring was observed. Lithiation occurred cleanly at the 2'-position of the benzene ring, as shown in Scheme 16, to yield compounds 38.

ril2'

"75°c

riT

r\

4'

E r\

R = F, CI.Br

37

38

Scheme 16 Chang et al. has developed an efficient copper-catalyzed aziridination route based on chelation of the pyridine nitrogen to copper . Yamamoto et al. used the chelation

269


of the 2-nitrosopyridine to promote the catalytic and highly enantio and diastereoselective nitroso Diels-Alder reaction . Itami and Yoshida et al. have studied the directing effect of the 2-pyridyl groups in detail. They have shown, through an X-ray crystal structure determination, that homocoupling reactions of alkenyl(2-pyridyl)silanes , illustrated in Scheme 17, and Pauson-Khand reactions proceed through formation of a copper complex in which the pyridine nitrogen is bonded to copper as in complex 39. II Ph^^ si A^J Me2

CuX, CsF P

Me CN,rt,3h

h

^ ^

P

h

Me2 39

Scheme 17 Pyridine-ethynylenes have received notice in the past year as a result of their biological activity as well as their physiochemical properties. These compounds have typically been formed using Sonogashira couplings between bromopyridines and terminal acetylenes . Extensions of this chemistry encompass a multi-component coupling reaction to give propargylic amines . Wolf et al. has demonstrated that the Sonogashira coupling can be accomplished in water under an air atmosphere . Moreover, Sonogashira coupling of a diethynylpyridine, in combination with copper catalyzed sp-sp carbon-carbon bond formation, developed by Eglinton and Galbraith, was used to prepare a pyridinophane . An alternative approach to using pyridine-ethynylenes was developed, which used a double elimination of p-substituted sulfone 40. This arises through deprotonation a- to the sulfone to give in situ formation of compound 41, which undergoes elimination of both the phosphonate and sulfone to generate the pyridylacetylene 42 . Likewise compound 42 can be prepared from the respective benzyl sulfone and pyridine-2-carboxaldhyde. rfî

BuLi, THF

'LMAv^SO2Ph

PhCHO CIP(O)(OEt)2

40

LiHMDS 84%

^ 5 .

([ 1 N

^ ^

42

S

K

r

^

T J ^ ^

BuLi, THF

|P**| N

OP(O)(OEt)2

J 1 ^ \

LiHMDS

-HOP(O)(OEt)2

PhSO2 \^>

f S

N^Y*^^1 PhSO2

41 Scheme 18

\j?

270

H.L. Fraser, M.B. Floyd and A. C. Barrios Sosa

Zard illustrated a radical cyclization onto the pyridine ring to generate bicyclic 6,5-and 6,6pyridine heterocycles as shown in Scheme 19. Work has also been done with pyridyl radicals. Burgos has studied the intramolecular heteroarylation of pyridyl radicals with arenesulfonamides to form biaryl compounds and Builla has accomplished an intermolecular addition of a heteroaryl radical onto an aromatic solvent . BOYS

CI^N^V"

DLp,DCE

'

C ! - W

Jô

R

) n

!

CIANAN;>n

Jô

DLP = [CH3(CH2)10CO]2O2

J^Q

n = 1, R = COCH2CH3; 84%

n = 1, R = COCH2CH3; 50%

n = 2, R = COCH3; 92%

n = 2, R = COCH3; 74%

Scheme 19

Adib has shown that pyridines undergo reaction with dialkyl acetylenedicarboxylates in the presence of isocyanates to produce functionalized 2-oxo-l,9a-dihydro-2//-pyrido[l,2a]pyrimidines 43 in good yield . The author postulates that the reaction proceeds through initial reaction of the pyridine 44 with the acetylenic ester 45, and the resulting anion then attacks the isocyanate 46 to yield a zwitterionic intermediate. The nitrogen of the zwitterionic intermediate adds to the pyridinium moiety thus generating the pyrido[l,2a]pyrimidines 43. R

ffS

U 44

R 1

R O2C-=^CO2R

1

R2-N=C=O

45

^ KKR2

CH2C 2

',

(fS

R1O2C^Y^° CO2R1

46

43

Scheme 20 Sarkar et al. has generated pyridine o-quinodimethane 47 through a formal imine tautomerization of 48 with subsequent intramolecular trapping to obtain the Anabasine ring system illustrated with compound 49 . Hoornaert and co-workers generated (IH)pyridinone o-quinodimethane, via thermolysis of [3,4-6]sulfolene pyridinone, which was trapped with various dienophiles to form bi- and tricyclic ring systems .

i ^

N

cAAc.

>

N ( /-p r)2 B cico e

^

i

^

cAA.b02Me

y

^ [

C/N^C,

Xylene 48

47

Scheme 21

i

49

> fc02Me


271

6.1.2.3 Pyridine A'-Oxides and Pyridinium Salts Pyridinium salts are involved in a wide variety of synthetically useful reactions. Many workers utilized the electrophilic nature of the pyridinium salts to incorporate substitution into the pyridine scaffold. Specifically, acylpyridinium salts have been reacted with Grignard reagents O4J0C2863; 04OL3553> and organozinc reagents O4J0C5219; 04JOC752> to form key carbon-carbon bonds. Charette utilized the addition of nucleophiles to 3-substituted pyridinium salts prepared from Af-methylbenzamide as illustrated in Scheme 22. This methodology was applied to the enantioselective synthesis of (-)-L-733061, a highly potent Substance P antagonist.

Recently, polymer-supported pyridinium reagents have become of interest. Tye et al. described the preparation of a polymer-supported Mukaiyama reagent 50 from Merrifield's resin, which was then used for the preparation of carbodiimides through the dehydration of thioureas and for the guanylation of primary amines . Swinnen et al. reported the preparation of a similar reagent, 50, from Wang resin, as shown in Scheme 23, and used it as a coupling reagent for the synthesis of esters or amides from carboxylic acids and corresponding alcohols or amines . Moreover, Taddei has prepared a polymer-supported Mukaiyama reagent with a spacer between the resin and the pyridine ring, compound 51, . This reagent was prepared from Merrifield's resin in three steps as shown in Scheme 23 and was utilized for the generation of ketenes for Staudinger cycloaddition reactions with imines. Solidphase chemistry has also been used in the preparation of biologically active pyridinium compounds ; here the molecule is built on the resin and is then cleaved off in a Zincke reaction to generate the pyridinium salt.

272


1,3-Dipolar cycloadditions of pyridinium ylides have been used to prepare indolizines. Woisel et al. reported reaction of bipyridinium ylides with an electron deficient propynamido-|3cyclodextrin forming the pyridinoindolizine-|3-cyclodextrin conjugates . Moreover, Wu has reported the reaction of pyridinium halides with 2,2-difluorovinyl tosylate in the presence of base to yield monofluorinated indolizines as shown in Scheme 24. When unsymmetrical pyridinium halides were used, a mixture of isomers represented by 52 and 53 was obtained. R2

Pyridine jV-oxides are also useful synthetic intermediates in organic synthesis. In the past year, two new methods for the preparation of pyridine A^-oxides have been disclosed. Sain et al. used bromine-T with catalytic ruthenium trichloride in alkaline acetonitrile/water to accomplish this oxidation . Zhong and co-workers performed this oxidation with trichloroisocyanuric acid in the presence of acetic acid and sodium acetate in acetonitrile/water . While metals have aided in the oxidation of pyridines to iV-oxides, they also have been used as effective catalysts for deoxygenation. Yoo reported the facile and efficient deoxygenation of A'-oxides with gallium in water . Pyridine A'-oxides have also been used in the presence of a ruthenium catalyst for oxidation of alkanes and terminal alkenes to give the unexpected "Wacker type oxidation" .

273


Picoline JV-oxide was used as an intramolecular catalytic group to secure stereochemical integrity of the phosphorus center in a stereospecific synthesis of dinucleoside phosphorothioate diesters .

6.1.3

QUINOLINES

Synthetic approaches to the construction of pyrrolo[3,2-c]quinoline systems were compiled in a review by Nyerges . Recent advances in the synthesis of the Martinelline alkaloids are also described. 6.1.3.1 Preparation of Quinolines The synthesis of quinoline derivatives using metal catalyzed processes continues to be of interest. A modified preparation of 2,3-dialkylquinolines was reported from nitroarenes and tetraalkylammonium halides via an in situ ruthenium-catalyzed reduction followed by an intrinsic amine exchange reaction using tin(II) chloride. One of the examples reported is shown below in Scheme 25.

a

+

Bu 4 NBr

NO 2

RuCI 2 (PPh 3 ) 3

^^x-^/

_ SnCI 2 »2H 2 O

(I I \ \S^ N ^v/

Scheme 25 A one-pot quinoline synthesis from 2-aminobenzyl alcohol 54 and a,p-unsaturated ketones using ruthenium-grafted hydrotalcite as the heterogeneous catalyst was also described . In this approach molecular oxygen was used for the oxidation of the ruthenium species and styryl quinolines, such as 55, were produced in good yields. Notably, other donors, such as 1-octanal and phenylacetonitrile were also reacted with 2-aminobenzyl alcohol 54 to give 3-amylquinoline 56 and 2-amino-3-phenylquinoline 57 in good yields.

a

ÔH

NH 2

LRu/HT-N, O2

2.

[fÎÎ

O

-^°\X^ T ^^\

M

I

1.Ru/HT-N,02

,

2. 1-octanal

kA N ^^p^ 0 ^ 84%

Kj^N^ 8 1 %

1.Ru/HT-N,02 rt^^r^^CN K^

5 6

/W^J^ ^ ^ N 90 %

Scheme 26

55

NH2 57

^ ^ o ^

274


In another report, 2-aryl-2,3-dihydroquinolinones were synthesized from 2-aminochalcones using indium(III) chloride supported on silica gel in a solvent-free system . Palladium chemistry was investigated to develop a convergent one-pot cascade sequence for the synthesis of 3-aryl naphthyridones and quinolinones as shown in Scheme 27. This approach relies on a palladium-catalyzed cross-coupling reaction of 2-bromonicotinaldehyde or 2bromobenzaldehyde 58 with 2-phenylacetamide 59 in the presence of cesium carbonate and xantphos. Good yields of product 60 were obtained following the cyclodehydration of the resulting amide intermediate .

Pd2(dba)3 Xantphos

59

58

60

X = C, N

T| K^f>

X = C (94%), N (91 %)

Scheme 27 Titanium catalyzed reactions were further investigated in the past year for the synthesis of quinolines. As part of the ongoing efforts to develop methods for the generation of compound libraries, titanium alkylidene reagents were treated with resin-bound esters followed by acid mediated cleavage to give arylammonium salts 61. 2-Substituted quinolines 62 were obtained upon oxidation of the ammonium salt 61 with manganese dioxide in high purity and moderate yields .

rV^JL

R^N(TMS)Boc 2. wash 3.10% TFA

resin

R

^V^^R1 ^=^NH

3

Mn

°z,

D2^Y^1

^^N^R1

CF3CO2

61 Scheme 28

62

The synthesis of azatitanacyles was achieved intermolecularly from the reaction of imines 63 and Grignard reagents in the presence of Ti(O-/-Pr)4. Treatment of the titanium species with electrophiles yielded the corresponding substituted tetrahydroquinoline 64 in good yields . N"^Ph ^jJJ \^N"~^ Bn 63

i.Ti(o-/-Pr)4 /-PrMgCI iiH2

° 94%

H ph y ^ ^ - ^ o ' ' 1

^ ^ N ^ 64

Scheme 29

^ ^

96:4

275


A variety of non-metal catalyzed processes for the synthesis of quinolines were also described in the literature. Several 2,4-disubstituted quinolines were synthesized in satisfactory yields by reaction of o-isocyano-|3-methoxystyrene derivatives with nucleophiles, such as alkyl or aryllithiums, lithium benzenethiolate or lithium dialkylamides . The formation of 6-sulfamoylquinoline-4-carboxylic acids was reported using Pfitzinger conditions. In this case quinolines were produced in moderate yields over the corresponding 2-oxo-l,2dihydroquinoline-4-carboxylic acids . A one-step methodology for the synthesis of 4-hydroxy-2-quinolones was described in which dimethyl or diethyl malonate was reacted with the 1-hydroxybenzotriazole ester of an jV-substituted anthranilic acid . Radical chemistry previously investigated by Naito and coworkers led to a formal synthesis of Martinelline . In other reports, Mannich reaction of a-ketohydrazones 65 gave (2aryl or alkylquinolin-3-yl)-phenyldiazines 66 in good yields. Conversion of the Mannich adduct 67 to the quinoline 66 derivative was achieved via an Aza-Friedlander reaction .

Rc

PhHN'N.7

65

67

^

N

~ B n

66 R = Me (73%), Ph (82%)

Scheme 30

Variations of the Friedel Crafts and Diels-Alder reactions continue to be of interest for the synthesis of quinolines. Intramolecular cyclization of propargyl trimethylsilyl ethers was achieved via a BF3OEt2 assisted ring-closing Friedel-Crafts reaction to produce 4(vinylidene)tetrahydroquinolines, which were isomerized and aromatized to give quinoline derivatives. A similar approach using TMSOTf as the Lewis acid provided isoquinoline analogs . One-pot Diels-Alder reactions mediated by FeCl3-NaI or sulfamic acid were reported for the synthesis of tetrahydroquinolines. In addition, a one-pot three-step liquid phase aza-Diels-Alder protocol using PEG 4000 as a soluble polymer support was developed for the synthesis of tetrahydroquinolines . An intramolecular aza Diels-Alder (Povarov) reaction was employed for a total synthesis of the alkaloid Luotonin A 68 (Scheme 31) and the formal synthesis of Camptothecin .

H

°v f

CL rO 1 N

X^NT I

i

2

R V*° R1

Dy(OTf) 3 (10mol%)

\

II

^l

X^N R 2 -V^° R1

n

—J

J

51%

T n N

V\

XN w^0 R2 k^ R1 = R2 = H ; X = CH

68

Scheme 31


276

Methods for the synthesis of quinoline bearing fluorine or difluoromethyl substituents were the focus of various reports. Ichikawa and co-workers described the synthesis of 3fluoroquinolines 69 by intramolecular cyclization of o-substituted p,|3-difluorostyrenes 70, which were generated as key intermediates from the reaction of a-trifluoromethylstyrenes with a nucleophile , as illustrated in Scheme 32. As an extension of this work, Ichikawa and co-workers also showed that CF2H-substituted quinoline frameworks, 71 (Scheme 32), could be generated via a cyanide ion catalyzed intramolecular cyclization of omethyleneamino-substituted a-trifluorostyrenes 72 . Notably, Piatnitski and coworkers reported that the reaction of (2-trifluoromethyl)aniline 73 with esters of arylacetic acids produced 4-fluorinated quinolinones 74 .

catKcN

F 70

r i 1 i ~F L

&

J

catKCN

f*

DBU ^

RXUX^

72

2

71 R2-CH2COOR r Base 1

II —R 73

69

H

Â^/^

., ., ^^^Si,

T

*"

2

"I ^Vî

]

L

R1 J

| N** s K V' ; s ^

*"

]

II

R1

H 74

Scheme 32 6.1.3.2 Reactions of Quinolines The hydrogenation of quinolines has been widely studied for the synthesis of a number of heterocycles. A solvent dependent regioselective hydrogenation in the presence of RJ1/AI2O3 was investigated for the synthesis of tetrahydroquinolines and decahydroquinoline analogs. A combination of long reaction times and use of hexafluoroisopropanol as the solvent often led to complete formation of decahydroquinolines in good yields . In another report, tetrahydroquinolines were also produced via a [Cp*IrCl2J2 catalyzed transfer hydrogenation reaction using 2-propanol as a hydrogen source . Various methods for the functionalization of quinolines were also investigated. Hydroxylated heteroarenes were reacted with acetylene in the presence of SnCU and an amine . An Ir-catalyzed addition of ethynyltrimethylsilane to quinoline 74 was used to generate 2trimethylsilylethynyl-l,2-dihydroquinoline 75 as shown in Scheme 33. In this procedure quinoline 74 was activated by phenyl chloroformate, although the addition of AgOTf was also needed to facilitate the functionalization of quinolines bearing electron-withdrawing substituents . This approach can also be applied to the synthesis of 1-trimethylsilylethyny 1-1,2dihydroisoquinoline 75, which are formed in good yields.

277

Six-membered ring systems: pyridines and benzo derivatives „.

|^^;5Y'Br

TMo

|

b

CICO2Ph

[lrCI(COD)]2

74

Rr

(^y^Y CO2Ph

TMS

80% 75

Scheme 33 The functionalization of two model substrates, namely 4-bromo-6-fluoro- and 4-bromo-7fluoro-2-(trifluoromethyl)quinoline, was investigated using iodine and trimethylsilyl groups as auxiliary substituents for the targeted introduction of a carboxy unit. Steric shielding by the trimethylsilyl groups and deprotonation-triggered iodine migration are believed to contribute to the regiocontrol of these reactions . The reaction of l-methyl-3,6,8-trinitroquinoline with enamines was performed for the synthesis of 4-acylmethylquionlones . A novel ring expansion of quinolines for the synthesis of benzoazepines was reported by Yadav and coworkers. Quinolines 76 (Scheme 34) were reacted with various diazocarbonyl compounds 77 in the presence of copper(II) triflate to generate the seven-membered azepine ring system 78 in good yields. Isoquinolines were also shown to undergo ring expansion under the same conditions . R-i

EtOÔ 76

0A U

77

C R2

°

OEt 78

Scheme 34 Solid phase chemistry has been an area of much investigation. Recently, solid phase supports were used for the synthesis of polycyclic tetrahydroquinoline based heterocycles using a ring closing metathesis and hetero Michael addition as the key steps . Solid phase supported quinolines were also used for the development of an iV-acyl dihydroquinoline//V-acyl quinolinium-switch based safety-catch linker that is prepared from a resin-bound iminium intermediate via an aza-Diels-Alder reaction . A multicomponent reaction was studied using Kobyashi's modification of the Grieco reaction for the synthesis of 4-phenylthio1,2,3,4-tetrahydroquinolines. Using solution phase and solid phase applications these intermediates were oxidized and pyrolyzed to provide a library of 2-substituted quinolines . 6.1.4

ISOQUINOLINES

A review by Chrzanowska and Rozwadowska summarizes two key strategies for the synthesis of isoquinoline alkaloids: stereochemically modified traditional methods and recent advances using the Cl-Ca connectivity approach. Literature from late 1993 to late 2003 is covered in this review.

278


6.1.4.1 Preparation of Isoquinolines Various isoquinoline derivatives were constructed using organometallic reagents. In one report, reaction of o-alkynylarylimines with allyltributylstannanes and allyl chloride, employing allyl palladium chloride dimer and Cu(OAc)2 as co-catalysts, resulted in the formation of 1,4diallyl-l,2-dihydroisoquinolines . A regioselective palladium-mediated C-H insertion was applied to the synthesis of the Amaryllidaceae alkaloids. Scheme 35 shows the synthesis of anhydrolycorine 79, which is a member of this class. The synthetic strategy relied on the intramolecular coordination of the amine group of the dihydroindole 80 to the metal and produced the desired framework in moderate yields . A similar bi-aryl-Pd reaction was optimized by the same group for the synthesis of benzonaphthazepines, which often result as a by-product of benzo[c]phenanthridone formation .

S î~ 5 mol %

„

-

KC

.

2 °3

80

f

I

—x

1

°W d Q

~^

[^—(

^r~-~7 IXjf .CO2Me

65%

I PdBrLol ii NHCbz Vjs**^

L

NHCbz

_

Scheme 36 A one-pot 4-component Ugi reaction and Pd-catalyzed intramolecular Heck reaction was developed for the synthesis of two types of isoquinoline scaffolds illustrated in Scheme 37. In this approach an amine, an aldehyde, a carboxylic acid, and an isocyanide react to provide a diversity of a-acylamino amides 81 and 82 which undergo a Pd-catalyzed intramolecular Heck and double bond isomerization reaction to generate the isoquinoline products 83 and 84

279

Six-membered ring systems: pyridines and benzo derivatives . .

A similar reaction sequence was reported by Gracias and co-workers

CHO ^ ^ 1

R -NC

CO2H ^ ^

(V 80-98%

R3

{J

HH2

/~

(T^f^ V^

K

I HI R1 ll 81

!H0 f2H K

^Y^V^ P d

R

^

H

W

%1

75-98%

I 83

o Oî r T ^ T ^ v ^ ? R 2

f k ( C H 2 ) 7 C O 2 M e

^ 1 ^^^(CH2)7CO2Me

130

^NHCbz

131

/

132

^N^(CH2)7CO2H H

133 Scheme 52 Finally, RRM was used to convert a diastereomeric mixture 134 to 135 and 136 into 137 in high yields.

a

U DCM 50°C

^

^ ^ ^

P

134

T

ll

r

f f-\

H 2 C=CH 2

N Ns

!

PAc

"RU"

^^CS Pr

C]

QAC

• IS

135

136

137

Scheme 53 Ring formation by reaction of a N-nucleophile on an electrophilic carbon atom continues to be a reliable route to piperidines. The examples shown in Scheme 54, 55 and 56 demonstrate recent applications of closure of nitrogen on an s;?3-carbon atom. Treatment of an aminoalcohol 138 with Ph3P/CBr4/TEA afforded the polyhydroxyindolizidine alkaloid precursor 139


287

. The reaction of a sulfonamidomesylate 140 with K2CO3/DMF gave the azasugar-type intermediate 141 . BnQ

°

MsO

pBn

H

H

BnO

pBn

138

139

HN^'"CO 2 Me SO2Ar

^NT'"C0 2 Me SO2Ar

140

141 Scheme 54

Cyclization of the N-Boc derivative of an aminoalcohol mesylate was used in a synthesis of enantiopure 3-hydroxy-4-phenylpiperidine derivatives from Z-phenylglycine . Alternatively, such 7V-Boc-aminoalcohol derivatives may be subjected to Mitsunobu reaction conditions, as in the preparation of 142, an intermediate in a route to 1-deoxy-Dgalactohomonojirimycin . O

cA .

\

AA

I

DEAD

o

\

/

w 142

Scheme 55 A double, regiospecific intramolecular cyclization was employed in the selective generation of 143, an intermediate in a new synthesis of nicotine .

I LH C \_J -mC02Me l7\-NHBn

6

NaH/THF. /^/~~N, "" [^ ^TH CO2Me B^n ° 143

Scheme 56

288


"Linchpin dialkylation" of primary amines continues to be a useful concept in the synthesis of piperidines. Such a ring closure was used in the synthesis of paroxetine intermediate 144 (Scheme 57). {^/r~~Y^-

XX -

182 Scheme 67

180

Radical chemistry has found some application in the synthesis of piperidines. An enhanced diastereoselectivity in the reductive cyclization of bromide 183 to the ?ra«,y-disubstituted piperidine 184 was found with fra(trimethyl)silane in place of tributyltin hydride (Scheme 68). t-BuO2C. Br

\

t-BuO2C. \

,1 J i-Pr- ^ N ^

TTMSS-AIBN

^K.

toluene, 90 °C

I J i-Pr" ^ N ^

Ts 183

Is 184 Scheme 68


293

Tributyltin hydride-promoted cyclization of enamide 185 via a 6-endo-trig process to give 186 showed 6:1 diastereoselectivity. Ph

I Ph

Ph

1 " ° R 185

R = Me TBTH-AIBN toluene, A

jf "1 Ph^NÔ Me 186

Scheme 69

A second 5-exo-trig cyclization of an intermediate occurred with the enamide 187 to give 188 . The tributyltin hydride-promoted ring expansion of 189 to 190 demonstrates the key step in a novel protocol for the conversion of electron deficient pyrroles to functionalized piperidines . Ph i%.

J l Jsv Ph^NÔ R

Ph R = 3-butenyl ^

ôc

^

Ph

toluene, A

w^NÔ ^—'

187

jJo/WPr

^

TBTH-AIBN

''JL X . 188

X=H 2

'°

TBTH-AIBN toluene, A

189

X^N^CO 2 i-Pr Boc

190

Scheme 70 Ring expansion reactions of 2-substituted pyrrolidines to piperidines have been useful in certain cases, particularly in the iminosugar area. A careful analysis of the formation and fate of the condensed aziridinium ion intermediate 191 was made for the Mitsunobu reaction of 192 to maximize formation of 193 relative to simple alkylation O4SL1711> (Scheme 71). The known conversion of chiral prolinol 194 to 195 was used in the synthesis of thymine PNA monomer 196 .


294 OBn B n

r

N

°^v

HO^^N;

, >

R0H

\ ^

DIAD ,

BnO. / W

192

RONAÔBn

N

^

^ - • • * \

B n

Bn

191

'"r>^

1.TFAA ,

Bn

2. DIPEA 3. H2O

94

U

193

TBSO..,^ V OH

LN^0H 1

OBn

Lft> \J

Bn

T B S O

-,

Q B

T^^,,NHBoc

LNJ

=ST T J

'

^ ^COaH

" 195

196 T = thymine

Scheme 71 Miscellaneous ring closure reactions involving carbon-carbon bond formation are shown in Scheme 72 and 73. An oxidation-cyclization-oxidation process was effected by PCC to convert alcohols 197 to 4-piperidones 198 . Intramolecular alkylation was used to covert chiral enaminone 199 to 200, a key intermediate in the total synthesis of lepadin alkaloids . OH

h i

_?U oX N X.NH2

/

>h 214

216

212

217

Scheme 75 The piperidine 213, prepared from 209 by reductive decyanation with Raney nickel, has been shown to be a versatile intermediate. This most simple example of 208 can react via its ringchain enamine tautomer to provide 3-substituted piperidines. For example, reaction of 213 with MVK provided 214 in 63% yield with 92% de . With vinylmagnesium bromide, 213 gave a separable mixture of diastereomers from which 215 was prepared by non-reductive removal of the chiral auxiliary followed by acylation. The key aza-Claisen rearrangement of 215 gave 10-membered ring lactam 216. A subsequent sequence of reactions gave (+)-(R)haliclorensin 217 . Other complex, chiral oxazolidines of this type have proved to be useful in natural product synthesis (Scheme 76). The epimeric esters 218 were separately converted to their respective Obenzylcarbinols 219. These were subjected to a desaturation-oxidation sequence to give 220. Lactam reduction followed by N- and O-hydrogenolysis gave the azasugars 221 .

Six-membered ring systems: pyridines and benzo derivatives ^ X O 2 M e I LMe

yy

^ ^ , - O B n f TMe

2.NaH,BnBr

\J

Ph

Ph 218

OH HOÂÔBn

1-PhSeBr

3. OsO4-Ba(CIO3)2

o^Nô

o, Q 219

^-^ P h ' ^

220

1.BH 3 -Me 2 S/ 2. H 2 ^ ^

OH

HO

297

YV"OH

^"^

H 221

Scheme 76 In related work esters 222 and 223 were each converted to the respective alkaloids (-)lupinine 224 and (-)-5-epitashiromine 225 by sequences which featured intramolecular reductive amination reactions . Reduction of advanced intermediate 226 with LAH, followed by hydrogenolysis and deketalization gave 1-deoxy-D-gulonojirimycin 227 .

1

X

°

~ ^ N ^ ° \ 2. PTSA

P°

I

1

h J 3 êt°ne-H?O ^ N ^ S

Ph

4. LAH 222

224

^,.CO2Me

1BH3/THF

rX»k^\J O

N

N Ph

o

^,--ÔH

2PTSA °

LJ,

acetone-H2O

/—'

3~Tb 223

*"

4. LAH

r-r\° H ^"^.A n O j —\ 226

N

°

N

••

^—' 225

HO f OH 1.LAH/THF , 2.H2-Pd(OH)2 HCI-MeOH

f

T

HO^,,XNJ H 227

Scheme 77 Modification of the piperidine ring using readily-available 2-piperidone-derived intermediates has been actively studied (Schemes 78 and 79). The lactam 228 has been shown to undergo Cu(OTf)2-catalyzed conjugate addition of organozinc reagents in the presence of asymmetric

298


phosphorus ligands. The resulting zinc enolates can be trapped with electrophiles, for example with acetaldehyde to give, after oxidation, 229 with 94% ee . O

u

X-NJ

1. Et2Zn-Cu(OTf)2

7 CO2Ph

Et

J[

toluene, -78 °C 2 . acetaldehyde

J

Cr>J co 2 Ph

228

229 Scheme 78

A synthesis of vinyl boronate 230 has been described. Coupling with a variety of aryl- and heteroaryl bromides to give 231 was effected with either of two palladium catalyst systems . Simple A^-protected 2-piperidones such as 232, when converted to their zinc enolates with the appropriate base present, have been found to react with aryl bromides to give coupling products 233 in generally useful yield .

V/0-B^N^ ^ 6 Cbz

ArBr . Desorption/ionization on silicon mass spectrometry (DIOSMS) uses porous silicon to generate gas-phase ions. The 1,3,5-triazine unit proved to be an effective scaffold to obtain cleavable linkers for porous silicon based mass spectrometry . Characterization and application of triazine based polyfluorinated triquaternary liquid salts, as solvents in rhodium(I) catalyzed hydroformylation of 1-octene, have been reported . 2-Chloro-4,6bisl(heptadecafluorononyl)oxy)-1,3,5-triazine has been used as a condensation reagent to obtain di- and tripeptides . Dihydro-l,2,4-triazine derivatives have been described as antimalarials due to their ability to inhibit multiple mutants of Plasmodium falciparum dihydrofolate reductase . Analgesic and antinflammatory activities of some 1,2,4-triazine derivatives have been described . A 1,2,4-triazine derived from 2-l(2,6-dichloroanilino)phenyl]acetic acid has been synthesized and its anti-inflammatory, analgesic, ulcerogenic and lipid-peroxidation activities tested . 1,2,4-Triazine TV-oxide derivatives have been studied as potential hypoxic cytoxins , . Sulfonamides incorporating 1,2,4-triazine moieties have been studied as inhibitors of cytosolic/tumor-associated carbonic anhydrase isoenzymes I, II and IX . A series of diamino-l,3,5-triazines 41 have been identified as novel 5-HT7 receptor antagonists . New 4,6-disubstituted 2-alkyl-l,3,5-triazines 42 and 43 showed interesting anticancer properties in different tumor cell lines . R1

Me y_)

N^N

"

x

41 1

X = H, F, R =H, F, Me, NH2, NMe2 R2 = (CHjkPh, (CH2)3Ph, (CHÔPh, R2 = (CH2)2O(p-FC6H4), (CH2)2-(m-FC6H4), R 2 = (CH2)2-(2-pyridyl), (CH2)2-(3-pyridyl), R2 = (CH2)2-(4-pyridyl), (CH2)2-(2-thienyl)

(CH2)2OH

VWÔH HO(CH 2 ) 2 - N ^(CH 2 ) 2 OH 42 R = CC(-Bu, R = NC(CH2CH2OH)2

V ^ 0Me

43 R = m-FC6H4 R = 2-thienyl, R = m,p-(OMe)2C6H3

Melamine derivatives bearing thiourea and thiouronium ions have been prepared as flavin receptors . Hemolysis and cytotoxicity activities of six dendrimers based on melamine have been evaluated. None of them showed acute in vivo toxicity . New

342

C. Ochoa, P. Goya and C. Gómez de la Oliva

inhibitors of the estrogen receptor bearing a 1,3,5-triazine core have been described . A synthetic creatinine receptor containing a 1,3,5-triazine moiety has been synthesized from polymerizable Lewis acidic Zinc(II)cyclen complexes and ethylene glycol dimethacrylate. This macrocycle is applicable for tasks in medicinal diagnostics or biotechnology . Simple synthetic routes to 1,3,5-triazinyl-dithiocarbamate derivatives which exhibit antimicrobial and antitubercular activities have been reported . Substituted chalcones and pyrazolines bearing a 1,3,5-triazine moiety have been synthesized and screened for antibacterial activity .

6.3.2

TETRAZINES

As in previous reviews, only a few reports dealing with tetrazines have appeared this year.

6.3.2.1 Synthesis and reactivity Original 1,2,4,5-tetrazines disubstituted by heterocyclic rings have been prepared and their electrochemical and spectroscopic properties studied . A bowl-shaped neutral radical with a core annulene system bearing a verdazyl radical 47 has been synthesized in two steps from aldehyde 44 and carbazide derivative 45, as a stable solid in air .

Electropolymerization of a verdazylthiophene derivative has been carried out to give solid materials with a high concentration of radical spins . The azaphilic addition of organometallic reagents on 1,2,4,5-tetrazines has been studied. Depending on the nature of the metal, azaphilic addition, reduction of the tetrazine or simple complex formation, was the predominant transformation and usually high selectivity was observed . Reaction of 3,6-diphenyl-l,4-dihydro-l,2,4,5-tetrazine with isobutyric anhydride yielded l-isobutyryl-3,6-diphenyl-l,4-dihydro-l,2,4,5-tetrazine and its structure was elucidated by X-ray analysis . A straightforward access to several novel high nitrogen materials 50 and their corresponding salts, based on nitroguanyl substituted tetrazines from 3,5-dipyrazolyl-l,2,4,5-tetrazine derivative 48 and nitroguanidine 49 has been reported .

Triazines, tetrazines and fused ring polyaza systems Me

NO,

V-, N

N

N'

-N-^Me I ^ N

M Me

343

HN^NH 2 1 N e

BuLi

RrfVSh * S ? 51

te

,/~R \^jj

P^N'%h 52

R = Me, Cl, Br, I, CH2CH2Br, allyl, CO2H, CO2Me, CO2Et,

Synthesis and characterization of several unsymmetrical bis- and tris-spirocyclic cyclotriphosphazenes including chiral l,l'-bi-2-naphthol derivatives have been reported . Synthesis of a bridged fluorophenoxycyclotriphophazene has been described . A novel C-bonded cyclotriphosphazene 54 has been prepared by a new synthetic procedure through the phosphinic acid derivative 53. Structural characterization including [ H,, l 3 C, 3 1 P and X-ray studies has been carried out .


Thioacylation reactions for the surface functionalization of dendrimers containing a phosphazene core have been described . Chiral nitroxide cyclotriphosphazene hybrid compounds have been prepared to examine the potential for the use of the cyclotriphosphazene framework as molecular scaffold to elaborate robust chiral paramagnetic multispin systems . Monobranched and hyperbranched dendrimers based on cyclophosphazene containing nitrile and phosphine donors, as well as their Fe and Ru complexes, have been synthesized. These cyclophosphazene dendrimers act as insulators between the organometallic centers . Chirality in cyclotriphosphazenes with one stereogenic center has been studied . The tridimensional character of the inter- and intradendrimeric charge and electroconductivity in four new dendrimers containing a cyclotriphosphazene core and tetrathiafulvalenyl substituents have been determined . A dendritic cyclotriphosphazene derivative bearing hexaxis(alkylazobenzene) substituents has been described as a photosensitive trigger . It has been confirmed that di-spiro derivatives from the reaction of cyclotriphosphazene with either 3-amino-lpropanol or N-methylethanolamine exist as cis and trans geometric isomers and are meso and racemic forms, respectively, as expected . 6.3.3.2 Miscellaneous triazahexacycles with other heteroatoms During studies of the reaction of-NHSiMe3 and -N(Me)SiMe3 derivatives of CI3PNSO2CI with acetonitrile and BCI3, six-membered polyheteratomic cycles containing N, P and S or N, P, and B atoms have been obtained . Reversible skeletal substitutions in diverse heterophosphazenes bearing B, As and Al atoms have been studied . 6.3.3.3 Tetrazaphosphorines A new method to obtain tetrazaphosphorine derivatives 57 by phosphodihydrazides 56 with A'-acylimidates 55 has been described .

reaction

of

Triazines, tetrazines and fused ring polyaza systems

6.3.4

345

FUSED [6]+[5] POLYAZA SYSTEMS

Publications in this category are, as usual, the most numerous, even though the purine and pyrimidine nucleosides have not been included due to the high number of examples reported.

6.3.4.1 Synthesis and reactivity A series of 5-substituted 3-methylisoxazole[5,4-rf][l,2,3]triazin-4-one derivatives has been synthesized to test their potential immunological activity . The utility of 1-N,Ndimethylaminopent-l-en-3-one in the synthesis of new l,2,4-triazolo[3,4-c][l,2,4|triazines has been described . Synthesis of new 8-aryl-l,2,4-triazolo[l,5-][l,2,4|triazines from 1,2-diaminoimidazoles, which were obtained under solvent free conditions, has been reported . Reaction of 6-substituted 4-amino-3-methylthio-4,5-dihydropyrazolo[2,3c][l,2,41triazin-5-ones with nitriles of sulfonylacetic acids has been investigated . Substitution reactions of 3-methyl-5-methylsulfonyl-l-phenyl-lf/-pyrazolo|4,3-e][l,2,4]triazine wth a range of C-, N-, O-, and S-nucleophiles afforded the corresponding 5-substituted derivatives . l,3,4-Thiadiazolo[2,3-c][l,2,41triazin-4-ones 61 have been prepared by one-pot condensation and cyclization of 4-amino-l,2,4-triazine-3-thion-5-ones 60 with various aromatic carboxylic acids in the presence of silica gel sulfuric acid in solventless conditions . NH 2 S

^NÔ

HN

O RCO2H / H2SO4

NT^N'Ns N

^Me 60

Me

R = Bn, p-MeC6H4, m-CIC6H4

^N^S^ 61

Hydrolytic degradation of different dihydroimidazo[l,5-a][l,3,5]triazinone derivatives afforded two new types of imidazole . Synthesis of trifluoromethyl substituted dihydrotetrazolopyrimidines and tetrahydrotetrazolopyrimidines and other triazolo- and tetrazolopyrimidines have been described . An expeditive synthesis of homochiral fused triazole- and tetrazole-piperazines from [5-amino alcohols has been reported . A novel Ugi five centre four component reaction (U-5C-4CR) of aldehydes 63, primary amines 62, trimethylsilylazide and 2-isocyanoethyl tosylate 64 afforded tetrazolopiperazine building blocks 65 .

346


SCV

R1NH2 62

+ R2CHo +

(CH2)2-^5

R2

M |

™SN3 .

^V^ Me

MeOH

63

Rl

N"VN-N \^ N ~N

64

65

R1 = Bn, p-MeCO2C6H4, m-MeCO2C6H4, CH2CH(OMe)2 R2 = i-Pr, p-MeOC6H4, p-MeCO2C6H4, Ph

Synthesis of triazolo[4,3-a|pyrimidines via reaction of hydrazonyl halides with ethyl 3,4dihydropyrimidine-5-carboxylate derivatives has been described . Synthesis of perfluoroalkyl[l,2,4]triazolo[l,3]thiazinones has been reported . Hydroxypurine derivatives 68 have been synthesized, in three steps, by diazotization of 2amino-4-hydroxypurine 66 followed by coupling with appropriate active methylene compounds under alkaline conditions to give compounds 67 which by treatment with chloroacetyl chloride yielded the corresponding azocyclobutanone derivatives 68 . OH

N

OH

N

\r\ ——

H2|AN^N

66

\T\;

HN^N^N

O
67

9"

CICH C0CI

2

,

Et3N/dioxane

JL j T ^ HN^N^N

R2 Cl

S8

The natural product (+)-agelasine D 73 has been synthesized for the first time from adenine derivative 71. The terpenoid moiety was readily available from the diterpene alcohol (+)-manool 69 .

Triazines, tetrazines and fused ring polyaza systems

347

A general method for the synthesis of 8-arylsulfanyladenine derivatives using a mild protocol for coupling 8-mercaptoadenine with a variety of aryl iodides has been described . Preparation of new 6,9-disubstituted 2-phenyladenines under conditions compatible with the use of thiomethyl resin for solid phase synthesis has been reported . 5-Amino-l-aryl-l//-imidazole-4-carbonitriles have been converted into 9-aryl-6aminopurines via imidate formation by treatment with triethyl orthoformate and acetic anhydride followed by reaction with ammonia . A simple and practical synthesis of 7- and 9-alkylated guanines starting from guanosine has been developed . Synthesis of 6O-benzylguanine, which is an important inhibitor of O-6-alkylguanine DNA alkyltransferase (AGT), and its conjugation with a functionalized hydrophilic linker have been achieved . Synthesis of 6-enaminopurine derivatives from 5-amino-4cyanoformimidoylimidazoles has been reported . Copper-mediated coupling of aminopurines with arylboronic acids has been explored and iV-arylated purines have been obtained . Reductive Heck reaction of 6-halopurines has been studied. Alkenylation of 9-benzyl-6-halopurines did not proceed under conventional Heck conditions . Reactions of 8-5//-purines with glycidol have been studied . A novel and direct method for the preparation of 4-amino-l,l,3,3-tetrasubstituted guanidines and of [l,2,4]triazolofused heterocyclic derivatives has been reported . Multigram scale syntheses of the important 8-styrylxanthine A2a adenosine receptor antagonists MSX-2, MXS-3 and KW6002 have been accomplished . A new and practical method for the synthesis of 1- and 1,3-disubstituted xanthines has been developed . Syntheses of protected (purin-6-yl)glycines 76 which are potential building blocks for stable covalent peptide-nucleic acid conjugates, have been achieved via Pd-catalyzed a-arylation of ethyl N(diphenylmethylidene)glycinate 75 with 6-iodopurines 74 . Ph

Ph

Y EtO2C I JL_^N

U^jC,?

+

Ph

P^-

C

CO

«> >*

Pd(OAc)2 2-(dicyclohexylphosphino)biphenyl

K 3 PO 4 /DM F

N |

N " * ^ ^

kNK>

R 74

R 75

76

R = Bn, tetrahydropyran-2-yl, 2,3,5-tri-O-acetyl-p-D-ribofuranosyl

One-pot synthesis of 6-mercaptopurines from 4,5-diamino-6-chloropurine, an aldehyde and elemental sulfur has been reported. The key advantage of this procedure is that H2S was generated in situ . An efficient conversion of 6-cyanopurines into 6alkoxyformimidoylpurines has been developed . Synthesis of diverse purine libraries has been optimized by a microwave assisted method using minivials . An efficient one pot three component synthesis of 7-oxo-l,7,8,8a-tetrahydroimidazo[l,2alpyrimidines has been described . A new imidazo[4,5-£>lpyridin-5-one derivative has been prepared in five steps from l-benzyl-4-nitro-imidazole via vicarious nucleophilic substitution of hydrogen-5 with the carbanion generated from chloroform and potassium tbutoxide . A new method to prepare carbamoylimidazo[l,5-a]pyridine-l,3-diones from an o-acetalmethylideneimidazolidine-2,4-dione has been described . An easy synthesis of 6-aryl-l-methyl-3-propyl-6,7-dihydro-lW-pyrazolo[4,3-A

Pr

H2N

77

O Me R~N-^^N

RNH 2

^ N ^f N

CH(OEt)3 Pr

N

p-xylene

lf

78

79

R = Ph, o-CIC6H4, p-CIC6H4, 0-BrC6H4, p-BrC6H4, o-IC6H4, p-IC6H4, o-NO2C6H4, p-O2NC6H4, o-MeC6H4, p-MeC6H4

A series of new l//-pyrazolo[3,4-£?]pyrimidin-4(5f/)-ones 84a-l has been regioselectively synthesized in four steps, via a tandem aza-Wittig reaction. The iminophosphorane 81, prepared from 5-aminopyrazole 80, reacted with phenyl isocyanate to give carbodiimide 82, which by reaction with primary or secondary alkylamines, afforded intermediate guanidines 83 that cyclized to the corresponding pyrazolopyrimidinones . PhCH2S

CO 2 Et

VVNH N

-N

^h

CO2Et

phCH2S

PPh3/Br2 2

•

PhCH2S

V^N=PP h 3 ^ N

80

~N

h

^

CO2Et

I>N=C=NPh i

81

Ph

82

RNH2 (or R2NH)

PhCH2S

?\

Ph

Nîl V \A,A ^ Ph

84a, R = n-Pr (86%) 84b, R = /-Pr (93%) 84c, R = n-Bu (66%) 84d, R = /-Bu (53%) 84e, R = f-Bu (94%) 84f, R2 = Et2 (79%)

N

P02Et

ohru c

Et0Na/Et H

°

NHR (or NR2)

84g, R2 = (n-amyl)2 (74%) 84h, R2 = (o-MeC6H4CH2)2 (80%) 84i, R2 = (p-MeC6H4CH2)2 (66%) 84j, R2 = (o-FC6H4CH2)2 (67%) 84k, R2 = (p-FC6H4CH2)2 (40%) 841, R2 = (o-CIC6H4CH2)2 (7%)

VNV N = C ' - N ^ i

m

"

NHR 2

(orNR )

83

Synthesis of 3,5-difunctionalized l-methyl-lH-pyrazolo[3,4-fc]pyridines involving palladium mediated coupling reactions has been reported . A novel synthesis of pyrazolo[3,4bjpyridines by condensation of 2-pyrone with 3-aminopyrazolone has been described .

6.3.4.2 Applications Pyrazolo[l,5-5]triazines have been evaluated as inhibitors of the photosynthetic electron transport chain at the photosystem II level. Some of the compounds exhibited remarkable inhibitory activity . The pyrrolo|2,l-/][l,2,4]triazine nucleus has been identified as a novel kinase inhibitor template which effectively mimics the well known quinazoline kinase inhibitor scaffold . Disubstituted A^-cyclopentyladenine analogues behaved as neutral antagonists with high affinity for adenosine Ai receptor . Biological evaluation of 1,2,3,7-tetrahydro6f/-purin-6-one and 3,7-dihydro-l//-purine-2,6-dione derivatives as corticotropin-releasingfactor (CRF) receptor antagonists has been carried out. Compounds within this series were found to be highly potent and selective antagonists . yV-Benzyl-/V-ethyl-2-(7,8dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide (AC-5216) has been described as a novel mitochondrial benzodiazepine receptor ligand with antianxiety and antidepressant like effects . Identification of new purine derivatives as inhibitors of phosphodiesterase 7 has been reported . Synthesis and evaluation of 2substituted 8-hydroxyadenines 88 - 91 as potent interferon inducers with improved oral bioavailabilities have been carried out . Some 9-benzyI-8-hydroxy-2-(2hydroxyethylthio)adenine derivatives 92 have been described as prodrugs with potent interferon inducing agents in monkeys . 2-Substituted O-6-cyclohexylmethylguanines 93 showed potent inhibitory activity of cyclin-dependent kinase-1 and kinase-2 . NH 2

NH 2

1

1

N Y VOH RX 88, 89, 90, 91,

N

^

R = n-Pr, X = CH 2 R =n-Pr, X = NH R = n-Bu, X =S R = n-Bu,X=O

/—\

OCH2—
\

10 examples, 56 - 96%

^ . PhMe, 100°C r~\ ^R MeO2C CO2Me 13 examples, 14 - 79%

When a methyl group is adjacent to the carbonyl function in a-oxoketenedithioacetals 3 a Vilsmeier reaction leads to chlorodienals which gradually cyclise to 2//-pyrans . The epoxyquinone 4 has been enzymatically desymmetrised and then converted into aldehydes 5 which undergo an electrocyclisation to the fused 2//-pyran 6 which spontaneously undergoes a [4+2] cycloaddition with a second molecule of 6, providing a total synthesis of (-)-epoxyquinols A and B O4TL3611>. This facile cycloaddition is blocked when the alcoholic function is protected as the alkoxysilanol and this enables a [4+4] dimerisation to occur, producing the epoxyquinol dimer 7 . The oxidation - 6TCelectrocyclisation - cycloaddition cascade noted for epoxyquinols and epoxyquinones has been studied; of the sixteen possible modes for the sequence, only two are observed. Intermolecular hydrogen bonding plays a major role in the outcome .

364

J.D. Hepworth and B.M. Heron O

Cl

/^L

OH

(i) POCI3-DMF (3 equiv.) RT, 12 h ^ W

JL

(ii) Et2O, RT, 48 h

MeS^SMe

/Ny^Q^v/V

°

70%

O

°"L^V'>:

*" L. Jr-SMe

3

SMe

;

°

OH

4

^cJ^J^°

|f

O

O

n

OH

^"^11 O

7

O

8h

0i H

L

5

Q 11

} H

/

HO

J

\

^V)

6H

6 (-) - epoxyquinol A (48%) (-) - epoxyquinol B (18%)

Transition metal-catalysed cyclisations feature in several syntheses of dihydropyrans. Both the norbornene-based bis-ene-yne and tetrayne participate in a cascade of Ru-catalysed metatheses under quite specific conditions to yield pentacyclic bis-dienes and bis-trienes containing the cyclopenta[6,6']dipyran unit .

T°ô0^

O^-O-Ô

Ms N N MS

^

\ / ^ 43% Reagents: (i) 5 mol% cat. 8, 5 mol% cat. 9, CH 2 =CH 2 , CH2CI2, 35 °C, 24 h

~i'

8 9 Grubbs1 catalysts

An allenylidene intermediate is proposed in the synthesis of cycloalkapyrans through reaction of propargyl alcohols with cyclic 1,3-dicarbonyl compounds; thiolate-bridged Ru2 complexes, 10, are essential catalysts . A chiral Sc complex, 11, catalyses the enantioselective Nazarov cyclisation which yields cycloalkadihydropyrans from substituted dihydropyrans which are effectively penta-l,4-dien-3-ones; the analogous dioxins behave in a similar manner . R

v^ +

\

OH

^

^ t . 10, NH4BF4

° v i

X ^ Q CICH2CH2CI, 60 °C X J ^

12 examples j

20 - 99%

X = O, CH2, CH2CMe2

X = CH2, O

O 10mol%cat. 11 MeCN, mol. sieve

M

e

S

^^

O . o J i R f |T T

^Ru^Ru^

f°-yA [ I

/"

^

>^

S M e

10

f\ R

10 examples 65-94%

(° ^ 1 ^ \f°'-/ V - N Sc—N.../ |\ \ ^ ^

11

1 Li] ^^^

Sequential Rh-catalysed etherification of the allylic carbonate using the Cu(I) alkoxide derived from the enantiomers of the alkenyl alcohols followed by a RCM occur with excellent regio- and enantiospecificity and lead to CM- and fraws-disubstituted dihydropyrans .

365

Six-membered ring systems: with O and/or S atoms

[

I

I

PMPO^/^^s^.

° '"' "

(Tuii)

OCO2f-Bu P M P C ^ A ^ ^

/ \ ^

(ijToi)

I 1

-

f' o '••'

PMPO 8 5 % PMPO g 8 % Reagents: (i) LiHMDS, P(OMe)3, Cul, THF; [RhCI(PPh3)3], P(OMe)3; (ii)cat. 8, CH2CI2, reflux

A one-pot synthesis of dihydropyranols features the diastereoselective cyclisation of ally lie alcohols formed by elimination of HNO2 from the Michael adduct between cz's-hex-3en-2,5-diones and [3-nitroalkanols (Scheme 1) . The Mn(III)-catalysed reaction of alkenes with (2-aryl-2-oxoethyl)malonates proceeds through a 6-endo-trig cyclisation involving the ketone function and leads to tetrasubstituted dihydropyrans 12 . 9 A

O^/ ^T

OH

ArÔ

R

O

° OH 10 examples, 53-77% Scheme 1

CO2Me

R1 ) =

MeO2C

AcOH

Ar

reflux

CO2Me

O

N R2

12 9exam

P|es.

37

- 79%

The hDA reaction between buta-l,3-dienes and glyoxylates continues to be a fruitful source of 2-substituted 3,6-dihydropyrans . The synthesis of dihydropyrans by the domino Knoevenagel - hDA reaction has been extended to a chiral sugar aldehyde and leads to cw-annulated polycyclic dihydropyrans 13 . Benzoylhemithioindigo 14 undergoes a photoinduced [4+2] head-to-head dimerisation. The dihydropyran adduct 15 undergoes complete thermal reversal and the system has potential as a molecular switch . Irradiation of (£,Z,£)-l,3,5-hexatriene-l,6-dicarboxylates in which the central double bond is part of a cyclohexene ring generates a tricyclic dihydropyran through an intramolecular DA reaction. Cleavage of the bicyclic acetal unit offers a route to fused functionalised 7-membered ring systems (Scheme 2) . X

OHC^N. ,, 0

(\ /TroÔ

+ +

/

^ <W"°^

°YK-°

c.

o

^Y-S J~ Ph kiJ-V^ 14 O

S.T /

0

l^JliÔ"0 i f f C

A _ / V / H3N(CH2)2NH3. (OAc)2 s~-O ''° MeCN, reflux

\

Hi

(O^V

\

463 nm, PhMe 70 °C, PhMe

h H9l3mP

"

degassed Et2O Scheme 2

S

PhOC \

/\H 3 examples ^^ 13 70-72% COPh •• o

~\\^Y^\ YVÔ ^"\^J \J / 15

, f T l ™ 69% l

v^S0^~0Me

366


Chiral Al-salen complexes enable pyranoquinolines to be obtained with high diastereoselectivity by an inverse electron demand DA reaction between dihydropyran and benzylidene aniline . Sulfamic acid effects the one-pot reaction between benzaldehyde, an aromatic amine and dihydropyran which leads to the same products (Scheme 3). An intramolecular version of the latter variant involves the imines derived from O-prenylsalicylaldehyde and gives isochromanoquinolines and sulfamic acid is also a suitable catalyst for the Pechmann synthesis of coumarins . O

4 examples? 81 - 92% Reagents: (i) NH 2 SO 3 H, MeOH, RT Scheme 3

O

MeO2C

6 examples, 68 - 88% Reagents: (i) BrCH2OMe, Lewis acid, Bu 3 SnH, Et3B/O2, -78 °C Scheme 4

|3-Alkoxyalkylidenemalonates are doubly activated radical acceptors and after initial addition the malonyl radical is aligned for either 5-exo or 6-endo cyclisation. The favoured cyclisation to the furan can be blocked whereupon good yields of tetrahydropyrans result in a Lewis acid catalysed process. Bulky radicals improve the diastereoselectivity (Scheme 4) . Malonates with a pendant hydroxy group undergo a Mn-catalysed radical cyclisation offering a route to tetrahydropyrans linked to a carbocycle 16 . A tandem radical cyclisation also provides a route to tricyclic molecules, e.g. 17, from enynes and diynes derived from methylcyclopentenones . MeO2C

C0 2 Me

~y

2 /-^

Mn(OAc) 3 ,

Cu(OTf)2

MeO 2 C

Co2Me

V

^

III

/^y

I

D

O u

K

Bu3SnH

K .

Spiroketals have been obtained by RCM of cyclic ketals 18 without loss of stereochemical integrity at the spiro linkage and a stereoselective solid-phase synthesis of 6,6-spiroketals has been reported in which aldol reactions of boron enolates are the key feature . Spiro orthoesters are accessible from thiophenyl ketene acetals and diols (Scheme 5) . O ^ ^ Or

10mol%cat.8

f JV^ ^ ^

OAc 18

O ^ ,

CH2CI2,RT 83%

.Or

J

f JY

\ ^ OAc 11 examples, 5 - 90%

^°-v^sph r

^

|

1 mol% CSA H0CH 2 CH 2 0H'

CH2CI2

oj? " \ [

>Xf

k ^

5 examples, 64 - 89% Scheme 5

2-(l-Tributylstannyl-l-butynyl-4-oxy)tetrahydropyrans rearrange to 2-(4-hydroxy-lbutynyl)tetrahydropyrans on treatment with BFs-etherate. This anomeric O -» C shift offers a route to single diastereoisomers of spiroketals through reduction of the alkyne function and an I2/HgO promoted cyclisation .

367

Six-membered ring systems: with O and/or S atoms SnBu3

^s

n j

^ - ^

^ ^

-£L ( I

II -J2-*RX J

-B~RX J-S

° ^>OH A A / ^

R-ÔÔ-Tj2

W

>f 2

^°tj

2

R= n - h e x y ^

Reagents: (i) BF 3 .OEt 2 , CH 2 CI 2 ,-10 °C; (ii) Raney Ni, H 2 , EtOH, RT (91%); (iii) l 2 , HgO, C 6 H 12 , reflux (68%)

6.4.2.2

[lJBenzopyrans and Dihydro[l]benzopyrans (Chromenes and Chromans)

Benzopyran-2-carboxylates are produced, though with only moderate enantiomeric excess, by the regioselective insertion of activated alkynes into a enantioisomerically enhanced oxapalladacycle . Ph3P, / P h 3 Pd

a

, T R1Ê=-R2 W V

>^co Et CICH2CH2ci [T IT

0

ref UX

'

2

I_

^V> II

Br I

ph

Pd(OAc) 2 2PArligand

^ ^ o ^ f S

y y ? * *

„

4 examples, 5 2 - 7 2 % 35 - 66% ee

19

U

K2CO3

f ^ l R L J

f T

y

DMA 1 4 5 - C ^ J 7 examples, 92 - 98%

Aryl bromides 19 are cyclised to dibenzo[6J]pyrans in high yield through an intramolecular Pd-catalysed biaryl synthesis; the process requires only low catalyst loadings and is efficient even with unactivated substrates . A variety of 2-substituted 2//-chromenes can be obtained from the facile reaction of 2-hydroxybenzaldehydes with vinylboronic acids in ionic liquid solvents . In a one-pot sequence also in an ionic liquid, a Knoevenagel condensation between O-prenylated salicylaldehydes and 4-hydroxycoumarins is followed by an intramolecular hDA reaction to yield cfs-fused chromano[4',3':4,5]pyrano[3,2-c]coumarins e.g. 20; small amounts of the corresponding chromone are also formed . In like manner, cz's-fused furopyranopyran derivatives have been obtained from sugar aldehydes .

f^Y°H°+ U. J k ^ ^ O H

+

f^ R

B(OH)2 BmimBF.

^V^)

(PhCH2)2NH

ks J 3 N

(CH2)2OTs R3

fir* ® R 2 fk^ r r RR2 k fy\R2

dbw° ^ ^ H ^ ^° ^ ^°

/ \ I II II A~~^ °^Y!\\ ^ R O ^ \ ^ 7 V 22 ^ / 9 examples, 62 - 82% Reagents: (i) substituted phenol, AcOH, H2SO4, RT

~* v°

5 examples 4 examples 30-70% 35-86% Reagents: (i) cat. 4-TsOH, PhH, reflux; (ii) 1 eq. 4-TsOH, PhH, reflux

Both cyclobutanones and the tertiary cyclobutanols derived from them behave as intramolecular alkylating reagents towards O-substituted aromatic rings under 4-TsOH catalysis yielding cyclobuta[c]chromans 23. The use of an equimolar amount of 4-TsOH results in subsequent fission of the cyclobutane ring and the formation of chromenes . Cycloaddition of rhodium carbenoids across the pyran double bond is not observed with photochromic naphthopyrans. Rather, naphtho[2,l-fr]pyrans are attacked at the electron-rich 8-position to give 24 and cycloaddition at the 5,6-bond of the naphthalene unit is accompanied by opening of the pyran ring in the case of the [1,2-6] isomer leading to 25. An intramolecular variant of this reaction yields the tetracycle 26 O4TL6151>. Ar r^*5^~~Y~-Ar

^^.t*

[l"

Ar

Mt ^ Y ^ V

0

"v

O

r^Âr

? l] (i>- r ^ N ^ T

C09Et

H

24 Reagents: (i) Rh2(OAc)4, N2CHCO2Et, CH2CI2, RT

MeO

Ar O

\ ^ ^ i-i

25

C

°2Et

r**wr

v^V^r -^Wt^~

rY\y \ ^ O H / ^

50

Reagents: (i) (PhCN)2PdCI2, benzoquinone, MeCN, 60 °C; (ii) 5 mol% Pd/C, H 2l MeOH, RT Scheme?

+

f

R

2

°C

f | f | k>. J k ~ y - k ~ ~ .-» CO Scheme 8 ^ ° 2S

When the aryl iodides 27 are treated with a Pd catalyst under basic conditions, variously fused derivatives of chromans are produced in good yields. The process involves a 1,4-shift of Pd from alkyl to aryl and a subsequent intramolecular arylation . Cyclopropanation of the alkene unit by the alkyne moiety in the enynes 28 yields the cycloprop[c]pyrans 29 which on treatment with acid afford chromans. This new benzannulation presumably proceeds by a retro DA opening of the pyran ring followed by cyclisation and dehydration . R1

/Â ^

« «_0 \_/

27

Ph

i \=/ r Y i k^X

J

° Reagents: (i) 5 mol% Pd(OAc)2, 5 mol% dppm, CsO2CCMe3, DMF, 100 °C

f

^\

R1 ^s.

ill C 3 JL s^ty) ° R2 ° R 28

29

F

f

-JiiL r f f ^ R^ K

7 examples, 52 - 97% 5 examples, 64 - 80% Reagents: (i) 5 mol% PtCI2, PhMe, 80 °C; (ii) either aq. HCI, THF, reflux or 4-TsOH, PhMe, reflux

The first example of the enantioselective cycloaddition of chiral enol ethers to o-quinone methides, derived from a protected salicylaldehyde by reaction with a Grignard reagent, generates three chiral centres in a one-pot process and provides chiral chromans 30. These products can be manipulated to give other chiral chromans and chromenes and are a source of chiral aliphatic benzylic carbon sites . A tandem R.CM - DA sequence applied to enynes derived from 1-iodophenol leads to 4-vinylchromans 31 and a hDA between phloroglucinol and citronellal features in a synthesis of the antimalarial Machaeriols A and B .

370


a

OBoc

R

-s^n T

CHO

I

+ s\sph M

RMgBr Et2O,-78°C-RT

^

1^

^ Y ^

7mol%cat.8 ^

KXQ^

^

X 65%

tJL J

R l

Ph

f ^ Y ^ M V ^ 6 examples k A ^ : ^ 62-88%

3

°Tf

°

^ \ k 5 mol% AuCI3, AgOTf _ r f > r ^ |

^ A 0 ^ CICH2CH2CI,120°C R ^JkJ

,,.

10 examples, 15-93%

J1

f^Y

+

^ ^ C H O

MeO oMe ^

Scheme 9

Bi(OTf)3.xH2O ^

^

MeCN, 0°C Scheme 10

T JT J " , ^ ^ ^ ^ major OMe

f

JT J"'OMe

^

x

^ ^ OMe

5 examples, 56 - 70%

Good yields of chromans, dihydrocoumarins and their benzologues result from the Aucatalysed cyclisation of terminal sulfonate esters of alkyl aryl ethers (Scheme 9) and Bi(OTf>3 catalyses the reaction between salicylaldehydes and 2,2dimethoxypropane which leads to 2,4-dimethoxy-2-methylchromans with one diastereomer being produced in large excess (Scheme 10). Pyrano[2,3-Z>]benzopyran has been obtained in a similar manner . A radical cation is involved in the direct synthesis of chromans by an intramolecular oxidative cyclisation of 3-arylpropanols 32 brought about by a hypervalent iodine(III) reagent and iodonium species catalyse the intramolecular arylation of alkenes which yields iodo-substituted chromans 33 . 3-Allenylchroman-4-ols result from a one-pot reaction between salicylaldehydes and 1,4-dibromobut-2-yne in which the intramolecular cyclisation of the intermediate ether is mediated by In metal

R1

R2O

iXJ 32

R 4 3c (F3>2CH.o R 1^ R

n

p|FAMK 10

" UCJ

„,_ ^ ^^ PIFA = Phl(CF3CO2)2 CH2Br

^ri2tir

R 4R3

8 examples, 43 - 57% K

~.

| ^ W

R

IPy2BF4

^J ^ T S T 1 ^ ^ ' 2

2

33 6 examples, 64 - 95%

o

OH

Reagents: (i) K2CO3, Kl, DMF; (ii) In, AcOH, DMF

f^r°VR

n =~

O OH 34

Xyloketals have been synthesised from phenols and enones through a one-pot sequence of Michael addition reactions and intramolecular condensations. In particular, an enantioselective synthesis of the tricyclic xyloketal D 34 has established the absolute configuration of the natural material . 6.4.2.3 [2]Benzopyrans and Dihydro[2]benzopyrans (Isochromenes and Isochromans) Nucleophiles e.g. ROH, C6HsNMe2, react with 2-alkynylbenzaldehydes in the presence of various electrophilic species e.g. h, PhSeBr, NBS, in a facile one-pot process to yield isochromenes that are fully substituted in the pyran ring (Scheme 11) .

371


Propargyl 2-iodobenzyl ethers can be hydrostannylated and distannylated on treatment with Bu3SnH in the presence of Mo CO/isonitrile complexes without loss of the halogen. The resulting halogenated stannylallyl ether 35 undergoes an intramolecular Stille reaction at 75 °C which yields 4-methyleneisochroman, though this isomerises to isochromene at slightly higher temperatures. The distannane yields a (stannylmethylidene)isochroman that can be further modified . ^^CHO f T ^^S^ ^ R

(')

J!" f ^ f O 15 examples ^f\^^ n " U , , ^ ^ | 1 - 93% f |f V T R ^ ^ S Vj^ SnBu 3

3 5

Reagent: (i) 1.2 eq. nucleophile (Nu),

75 °C f ^ V ^ Q I 68%" k A ^ Pd(PPh3)4 || PhMe '

90 °C r V ^ j-*-L II 7 9 %

1.2 eq. electrophile (E), K2CO3, CH2CI2, RT Scheme 11

T J

^ ^ ^ ^ J

Formation of the l//-[2]benzopyran system by a 6-endo-dig cyclisation is favoured over the 5-exo-dig route to isobenzofurans in the Pd-catalysed oxidative carbonylation of 2-alkynylbenzyl alcohols when an electron-releasing group is present at the alkyne terminus and by the absence of a substituent a to the hydroxy function. Similar results obtain when 2-alkynylbenzaldehydes are used as substrates . Annulation of alcohols to the latter reactants yields the isochroman exclusively under catalysis by Cul and the Pd-catalysed insertion of isonitriles into 2-(2-bromophenyl)ethanols affords isochromans 36 . R2R3

CR 1 CO 2 R 4

[^YÔH L II ^ > ^ ^ ^ ^-

Pdi2, KI, co R 4 nH n R T ' ROH,O2, RT

R

1

fs^Vy1 L jJ / ^

/

+

- ^^ R 3R

CO 2 R 4

r < ^^r 5 *r' R i L II A 4 examples ^^sj^-Ô R3 R 2

10.36o/o

O

R2 I*=SSV'~V-D1

L I ^^^Br

OH

R3NC, NaONBu ^ \ ^ ^ ^ , R 2 PhMe, reflux \ T T~R 1 > 5mol%PdCI2 ^ ^ V 0 ' eXa ^' eS 10mol%dppf » 63-84/o NR3 36

1 f|

OH •

1 ]\ ^]

1 9

MeoAAA^ Meu y y O OMe 37

The cyclisation of chiral benzylic alcohols into separable diastereomeric mixtures of isochromans is promoted by Hg(OAc)2. Under oxidative conditions, this Hg-mediated process yields chiral 4-hydroxyisochromans (Scheme 12). Both types of product are readily oxidised to isochromanquinones . This methodology features in the first synthesis of ventiloquinone J 37 and in syntheses of related quinones . The synthesis of enantiopure isochromanquinones, especially those derived from insect pigments, have been achieved from tethered phenolic lactaldehydes utilising TiCUisomerisation of dioxolanes to generate the isochroman ring system . A Michael addition is used to generate the isochroman ring of a pyranonaphthoquinone isolated from Streptomyces sp. .

372


WJk k*O... k f ^ R

R

^ A SV"-

K

OH OH Reagents: (i) Hg(OAc)2, NaOH, NaBH4, aq. THF; (ii) Hg(OAc)2, NaOH, NaBH4, O2, DMF Scheme 12

5-Aryl-l,3-dioxolanes undergo a TiCU-promoted Pictet-Spengler rearrangement to give 4-hydroxyisochromans. Bulky substituents at C-2 and C-4 of the dioxolane moiety result in formation of the m-l,3-disubstituted isochroman while the 2,4-dimethyl derivative affords mainly the fraMS-diastereomer . /\^Br

Br OH

XX n ^^yy«^r R1

6.4.2.4

TiCI

Ph

R2

Ph

< rÂ" ^r) rh ° ->y Ph \ U --Pies P h > ^ C J £ p h j ^ i p h

°

AgCIO4H2 Ph

°MaRi

Scheme13

33%

Pyrylium Salts

The conversion of phenyl-substituted cyclopentadienes into pyrylium salts is catalysed by Ag+ ions (Scheme 13). The heteroatom is considered to be derived from moisture, present in the AgClCU catalyst, which inserts into the cyclopentadiene ring . A major role of pyrylium salts is as synthetic intermediates. For example, the hindered base 4-ethyl-2,6-diisopropyl-3,5-dimethylpyridine results from the rapid diacylation of 3-ethylpent-2-ene, obtained in situ from the pentanol, with isobutyric anhydride and subsequent reaction with ammonia . The l-(3-chloropropyl)benzo[c]pyrylium derivative 38, obtained from the acylation of 3,4-dimethoxyphenylacetone with 4-chlorobutanoyl chloride, reacts with ammonia to give benzo[/]indolizinium salts and with hydrazine to form quinolino[2,l-6]pyridazinium salts through a double cyclisation process in which the 3-chloropropyl side-chain is involved . It is proposed that the benzo[c]pyrylium cation 3 9 , produced from oalkynylbenzaldehydes by AuBr3 catalysis, behaves as the 4n component in an inverse electron demand DA reaction with enols. Dehydration and bond rearrangement leads to naphthalene derivatives. Simple a,|3-unsaturated aldehydes can also be benzannulated in this way .

Meo

Meo Meo Y Y Y ^ ^ rrxio! _ ^ L YYV MeO^-^S^X MeO^^Y°CI E*°H M e O ^ ^ f N MeOH

X = NH, 76% K^

l}a

X = O, 51%

5

V

cat.AuBr3

^^N& ^-R1

jf®^

1,4-dioxane ^ ^ Y ^ R 100°C

[

®AuBr3 39

1

Rl

k ^

95% >—/

^R3 {U^R2

^ T X

"" /-ÎlXoH Br3Aue^3

^^V^R^ J

J^ , UK 7 examples, 64 - 80%


373

Interest continues in the potential value of flavylium salts in read-write systems , as photochromic materials and as photosensitisers in photodynamic therapy . 6.4.2.5

Pyranones

The regioselectivity of the Ni-catalysed cycloaddition of CO2 to asymmetrical tethered diynes 40 is controlled by the relative sizes of the terminal substituents and to a lesser extent by the nature of the catalyst. The bulkier group tends to occupy the 3- rather than the 6-position . A theoretical study of the Ru-catalysed reaction of ethyne with CX2 to afford 27f-pyran-2-ones suggests that reaction with CS2 is the most favourable . 10mol%Ni(COD)2 MeO2C / — = ~ R

MeOÂ

20 mol% ligand 41

—

\

^ M e O

MeO2C/V-1wkQ

CO2 PhMe,60°C

4Q

R

I MeO2C-—^-o

2

C ^ ^

P ^

Ar'N\/N-Ar

o

MeO-.c'V-'Sxkn

^

2

^

Ar = 1,3,5-Me3C6H2

0

41

6 examples, 57 - 83% R

R

Y / ° [Ruc,2(co)3l2

RP

PhMe, reflux"

ff\R R

y\A>

/ ^ Scheme 14

R

4 examples 79 9 3 % "

O OH

f

+

I

0.00^R

I 1

anhyd.EbO R I - V ^ P "

^V

&KK 4

42 examples, 70 - 92%

Cyclobutenones undergo a Ru-catalysed ring-opening — dimerisation sequence which leads to 3,4,6-trisubstituted pyran-2-ones (Scheme 14) . 4-Chloropyran-2ones have been obtained from acetonide-protected 4,5-dihydroxy-2-chloroglycidic esters by treatment with MgCk , 4-aroyl derivatives from mandelic acid and 1,2-diaroylethenes and 4-formylpyran-2-ones from the monoacetal of but-2yndial . 1,3-Diketones react with readily available (chlorocarbonyl)phenyl ketene to provide a facile synthesis of 5-acylpyran-2-ones 42 and arylpropanones afford 5-aryl-4-oxo-4//-pyran-3-carboxaldehydes in a Vilsmeier-Haack reaction . Pyran-2-ones are useful synthetic intermediates. Many reactions involve DA cycloaddition followed by lactone ring opening. 3-Alkynyl tethered pyranones undergo an intramolecular DA reaction which subsequently yields cyclohexene-fused macrolactams (Scheme 15) . The DA reaction between 3-benzoylaminopyranones and alkynes is a source of highly substituted anilines and 3-phenylamino derivatives provide a-amino acid esters following addition of electron-deficient dienophiles . In the solid state, benzophenones efficiently photocycloadd to the 5,6-bond of pyran-2-ones to give oxetanes e.g. 43 . Highly regioselective Suzuki coupling can be achieved at either the 3- or the 5-positions of 3,5-dibromopyran-2-one by variation of the reaction conditions (Scheme 16) .

374 9

Br


-*^~H~.)

Rl

,,

n=1-4

X

MeO2C

R O H 2 examples, 91 - 96%

R

4 examples, 10 - 69% Scheme 15 9 O^syBr

ArB(OH)2 10mol%Pd(PPh3)4

WJ

DMF, Na2CO3 Cul,50°C

Ar

8 examples, 7 1 - 9 1 %

OR

9

ArB(OH)2

O^V'Br

PhMe, K2CO3

^r

100 °C

Scheme 16

4 3

°

10mol%Pd(PPh3)4

kJ

'

o^Sr'Ar

k^

1

^ 8 examples, 40 - 90%

The Baylis-Hillman reaction of pyran-4-ones and chromones with aldehydes is efficiently catalysed by NaOMe or DBU and when applied to salicylaldehyde and cyclohexenone a tetrahydroxanthen-1-one results possibly via a domino Michael addition and intramolecular aldol condensation . Synthesis of dihydropyranones from ketones using the hDA reaction has been reviewed . Enantioselective syntheses of dihydropyran-4-ones from aldehydes by this route can be achieved using chiral Rh catalysts and Ti complexes . Their synthesis from hindered a-ketoesters and Danishefsky's diene has been optimised using a high throughput screening approach . Use of the electron-rich Brassard's diene in the hDA reaction yields dihydropyran-2-ones using TADDOL derivatives which encourage asymmetric hydrogen bonding activation . Intramolecular DA reactions of 1,6,8-nonatrienes have been studied and a total synthesis of the complex polycyclic pyranones, the macquarimicins, involving a transannular DA, has resulted . Several syntheses of dihydropyran-2-ones use smaller ring systems as precursors. A direct conversion of cyclopropylidene acetates into 4-halo-5,6-dihydropyran-2-ones occurs on treatment with Cu(II) halides. The products undergo a Pd-catalysed cross coupling with terminal alkynes . CO^R1 ^ R2 CuX-2,85°C »- A , f ^ ^ ~°\ /7—\

Pd(OAc)2,CO

>=\

( A )

—

f-Bu

h°\

- ^ - ~ jT~i,

DMS M eOH 2°5o c tlJ-X)

40

«u

^V-OH r=\

\

V

^

^

O

(Ô2,THF

\

-60°C-RTI

||

ao 2 c^>^

THF

81%

Y N1 J

| < V Y M

J^

^ r ^ 0H

47

f W 41% \ 46

I

O-\f*% L

O

o

°

9

LiOf-Bu

MeOzC^^^

y-J(

(-Bu

SPh

ri^V^

]indoles. The proline-catalysed aldol reaction of tetrahydro-4//-thiopyran-4-one with aldehydes, which is accelerated by water , gives the anti adducts with high diastereo- and enantioselectivity; DMSO is the solvent of choice for aliphatic aldehydes and moist DMF for aromatic examples (Scheme 23). Desulfurisation of these thiopyrans with Raney-Ni gives products equivalent to aldol products derived from pentan-3-one . High yields of hydroxythioxanthones are readily obtained with good regioselectivity when a mixture of alumina and methanesulfonic acid is used to effect the reaction between thiosalicylic acid and phenols and a one-pot conjugate addition - aldol reaction sequence provides benzo[Z>]thioxanthene-6,l 1-diones from naphthoquinone and 2-acylthiophenols (Scheme 24) . O

O

Ho

>*\

I

S ^

+

I

,|

L-proline^

R ^

DMSO

RT

>

OH :

II

^

^

R

O

OH

II

+

E

k

S ^

I

^ V ^ A - R

E

S^

n

0

'

° 'yf!^H

kA^ 0

E

=

R

7 examples, 70 - 94% O H O R2

R2 C

rf^YTl

OH

J I X

EtOH, T H F [

15 examples, 10 - 92% Scheme 23

nu

O

Raney-Ni t

HS^4I

(i) EtOH or THF reflux, Ar r * * * V ^ S r S f ^

^ ^ Scheme 24

1 8 examples

" U ^ s A ^ " 25"75% °


380

Naphtho[2,l-6]thiopyran-l'-ylidene-9//-thioxanthenes function as light-driven molecular motors which show a preferential clockwise rotation of one half of the molecule . 6.4.4

HETEROCYCLES CONTAINING TWO OR MORE OXYGEN ATOMS

6.4.4.1

Dioxins and Dioxanes

Endoperoxides derived from the cycloaddition of singlet oxygen to butadienes are readily converted into the epoxides. The epoxy oxygen is close to the peroxide unit, resembling the trioxane moiety of artemisinin and the epoxides show antimalarial activity (Scheme 25) . An electron transfer mechanism appears to be operating in the photooxidation of the electron-rich alkene 61 which is quantitatively converted to the ewefo-peroxide when sensitised by C6o deposited on alumina or silica . R1 J

R1 I

R2

R2

R1 i t

R1

R2

R2

. An

61

An

ArfAn A n = 4 M

Reagents: (i) 0 2 , Rose Bengal bis-(Et3NH) salt, CH2CI2; (ii) m-CPBA, CH2CI2 Scheme 25

" e0C 6 H 4

2,3-Dihydroxynaphthalene and 9,10-diacetoxyphenanthrene react with 1,2-diols and 1,2-dithiols in a one-pot synthesis of annulated 2,3-dihydro-l,4-dioxins and -1,4-dithiins (Scheme 26) . The reaction of 2,3-dihydroxynaphthalene with 1,2dihalogenated aromatic compounds leads to linearly annulated dioxins; of particular interest are tri- and tetra-dioxins and various hetero-fused dioxins e.g. 62 (34%). Several examples yield cation radical salts on electrocrystallisation . Linear arrays of fused pyrandioxin-cyclohexane rings as found in natural products derived from the milkweed family have been described e.g. 63 . Catechol undergoes a Pd-catalysed tandem asymmetric allylic substitution on reaction with 1,4-diacyloxybut-2-enes to give 2-vinylbenzo-l,4-dioxanes with good enantioselectivity in the presence of a chiral P-ligand 64 .

^Y\OH

HX +

^R 4-TSOH r ^ Y ^ Y x i R

^yYOsfTSvl

9 examples, 62 - 95%

62

Scheme 26 0

J^h. 1 J. f

0 B z

O

^ JL J

''o^^-^ 63

AcO^

catechol, K 2 CO 3 ^-OAc rpH/p H ^rn ' L [Pa(C3H5)CI]2 CH2CI2,RT

sss^X-/' 8 7 % i 6 2 % e e

J~\^_/=\ L / N / ^ / ^

Ph2P ^

381

Six-membered ring systems: with O and/or S atoms 6.4.4.2

Trioxanes

Several reports discuss the chemistry behind the antimalarial behaviour of artemisinins O4ACR397, 04AG(E)1381, 04JMC2945>. The important role of the peroxyketal unit in the antimalarial activity shown by endoperoxides derived from Eucalyptus grandis leaves has been recognised . There is continued interest in the synthesis of novel derivatives of the artemisinin system with a view to optimising the biological activity. Dimers with ester, ether and phosphate linkers have been obtained from 10|3-(2-hydroxyethyl)deoxoartemisinin 65 and their antimalarial and antitumour properties have been investigated . O-Acetyldihydroartemisinin undergoes a TMS triflate-catalysed coupling reaction with yV-hydroxyphthalimide to provide the O-aminodihydroartemisinin 66 which readily forms oximes with carbonyl compounds while retaining the endoperoxide unit . Enhanced stability towards acidic conditions and water is shown by IO-CF3 artemisinin derivatives 67 O4JMC1423, 04JMC2694>. Dihydroartemisin has been converted into the 10-thioacetaland 10-sulfonyl- 68 artemisinin derivatives. The latter undergo a Ramberg-Backlund rearrangement to give the 10-alkylidene deoxoartemisinin .

H*

T' H

HA

y^*

T'H

H
K rt, 36 h

Hi

45

110-120 °C 4-6h

H

H .

\=J

H

R = H, CH3, Cl, F

cis/trans 46

A new route for the synthesis of 50 (YM087), an arginine vasopressin antagonist, has been reported by Tsunoda et al. . The imidazolobenzazepine 49 was a key intermediate in this new route which involved benzazepinone formation from the amino ester 48 (obtained in turn in two steps from 47) followed by elaboration of the imidazole ring fusion.

O

HN-\

R3

(XT^~ CO -^ CO R2 ... I

1

47 R = H, R = H P Ri = p-Tos, R 2 =H ( i ' ) L _ 4 8 R 1 =p . T o S | R 2= (CH2)3CN ( 0

1

HNA N

l— R^ = NH2

JfY40

3

, iv/ ,| R = P-Tos, R = H ' V W R 1 = p-Tos, R3=H (V)L — - R1 = P-Tos, R3 = Br /

(ix)c:R:=N02

R'1

R1

2

1

, R = p-Tos < w l ) U 4 9 R1 = H

H N

^ N HCI

LJ^

X^N-C^0

( j ^ p fj 5Q R 4-k^J Reagents: (i), p-TosCl, pyridine; (ii), 4-chlorobutanenitrile, K2CO3, KI, 2-butanone; (iii), (-BuOK, DMF; (iv), AcOH, HCI; (v), pyridinium hydrobromide perbromide, CHC13; (vi), ethanimidamide monohydrochloride, K2CO3, CHCI3; (vii), H2SO4, AcOH; (viii), 4-nitrobenzoyl chloride, DMF, pyridine monohydrochloride; (ix), H2, Raney nickel, MeOH; (x), biphenyl-2-carboxylic acid, oxalyl chloride, DMF, CH2C12> MeCN, pyridine, HCl-AcOEt. An elegant and efficient synthesis of 6,11-dihydro-l l-ethyl-5//-dibenz[6, c]azepine derivatives 53 has been described which involves a BF3-catalysed aromatic amino-Claisen rearrangement of 51a-d to 52a-d followed by an intramolecular alkene Friedel-Crafts alkylation (acid catalysed) to access the 7-membered ring in 53 in high yield. With the amino-Claisen rearrangement of 51e, an inseparable mixture of 54e and 54e' was obtained, since in this case both ortho positions in 56 are free for the rearrangement .

396

J.B. Bremner

53a-d (78-85%)

52a-d (72-85%)

Reagents: (i), BrCH 2 CH=CH 2 (2 equiv), DMF, rt or acetone, K.2CO3, reflux, 6-7 h; (ii), BF 3 .OEt 2 (I equiv), sulpholane (3-5 mL), 140-155 °C, 2-3 h; (iii), coned H 2 SO 4 , 80-90 °C, 1.5-2.5 h.

Electrophilic cyclization of the carbamate 55 resulted in formation, in moderate yield, of the xantheno[l,9-c

o

£t

54% ^ J ^ N '

NO O

.^XOOH 99%

^ ^ N ^ Y ^ E t 91 O

(y)|

°,

65% [ f ^ f

Et

V^Q

90

89 N O

Reagents: (i), EtNH2, rt; (ii), isoamyl nitrite, cat., TFA in PhMe at rt; (iii), EtNH2, rt; (iv), Et3N in MeCN followed by CICOOEt, heating; (v), TFA/urea, heating in EtOAc.

l,4-Benzazepine-2,5-diones have been prepared in a new route via copper-catalysed intramolecular TV-arylation of amides; yields ranged from 50-99% . DNA-interactive pyrrolo[2,l-c][l,4]benzodiazepine derivatives have been a major focus of synthetic activity. Polymer-supported diimide and diphenylphosphine reagents have been utilised by Kamal and co-workers to prepare the derivatives 92 (R = H; 7-Me; 7-C1; 7-OMe; 7-Br; 9-Br; 7-OMe, 8-OMe, 7-OMe, 8-OBn) efficiently from the corresponding azides 91; the methodology was also applied to the synthesis of the natural product DC-81 (92, 7-OMe, 8-OH) .

R

Q-C—Q

ocH

tA C O O H

j° » H

Vj.CH2CI2,rt 97-99%

fOOCH, R

-O^NQ 91 O

95 . 99 o /o

|O"PPh2 I CH2CI2, rt H

O

92 O An efficient route to the synthesis of the cytotoxic pyrrolo[2,l-c][l,4]benzodiazepines 9799 with conjugated C2-acrylyl substituents based on a Heck coupling of 96 to introduce this C2 side-chain. The route started from the nitro benzoic acid 93, and proceeded via standard transformations to 94, which was then cyclised to the 7-membered ring derivative 95 on oxidation of the primary alcohol to the aldehyde .

402

J.B. Bremner

Me0

-Y^^N°2

(i)

MeO-^CO 2 H

MeO^^X

OTBS

ÔTBS ;'

(iv) ^ O y ^ Y

M e O ^ Y ^ "

MeOÂ^^

o 93

uw V

TrocÔX L

N H

(vi) ^ 0

o

r,\\\— X = NO,

. ,,

X = TBS

X = NHTroc J 0(

Me

' l

N

Tro

(iv),(v)

A

(vi)

131 SMe

f

S

132 NH

Reagents: (i), NH 2 OH, Pyridine; (ii), n-BuLi, TsCl, THF, -78 °C to rt; (iii), dioxane, NEt3> rt; (iv), Lawesson's reagent, PhMe 90 °C; (v), Me 3 OBF 4 , CH 2 Cl 2 ; (vi), NH 4 Cl, EtOH, reflux.

The 1,4-oxazepanes 133 were prepared by a ring closing reaction of epichlorohydrin with the appropriate TV-benzyl ethanolamine derivative and subsequent introduction of the second aryl substituent group (A). These 1,4-oxazepanes were assessed as selective dopamine D4 receptor ligands. For example the compound 133 (R1 = OCH2CH3, R2 = H, R3 = Cl, R4 = R5 = R6 = H, R7 = Cl, X = O, Y = C) had a K; of 7 nM at this receptor .

R

R2

yvR3

CV ÎNT

I

R5 1^

133 ^ " R

p6 7

Ohno and co-workers have reported the development of a highly regio- and stereoselective synthesis of 1,4-oxazepine systems based on Pd(0)-catalysed cyclisation of aminopropanol derivatives containing bromoallene moieties. In this reaction the latter group acts as an allyl dication equivalent and exclusive intramolecular attack by the hydroxyl group occurs at the central allene atom. Examples of this elegant cyclisation reaction include the conversion of 134 to 135, and of 136 to 137, plus a small amount of 138. These are the first examples of 7membered ring formation via cyclization of bromoallenes, and the process can be extended to 8-membered ring formation and also to 1,4-diazepines and 1,5-diazocines . Bn

TS

V^ ^ '

V

^ 0 134 5

I Ts'

'^,.Br

^ . .

v 136

H H

D

^-Br

\ H OH

Pd(PPh3)4(10mol%) NaH(1.5equiv)

B n

V^^\

EtOH: THF = 1 : i " rt.1.5h Pd(PPh3)4(10mol%)

~NW° 1 3 5 6 0 %

\/v/vnn

NaH(1.5equiv)

Y^ÔBn "

BnOH:THF=1:1 rt, 1.5h

T s

°Et

Ts-N \ 137

O / 81 o /o

BnO >vJL^

y^f

+ -rc-N O l s N/ 1 3 8 6o/o

The synthesis of a 1,4-oxazepane based 1,6-anhydro-P-D-hexopyranose, 142, has been reported in good overall yield (48%) from the tosylate 139, via the derivatives 140 and the

409

Seven-membered ring systems

epoxide 141. Formation of the 7-membered ring was achieved in the last step by intramolecular attack of the amino group on the epoxide to give 142 .

n U~J

(l)

K?

°; allyl, which was subsequently appended to a polysilane backbone ; urea, as a precursor to dynamic self-assembly via //-bonding ; salicylaldimine Schiff bases ; and benzothiazole representing the simple conversions; whereas, di(monosubstituted benzocrown)s have also been prepared in analogous ways and studied, generally as either supramolecular complexes or macromolecular constructs O4MCP801; 04PM7389>. Aryl-expanded crowns have been used as the molecular shuttle between multiple recognition sites or stations . In situ threading during polymerization has been of continued interest; thus, 6w(carboxy-l,3-phenylene)-(3x+2)-crown

420

G.R. Newkome

ethers-x 1 with 26-, 20- or 14-membered rings have been created to better understand topological properties in assembly processes . Double-armed lariat ether derivatives possessing pyrene moieties at each end of two side chains thus (3«+l)-crown-» derivatives (n = 4 - 6) and 3m-crowns-m {m = 5, 6) have been synthesized and their complexation behavior was evaluated by fluorescence spectroscopy . The multifunctional 5,8-dimethoxy-6,7dihydroxymethyl-l,4-dihydro-l,4-methanonaphthalene was used to synthesize the symmetric te-methanonaphthalene-fused crown ethers 2 . Mono- , di- O4J0C6938; 04TL3387>, and multiple bridged calix[w]arenes continue to offer rigid polyfunctional cores for capping and selective complexation. The synthesis of rigid tube-shaped structures was derived from tetrafe(bromomethyl)calix[4]resorcinarene, which was treated with phydroxybenzaldehyde to create the tetraether-aldehyde that was condensed with resorcinol to form the new desired aromatic rim .

An improved route, which circumvents the oligomer formation, of 2,11,20,29-tetraoxa[3.3.3.3]paracyclophane 3 has recently appeared . A series of new macrocycles 4 and 5, has been synthesized in one-step from simple monomers by sequential Claisen-Schmidt condensations and offers interesting avenues to calixarene/crown hybrids . A novel family of two rectangular and two square ninhydrin-based cyclophanes, e.g. 6, has been prepared in variable (8 - 43%) yields from simple components . Intramolecular McMurry coupling of dialdehydes derived from xylenyl dibromide and 4hydroxybenzaldehyde generated cw-stilbenophanes as well as cyclophane diols . Related crownophanes containing both fluorenone and stilbene subunits have been synthesized and shown to be possible alternatives to benzocrown ethers, as components in supramolecular construction . New Cjv cavitands 7 with protective side chains were prepared and their host-guest properties evaluated .

8.3

CARBON-NITROGEN RINGS

Over the past decade, cycloZ)w(paraquat-p-phenylene) has been the benchmark compound in the design of molecular switches, in 7c-7i-stacking, and related dynamic processes and this continues in redox-controllable amphiphilic [2]rotaxanes .

Eight-membered and larger ring systems

421

It has been thirty years since the work of Richman and Atkins first described the cyclization process that has become the standard procedure to construct polyazamacrocycles. This fundamental procedure for basic aza-structures continues to be used but modified to incorporate other subunits, e.g., resorcinol or 6,6"te(bromomethyl)[2,2':6\2"]-terpyridine . Treatment of 1,4,7,10,13,16,21,24octaazabicyclo[8.8.8]hexacosane with triethylorthoformate at 120 °C in dry xylene gave a new imidazolidinium-based macrobicycle 8, which was internally empty as well as possesses a pseudo-C3 symmetry . The aryl-related compound 9 was prepared (50%) by the macrocyclization of l,3,5-/m(bromomethyl)benzene with iV,./V',./V"-3,3',3"-hexatosyl-6,6\6"nitrilotri(3-azahexylamine) . Treatment of 2 equivalents of indole-3-aldehyde with substituted xylyl dibromides or 4,4'-6iXbromomethyl)-l,l'-biphenyl gave the corresponding ftwalkylated precyclophane, which underwent a McMurry coupling with low valent titanium to give the respective 1:1- and 2:2-indolophanes (e.g. 2:2-10) .

422

G.R. Newkome

An alternative route to large azamacrocycles utilized an initial Schiff base intermediate, followed by reduction; different components have recently been used: [1 + 1] condensations: 2,6,9,12,16-pentaza[17](2,6)pyridophane ; [2 + 2] condensations with 2,6pyridinedicarboxaldehyde with 3,3-diamino-iV-methyldipropylamine or 6w(3-aminopropyl)amine as well as TV^l-naphmylmemylazaethyO-TVjN-dKaminoethyOamine ; 4-alkoxy-2,6-diformylpyridine with 4,4'-di(aminomethyl)biphenylmethane ; (S,S)-6,6'-fc(4-ethyoxyphenyl)-2,2'-dihydroxy-33'-diformyl[l,r]-binaphthalenyl with l,2-diphenylethene-l,2-diamine ; l,10-phenanthroline-2,9-dicarboxaldehyde with 4,7,10-/r;s(/>tolylsulfonyl)-4,7,10-triazatridecane-l,13-diamine ; l//-pyrazol-3,5-dicarboxaldehyde TV-(l-alkyl)-AyV-di(aminoethyl)amine ; and [3 + 3] condensations: 2,6-diformylpyridine with fra«5-cyclohexane-l,2diamine. The acid-catalyzed condensation of resorcinol or 2-methylresorcinol with 2 equivalents of an acetoxymethylpyrrole gave 6w(pyrrolylmethyl)benzenes, which are precursors for novel benzoporphyrins using the MacDonald methodology . Carbaporphyrinoid systems with semiquinone, cycloheptatriene or indene subunits have been prepared and treated with Ag(I)OAc to generate the stable Ag(III) derivatives , also see: . cw-Doubly TV-confused porphyrins of the A2B2-type with different mesosubstituents were prepared by the condensation of aryl-substituted TV-confused dipyrro- methanes and substituted benzaldehydes . Porphyrins can not only be TV-confused but now inverted as well as dimeric and there are doubly TV-fused pentaporphyrins . The reaction of a dipyrro-methanedicarbinol with 2,2'-bipyrrole and/or corrole was investigated; after consideration of reaction parameters, a model reaction afforded 5,10,19,24,29,38-hexaphenyl[34]octaporphyrin (1.1.1.0.1.1.1.0) and/ meso-triphenylcorrole . A novel transformation was observed when calix[n]arene (n = 4 or 6) was oxidized to generate the cyclic poly-l,4-diketone 11, which when subjected to Paal-Knorr conditions gave (12, n = 3); whereas, it was treated with hydrazine gave the isopyrazole-based macrocycles 13 .

8.4

CARBON-SULFUR RINGS

A series of macrocyclic, oligomeric (thioarylene)s was prepared in one-step from biphenyl ether, biphenyl, biphenyldisulfide or biphenylmethane with dichlorodisulfide in the presence of trace amounts of iron powder under high dilution conditions; these macrocycles undergo ring-opening polymerization to generate linear polymers under mild conditions . Spontaneous ring-opening polymerization of macrocyclic [-1,4-SC6H4-CO-C6H4-


423

]„ (« = 3 or 4), in which the thioether linkages are para to the ketonic functionality, occurs during rapid, transient heating to 480 °C to afford a soluble, semi-crystalline poly(thioether ketone) of high molar mass . Cyclic 6w(l,3-butadiyne)s 14 and 15, with sulfur centers placed in the a-position to the 1,3-butadiyne moieties were synthesized either by a Glaser coupling of the corresponding open-chain dithi-a,co-diynes or by a four-component cyclization from reacting a,oo-dithiocyanatoalkanes with dilithium-l,3-butadiynide . The 4,7,10-trithiatrideca-2,ll-diyne reacted smoothly at 25 °C with [Ru(CO)2(PPh3)3] to form {Ru(CO)(PPh3)[r)4-S(C2H4SC=CMe)2CO-K5']}, a cyclopentadienone complex, in which the unique sulfur atom is also coordinated to the metal center but may be displaced by dppe to provide {Ru(CO)(dppe)[774-S(C2H4SC=CMe)2CO]}; the 2,8-decadiyne failed to cyclized even at elevated temperatures .

8.5

CARBON-SELENIUM RINGS

The four-component cyclization, see above, from reacting a,oo-diselenocyanatoalkanes with dilithio-l,3-butadiynide afforded either the cyclic dimer 16 or trimer 17 . 8.6

CARBON-OXYGEN/CARBON-NITROGEN

The initial supramolecular complexation of the fc-naphthyl crown 18 with pyrometallitic diimide was shown by the presence of a visual highly colored charge transfer system, which was subsequently treated with a second-generation Grubbs' catalyst to form a catenane 19 . A one-step, self-assembly of [3]catenanes 20, which utilized l,2-6w(4,4'bipyridinium)ethane-24-crown-8 motif possessing a terphenyl spacer in the presence of dibenzo24-crown ether has been reported; interestingly, a host-guest adduct with a third sandwiched crown ether was observed.

424 8.7

G.R. Newkome CARBON-NITROGEN-OXYGEN RINGS

A general procedure for the synthesis of cryptands from the corresponding diazacoronand by means of a high-pressure double amidation using diverse dicarboxylic acids has appeared and should prove to be quite useful . The attachment of functionality onto a macrocyclic

Reproduced with permission From the Royal Society of Chemistry's Chemical Communications, 2004,138-139.

system is most easily accomplished by the use of an incorporated iV-substituted aza-component, e.g., mono-A'-substitution: phenyl , 2,2-diphenyl-2//benzo[/]chromenyl , 1-pyrene , or simple removable protecting group ; di-A^-substituted crowns: -benzyl , -pyrenylacetamide


425

, -methylcarbonylethoxide , linear amine terminated PEGs , -4-pyridinyl , -(5-tert-butyl-2-hydroxybenzyl) ; the attachment azacrown ethers to calixarene , biphenyl , cyclen , bridging calixarenes O4T5041; 03TAL709>, acridone , glucose or mannose , c«-l,3,5,7-tetraoxadecalin , diphenylglycolurilbased receptors , or l,l'-binaphthocrowns . An unusual reaction course occurred when l,10-diaza[18]crown ether was treated with di(2-iodoethyl)ether under highpressure (10 kfiar) to afford a to-quaternary spiro salt 21, as the major product; whereas, the use of l,8-diiodo-3,6-dioxaoctane leads to the anticipated [2.2.2]cryptand . A novel ring-transformation of benzocrown ethers, as a synthon, to generate functionalized azacrown ethers has appeared . The cyclopolymerization of 1,14- fe(4-isocyanatophenoxy)-3,6,9,12-tetraoxatetradecane was conducted in DMF using MeLi affording a gel-free linear polymer (King's repeating unit 22), and not the Iwakura's repeating moiety 23 .

The nitrogen component is commonly introduced into the crown ether framework in order to create a specific binding site; specific moieties are: piperazine , pyridine O4JIPM97; 04JIPM151; 04TA2803; 04CC152>, phenanthroline O4JIPM81; 04IC1895; 04ACIE2392; 04CC474; 03HCA4195>, bipyridine O4ACIE4482; 04TL4719; 04CC152>, terpyridine , porphyrin , and acridone . The synthesis of core-modified mono-meso-free monooxacorroles has been accomplished in three different [3 + 1] acid-catalyzed condensations and coupling methodologies ; the related oxasmaragdyrin- and oxacorrole-ferrocene conjugates have also been reported . Under Rothmund condensation conditions, phenylpropargylaldehyde with 4,7dihydro-2//-isoindole at low temperatures gave 5,10,15,20-tetrafai(phenylethynyl)porphyrins bearing bicycle[2.2.2]octadiene substituents, which undergoes a retro Diels-Alder reaction to generate the corresponding benzoporphyrin . Numerous aza- and/or oxa-bridged calix[2]arene[2]triazines (e.g., 24), affording access to novel new supramolecular platforms, have been prepared via a high yield, efficient fragmentation coupling procedure utilizing cyanuric chloride with resorcinol, 3-aminophenol, m-phenylenediamine, and N,N'dimethyl-m-phenylenediamine O4JA15412>.

426

G.R. Newkome

Sauvage and his colleagues continue to create novel catenaries 25 and 26, and rotaxanes as they expand the synthetic frontiers in the area of light-driven machine prototypes . A new class of molecular machine 27, based on a light-driven molecular hinge, has been reported; the closed-open mechanism can be driven by alternating irradiation between UV and visible light . Although it is impossible address lactams in this review, Vogtle et al. have created "an unprecedented example of diastereoisomerism" by the reaction of topologically chiral molecular knots (knotanes) bearing hydroxy moieties with centrochiral (15r)-(+)-camphor-10-sulfonyl chloride . They have expanded this series of knotanes into linear and branched tetraknotanes; due in part to their structural relationship to cyclophanes, they proposed the term "knotanophane" for the class of these assemblies .

8.8

CARBON-SULFUR-OXYGEN RINGS

New oligomeric calix[4]arene-thiacrown-4 was prepared via the condensation of 5,11,17,23-tetra-?ert-butyl-25,27-6w(4-aminobenzyloxy)calix[4]arene-thiacrown-4 with adipoy 1 dichloride; the oligomerization process was limited to the inclusion of only five or six calixarene units per chain . A novel series of thia-l,3,4-oxadiazolophanes, possessing the desired internal C,S,O-ring, was synthesized from l,4-6w(5-mercapto-l,3,4-oxadiazol-2yl)butane and various 1 ,o)-dihaloalkanes in the presence of KOH . Bridging ofp?ert-butylthiacalix[4]arene generated l,3-dihydroxythiacalix-[4]arene-monocrown-5, the 1,2alternate thiacalix[4]arene-6wcrown-4 and -5 as well as 1,3-alternate thiacalix[4]arene6wcrown-5 and -6 depending on the metal carbonate and oligo-ethylene glycol ditosylate that


All

were presented . A series of macrocyclic (arylene sulfide)s oligomers was synthesized by treatment of 4,4'-oxyfe-(benzenethiol) with numerous difluoro compounds, e.g. 4,4'-difluorobenzophenone, &u(4-fluorophenyl)sulfone or l,3-6w(4-fluorobenzoyl)benzene, in DMF in the presence of K2CO3 under high dilution conditions . Metallo-receptors 28 were prepared by palladation of the 42- and 54-membered crown ethers 29 possessing two pincer ligands; the macrocycles were constructed in a described step-wise manner . Treatment 2,3,6,7-tetrafe(cyanoethylsulfanyl)tetrathiafulvalene with l,17-diiodo-3,6,9,12,15pentaoxa-heptadecane in the presence of cesium hydroxide afforded (Z,E)-?>,6(l)-bis(2cyanoethy l-sulfanyl)-2,7(6)-(4,7,10,13,16-pentaoxa-1,19-dithianonadecane-1,1 diyl)tetrathiafulvalene via an in situ deprotection followed by macrocyclization .

8.9

CARBON-NITROGEN-SULFUR RINGS

Core-modified 5,20-diphenyl-10,15-ditolyl-thia-/>-benziporphyrin was prepared from the condensation of l,4-6w(a-hydroxybenzyl)benzene with 5,10-ditolyl-16-thia-5,10,15,17tetrahydrotripyrrin with BF3-OEt2 ; the NMR data supported a rapidly rotating phenylene ring. Condensation of l,co-Z>w(4-amino-l,2,4-triazol-3-ylsulfanyl)alkanes with 1,36;5(2-formylphenoxy)-2-propanol gave (40 - 50%) the intermediate imines, which were reduced (65 - 70%) with NaBH4 to yield the corresponding 13-hydroxyazathiacrown ethers 30 . The one-step capping of C3-symmetrical nucleophiles, e.g., homo-rra(pyrazolyl)methane, with l,3,5-/rw(bromomethyl)benzene under high dilution conditions in DMF at 55 °C using K2CO3, as base, gave (28%) the desired macrobicycle 31 . The coordination chemistry of new pyridine-based, N2S2-donating 12-membered macrocycle 2,8dithia-5-aza-2,6-pyridinophane with diverse metal(II) ions was demonstrated in both solution and the solid state . A rapid, one-flask, synthetic route to mono- and trifunctionalized 21-thiaporphyrins using simple precursors, e.g., 2-[a-(aryl)-a-hydroxymethyl]thiophene, with two equivalents of aryl aldehydes and three equivalents of pyrrole has been accomplished . The synthesis and spectroscopic properties of thia-, dithia-, and oxathia-tetrabenzoporphyrins quantitatively prepared by pyrolysis (230 °C, 30 min, in vacuo) of the corresponding macrocycles 32 .

428

G.R. Newkome

Although 3,ll,19-trithia[3.3.3]pyridinophane 33 was previously isolated as a sideproduct in the reaction of 2,6-Z?/.s(bromomethyl)pyridine and thioacetamide; an improved (overall 50%) procedure has appeared, in which 2,6-&/s(thiolmethyl)pyridine was reacted with two equivalents of 2-bromomethyl-6-(hydroxymethyl)pyridine to give a diol, which was treated with SOC12 to afford (90%) the fc-chloromethyl derivative that was then cyclized (70%) with Na2S under high dilution condition. New dehydroannulene-type cyclophanes 34 possessing a conjugated helical framework comprised of thiophene and pyridine subunits have recently appeared . 8.10

CARBON-PHOSPHORUS-SULFUR RINGS

Treatment of PhP(CH2CH2SH)2 with C1CH2CH2C1 in the presence of Cs2CO3 afforded the PhP(CH2CH2SCH2)2 (9PS2), which was difficult to isolate in view of the related macrocycles; once the composition of products was characterized, the desired dimer [PhP(CH2CH2SCH2)2]2 (18P2S4) was isolated in ca. 90% yield by the slow addition of 1,2dichloroethane to above dithiol and Cs2CO3 . 8.11

CARBON-SELENIUM-OXYGEN RINGS

Treatment of C1CH2(CH2OCH2)2CH2C1 with Na2Se in liquid ammonia was less satisfactory than the below tellurium example but, however, did give variable yields of 1,10diselena-4,7,13,16-tetraoxacyclooctadecane, which can be obtained from the same reagents in


429

EtOH under high dilution conditions; the 1 -selena-4,7-dioxacyclononaane was isolated in only trace amounts .

8.12

CARBON-TELLURIUM-OXYGEN RINGS

l,10-Ditellura-4,7,13,16-tetraoxacyclooctadecane has been prepared in good (50 - 55%) yields from Na2Te and ClCFtyCFtOCI^^CFbCl in liquid ammonia; a minor (ca. 4%) isolated by-product was l-tellura-4,7-dioxacyclononaane . 8.13

CARBON-TELLURIUM-NITROGEN RINGS

The metal-free condensation of 6w(2-formylphenyl)telluride with a series of diamines afforded the macrocyclic tellurium Schiff base macrocycles; attempted complexation with Pt(II) and Hg(II) afforded transmetalated products . Reduction of the Schiff base components of these chalcogenaza macrocycles gave rise to more robust and flexible macrocycles, which form the desired Pd(II) Te,N,N,Te-complex . The related Sederivatives are also therein reported. 5,10-Diphenyl-15,20-di(4-methoxyphenyl)-21-telluraporphyrin was prepared (18%) by the acid-catalyzed condensation of 2,5-Z>w(l-phenyl-lhydroxymethyl)tellurophene, pyrrole, and 4-methoxybenzaldehyde, followed by oxidation with jc-chloranil . 8.14

CARBON-NITROGEN-SULFUR-OXYGEN RINGS

The step-wise construction of the calixarene 35 was accomplished by treatment of 2lithiothiophene with acetone, then the acid-catalyzed reaction with furan to afford 2-(2'- thienyl)2-(2'-furanyl)propane, which was dilithiated then reacted with 2,2-(2'-pyrroyl)-propane to generate (39%) desired octamethylcalixarene . A simple synthesis of related N3S, N2S2, N2O2, N2SO, and N2OS porphyrins from readily available precursors has recently appeared .

8.15

CARBON-PHOSPHORUS-NITROGEN-OXYGEN RINGS

A remarkable high yield [1 + l]-macrocyclization of a 1,3,5-framethylated calix[6]arene with /ra(2-formylphenyl)phosphine gave (91%) a fra-imine intermediate, which was reduced to afford the desired C3V-symmetrical PN3-calix[6]cryptand 36; the ability of the cavity to host ammonium guests was demonstrated by NMR studies . The related non P-

430

G.R. Newkome

centered calix[6]azacryptand has also recently appeared and transformed into a zinc "funnel" complex has been formed . 8.16

CARBON-METAL RINGS

The self-assembly of supramolecular isomers of [cw-(PEt3)2Pt(L)]2, where L = topologically different 6,6'-fe(alkynyl)-l,l'-binaphthalenes afforded the chiral metallocyclo-

37 phane 37, which was shown to be too rigid thus preventing reaction with Ti(O-/-Pr)4 to form the active catalytic site for enantioselective diethyl zinc additions to aryl aldehydes . The simple noncyclic counterpart is, however, an effective ligand for this chiral catalytic transformation. 8.17

CARBON-NITROGEN-METAL RINGS

weso-Pyridine-appended zinc(II) porphyrins and their meso-meso-linked dimers have been spontaneously assembled into tetrameric porphyrin squares and porphyrin boxes, respectively; the boxes were shown to be constructed by a homochiral self-sorting assemble process

. The 6w-ferrocene 38 was prepared by treatment of 4,4'-bipyridine with two equivalents of 1,1 '-di(chloromethyl)ferrocene under high-dilution conditions .


431

A multicomponent reaction involving ethylenediamine-palladium(II), 2-pyrimidinol derivatives, and 4,7-phenthroline (4,7-phen) afforded heterotopic cyclic metallomacrocycles of the type [Y>dn(en)n(\i-N,N'-L)m(\x-N,N' -4,7-phen)n.mf"-m* . Kinetic self-assembly of two different C,N,Pd-rings 39 and 40, by cross-catenation of Pd(II)-linked rings, which are differentiated by alkoxy side chains, and in which homocatenation of one is kinetically unfavorable, has been demonstrated ; these authors have demonstrated molecular self-assembly to obtain a desired product 41 by a "programmed pathway". The first examples of discrete 3D supramolecular cages formed from either l,2-6«(3-pyridinyl)ethyne or its related diyne and organoplatinum reagents have appeared . A series of chiral molecular squares based on [M(dppe)] 2+ metallo-corners [M = Pd or Pt, and dppe = 5w(diphenylphosphino)ethane] and new angular bipyridine bridging ligands, derived from 1,1'binaphthyl, has appeared . 8.18

CARBON-OXYGEN-NITROGEN-METAL RINGS

The synthesis and use of 7,16-(di-4-pyridinyl)-l,4,10,13-tetraoxa-7,16-diazacyclooctadecane, prepared from the commercially available azacrown ether and 4-bromopyridine,

432

G.R. Newkome

with different mono- and di-platinum connectors lead to C,Af,O,/Y-macrocycles . A series of homo-cavitand cages 42 has been instantaneously generated by treatment of tetra£w(4-pyridinyl)cavitand and related extended relatives with Pd(dppp)(OTf)2 (dppp = 1,3di(diphenylphosphino)propane] ; also see for a related example. A [2]catenane containing a zinc(II) porphyrin, a gold(III) porphyrin, and two free phenanthroline binding sites as well as the corresponding copper(I) phenanthroline complex has been constructed and evaluated in photoinduced processes . The self-assembled dimeric macrocycle between 4,4'-Ws(4-pyridinylmethoxy)biphenyl and (en)Pd(NC>3)2 was formed and its interaction with different cyclodextrins resulted in the formation of [2]catenane 43 or [2]pseudorotaxanes 44 depending on cavity size . The reaction of a ligand


433

consisting of two terminal pyridines attached to a central 1,10-phenanthroline (phen) and the complex Ru(phen)2(MeCN)2(PF6)2 has been evaluated .

8.19

CARBON-SULFUR-NITROGEN-METAL RINGS

The self-assembly of ligands based on a pyrrole framework possessing dithiocarbamate end groups when treated with zinc(II), nickel(II) or copper(II) afforded a series of neutral, dinuclear metallomacrocycles or trinuclear metallocryptands 45 . 8.20

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04MM3996 04MM7514 04MRC808 04NJC870 04OBC3051 04OBC3409 04OBC3442 04OL549 04OL671 04OL747 04OL861 04OL1079 04OL1393 04OL2596 04OL3257 04OL3261 04OM81 04OM4513 04PI1845 04PM7389

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438

INDEX Acetogenins, 9 Adenines, 8-arylsulfanyl, 347 (+)-Agelasine D, 346 Agelastatin A, 118 Alboatrin, 146 Alkenyloxazoline-titanium complexes, 253 £-Alkylideneoxindo!es, 123 Z-Alkylideneoxindoles, 123 N-Alkynylpyrrole, 114 Alliacol A, 11 Allosedamine, 284 Altohyrtin A, 19 Aluminacyclopentanes, 88 Ambruticin, 17 1,3-Amino alcohols, from isoxazolines, 243 2-Amino-3-cyanopyrroles, 110 Aminoglycoside, 16 5-Aminopyrazoles, 172 2-Aminopyridine, 90 2-Aminothiophenes, 86, 89 6-Amino-Y-butenolide, 144 Amphidinolide P, 75 Amythiamicin, 197,210 Anahydrochatancin, 22 Angucyclines, 25 Angustilodine, 134 Anhydrocorinone, 25 Anhydrolycorine, 278 Arborescidine B, 134 Artemisinin, 381 Aspicillin, 5 Asteltoxin, 12 Atorvastatin, 111 l-Aza-2-siloxydienes, 291 1-Azaallylic anions, 64 2-Azabicyclo[2.1.1]hexane, 66 3-Azabicyclo[3.3.1]nonane, 157 Aza-diene, 264 Azaenyne allenes, 262 5-Azaindolizines, 305 bis-7-Azaindolylmaleimides, 134 2-Azanorbornane-oxazoline ligands, 250 Azaphilic reactions of tetrazines, 342 Azapolycyclics, 23 Azasugars, 296 Azatantalacyclobutene, 78 Azatitanacyles, 274 Azepanones, 3-amino, synthesis by electrooxidation 390 Azepine, 93 Azepine, from azetidinone, 394 Azepines, 389-390

Azepines, fused, 390-397 Azepines, synthesis by radical cyclisation, 391 Azepino[3,4-6]indole-l,5-dione, 129 Azepinones, by ring-closing metathesis, 389 Azetidin-2-ones, 4-trichloromethyl, 67 Azetidin-2-ones, (ran.?-3-amino-4-alkyl, 67 Azetidine-2,3-diones, 68 Azetidine-2,4-dicarboxylic acid, 65 Azetidine-3-carboxylic acid. 65 (S)-2-Azetidinecarboxylic acid, 65 Azetidines, 2-cyano, 65 Azetidines, 64-72 Azetidines, N-tosyl, 65, 66 3-Azetidinones, 64-72 2-Azetidinones, fused polycyclic, 70-72 2-Azetidinones, monocyclic, 66-70 Azeto[2,l-6]quinazolines, 66 Azimic acid, 289 4//-Azino[l,2-x]pyrimidin-4-ones, 351 Aziridination, 268 Aziridines, 291 Aziridines, methylene, 144 Azirines, 15 Azlactones, 249 Azoniadithia[6]helicenes, 92 Azuliporphyrins, 103, 119 Baconipyrones, 20 Bacterial DD-peptidase, 70 Belactosin A, 75 l,4-Benzazepin-3-ones, 409 Benzazepine, 279 l,4-Benzazepine-2,5-diones, 401 2-Benzazepines from ketyl radicals. 391 3//-3-Benzazepines, 392, 393 1-Benzazepinones, tetrahydro, from aminophenylbutanol, 391 Benzimidazo[l,2-c]quinazolines, 185 Benzimidazoles, 182 Benzo[4,5]imidazo[2,1 -a]phthalazines, 185 5//-Benzo[6,7]cyclohepta[rfjpyriniidine-2-amine, 317 Benzo[ft]l,4-oxathiepin-2-one, /rans-octahydro, 410 Benzo[6]carbazole-6,ll-dione, 131 Benzo[A]furans, 158-163 Benzo[6]furoindoles, 109 Benzo[6]naphtho[2,3-e][l,4]dioxins, 56 Benzo[6]naphtho[rf]furans, 46 Benzo[6]seleno[2,3-6]pyridines, 102 Benzo[A]tellurophene, 84 Benzo[i]thieno[2,3-a]pyrrolo[3,4-e]carbazoles, 101 Benzo[6]thieno[2,3-rf]pyrimidine, 95 Benzo[A]thiophen-2-ones, 86 Benzo[A]thiophene 1,1-dioxide, 94 Benzo[A]thiophene-2-carboxylic acids, 86

Index Benzo[6]thiophene-3-boronic acid, 91 Benzo[A]thiophene-5',S-dioxide, 101 Benzo[6]thioxanthene-6,11-diones, 379 Benzo[c]coumarins, 375 Benzo[c]furans, 163-164 Benzo[c]furyl rhenium carbene complex, 163 Benzo[e]phenanthridone, 278 Benzo[c]pyrylium cation, 372 Benzo[c]B-carboline, 120 Benzo[rf][l,2,3]triazin-4(3//)-ones, 350 2//-Benzo[/]chromenyl, 424 Benzo[/]indolizinium salts, 372 Benzo[g]phthalazine-1,4-dione, 307 Benzo[g]pyridazino[l,2-6]phthalazine-6,13-diones, 307 5//-Benzocyclohepta[ 1,2-]indole, 113 3,4-Dihydroisoquinoline-l(2//)-one, 279

Index 3,6-Dihydropyrans, from buta-l,3-dienes and glyoxylates, 365 1,4-Dihydropyridines, 265 3,4-Dihydropyrrolo[l,2-a]pyrazines, 116 Dihydrotriazines, from dicyandiamide and acetone, 339 3(S),17-Dihydroxytanshinone, 158 3,4-Dinitrothiophene, 93 Dioxanes, 380 2,2'-bi-l,3-Dioxepanyi, 406 Dioxepines, 406-407 Dioxetanes, 72-76 Dioxins, 380 l,3-Dioxolan-2-ones, 4-alkylidene, 230 Dioxolanes, fluorous. 229 1,3-Dioxolanes, 227-230 Dioxolanes, from diazo compounds and aldehydes, 228 Dioxolanes, sulfur-containing, side-chain fluorination, 229 Bis(Dioxolanones), from tartaric acid and aldehydes, 228 Dioxolanones, from epoxides and CO2, 227 1,3-Dioxoles, 227-230 Diphenylimidoylketene, 64 1 //,7//-Dipyrazolo[l ,2-a: \',2'-d][l ,2,4,5]tetrazines, 354 l//,7//-Dipyrazolo[l,2-a:r,2'-rf][l,2,4,5]tetrazines, 354 3,5-Dipyrazolyl-1,2,4,5-tetrazines, 342 Dipyrido[l ,2-a :3',2'-rf]imidazole, 185 Dipyrrolo[ 1,2-a:2', 1 '-c]pyrazines, 326 Discodermolide, 23 1,10-Diselena-4,7,13,16-tetraoxacyclooctadecane, 428 l,3-Diselenole-2-thiones, 231 Dispacamide A, 118 2,4-Distannacyclobutanediide, 78 1,10-Ditellura-4,7,13,16-tetraoxacyclooctadecane, 429 2,8-Dithia-5-aza-2,6-pyridinophane, 428 l,4-Dithian-2-ones, from 2,2-disulfonyloxiranes and 1,2-dithiols, 382 Dithianes, 381-382 1,3,2-Dithiaphosphetanes, 76 Dithieno[2,3-6:2',3'-cf]thiophene, 87 Dithieno[3,2-6:2',3'-d]phospholes, 92 Dithieno[3,2-6:2',3'-rf]thiophene, 98 Dithienosilole, 92 Dithienothiophene, 97 2,2'-bi-l,3-Dithiepany], 406 Dithiepines, 406-407 1,2-Dithiin 1-oxides, dihydro, 381 [l,2]Dithiin, 88 [l,4]Dithiin, 91

441 [l,3]Dithiolane, 85 1,3-Dithiolanes, 230-233 1,2-Dithiolanes, 233 bis(l,2-dithiole-3-thione), 233 1,3-Dithioles, 230-233 1,2-Dithioles, 233 Dithiolethiones, 231 2,2'-Dithiophene, 92 2,5-Dititanabicyclo[2.2.0]hex-l-ene, 78 Dragmacidin F, 117, 134 Duocarmycin SA, 124 Ebelactone A, 75 Eleutherobin, 18 Elocamine, 128 (3-Enaminoketones, 240 (-)-Ephedradine A, 162 Epibatidine, 24 Epilupinine, 3, 4 5-Epitashiromine, 297 Epothilone, 149, 209, 210 (-)-Epoxyquinols A and B, 363 Epoxyquinols, 20 Ergocryptine, 134 Ergot alkaloids, 9 Erinacine C, 27 Erythrina alkaloids, 280 (7,10-Ethano)-l,2,4-triazolo[3,4-a]phthalazines, 355 bis(Ethylenedithio)tetraselenafulvalene, 231 bis(Ethylenedithio)tetrathiafulvalene, 231 1,10-seco-Eudesmanolides, 143 Eunicellins, 21 Ezetimibe, 66 Farnesyltransferase, 163 Fascaplysin, 120 Fastigilin C, 8 Febrifugine, 290 Ferrocene-oligothiophene-fullerene triads, 100 Flavonoids, o-iodoacetoxy, 159 Fluorenopyran-thioxanthenes, 43 5-Fluoropyrazolin-3-ones, 172 Fluorous solid-phase extraction, 243 3-Formylchromone, as synthetic inermediate, 376 (~>Frondosin B, 159, 160 Frontalin, 17 Fuchsiaefoline, 135 [60]Fullerene, 96 Fumagillin, 18 Funebral, 110, 119 Funebrine, 110, 119 (-)-Funebrine, 244 Furan amino acids, 149 bis-Furan, 16 Furan, 2-cyano, 144 Furanomycin, 13

442

Index

Furanones, 2, 9 3-Furanones, 9 Furanophane, 18, 22 2,4-Furanophanes, 150 Furanose, 16 Furans, biologically active, 143 Furans, from 1,2-propadienyl ketones, 151 Furans, from l-alkyne-5-ones, 150 Furans, from 2-(l-alkynyl)-2-alken-l-ones, 153 Furans, from 2,4-disubstituted-2,3-butadienoic acids, 151 Furans, from 2-alkenyl 1,3-diketones, 153 Furans, from aldehydes, DMAD and cyclohexyl isocyanide, 154 Furans, from alkylidenecyclopropane, 154 Furans, from alkylidenecyclopropanyllithium and /V,/V-dimethyl amides Furans, from alkylidenecyclopropyl ketones, 153 Furans, from epoxyalkynyl esters, 153 Furans, from y-aroyloxy butynoates, 153 Furans, naturally occurring, 142-143 Furans, properties, 143-145 Furans, sulfonyl, 152 Furans, synthesis, 149-155 Furazanobenzo-1,2,5-thiadiazoIe, 218 2-Furfuraldehyde, 1 FuroP^-AJindenotS^-Zlnaphtho[l,2-6]pyrans, 55 Furo[2,3-6]naphth-l-ols, 55 Furo[2,3-c]pyridines, 154 Furo[2,3-rf)pyrimidine-l(2//),3(4//)-diones, 311 Furo[2,3-rf]pyrimidines, 320 Furo[2,3-A]benzopyrans, 49 Furo[2,3-;]naphtho[ 1,2-6]pyran, 55 Furo[3,2-/]naphtho[2,l-6]pyrans, 52 Furo[3,2-y]naphtho[l,2-6]pyrans, 55 Furo[3,4-/]naphtho[l ,2-6]pyrans, 54 Furocarbazoles, 109 Furoclausine A, 126 Furoclausine A, 162 Furocoumarins, dihydro, 157 Furoflavonoids, 159 Furofuran lignans, 155 Furoisoxazoline, 13 Furoxans, 239 l,l-Bisfuryl-l-[5-(tri-2-furylmethyl)]furylmethane, 151 2-Furylcarbenoids, 154 Furyldifluoromethyl aryl ketones, 150 2-Furylstannane, 152 (—)-Galanthamine, 161 Garner aldehyde, 254 Gilbertine, 135 Glycine anion equivalents, 228 C-Glycosyl nitrile oxides, 239 Gold(III) porphyrin, 432

Goniothalamin, 75, 374 Guanine, 6-O-benzyl, 347 Guanines, 7- and 9-alkylated, 347 Haliclorensin, 296 Hapalindole Q, 131 Herbimycin, 17 Heterohelicenes, 87 HetPHOX, 251 Himbacines, 21 Homoerythrina alkaloids, 280 Homophenylalanines, 5 P-Homoprolines, 246 Homotryptamines, 127 Hydropyrones, 2, 27 Hydroxybutenolide, 7 Hydroxycotinine, 215 (3'./?,5'S>3'-hydroxycotinine, 244 6|3-Hydroxyeuryopsin, 152 4-Hydroxyisochromans, from 5-aryl-l,3-dioxolanes, 372 (3-Hydroxyketones, from isoxazolidines, 242 Hydroxynaphtho[2,l-6]pyrans, 56 (±)-8a-Hydroxystreptazolone, 250 Hyellazole, 135 Hyperalactone C, 10 Imidazo[ 1,2-a]pyrazin-3(7W)-ones, 326 Imidazo[l,2-a]pyridines, 184, 185, 321 Imidazo[l,2-a]pyrimidines, 310, 347 Imidazo[l,2-a]quinoxalines, 355 Imidazo[l,2-6]pyrazol-2-ones, 184, 186 Imidazo[l,2-6]pyridazines, 308 Imidazo[l,2-c]pyrimidine, 320 Imidazo[l,5-a][l,3,5]triazinones, 345 Imidazo[4,5-6]pyridin-5-ones, 347 Imidazo[4,5-A]pyridine-2-ones, 185 Imidazo[4,5-e][l,2,5]triazepines, 356 l//-Imidazo[4,5-g]phthalazine-4,5-diones, 356 Imidazolobenzazepines, 395 Imidozirconocenes, 78 Iminooxathiolium salts, 231 Iminosugar, 293 Iminothiazolidin-4-ones, 202 Indacenes, 120 Indazoles, 174, 176 Indeno- [3,2-a]naphtho[2,3-6]furans, 55 5//-Indeno[l ,2-c]pyridazin-5-ones, 305 l//-Indeno[l,2-rf|pyrimidine-2,5-diones, 314 Indeno-[3,2-a]naphtho[2,3-6]furans, 55 Indole-2-boronic acid, 131 Indole-4,7-quinones, 125 Indolecarboxamides, 132 Indolizidine, 286 Indolizines, 272 Indolo[2,3-a]carbazole, 120, 132

Index Indolo[2,3-a]quinolizin-4-ones, 130 Indolo[2,3-6]quinoline, 134 lndolo[3,2-a]carbazoles, 129 Indolo[3,2-6]carbazoles, 129 Indolocarbazostatins, 134 1:1 -Indolophanes, 421 2:2-Indolophanes, 421 Indomethacin, 120 iso-lngenane, 27 Ingenol, 27 (+)-Inophyllum B, 367 Inositols, 21 1,2-Iodoxetane 1-oxide, 78 Ionic liquids, 87, 110, 114, 119, 128, 188, 199 IPB-BOX, 253 Isatins, 73 Isoavenaciolide, 13 Isobenzofuran, 371 Isochromanoquinolines, 366 Isochromanquinones, 371 Isochromans, 370-372 Isochromenes, 370-372 Isopenicillin /Vsynthase, 70 Isoquinolines, 277 Isothiazoles, 211 Isoxazole[5,4-rf][l,2,3]triazines, 345 Isoxazoles, 238-241 Isoxazoles, 3-acetyl, from nitrile oxide 1,3-DCs, 238 Isoxazoles, 4,5-dihydro-3-acetyl, from nitrile oxide 1,3-DCs, 238 Isoxazoles, from nitrile oxides and terminal alkenes, 238

Isoxazolidines, 4,5-bis(spiro)-cyclopropane, 246 Isoxazolidines, 3,3-dinitro, 246 Isoxazolidines, 243-247 Isoxazolidines, 5-spirocyclopropane, 246, 247 Isoxazolidines, bis-spirocyclopropanated, 69 Isoxazolines, 241-243 Isoxazolines, fluorous-tagged, 243 Isoxazolines, from 1,3-DC, 243. 244 Isoxazolines, from disaccharides, 243 Isoxazolinopyrroles, 241, 242 Isoxazolo[3',4':4,5]thieno[2,3-A]pyridines, 90 Isoxazolo[4,5-c]azepin-4-ones, 394 Isoxazolo[4,5-c/]pyrimidinones, 322 2-Isoxazolyi-1,3,5-triazin-2-ones, 338 Jusbetonin, 134 Kalkitoxin,201,202,210 Kendomycin, 158, 159 Knotanophane, 426 Kopsifolines, 134 Lactacystin p-lactone, 75 p-Lactams, 1-acyl, 67 P-Lactams, 3-alkyl-4-aryl, 68 P-Lactams, 4-unsubstituted, 67

443 P-Lactams, amino acid-derived, 65 P-Lactams, fused polycyclic, 70-72 P-Lactams, fused to a sultam, 71 P-Lactams, monocyclic, 66-70 p-Lactams, spirocyclic, 69 P-Lactams, strained ring-fused, 71 P-Lactams, tetracyclic, 71 p-Lactams, p-branched a-phenyloxazolidinyl, 67 P-Lactones, 72-76 Lamellarins, 109, 117, 118 Lapidilectine B, 135 Lasonolide, 19 Lasubine, 285 Lepadin alkaloids, 294 2-Lithiofuran, 16 2-Lithioindole, 128 Lituarine, 8 Lundurine D, 134 Luotonin A, 275 Lupinine, 297 Lysergic acid, 133, 134 Macrodasine A, 134 Macrosphelides, 5 Manzacidin, 119 Manzamine, 134 Martinelline, 273, 275 (-)-Massoialactone, 374 Massoialactone, 75 6-Mercaptopurines, 347 Mercuracarborands, 418 Meridianins, 134 Merocyanine, 38 Mersicarpine, 134 Metallocryptands, 433 Metallomacrocycles, 431, 433 Methyl palustramate, 292 Methylenecyclobutanes, 246 2-Methylenetetrahydrofurans, 156 3-Methylenetetrahydrofurans, from methylenecyclopropanes and aldehydes, 156 3-Methylenetetrahydrofurans, from propargyl allyl ethers, 157 Montmorillonite clay, 110, 128, 176 Morphinans, 22 Morpholino furan, 25 Munchnones, 111 Murrayafoline A, 126 Murray anine, 126 Mycalazals, 117 (+)-Mycoepoxydiene, 147 Mycophenolic acid, 124 Nagelamides, 117 (-)-Nakadomarin A, 149 2//-Naphtho[l,2-6]pyrans, 35, 39-41, 48, 49, 51-53,

444 55,57,58 Naphtho[2,l-6]coumarins, 375 Naphtho[2,l-6]furans, 52 3//-Napritho[2,l-6]pyrans, 35, 39-42, 44, 46, 50 Naphtho[2,l-6]pyrans, 44, 45, 48-50, 58, 368 Naphtho[2,l-6]thiopyran-l'-ylidene-9//thioxanthenes, 380 4//-Naphtho[2,l-c]pyrans, 56 Naphtho[2,1 -J] [1 ]benzofuro[2,3-/i]naphtho[l ,2A]pyrans, 54 2//-Naphtho[2,3-i]pyrans, 34, 48 Naphtho[2,3-c]thiophene, 90 2//-Naphtho[3,2-6]pyrans, 51 Naphtho[i]cyclopropene, 90 Naphthopyrans with heterocyclic substituents, 41-44 Naphthopyrans, 34, 36-38, 441 Naphthopyrans, hetero-fused, 52-58 Naphthopyran-thioxanthenes, 43 [1,4]-Naphthoquinones, 263 Naphthyridones, 274 Nemorensic acid, 10 Neotanshinlactone, 152 Nicotine, 215, 287 3-Nitrobenzo[6]thiophene, 94 Nitrocoumarin, 109 Nitrogen-stabilized oxyallyl cations, 144 Nitrones, 1,3-dipolar cycloadditions, regioselectivity, 246 Nitrones, catalytic asymmetric 1,3-dipolar cycloadditions, 244 Nitrones, sugar derived, 244 (5/J)-4-Nitrosobenz[c]isoxazoles, 241 Nojirimycin, 13 Norbelladine, 279 Norstatine, 248 Norsuaveoline, 249 Norzoanthamine, 145 Nosiheptide, 120, 121 1,4,7,10,13,16,21,24Octaazabicyclo[8.8.8]hexacosane, 421 Octamethylcalixarene, 429 Octaporphyrin, 422 Oligopyridines, 120 Orthoesters, spiro, 227 7-Oxabenzonorbornadiene, 148 Oxabenzonorbornadienes, 143 7-Oxabicyclo[2.2.1]hept-2-enes, 3, 13, 147 8-Oxabicyclo[3.2.I]oct-6-enes, 147 Oxabicyclo[3.2.1]octane, 13, 18 Oxabicyclo[3.2.1]octene, 3, 15, 27 Oxacorrole-ferrocene conjugates, 425 Oxadiazole, 25 1,3,4-Oxadiazoles, 2-amino, 256 1,2,4-Oxadiazoles, 188 1,3,4-Oxadiazoles, 190

Index Oxadiazoles, 256-257 1,3,4-Oxadiazoles, 257 [l,2,4]Oxadiazoles, 5-isoxazol-4-yl, 239 bis[l,2,4-Oxadiazolo[l,5]benzodiazepine], 405 1,2,4-Oxadithiolanes, spiro, 234 Oxalactimes, 249 Oxaphosphetanes, 77 1,2-Oxaselenolane, spiro, 233 Oxasmaragdyrin-ferrocene conjugates, 425 Oxathianes, 382-383 1,2-Oxathiazoles, 233 l,4-Oxathiin-2-ones, 383 1,3-Oxathiolanes, 233 1,2-Oxathiolanes, 233 1,3-Oxathiolanes, 233 1,3-Oxathioles,233 1,4-Oxazepanes, 408 1,4-Oxazepinones, 407 Oxazino[4,5-rf]pyrimidines, 313, 352 Oxazirconacyclooctene intermediate. 146 5//-Oxazol-4-ones, 249 Oxazoles, 247-250 Oxazoles, 5-methylene-4,5-dihydro, 248 Oxazoles, from 4-bromomethyl-2-chlorooxazole, 249 Oxazoles, from aldehydes or ketones and a-alkyl-aisocyanoacetamides, 248 1,3-Oxazolidine, 112 Oxazolidine-2-thiones, 256 Oxazolidines, 254-256 1,3-Oxazolidines, 2-perfluoroalkyl, 256 2-Oxazolidinones, N-v'my\, 255 bis(Oxazolines), fluorous, 252 bis(Oxazolines), spiro, 252 Oxazolines, 250-254 1,8-bis(Oxazoliny l)anthracene, 252 bis(Oxazolinyl)thiophenes, 96 a-Oxazolinylalkanamides, 253 Oxazolinylcarbene-rhodium complexes, 252 l,3-Oxazolium-5-oxides, 111 Oxazolo[2,3-a]pyrimidines, 318 Oxazolo[3,2-a]pyridin-5-one, 130 Oxazolo[3,4-tf]indoles, 115 1,3-Oxazolo[4,5-rf]pyridazinones, 249 l,3-Oxazolo[4,5-rfJpyridazinones, 307 Oxazolo[5,4-rf]pyrimidines, 320 Oxazoloisoquinolinone, 282 5(4//)-Oxazolones, 249 Oxepines, 397-398 Oxetan-2-ones, from 5,6-dihydropyran-2-ones, 374 Oxetanes, 12,72-76 Oxetanes, from pyran-2-ones, 373 2-Oxetanones, 72-76 Oxetes, 72-76 Oxetin, 72 Oxidopyrylium ions, 26

Index 7-Oxo-1,7,8,8a-tetrahydroimidazo[ 1,2-a]pyrimidines, 186 11-Oxo-lOa-steroids, 22 4-Oxobenzopyran-3-carbaldehyde, as synthetic inermediate, 376 Oxocrinine, 279 Palustrine, 213 Pancratistain, 130 Paroxetine, 288 Pateamine A, 70 Patulin, 9 Peicrinine, 279 Pentacene, 97 Pentaphyrins, 119 Pentaporphyrins, 422 2,6,9,12,16-Pentaza[ 17](2,6)pyridophane, 422 Perophoramidine, 135 Phakellins, 117 Phenanthrene, 282 Phenanthrolin-7-ones, 263 [2,3-*]Phenazine-6,l 1-diones, 356 Phenserine, 134 Phenylmorphan, 163 Phoboxazole, 19 Phomopsolide D, 17 Phorbol, 27 Phospharhodium metalacycle, 77 Phosphine oxazolines, 250 Phosphinite-oxazoline N,P ligands, 250, 251 Phosphino-benzyloxazolines, 251 Phosphorus heterocycles, four-membered, 76-78 Photochromic Properties, 38-39 Pinitol, 21 Pinnaic acid, 284 Pipecolic acid, 288 Piperidine alkaloids, 283 Piperidines, 283 Pityriabins, 134 Plakohypaphorines, 134 Polycyclic ether toxins, 362 Polyspiro-1,3-oxathianes, 383 Porphyrins, 97, 119,418,422,430 Prodigiosin, 118 Prostaglandins, 3 [2]Pseudorotaxanes, 432 Pteridines, 351 6//-Purin-6-ones, 349 l//-Purine-2,6-diones, 349 9//-Purines, 349 (+)-8-e/M-Puupehedione, 368 Pyran-2-ones, as synthetic intermediates, 373 Pyran-2-ones, from cyclobutenones, 373 Pyranigrin D, 117 Pyrano[2,3-a]carbazoles, 49

445 Pyrano[2,3-i]benzopyran, 370 Pyrano[2,3-6]carbazoles, 48 Pyrano[2,3-e]carbazoles, 47 5//-Pyrano[2,3-rf]pyrimidine-2,4(l//,3//)-diones, 313 Pyrano[2,3-oQpyrimidines, 313, 352 8//-Pyrano[2,3-e]indole, 49 6//-Pyrano[2,3-/]benzimidazole-6-ones, 184 2//-Pyrano[2,3-/]isoquinoliness, 52 Pyrano-[2,3-g][l]benzopyrans, 50 7//-Pyrano-[2,3-g]benzothiazoles, 47 7//-Pyrano-[2,3-g]benzoxazoles, 47 Pyrano-[2,3-g]indole, 48 Pyrano[3,2-a]carbazoles, 47 Pyrano[3,2-A]pyrrole, 117 Pyrano[3,2-c]carbazoles, 49 Pyrano[3,2-c]xanthenes, 51 Pyrano[3,2-e]benzo[g]indoles, 55 7//-Pyrano[3,2-e]indoles, 46 Pyrano[3,2-g][l]benzopyrans, 50 Pyrano[3,2-/]naphtho[2,l-6]pyrans, 56 Pyrano[4',3':4,5]thieno[3,2-e]triazolo[3,4A]pyrimidine, 310 Pyranocarbazoles, 47 Pyranols, dihydro, from cis-hex-3-en-2,5-diones and P-nitroalkanols, 365 Pyranonaphtho[l,2-6]pyrans, 56 Pyranones, 373-375 2//-Pyrans, 33 Pyrans, 363-367 Pyrans, diaryl, synthesis, 35-38 4//-Pyrans, from alkylidenecyclopropyl ketones, 363 2//-Pyrans, from a-oxoketenedithioacetals, 363 Pyrazines, 323 Pyrazino[l,2-a]indoles, 130, 327 Pyrazino[l,2-a]pyrazine, 326 l//-Pyrazino[l,2-o]quinoline-4,6-diones, 325 l//-Pyrazino[2,l-A]quinazolin-5-ones, 325, 354 l//-Pyrazino[2,l-A]quinazoline-3,6-diones, 326 Pyrazino[2,3-e][l,2,4]thiadiazines, 323 Pyrazino[2,3-g]quinoxalines, 326 Pyrazino[5",6":4,5;3",2":4',5']dithieno[3,2-rf:3',2'rf]dipyrimidine-4,8(3//,9//)-diones, 325 Pyrazino[5,6-6]indole, 325 Pyrazole-5-carboxamides, 176 Pyrazolo[l,5-]pyridazinium salts, 372 Quinolinones, 274, 276 2//-Quinolizin-2-ones, 316 Quinoxalin-2-ones, 338 Quinoxalines, 352 Quinquethiophene, 99 Rancinamycin, 21 l-P-D-Ribofuranosyl-l,3,5-triazin-2-one. 338 Ring-chain tautomerism, 33 Rocaglaol, 163 Roccellaric acid, 12 Roseophilin, 118

Index [2]Rotaxanes, 420 Rutaecarpine, 135 S transfer reagents, 381 Salicylaldimine Schiff bases, 419 Salinosporamide A, 75 Sarcodonin, 323 Sauveoline, 135 Sceptrin, 118 Sclerophytin A, 13 Scytonemin, 134 Secosyrin, 10 (-)-Secosyrin, 145 Selenacephems, 71 2,1,3-Selenadiazoles, 222 Selenapenams, 71 Selenazadienes, 221 Selenazoles, 221 Selenolo[2,3-6]selenophenes, 102 Selenolo[2,3-A]thiophenes, 102 Selenophene materials, 84 2-Selenoxo-2//-pyridine, 102 Showdowmycin, 7 Siastatin B, 69, 285 (-)-Siccanin, 368 Siculine, 279 4-Sila-3-platinacyclobutenes, 78 Silacyclobutenes, 77 Silicon heterocycles, four-membered, 76-78 bis(Silyloxy) butadienes. 240 Silyloxyfurans, 9 Siphonodicidine, 150 Solvatochromism, 38 Sphydrofuran, 8 Spiro orthoesters, 366 Spiro[chroman-3,3'-(2'//)-benzofurans], 162 Spiro[furo[2,3-rf]pyrimidine]pyrimidines, 317 Spiro[pyrimidine-6,3'-2',3'-tetrahydrobenzofuran]2,4-diones, 162 6,6-Spiroketals, 366 Spirooxindole, 133 Spiropyrans, 16, 19 Spirotryprostatins A and B, 128 Stemoamide, 9 c/j-Stilbenophanes, 420 Strychnine, 134 Subarine, 266 3-Sulfenylindoles, 127 Sulfinylthiophenes, 93 SulfomycinI, 210 Sultams, 212, 214, 215, 216 (3-Sultams, 76 P-Sultones, 76 Swainsonine, 285 Sylvan, 11

447 (-)-Tabtoxinine-(i-lactam, 69 Tautomycin, 7 Taxol, 20 Taxol, 73 21-Telluraporphyrins, 103 Tenuecyclamides, 210, 249 Terpyridines, 120 2,2'-2,3"-Terthiophene, 96 1,3,6,8-Tetraazatricyclo[4.3.1.l]undecane, 353 2-Tetrahydrofuran ethers, 148 Tetrahydrofuran, 2,5-divinyl, 147 Tetrahydrofurans by radical-mediated cyclisation, 155 Tetrahydrofurans, 2-ethynyl, 149 Tetrahydrofurans, from a zirconacyclopentene and an aldehyde, 156 Tetrahydrofurans, from hexa-l,5-dienes, 155 Tetrahydrofurans, from organotellurium compounds, 156 Tetrahydrofurans, properties, 145-149 Tetrahydrofurans, synthesis, 155-158 1,2,3,4-Tetrahydroquinolines, 277, 279 Tetrahydro-B-carbolines, 130 Tetrahydrothiophen-3-ones, 96 Tetranitromethane, 246 2,1 l,20,29-Tetraoxa[3.3.3.3]paracyclophane, 420 1,4,10,13-Tetraoxa-7,16-diazacyclooctadecane, 431 Tetraoxaquaterenes, 151 Tetraselenafulvalenes, 231 Tetrathiafulvalenes, 84,418 Tetrazaphosphorines, 344 1,2,4,5-Tetrazines, 342 Tetrazines, 342-343 Tetrazolopiperazine, 192 Texaphyrin conjugates, 109 Thia-l,3,4-oxadiazolophanes, 426 1,2,3-Thiadiazoles, 216 1,2,4-Thiadiazoles, 218 1,2,5-Thiadiazoles, 218 1,3,4-Thiadiazoles, 219 l,3,4-Thiadiazolo[2,3-6]-6,7,8,9tetrahydrobenzo[6]thieno[3,2-e]pyrimidine-5(4W)ones, 314 l,3,4-Thiadiazolo[2,3-e][l,2,4]triazines, 345 21-Thiaporphyrins, 428 1,4-Thiazepinones, 407 1,2-Thiazine 1-oxides, 399 Thiazoles, 197 Thiazolidine-2-thioneazetines, 66 2-Thiazolin-4-one, 199 Thiazolines, 198 Thiazolium salt, 208 Thiazolo[3,2-a]benzimidazoles, 185, 200 Thiazolo[3,2-a]pyrimidin-7-ones, 316

448 Thiazolo[3,4-a]quinoxalin-4-one, 201 Thiazolo[3',272,3][l,2,4]triazino[5,6-6]indoles, 354 Thiazolo[4,5-c]pyrido[l,2-a]pyrimidines, 312 Thiazolo[5,4-c]pyridine, 199 Thieno[2,3-6]benzothiopyran-4-one, 90 Thieno[2,3-6]carbazole, 101 Thieno[2,3-6]indole, 135 Thieno[2,3-6]pyridines, 90 Thieno[2,3-6]thiophenes, 87 Thieno[2,3-c]pyridines, 90 Thieno[2,3-rf:5,4-

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