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

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.

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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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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 <94PHC36>, Vogel <90BCB395> and Wright <01CI17>. Synthesis and functionalization of furans are not covered but have been extensively reviewed elsewhere <82AHC167; 82AHC237>.

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] <97TA1623; 99TA2237; 01EJO2955; 02H209; 02TL4753; 02CEJ4255; 02JOC2919; 03OBC3592> and [4+3] reactions <98AG(E)1266; 99JOC3394; OOOL883; 00CEJ684>. 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 <03TL7411; 99EJO2655> 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 <98JOC6914> 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 <98JNP673> has used furan 33 as a precursor to a ketoaldehyde, Raczko used it as a diketone synthon in 36 and Miles <03TLl 161> as a ketoacid for Vitamin D analogs 41 (Scheme 4).

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

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 <96TL6I25>, aspicillin 48 <97TL8883> and the macrosphelides 51 <01TL2817; 02TL4381> (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 <04HCA106> 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 <00JOC6153> 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 <03TL4467; 04TL5207> 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 <05OL27> 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 <99JOC5427> 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 <97T5123> 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 <04OL3861> 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 <97JOC6359> 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 <92JA8349> 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 <00JA4295> 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

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

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 <95TL7175> 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 <03BMCL3261> in the search for antagonists of quorum sensing bacteria. Casiraghi has made wide use of this reaction in an approach to acetogenins <00JOC2048> and sugars <99SL1333> such as the condensation of threose derivative 87 with a siloxyfuran to give 88 as a single diastereomer. Martin <01JA5918> 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 <97SL568>. 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 <01JCS(P2)1624> which has been studied in an asymmetric version <03ARK43>. 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 <04JNP1039> 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 <05OL387> 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 <00CC465> 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 <01TL5841> 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 <04OL465> featuring the use of an anisyl group as a carboxylic acid surrogate and an approach to medium ring oxacycles <01OL861>.

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

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 <03JA36; 04JA9106> 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 <04SL306>. 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 <98JA509> 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 <97TL5623> 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 <01OL1315> and other terpenoid skeletons <03OL941>. A well-known furan cycloaddition leading to 2,3dihydrofurans in the Paterno-Buchi reaction which has been recently reviewed <03COC1443>. A classic example of the power of this reaction is found in the Schreiber synthesis of asteltoxin <83JA6723>. 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).

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

13

Vogel and Jager described a novel route to analogs of nojirimycin based on the cycloaddition of a nitroalkane with furan <98CAR25>. 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 <00AG(E)910> 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 <04OL3241> 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 <96TL629> 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 <03TL2729> 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).

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

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 <02AG(E)4560> 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 <05OL131> 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 <95TL4599> 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 <99TL1783; 97TL6929; 02T3801>. 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 <01CC695> 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 <02OL1771> 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 <99T3561>. 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 <03T6819>. Ogasawara <97S509> 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 <03TL8227> 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 <04TL6407> 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 <02T5441> 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 <99JA6563> utilized this sequence en route to eleutherobin while Casiraghi <97TA2975> 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).

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

19

Scheme 24 Hoffmann has disclosed several reports using the meso ketone 191 to prepare key pyran fragments of lasonolide <99EJO2991>, bryostatin <01OL929> and phoboxazole <99TL4527>. Compound 192 was prepared in homochiral form by oxidative cleavage of the olefinic bridge <00EJO2195>. 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 <01OL4275> with styrene and the Grubbs' catalyst to give diene 195. Recently, the homochiral 196, prepared from the condensation product of furan and tetrabromocyclopropene <04JOC6931>, was shown to undergo a highly regioselective opening to produce 197 in good yield. An intramolecular domino process has also been reported by Wright <02AG(E)4560> 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 <00T2313> 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 <02AG(E)3192; 02TL9155> 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 <04TL5007; 03SL735> 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 <01OL107> and taxol <02H479>. 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).

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

21

Wright <05TL2789> utilized the IMDAF reaction of a 2,3-annulated furan 212 in an approach to the eunicellin diterpenes while Takadoi <02BMCL3271> 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 <96TA3535>, rancinamycin III <99TA3431> 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 <03T3643> 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 <99SL87> 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 <01TL7041> 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 <02EJO1051> 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 <99TL2765; 03JOC6847> 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).

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

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 <02OL1515>. Padwa <00OL3233> 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 <04OL2189; 02JOC3412;01JOC3119>. 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 <96TL8957; 01JOC2400> which they have applied to the C1-C6 subunit of discodermolide <01T6751>. 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 <96SL135> 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 <96SL703> 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 <99SL1609; 02T10469> through reaction of a resin-bound furan with maleic anhydride. Lautens has developed an exciting route to polycyclic cage compounds such as 251 <97JOC4418> using a pincer cycloaddition reaction. Extensive dehydration of IMDAF products provides a direct route to aromatic compounds (Scheme 34). Moreno <04SL1259> has reported a one-pot synthesis of phenols such as 253 by cyclocondensation of furan and an

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

25

activated acetylene under a mixture of Lewis acid and microwave catalysis. Padwa <97JOC4088> 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 <02TL943> 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 <95T7347> of the angucyclines. Boger <02JOC7361> 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 <99SL240> 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 <00JOC6307> 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 <02TL1705>. 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 <01JA3243> and colchicines <98JOC2804; 00T10175> with the conversion of 270 to 271 as the key step. Wright used an intermolecular addition to annulated furan 272 <99OL1535> to give 273, an

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

27

intermediate for erinacine C. Annulations on the oxabicyclo[3.2. ljoctene nucleus have also been shown as in Lautens' <95JA1954> conversion of 274 by an anionic addition and by Cha <01JA5590> in their formal total synthesis of phorbol. Harmata has used the intramolecular variation to give model compounds for ingenol <95TL1397> and widdrol <04H583> (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 <04HCA1493> and Lautens' synthesis of callystatin A <02S1993> (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 <97JA7897>. Magnus has also used this approach in a synthesis of the cyathin skeleton <99T3553> (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 <03SCI1613; 04JA14095> (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

REFERENCES

82AHC167 82AHC237 83JA6723 90BCB395 92JA8349 94PHC36 95JA1954 95JCS(P1) 95T7347 95TL1397 95TL4599 95TL7175 96SL135 96SL703 96T629 96TA3535 96TL6125 96TL8957 97JA7897 97JCS(P1) 97JOC4088 97JOC4418 97JOC6359 97SL568 97S509 97T5123 97TA1623 97TA2975 97TL5623 97TL6929 97TL8883 98AG(E)1266 98CAR25 98JA509 98JNP673 98JOC2804 98JOC6914 99FJO2655

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30 99EJO2991 99JA6563

D.L. Wright

H. Beck, H.M.R. Hoffmann, Eur. J. Org. Chem. 1999, 2991. X.T. Chen, S.K. Bhattacharya, B.S. Zhou, C.E. Gutteridge, T.R.R. Pettus, S.J. Danishefsky, J. Am. Chem. Soc. 1999,121, 6563. 99JHC1337 A.D. Mance, B. Borovicka, B. Karaman, K. Jakopcic, J. Heterocycl. Chem. 1999, 36, 1337. 99JOC3394 S.Y. Cho, J.C. Lee, J.K. Cha, /. Org. Chem. 1999, 64, 3394. 99OL1535 D.L. Wright, C.R. Whitehead, E.H. Sessions, I. Ghiviriga, D.A. Frey, Org. Lett. 1999, /, 1535. 99SL87 E. Couche, R. Deschatrettes, K. Poumellec, M. Bortolussi, G. Mandville, R. Bloch, Synlett 1999, 87. 99SL240 C. Descoins, G.V. Thanh, F.D. Boyer, P.H. Ducrot, J.Y. Lallemand, Synlett 1999, 240. 99SL1333 G. Rassu, F. Zanardi, L. Battistini, G. Casiraghi, Synlett 1999, 1333. 99SL1609 K. Paulvannan, T. Chen, J.W. Jacobs, Synlett 1999, 1609. 99T3553 P. Magnus, L. Shen, Tetrahedron 1999, 55, 3553. 99T3561 S.F. Martin, C. Limberakis, L.E. Burgess, M. Hartmann, Tetrahedron 1999, 55, 3561. 99TA2237 O. Arjona, F. Iradier, R. Medel, J. Plumet, Tetrahedron: Asymmetry 1999, 10, 2237. 99TA3431 O. Arjona, F. Iradier, R. Medel, J. Plumet, Tetrahedron: Asymmetry 1999, 10, 3431. 99TL1783 G.V.M. Sharma, V.G. Reddy, P.R. Krishna, Tetrahedron Lett. 1999, 40, 1783. 99TL2765 A. Toro, Y. Wang, P. Deslongchamps, Tetrahedron Lett. 1999, 40, 2765. 99TL2769 A. Toro, Y. Wang, M. Drouin, P. Deslongchamps, Tetrahedron Lett. 1999, 40, 2769. 99TL4527 P. Wolbers, A.M. Misske, H.M.R. Hoffmann, Tetrahedron Lett. 1999, 40, 4527. 00AG(E)910 P.J. Zimmermann, 1. Blanarikova, V. Jager, Angew. Chem. Int. Ed. 2000, 39, 910. 00CC465 T.J. Donohoe, J.B. Guillermin, C. Frampton, D.S. Walter, Chem. Commun. 2000, 465. 00CEJ684 C.B.W. Stark, S. Pierau, R. Wartchow, H.M.R. Hoffmann, Chem. Eur. J. 2000, 6, 684. 00EJO2195 H. Kim, H.M.R. Hoffmann, Eur. J. Org. Chem. 2000, 2195. 00JA4295 P.A. Jacobi, K. Lee, J. Am. Chem. Soc. 2000,122,4295. 00.IOC2048 F. Zanardi, L. Battistini, G. Rassu, L. Auzzas, L. Pinna, L. Marzocchi, D. Acquotti, G. Casiraghi, J. Org. Chem. 2000, 65, 2048. 00JOC6153 K.D. Freeman-Cook, R.L. Halcomb, J. Org. Chem. 2000, 65, 6153. 00JOC6307 G. Rassu, L. Auzzas, L. Pinna, L. Battistini, F. Zanardi, L. Marzocchi, D. Acquotti, G. Casiraghi, J. Org. Chem. 2000,65, 6307. 00OL883 H. Beck, C.B.W. Stark, H.M.R. Hoffmann, Org. Lett. 2000, 2, 883. 00OL3233 A. Padwa, M. Dimitroff, B. Liu, Org. Lett. 2000, 2, 3233. 00OL3683 J.L. Acena, O. Arjona, M.L. Leon, J. Plumet, Org. Lett. 2000, 2, 3683. 00T2313 H.Y. Chen, R. Caughey, R.G. Liu, M. McMills, M. Rupp, W.H. Myers, W.D. Harman, Tetrahedron 2000, 56, 2313. 00T10175 J.C. Lee, J.K. Cha, Tetrahedron 2000, 56, 10175. 01CC695 M. Harding, A. Nelson, Chem. Commun. 2001, 695. 01CI17 D.L. Wright, Chem. Innovation 2001, 31, 17. 01EJO2955 S. Jarosz, M. Mach, K. Szevvczyk, S. Skora, Z. Ciunik, Eur. J. Org. Chem. 2001, 2955. 01JA3243 J.C. Lee, J.K. Cha, J. Am. Chem. Soc. 2001,123, 3243. 01JA5590 K. Lee, J.K. Cha, J. Am. Chem. Soc. 2001, 123, 5590. 01JA5918 S. Liras, C.L. Lynch, A.M. Fryer, B.T. Vu, S.F. Martin, J. Am. Chem. Soc. 2001, 123, 5918. O1JCS(P1)1624 M.A. Brimble, T.J. Brenstrum, J. Chem. Soc, Perkin Trans. 1 2001, 1624. O1JCS(P1)2969 M.J. Alves, N.G. Azoia, J.F. Bickley, A.G. Fortes, T.L. Gilchrist, R. Mendonca, J. Chem. Soc. Perkin Trans. 1 2001, 2969. 01JOC2400 O. Arjona, R. Menchaca, J. Plumet, J. Org. Chem. 2001, 66, 2400. 01JOC3119 A. Padwa, M.A. Brodney, M. Dimitroff, B. Liu, T.H. Wu, J. Org. Chem. 2001, 66, 3119. 01OL107 O. Arjona, R. Menchaca, J. Plumet, Org. Lett. 2001, 3, 107. 01OL861 T.J. Donohoe, A. Raoof, I.A. Linney, M. Helliwell, Org. Lett. 2001, 3, 861. 01OL929 A. Vakalopoulos, T.F.J. Lampe, H.M.R. Hoffmann, Org. Lett. 2001, 3, 929. 01OL1315 C. Bohm, O. Reiser, Org. Lett. 2001, 3, 1315. 01OL4275 D.L. Wright, L.C. Usher, M. Estrella-Jimenez, Org. Lett. 2001, 3,4275. 01T6751 O. Arjona, R. Menchaca, J. Plumet, Tetrahedron 2001, 57, 6751. 01TL2817 Y. Kobayashi, H.P. Acharya, Tetrahedron Lett. 2001, 42, 2817. 01TL3603 A. Yoshida, H. Takayama, Tetrahedron Lett. 2001, 42, 3603. 01TL5841 T.J. Donohoe, J.B. Guillermin, A.A. Calabrese, D.S. Walter, Tetrahedron Lett. 2001, 42, 5841. 01TL7041 O. Arjona, G. Lorenzo, R. Medel, J. Plumet, Tetrahedron Lett. 2001, 42, 7041.

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 <74BSF2117, 75AHC(18)159, 80IZV1011, 83AHC(34)249, 95AHC(62)77, 02JOC2234>. 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 <71MI1, 92MI1, 98MI1, 99MI1, 00CRV1685, 01PAC639, 03ARPC277, O3MI1>, 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 naphtho- pyrans, 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 <66JA5931>, 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 <03H(60)843> 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 <75AHC(18)159, 77HC(31)11, 84CHEC-I(3)757, 96CHEC-II(5)351> 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 <60JCS5148, 64JCS5228, 70JCS(C)1758>.

Similarly, the widely used route <83JCS(P 1)827, 94JCS(P1)1925, 92USP5106998> 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 <78S886, 82AG(E)247>, is not appropriate for the diaryl derivatives because of low yields even when /-butoxide is used as the condensing reagent <54JA1080>.

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 <83S845>. This methodology has been adapted for the synthesis of a 2,2-diaryl-2//-naphtho[l,2-6]pyran (Scheme 2) <97MCLC(297)123>. In a reversal of roles, a metallated heterocycle reacts with 2-hydroxy-l-naphthaldehyde to give naphthopyrans e.g. 7 (Scheme 3) <91CL2159, 92CL2257, 93JA6442, 96BCJ1023>.

36

J.D. Hepworth and B.M. Heron

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) <79JOC803> 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) <97HCA725>.

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 <73HCA2981, 94TL6405, 96JCR(S)338>, derived from the alkylation of a naphthol with a haloalkyne, to substituted naphthopyrans 10 (Scheme 5) reported by Iwai and Ide <62CPB926, 63CPB1062>. Catalysis by Cu(I) or (II) has been noted for the synthesis of aryl dimethylpropargyl ethers <94TL6405> 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

Synthesis and photochromic properties of naphthopyrans

37

In a substantially modified version of this protocol that yields diarylnaphthopyrans in a single step and in good yield <91USP5066818>, readily available 1,1-diarylprop-2-yn-l-ols <66BSF2885, 01DP(49)65>, 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. <00DP(47)73, 00DP(47)219, 03T2567> and has recently been adapted for the solid-state synthesis of naphthopyrans <00OL2133>. 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 <03OL4153>.

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 <01DP(49)65>.

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 <51OR(6)1, 82JCS(P1)16O5> 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 <96USP5514817>.

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J.D. Hepworth and B.M. Heron

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 <01PAC639>. 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 <97TL3075, 99WOP31081, 02PPS803, 03JMAC727>. 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 <99MI1>. 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 <04BCJ1803>. The addition of epoxy compounds during the manufacture of photochromic ophthalmic lenses can have a beneficial effect on the kinetic performance of the photochromes <02WOP44258>. 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) <98JCS(P2)1153, 98JPP(115)123, 02JPP(149)83, 02JPC(106)9236>. 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 <97DP(35)339>. 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 <02PCCP180>. The isomers of the ring-opened 3,3-bis(4fluorophenyl)-3//-naphtho[2,l-6]pyran have been studied by 19F NMR spectroscopy <98JCS(P2)1153> and comprehensive NMR data are available for a range of naphthopyrans <95MRC977, 99MRC159>. 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

Synthesis and photochromic properties of naphthopyrans

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 <00CC1339>.

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* <97HCA1122>. 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)] <98MI1>. 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 <91USP5066818>. The lifetime of the open form increases with increasing size of the ortho substituent <03H(60)843>. 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 <96PAC1395, 97MCLC(297)131>. Dramatic increases in colourability follow the introduction of a 6-MeO <96USP5520853> or, better, a 6-amino function <94WOP22850, 03USP6525194> 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 <98WOP45281>.

40

J.D. Hepworth and B.M. Heron

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 <99MI1, 02DP(54)79>;{ Data recorded for aliphatic acrylic polymer <96PAC1395>

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)] <00MCLC(344)217>. 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) <97MCLC(297)131>.

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 <94MI1> promoted a faster ring closure and represented a significant

Synthesis and photochromic properties of naphthopyrans

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

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

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

Notes: fData recorded for PhMe solutions <04H(63)567>; [ ]' Data recorded for polymethacrylate <98MI1>

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 <04H(63)567>. 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 naphtho- pyrans. 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 <96USP5552091, 01DP(49)65, 03EJO1220>. 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

J.D. Hepworth and B.M. Heron

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) <03EJO2799>.

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 <99MI1> <98HCA1293> <98HCA1293> <98HCA1293> <00JPOC523> <97JP09124645> <97EUP0778276> <97EUP0778276> <97EUP0778276>

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 <99HC123>. 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 <01SM(124)23, 02APL4297>. 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,

Synthesis and photochromic properties of naphthopyrans

43

these compounds have similar photochromic properties to the simple 3,3-diphenyl derivative <00HCA3043>. 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) <02JA1582>. 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) <03PP(78)558>.

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 <02T9505>. 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 <04HCA1400>. 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 <04T2593>.

44

J.D. Hepworth and B.M. Heron

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 <95WOP05382, 96USP5527911>. 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 <95WOP05382, 00DP(47)219>. 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 <03T2567>. 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 <02T1709>.

Synthesis and photochromic properties of naphthopyrans

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 <95WOP05382>. 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 <96CJC1649>. 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 <96JP08295690>. 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 <98JPP(114)185>. 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 <95WOP05382, 03OL4153>.

46

J.D. Hepworth and B.M. Heron

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 <95USP5429774>. The hydroxydibenzofurans and analogous thiophene derivatives are accessible from trihydroxybiphenyls through cyclisation with KOH or P4S10, respectively and the hydroxybenzo[6]naphtho[. .OMe MeO (i), (») VN

/=\

(iii) -OH N

OMe

^max 454, 624 nm (ethyl cellulose resin) Reagents: (i) resorcinol, AcOH, H2SO4, reflux; (ii) MeOH, c. H2SO4; (iii) 4-TsOH, PhMe, RT Scheme 13

A series of azolo-fused benzopyrans has been synthesised through the reaction of Ti phenolates derived from the hydroxybenzazole with 3,3-diphenylpropenal; the propargylation route reportedly failed, although others have synthesised pyrano[3,2-e]indoles by this method <95WOP05382>. The Ti-promoted reaction is regiospecific, with cyclisation occurring to give the angular isomer from the 5- and 6-hydroxy compounds <94JCS(P1)2591>. Ph Ph X = N , CH Y = O, S, NR2, Se 6 examples 28 - 56%

A characteristic feature of all these compounds, which are formally related to 3//-naphtho[2,l-6]pyran, is the presence of two absorption bands in the spectra of the open forms. The effect of the pyrrole ring in 7//-pyrano[3,2-e]indole is a small blue shift of the major absorption band to 428 nm (3,3-diphenyl-3//-naphtho[2,l-6]pyran Xmax = 430 nm), but N-methylation leads to a red shift. The colourability of this band remains similar to that of the naphthopyran but the overall colour is influenced by the weaker band at ca, 520 nm. For example, the angular isomer derived from 5-hydroxyindole and l,l-dianisylprop-2-yn-l-ol

Synthesis and photochromic properties of naphthopyrans

47

exhibits a warm brown colour on irradiation <95WOP05382>. The major effect of the fused pyrrole ring is a dramatic reduction in the rate of bleaching relative to the appropriate angular diphenyl substituted naphthopyran (2 or 3). Introduction of a second heteroatom into this pyrrole ring results not only in small blue shifts but also a considerable loss of colourability that is particularly apparent in the selenazole derivative. The fade rate is also enhanced and so these molecules are weakly coloured and fast fading. Further blue shifts and loss of colourability are noted for the 7//-pyrano-[2,3-g]benzoxazole and benzothiazole with similar fast fade kinetics <98JPP185>. Both linear and angular pyranocarbazoles can be obtained, sometimes as a mixture depending on the location of the hydroxy group, by the electrocyclisation of prop-2-ynyl ethers derived in situ from hydroxycarbazoles <95WOP05382>. Of course, blocking alternative sites for ring closure prevents isomer formation. Again, the Ti-catalysed reaction with a,(3-unsaturated aldehydes yields only the angular isomer <01HCA1163, 96USP5527911>. Further photochromes result from prior N-methylation of the carbazole precursors <99MI2>.

pyrano[3,2-a]carbazole R = H, \max = 443, 590 nm (PhMe) R = Me, Xmax = 456 nm (PhMe)

pyrano[2,3-c]carbazole max = 460, 549 nm (PhMe)

The pyrano[3,2-a]- and -[2,3-c]carbazoles absorb at higher wavelength than the related naphtho[2,l-6]pyran with the [2,3-c] isomer having the highest Xmax 460 nm. The nonmethylated compounds exhibit two absorption bands giving broad coverage of the visible region and appearing rather dull brown in colour. On the other hand, the JV-methylated derivatives have a single band and are yellow-orange in solution. JV-Methylation of the pyrano[3,2-a]carbazoles presumably prevents the open form achieving complete planarity thereby hindering conjugation between the gem phenyl groups and the other aromatic rings. This steric hindrance is apparent in the relative instability of the open forms of these yV-methylated compounds as reflected by their appreciably faster fade <01HCA1163, 01MRC637>. A Cr(CO)3 moiety has been introduced into benzopyrans and their benzofuro and carbazole derivatives. The site of substitution is controlled by the amount of Lewis acid used. Substitution in the gem diphenyl unit can result in appreciable broadening of the absorption range to ca. 650 nm <00AOC686>. Hetero-/-fused derivatives of indeno[/i]benzopyrans result from the chromenylation of fluoreno[3,4-6][l]benzofuranols and related S andNMe analogues. The furo- 25 and thieno26 [2,3-/]benzopyrans show absorption bands between 450 - 530 nm and 550 - 640 nm according to the substituents on the gem diaryl function and generally appear as various shades of brown. The half-lives vary between 1 and 6 minutes, with the thiophene analogues exhibiting faster fade rates than the furan derivatives. The closed form of the sole pyrano-

48

J.D. Hepworth and B.M. Heron

[2,3-g]indole example absorbs in the visible region and is yellow; the open form has Xmax 480, 590 ran and a half-life of 30 minutes <01WOP34609>.

2.3.2.1.2 5-Membered heterocyclic rings fused across the g-face. The linear isomer e.g. 27, derived from the chromenylation of benzofurans (see 2.3.2.1.1) unlike the corresponding naphtho[2,3-6]pyran is photochromic and shows better colourability, though faster fading, than the naphtho[2,l-6]pyran <96CJC1649>. In a similar manner, the TV-methylated pyrano[2,3-6]carbazoles 28 and the [3,2-6] analogues 29 exhibit photochromism at room temperature. The single absorption band shown by the [2,3-6] series is red shifted with respect to naphtho[2,l-6]pyran and the intensity is also greater. The colourability is particularly enhanced by the introduction of a 2thienyl group at the 8-position. Again, faster fading characteristics are observed relative to the parent diphenyl substituted naphthopyrans <01HCAl 163>.

2.3.2.1.3 5-Membered heterocyclic rings fused across the ft-face. Application of the Stobbe condensation - ring closure sequence to thiophene aldehydes produces hydroxybenzothiophenes from which methyl thieno[2,3-/i][l]benzopyran5-carboxylates 30 and their [3,2-/z] isomers 31 were obtained. The 7t-electron rich thiophene brings about a ca. 15 nm red shift of Xmax of the ring opened forms of both isomers relative to the corresponding 2//-naphtho[l,2-5]pyran (X.max 490 nm, i\n = 450 s). As expected, because of their relationship to naphtho[l,2-fr]-pyrans, the /z-fused compounds show a slow thermal fade, although this can be modified by substitution in the 2,2-diaryl rings. However, the rate of fading of the [2,3-h] isomer 30 is two orders of magnitude slower than that of the [3,2-h] analogue 31. The influence of substituents in the geminal diary 1 moiety is as noted for the naphthopyran system <00DP(47)73>. The /z-fused benzothienobenzopyrans also show slow fading. The direction of hetero ring fusion controls Xmax, with the [3,2-/)] isomer 32 absorbing to the red of the [2,3-h] compound 33 and with enhanced colourability. In the fading process,

Synthesis and photochromic properties of naphthopyrans

49

the latter molecule retains some colour for a considerable time <98MI1, 00JP344762, 03T1709>. The furo[2,3-A]benzopyran 34 system is more bathochromic than the more aromatic thieno (30, 31) and benzothieno (32) analogues and is also the fastest fading derivative <00MCLC(344)229>.

In accord with the properties of naphtho[l,2-5]pyrans whose fusion they possess, pyrano[3,2-c] and [2,3-a] carbazoles exhibit two absorption bands, the higher wavelength band significantly red-shifted but of reduced intensity, and are very slow fading. This behaviour is indicative of extensive 7i-electron delocalisation throughout the molecule <01HCA1163>. Relatively slow fading has been noted even when the gem substituents contain amino groups, a feature which dramatically increases the fade rate of benzo- and naphtho-pyrans <00JP229972>. A similar situation obtains for the corresponding naphtho[2,l-6]pyrans <00JP229973>. The one example of an 8//-pyrano[2,3-e]indole 35 exhibits a divergence of the two absorption bands accompanied by an appreciable loss of colourability and very slow fading. Cleavage of the C—O bond occurs on solvation <98JPP185>. 2.3.2.2

6-Membered rings

2.3.2.2.1 6-Membered heterocyclic rings fused across the/-face. Fusion of a pyranone ring across the 5,6-bond of benzopyran has been achieved by reaction of 6- and 7-hydroxycoumarins with l,l-diphenylprop-2-yn-l-ol. In the latter case, fusion across the g-face is the predominant product. The two/-fused benzopyrans show quite different photochromic behaviour. Only one strong absorption band, Xmax491 nm, is shown by the ring opened form of pyrano[3,2-/][l]benzopyran-3-one 36 whereas the [2,3-/][l]benzopyran-2-one 37 shows two weak, broad bands centred at 429 and 562 nm, observations which mirror the spectral characteristics of the [2,1-6] and [1,2-6] naphthopyrans which they resemble. In keeping with their different colourability, the latter exhibits a much faster fading, though the open forms of both compounds are less stable than the naphtho[2,l-6]pyran <02HCA442>. Both red shifts and increases in colourability result from the introduction of an ester function at the 3-position of the hydroxycoumarin precursors <03HCA3244>.

50

J.D. Hepworth and B.M. Heron

Annulation of a chromone moiety is achieved by the reaction of hydroxyxanthones with diphenylpropynol; both 2- and 3-hydroxyxanthones yield only angular pyranoxanthones. Again, the mode of ring fusion has a significant effect on the photochromic properties, with the pyrano[3,2-a]xanthenone having only one absorption band but the [2,3-c] isomer 38 showing two bands which cover much of the visible region. A heteroatom at the 5-position of the benzopyran appears necessary for splitting the absorption into two bands. Both compounds show good colourability with very fast bleaching O1HCA117>. 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 <99DP(40)157>. 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 <96USP5527911, 97HCA725>. Examples containing a 3-naphthyl-3-phenyl unit, prepared by the propargylation route, show similar photochromic behaviour with ti/2 of ca. 45 s <96JP08295690>.

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 <97USP5702645>. 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 <98USP5840926>. The

Synthesis and photochromic properties of naphthopyrans

51

isomeric naphthodipyran 41 derived from 1,5-dihydroxynaphthalene is slower to fade with Xmax 508 nm (ethyl cellulose) <95USP5464567>.

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 <02HCA442>. 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 = CC^Et. The enhanced colourability is particularly interesting in view of the fast fading shown by these compounds <03HCA3244>. 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 <00WOP15631>.

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 <02HCA442>. 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 <01HCA117>. It is noteworthy that 44 could not be

52

J.D. Hepworth and B.M. Heron

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 <97HCA725>.

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 <99WOP24438>.

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, >^ax 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 <95USP5674432>. 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-

Synthesis and photochromic properties of naphthopyrans

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 <98WOP28289>. 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 <97WOP21698>.

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 <98WOP32037>.

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 <01 WOP32661>.

54

J.D. Hepworth and B.M. Heron

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 <98USP5811034>.

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 <00WOP77007>.

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 <01WOP36424>. 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

Synthesis and photochromic properties of naphthopyrans

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 <04USP0215024>. Ar

3 7

Th

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

Ar

Ari

Ar2

>=<

\_o

Ar1 = 4-MeOC6H4

\ _ /

^

Ar2= 4-Me2NC6H4

kmax = 450, 580 nm (CHCI3) 53

Xmax = 480, 578 nm, t1/2 = 43 s (CHCI3) 54

2,3-Dihydrobenzofuran is also the starting point for the synthesis of indeno[3,2-a]naphtho[2,3-Z>]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 <03WOP044022>. 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 <03WOP025638>. 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) <00WOP31080>. 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 <99WOP23071>. Absorption bands are shifted to the red when amino substituents are

56

J.D. Hepworth and B.M. Heron

introduced into the diaryl unit of this and the isomeric/fused indole derivatives, but the halflives are between 2 and 3 minutes <00JP229974, 00JP229975>. OAc

OAc

r

OAc

f ^ Y i (i)'(ii,) ^ i f n (iii) ^NpCO2H ^A^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 <95USP5674432>. 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 <99WOP28323>. 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 <00WOP02884>. OAc

f^Tl

OAc

(i)

^V-CO2H

' ("I ^ ] T i

Af

OAc

(iii)

^AA 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) <03USP0168645>. With appropriate gem diaryl substitution in the pyran ring, these molecules show two absorption peaks between 440 - 610 nm and are fast fading.

Synthesis and photochromic properties of naphthopyrans

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 <00WOP02883> and with benzimidine to give a l,3-oxazin-4one 58 <00USP6153126>. 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 <00WOP02883>. 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

J.D. Hepworth and B.M. Heron

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 <00USP6149841>. 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 <00JP344761, 00JP344762>. 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) <02USP6379591>.

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 <03WOP080595>. Quinolizine fused naphthopyrans 66 absorb between 522 and 588 nm depending upon the aryl substituents and have tm of 2 - 3 minutes <00JP229976>.

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 naphtho- pyrans 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

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Synthesis and photochromic properties of naphthopyrans 00JP229976 00JP344761 00JP344762 00JPOC523 00MCLC(344)217 00MCLC(344)229 00OL2133 00USP6149841 00USP6153126 00WOP02883 00WOP02884 00WOP15631 00WOP31080 00WOP77007 01DP(49)65 01HCAI17 01HCA1163 01MRC637 01PAC639 01SM(124)23 01WOP32661 01WOP34609 01WOP36424 02APL4297 02DP(54)79 02HCA442 02JA1582 02JOC2234 02JPC(106)9236 02JPP(149)83 02OL3143 02PCCP180 02PPS803 02T1709 02T9505 02USP6379591 02WOP44258 03ARPC277 03EJO1220 03EJO2799 03HCA3244 03H(60)843 03JMAC727

61

J. Momota, Y. Omuro, Japanese Patent, JP 229976, 2000. H. Nago, J. Momota, Japanese Patent, JP 344761, 2000. Y. Kawabata, J. Momota, Japanese Patent, JP 344762, 2000. N. Rebiere, C. Moustrou, M. Meyer, A. Samat, R. Guglielmetti, J-C. Micheau, J. Aubard, J. Phys. Org. Chem. 2000, 13, 523. A. Kumar, B. Van Gemert, D.B. Knowles, Mol. Cryst. Liq. Cryst. 2000, 344, 217. CD. Gabbutt, J.D. Hepworth, B.M. Heron, S.M. Partington, Mol. Cryst. Liq. Cryst. 2000, 344, 229. K. Tanaka, H. Aoki, H. Hosomi, S. Ohba, Org. Lett. 2000, 2, 2133. A. Kumar, US Patent, US 6,149,841, 2000. A. Kumar, US Patent, US 6,153,126, 2000. A. Kumar, PCTInt. Appl. WO 02883, 2000. A. Kumar, PCT Int. Appl. WO 02884, 2000. Y-P. Chan, PCT Int. Appl. WO 15631, 2000. O. Breyne, PCT Int. Appl. WO 31080, 2000. O. Breyne, Y-P. Chan, P. Jean, PCT Int. Appl. WO 77007, 2000. CD. Gabbutt, J.D. Hepworth, B.M. Heron, S.M. Partington, D.A. Thomas, Dyes Pigm. 2001,49,65. P.J. Coelho, L.M. Carvalho, J.C. Silva, A.M.F. Oliveira-Campos, A. Samat, R. Guglielmetti, Helv. Chim. Ada 2001, 84, 117. M.M. Oliveira, L.M. Carvalho, C. Moustrou, A. Samat, R. Guglielmetti, A.M.F. Oliveira-Campos, Helv. Chim. Ada 2001, 84, 1163. M.M. Oliveira, L.M. Carvalho, C. Moustrou, A. Samat, R. Guglielmetti, A.M.F. Oliveira-Campos, Magn. Reson. Chem. 2001, 39, 637. H. Bouas-Laurent, H. Diirr, Pure Appl. Chem. 2001, 73, 639. A. Yassar, N. Rebiere-Galy, M. Frigoli, C. Moustrou, A. Samat, R. Guglielmetti, A. Jaafari, Synth. Met. 2001, 124, 23. Y-P. Chan, O. Breyne, P. Jean, PCT Int. Appl. WO 32661, 2001. C. Mann, M. Melzig, U. Weigand, PCT Int. Appl. WO 34609, 2001. Y-P. Chan, O. Breyne, P. Jean, PCT Int. Appl. WO 36424, 2001. A. Yassar, F. Gamier, H. Jaafari, N. Rebiere-Galy, M. Frigoli, C. Moustrou, A. Samat, R. Guglielmetti, Appl. Phys. Lett. 2002, 80, 4297. CD. Gabbutt, T. Gelbrich, J.D. Hepworth, B.M. Heron, M.B. Hursthouse, S.M. Partington, Dyes Pigm. 2002, 54, 79. N.M.F.S.A. Cerqueira, A.M.F. Oliveira-Campos, P.J. Coelho, L.H.M. de Carvalho, A. Samat, R. Guglielmetti, A Helv. Chim. Ada 2002, 55, 442. W. Zhao, E.M. Carreira, J. Am. Chem. Soc. 2002, 124, 1582. M.P.S. Ishar, R. Singh, K. Kumar, G. Singh, D. Velmurugan, A.S. Pandi, S.S.S. Raj, H.K. Fun, J. Org. Chem. 2002, 67, 2234. S. Jockusch, N.J. Turro, F.R. Blackburn, J. Phys. Chem. A 2002, 106, 9236. H. Gorner, A.K. Chibisov, J. Photochem. Photobiol. A 2002,149, 83. S. Delbaere, J-C. Micheau, G. Vermeersch., Org. Lett. 2002, 4, 3143. J. Hobley, V. Malatesta, K. Hatanaka, S. Kajimoto, S.L. Williams, H. Fukumura, Phys. Chem. Chem. Phys. 2002, 4, 180. F. Ortica, A. Romani, F. Blackburn, G. Favaro, Photochem. Photobiol. Sci. 2002, /, 803. M.M. Olivera, C. Moustrou, L.M. Carvalho, J.A.C. Silva, A. Samat, R. Guglielmetti, R. Dubest, J. Aubard, A.M.F. Oliveira-Campos, Tetrahedron 2002, 58, 1709. P.J. Coelho, L.M. Carvalho, S. Abrantes, M.M. Oliveira, A.M.F. Oliveira-Campos, A. Samat, R. Guglielmetti, Tetrahedron 2002, 58, 9505. O. Breyne, US Patent, US 6,379,591, 2002. M.S. Misura, F.P. Mallak, PCT Int. Appl. WO 44258, 2002. S. Kobatake, M. Irie, Ann. Rep. Prog. Chem. Sed. C 2003, 99, 277. CD. Gabbutt, B.M. Heron, A.C. Instone, D.A. Thomas, S.M. Partington, M.B. Hursthouse, T. Gelbrich, Eur. J. Org. Chem. 2003, 1220. M. Frigoli, C. Moustrou, A. Samat, R. Guglielmetti, Eur. J. Org. Chem. 2003, 2799. N.M.F.S.A. Cerqueira, L.M. Rodrigues, A.M.F. Oliveira-Campos, L.H. Melo de Carvalho, P.J. Coelho, R. Dubest, J. Aubard, A. Samat, R. Guglielmetti, Helv. Chim. Ada 2003, 86, 3244. CD. Gabbutt, B.M. Heron, A.C. Instone, Heterocycles 2003, 60, 843. M. Zayat, D. Levy, J. Mat. Chem. 2003, 13, 727.

62 03PP(78)558 03MI1 03OL4153 03T2567 03TL259 03TL1903 03USP0168645 03USP6525194 03WOP025638 03WOP044022 03 WOP080595 04BCJ1803 04HCA1400 04H(63)567 04T2593 04USP0215024

J.D. Hepworth and B.M. Heron F. Ortica, C. Moustrou, J. Berthet, G. Favaro, A. Samat, R. Guglielmetti, G. Vermeersch, U. Mazzucato, Photochem. Photobiol. 2003, 78, 558. Photochromism Molecules and Systems, eds. H. Durr, H. Bouas-Laurent, Elsevier (Amsterdam), 2003. W. Zhao, E.M. Carreira, Org. Lett. 2003, 5, 4153. M-J.R.P. Queiroz, P.M.S. Plasencia, R. Dubest, J. Aubard, R. Guglielmetti, Tetrahedron 2003, 59, 2567. S. Delbaere, G. Vermeersch, Tetrahedron Lett. 2003, 44, 259. L.M. Carvalho, A.M.S. Silva, C.I. Martins, P.J. Coelho, A.M.F. Oliveira-Compos, Tetrahedron Lett. 2003, 44, 1903. X. Qin, J.T. Ippoliti, US Patent, US 0168645,2003. J. Momoda, S. Matsuoka, H. Nagou, US Patent, US 6525194, 2003. X. Qin, PCTInt. Appl. WO 025638, 2003. X. Qin, PCT Int. Appl. WO 044022, 2003. C. Mann, M. Melzig, U. Weigand, PCT Int. Appl. WO 080595, 2003. K.. Sugita, Y. Goto, M. Ono, K. Yamashita, K. Hayase, T. Takahashi, Y. Ohga, T. Asano, Bull. Chem. Soc. Jpn. 2004, 77, 1803. M.A. Salvador, P.J. Coelho, H.D. Burrows, M.M. Oliveira, L.M. Carvalho, Helv. Chim. Acta2004, 87, 1400. CD. Gabbutt, J.D. Hepworth, B.M. Heron, D.A. Thomas, C. Kilner, S.M. Partington, Heterocycles 2004, 63, 567. P.J. Coelho, M.A. Salvador, M.M. Oliveira, L.M. Carvalho, Tetrahedron 2004, 60, 2593. X. Qin, US Patent, US 0215024, 2004.

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 <04CRV2353>. A report reviewing synthetic methods for azaheterocyclic phosphonates, including the synthesis of azetidines, has appeared <04CRV6177>. 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 <04OBC3518><04JOC1909>. 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 <04TL3355>.

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 <04EJO4471>. 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 <04BMCL5579>. The structures of two natural enantiomeric azetidine-type amino acids, monascumic acids, were established to be 2-isobutyl-4-methylazetidine-2,4dicarboxylic acid <04JNP479>. A practical process for the preparation of azetidine-3carboxylic acid has been published <04SC3347>. The crystal structure determination of (S)JV-nitrosoazetidine-2-carboxylic acid reveals that the azetidine N atom is slightly pyramidalized <04MI181>. The [2+2] photocycloaddition of some difluoro-[(methylaminoK-7V)-alkenonato- K-C]-boron complexes with fraws-stilbene gave azetidines 5 together with cyclobutane derivatives <04HCA292>.

2-Cyanoazetidines prepared from p-amino alcohols, are converted into enantiopure azetidine-containing vicinal diamines 6 using a sequence of nucleophilic addition and reduction <04EJO3893>. 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 <04TL2193>. 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 <04JMC2453>. 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 <04TL3607>. 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 <04BMCL2253>.

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 <04SL2751>. A synthesis of stereodefmed enantiomerically pure 2-alkenyl azetidines 9 has been described using Wittig olefination as the key step <04TL7525>. 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 <04JOC2703>. 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 <04OL1669>. 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 <04H217>. 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 <04TA489>. 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 <04EJO2636>.

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 <04OL4829>.

4.3

MONOCYCLIC 2-AZETIDINONES (0-LACTAMS)

A review on the asymmetric synthesis of p-lactams through the Staudinger reaction has been published <04MI1837>. A review on the catalytic asymmetric synthesis of |3lactams has appeared <04ACR592>. The preparation of P-lactams using the Kinugasa reaction has been reviewed <04AG(E)2198>. A report reviewing synthetic methods for azaheterocyclic phosphonates including the synthesis of P-lactams has appeared <04CRV6177>. A review on the formation of lactams via rhodium-carbenoids <04EJO3773>, as well as a review on the Pummerer reaction <04CRV2401>, 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 <04MI1813>. The use of P-lactams as intermediates for the synthesis of organic molecules has been reviewed <04MI1889><04MI1921>. A review on penicillin- and cephalosporin-derived P-lactam inhibitors has been published <04MI1951>. A review on p-lactam cholesterol absorption inhibitors has been published <04MI1873>. 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

Four-membered ring systems

67

<04AG(E)4653>. The synthesis and anti-HMCV (human cytomegalovirus) activity of 1-acylP-lactams derived from phenylalanine has been studied <04BMCL2253>.

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 <04OL2749>. N-N Bond cleavage in cycloadducts 18 and 19 afforded free azetidinones in high yields <04CEJ737>. 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 <04OL4443>.

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 <04TL6563>. The preparation of |3-lactams via ring closures of unsaturated carbamoyl radicals derived from 1 -carbamoyl-l-methylcyclohexa-2,5-dienes <04OBC421> or from carbamoyl radicals drived from oxime oxalate amides has been accomplished <04OBC716>. The reactivity of a new class of radicals, the |3-lactamido iV-sulfonyl radicals 21, has been studied <04OL921>. 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 <04JA444>. The preparation of P-lactam 23 bearing an N - 0 bond has been achieved <04OBC1274>. 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 <04EJO1357><04T6895>.

68

B. Alcaide and P. Almendros

Various iV-cinnamyl azetidin-2-ones have been synthesised starting from cinnamyl azide <04SL979>. 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 <04SL2824>. 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 <04JOC3558>. 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 <04SL1637>. 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 <04EJO2205>.

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 <04T2035>. P-Lactam-forming photochemical reactions ofNtrimethylsilylmethyl- and jV-tributylstannylmethyl-substituted (3-ketoamides have been reported <04JOC1215> 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 <04JOC826>. A 3-phenyl 3-hydroxy-Plactam has been prepared by LHMDS-induced cyclization of an aminodioxolanone <04JOC9059>. 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 <04S1471>. It has been reported that application of a new dimeric cyclophane ligand enhances diastereo- and enantioselectivity in the catalytic synthesis of P-lactams <04JOC4531>. The stereoselective synthesis of derivatives of azetidinone 30, a key intermediate to 1-P-methylcarbapenem, has been achieved <04JOC3194><04T867><04TA3841><04OL1653>.

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 <04TL4085>. 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 <04JOC5439>. A new polymer-supported reagent has been used for the preparation of P-

Four-membered ring systems

69

lactams using the Staudinger reaction under sonication <04JOC9316>. 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 <04TL8191>. The synthesis and conformational stability of the cyclic peptidomimetic 32 and analogs containing a (S/J^S^-configured p-lactam moiety have been described <04EJO4379>. 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 <04JCR(S)558>. 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 <04JST181>.

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 <04TL6429>. Preparation of proline-derived spiro p-lactams 34 can be achieved by the [2+2] cycloaddition of unsymmetrical cyclic ketenes with imines <04JOC5766><04JOC7004>. 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 <04EJO4158>. 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 <04OL2507>. The spiro P-lactam framework has been prepared by reaction of imines with ketenes generated from JV-acyl-thiazolidine-2carboxylic acids <04T93>. 2-Azetidinones 36 bearing the indole spiro-p-lactam moiety of the chartellines were synthesized <04CL440><04SL2025>.

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 <04SL2776>, alicyclic P-amino acids <04TA2875>, Ppeptides <04OL4239>, bridged cispentacin <04TA573>, l,4-diazabicyclo[4,4,0]decanes and

70

B. Alcaide and P. Almendros

l,4-diazabicyclo[4,3,0]nonanes <04TL4657>, carbo- and heterocyclic nucleoside analogues <04S543><04S2517>, pateamine A <04JA10582>, y-alkylaminopentenoates <04.TOC5974>, and y-lactams <04JOC993>. The synthesis of a collection of bicyclic fused azepinones 37 via an intramolecular p-lactam ring-opening strategy has been reported <04OL3361>. 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 <04OL1765>. The synthesis of medium ring nitrogen heterocycles can be achieved via a tandem copper-catalyzed C-N bond formation-P-lactam ring expansion process <04JA3529>.

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 <04JOC7965> as well as a study on penicillins as p-lactamase-dependent prodrugs have been described <04CC2332>. The X-ray crystal structure of an acylated p-lactam sensor domain has been reported <04JA13945>. The reaction mechanism of hydrolysis of a common |3-lactam substrate (cefotaxime) by monozinc |3-lactamase has been investigated <04JA12661>. The unusual bifunctional catalysis of epimerisation and desaturation by carbapenem synthase has been analyzed <04JA9932>. The Mossbauer spectra of isopenicillin N synthase has been studied <04JA9494>. The inhibition of a bacterial DD-peptidase by the newly prepared peptidoglycan-mimetic P-lactam 39 has been described <04JA8122>. A sensitive and reagentless biosensor for p-lactam antibiotics such as cefuroxime 40 has been constructed from a modified class A |3-lactamase <04JA4074>. 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 <04CEJ2977>. 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 <04JA7652>. The kinetics and mechanism of hydrolysis of A^-acyloxymethyl derivatives of azetidin-2-one have been studied <04JOC3359>. A kinetic analysis has been reported of the hvdroxvaminolvsis of 6-lactam antibiotics <04OBC651>.

A method has been established to synthesize 6-methylidene penem compounds, which involves an aldol-type condensation on 6-bromopenem with aldehydes <04JOC5850>. SAlkyl dithioformates, generated by a cycloreversion process, react as 1,3-dipolarophiles with

Four-membered ring systems

71

P-lactam-based azomethine ylides to provide, after elimination of MeSH, C2-unsubstituted penems 41 <04OL2781>. It has been reported that selenapenams and selenacephems can be prepared by nucleophilic and radical chemistry involving benzyl selenides <04OBC2612>. The synthesis of bicyclic P-lactam 42 has been accomplished by radical cyclization <04OL4053>. 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 <04CC2114>.

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 <04S237>. 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 <04AG(E)3445>. Via the Ugi 4-centre 3-component reaction, bicyclic cis-2azetidinone derivatives have been synthesized from cyclic p-amino acids <04MI215>, and a synthesis of strained ring-fused p-lactams 45 by Ugi reaction of P-keto acids in aqueous solution has been described <04SL1425>. 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 <04EJO4397>. 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 <04TL3589><04S1696>.

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 <04S2665><04EJO4840>. 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 <04TL7255>.

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

72

B. Alcaide and P. Almendros

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 <04S2965><04SL1249>. 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 <04EJO4177>. 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 <04EJO535>. 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-. Racemic as well as optically pure fused tricyclic |3-lactams have been regio- and stereoselectively prepared via intramolecular nitrile oxide-alkene cycloaddition reactions of 2-azetidinonetethered alkenyl oximes or nitro alkanes. The process is more efficient when the nitrile oxide moiety is separated by a methylenic group, rather than being directly linked to the C-4 position of the four-membered ring <04MI137>.

Key: i) n-Bu3SnH, AIBN. ii) R 2 CH 2 COCI, Et 3 N.

4.5 OXETANES, DIOXETANES, OXETES AND 2-OXETANONES (£LACTONES) A review on the Paterno-Biichi photocycloaddition reaction to give oxetanes has been published <04ACR919>. The chemistry of dioxetanes as highly efficient chemiluminescent substrates has been reviewed, focusing on their molecular design and synthesis <04MI27>. An overview on the total syntheses of natural products containing a-substituted a-amino acid structures, including |3-lactones, using the rearrangement of allylic trichloroacetimidates (Overman rearrangement) on sugar scaffolds followed by further transformations has been reported <04MI693>. A report reviewing halo- and selenolactonization including the synthesis of (3-lactones has appeared <04T5273>. It has been reported that the [2+2+2] cycloaddition reaction between quadricyclane and hexafluoroacetone affords a tricyclic oxetane which is stable to both acids and bases <04JFC1543>. Synthetic, physicochemical and biochemical studies of l',2'-oxetane constrained adenosine and guanosine modified oligonucleotides, and their comparison with those of the corresponding cytidine and thymidine analogues have been carried out <04JA11484>. The coordinate anionic ringopening polymerization of oxetanes promoted by an aluminum benzyl alcoholate has been studied <JPS(A)4570>. 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 <04TA2667>. Pseudoenantiomeric analogues of the

Four-membered ring systems

73

antibiotic oxetin have been prepared from L-rhamnose by efficient SN2 reactions in oxetane rings <04TA2681>. 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 <04TA3263>. 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 <04OL1481>.

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 <04MM5274>. A novel cytotoxic oxetane diterpenoid <04MI581> as well as three new 14-P-benzoyloxy taxoids containing an oxetane ring have been isolated from plants <04JNP905>. A steroidal oxetanyl ester was synthesized in eight steps as a biomimetic model of taxol oxetane <04HCA3613>. It has been reported that the solid-state photocycloaddition reactions of 2-pyrones with benzophenone derivatives afford highly siteand regioselective oxetanes <04H1541>. 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 <04MI383>. 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 <04JA2838>. The Paterno-Buchi reaction between benzoin derivatives and furans has also been examined <04TL3877>. 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 <04OBCl 113>.

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 <04OL4893>. 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 <04EJO1424>. 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

B. Alcaide and P. Almendros

have been developed <04T3599><04T4133>. The 1:1 molecular complex between oxetane and water has been investigated using free-jet milimeter-wave spectroscopy <04CEJ538>. The one-step synthesis of Y-hydroxy-a,a-difluoromethylphosphonates 57 by an oxetane ringopening reaction has been accomplished <04OL3747>. [3-Glycosides result from the reaction of per-O-benzylated glucosyl(galactosyl) iodides with oxetane <04OL973>.

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 <04JOC2332>. A 1,2-dioxetane has been used in a chemiluminescence enzyme immunoassay for determination of human chorionic gonadotropin <04MI71>. 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 <04TL3779>. A theoretical study on oxete formation via ketene-acetylene [2+2] cycloaddition has been published <04OBC195>. The olefmation of ketones via ynolates involves an initial cycloaddition to give p-lactone enolates <04JOC3912>. Hyperconjugative effects have been found to be responsible for the stereoselective ring-opening reactions of oxetenoxides 59 <04OL3945>. 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 <04AG(E)6358>. The catalytic asymmetric acyl halide-aldehyde cyclocondensation reaction of substituted ketenes <04JA14> as well as the enantioselective ketene-aldehyde cycloaddition catalyzed by a cinchona alkaloid-Lewis acid system <04JA5352> 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 <04AG(E)6493>. 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 <04JOC8979>. 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

Four-membered ring systems

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 <04OL373>. The synthesis and ring opening polymerization of the a-methyl-(3pentyl-p-propiolactone (MPP) 64 have been detailed <04T7177>.

Studies directed towards the synthesis of ebelactone A 65 have been carried out <04OBC1051>. Enantioselective total synthesis of belactosin A 66 and its homoanalogue belactosin C have been achieved <04OL2153><04CC510>. The first enantiospecific total synthesis of salinosporamide A 67 has been reported <04JA6230>. A stereocontrolled synthesis of racemic lactacystin P-lactone 68 has been achieved <04AG(E)2293>. The crystal structure of 6a,7P-acetoxyvouacapan-17p-lactone, which is a natural furan diterpene, has been published <04MI1208>.

The P-lactone nucleus has been used as a versatile intermediate in organic synthesis. Knoevenagel reaction products can be obtained from methylene |3-lactones <04T6777>. Dipropionate equivalents have been generated from P-lactones and used for the synthesis of the C1-C27 portion of the aplyronines <04TL4847><04JOC1270>. The catalytic carbonylation of P-lactones to give succinic anhydrides has been accomplished <04JA6842>. Total syntheses of amphidinolide P, goniothalamin 69 and massoialactone 70 have been reported using a p-lactone-ring expansion by a translactonization process <04JA13618><04T1659>.

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 <04ACR297>. The preparation of the tricyclic thietanes 71 through the irradiation of Af-butenyl-5-thioxopyrrolidin-2-(thi)ones has been described <04JOC33>. A facile Rh(II)-catalyzed reaction of thietanes with diethyl diazomalonate leading to highly substituted tetrahydrothiophenes along with allyl thioethers has been described <04TL5759>. 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 <04OL1313>. 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 <04JA3132>.

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 <04OL201>. 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 <04CC956>. 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 <04JOC339>.

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 <04TA2213>. Trapping the transient benzyne complex Cp2Zr(r|2-C6H4) with diacetylenic phosphanes resulted in the formation of fused benzo-zirconacyclohexadiene-phosphacyclobutene rings 79 <04T1317>. 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 <04TL1331>.

Four-membered ring systems

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 <04JA10198>.

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

A bis(thiophosphinoyl)methanediide palladium complex has been fully characterized <04AG(E)6382>. A phosphacyclometallated Pt(ll) compound has been detected <04CC2399>. 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 <04AG(E)4876> <04AG(E)4880>. The reactivity of diradicals 85 has also been reported <04JA1344>. The synthesis and structure of the 1,3-diphosphacyclobutadienediide 86 have been achieved <04AG(E)637>. Four-membred phosphairidium metalacycles have been generated <04CEJ4063>. Oxaphosphetanes have been postulated as intermediates in condensation reactions <04JA4118><04JOC5159>. It has been reported that the thermal decomposition of the fluoroanalogue of Wilkinson's catalyst occurred to produce a phospharhodium metalacycle <04JA3068>. The synthesis and X-ray analysis of the four-membered ring 2,3dihydro-l,3-phosphasiletes 87 have been reported <04AG(E)3474>. The formation of the stable, lattice-framework disilene 88 has been described <04AG(E)4610>. Stable cubic phosphorus-containing radicals have been obtained <04AG(E)502>.

The synthesis of ;?-(l-methylsilacyclobutyl)styrene has been recorded <04T7197>. Single crystals of ferrous siloxanes have been obtained <04AG(E)3832>. A zirconacyclobutene-silacyclobutene has been obtained and reacted with nitriles to give pyrrolo[3,2-c]pyridines <04JA7172>. Some diradicals with four-membered rings, 2,4disilacyclobutane-l,3-diyls, have been designed and shown to have singlet ground states and

78

B. Alcaide and P. Almendros

to be more stable than the a-bonded isomers, 2,4-disilabicyclo[1.1.0]butanes <04JOC4245>. The synthesis of the digermadisilene 89 has been published <04JA4758>. The isolation of a radical anion of a cyclotetrasilane has been achieved <04AG(E)l 124>. The isolation and ring-opening of new l-sila-3-metallacyclobutanes leading to a new class of organometallic polymer have been reported <04JA1326>. 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 <04CEJ416>. 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 <04AG(E)6703>. The synthesis and ring opening reactions of the 2-silabicyclo[2.1.0]pentane 91 have been described <04CC238>. The azatantalacyclobutene complex 92 has been fully characterized <04OL2519>. Carboamination reactions have been catalyzed by cyclic imidozirconocenes <04AG(E)5372>.

The preparation of the cycloaminoboranes 93 has been described <04JA2698>. The synthesis and structural characterization of an azatitanacyclobutene has appeared <04CC704>. The synthesis and characterization of the biradicaloids l,3-diaza-2,4distannacyclobutanediide 94 and l,3-diaza-2,4-digermacyclobutanediide 95 have been reported <04AG(E)4500><04JA6510>. The bicyclic diazetidine 96 has been prepared through the rearrangement of a mesoionic compound <04JA700>.

The synthesis of the tetracoordinate 1,2-iodoxetane 1-oxide 97 and its application as an oxidizing reagent have been achieved <04TL8173>. A four-membered tetranuclear alumoxane and the gallium congener have been prepared and characterized <04AG(E)4940>. The isolation, dynamic NMR study and X-ray characterization of the bis-sulfonium zirconocene-ate dimer 98 has been reported <04CC678>. The formation of the 1titanacyclopent-3-yne and a 2,5-dititanabicyclo[2.2.0]hex-l-ene 99 has been described <04CC2074>. The isolation of the stable 1,2-digermacyclobutadienes 100 has been published <04JA5062>.

Four-membered ring systems 4.8

79

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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

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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 <04BCJ195>, while the synthesis, properties and applications of bis(ethylenethio)tetrathiafulvalenes have been reviewed in detail <04CR5289>. 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 <04CM4748>. An account on the role of single-site catalysts in the hydrodesulfurization of thiophenes has been provided <04JOM(689)4277>. Fused thiophene systems, for example thienopyridazines <04PS321>, and thienopyrimidines <04RCB487> have also been covered. A review concerning the chemistry and properties of benzo[6]tellurophene, dibenzo[6,. Various aspects on the aromaticity of thiophene and its Se and Te analogs have been discussed in an account on the aromaticity of heterocyclic compounds in general <04CR2777>. Finally, an excellent monograph detailing the best synthetic methods in thiophene chemistry has become available . 5.1.2 THIOPHENE RING SYNTHESIS A considerable number of new thiophene syntheses providing new useful derivatives, as well as further extensions of existing methods have been described during the reporting

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

85

period of this chapter. Thionation of the bis(acylsilane) 1 with (TMS)2S gave the unsymmetrically disilylated thiophene 2 with co-formation of the corresponding furan 3 as the minor product <04TL87>. n II

(TMS)2S CoCI2-6H2O

•HPS-J^Y™8

1

n—\

-MS™

li~\

T I P S ^ T M S -TIPS^o^TMS

°

2

3

A facile and efficient synthetic route to densely substituted thiophenes based on base induced cyclization reaction between thioamides derived from morpholine and a-haloketones has been reported. Thus, the thioamides 4 were subjected to treatment with the haloketones 5 (R1 = H, Ar, Me) under basic conditions to provide the tetrasubstituted thiophenes 6. Likewise, the reaction was also demonstrated to give good yields of thiophenes when the haloketones were replaced with 2-bromo-3-oxobutyric acid derivatives or propargyl bromide <04T6085>. Ar

<^O I I

Br

4

K 2 CO 3 , PhMe, A

R 2

\—(

5

6

In a practical and simple synthesis of the valuable 3,4-ethylenedioxythiophene (EDOT) 7, 2,3-dimethoxy-l,3-butadiene 8 underwent transformation to 3,4-dimethoxythiophene 9 upon treatment with sulfur dichloride. Displacement of the methoxy groups with ethylene glycol in the presence of an acid catalyst finally gave the desired compound 7 <04TL6049>. 9Me •^/t^

<W

SCI2, NaOAc hexanes ,

60%

M e

° °M V~^

e

HOCH2CH2OH p-TsOH, PhMe

V

8

65%

>

O O V - /

^S^

9

7

Treatment of diester 10 with diethyl oxalate in the presence of base gave the disodium salt 11, which was thereafter alkylated to afford the tetrasubstituted thiophene 12. This material was subsequently used as a precursor for preparation of 3,4-dimethoxythiophene 9 <04T10671>. In a similar series of reactions involving glyoxal and suitable sulfides, several cyclobutane substituted 2,5-diacylthiophenes were synthesized <04HC26>. (E,OC)2

MeO 2 C^S^CO2Me

Na0Me

NaO

•

ONa

f\

MeO 2 C-^ s - s ^^CO 2 Me 11

MeO OMe

—^

64%

J% MeO 2 C-^^ s '^^CO2Me 12

In an intriguing sequence involving a base-induced ring opening of a [l,3]dithiolane as the key-step, a number of thiophenes 13 were prepared by treatment of the butadiene 14 with amines, followed by ring closure of the intermediates 15 with base in aqueous DMSO <04H(63)1281>.

86

T. Janosik and J. Bergman HNR1R2

V°2 9 S^J^^Kr V-S

*}°2 9 '

EtOH

Cl

NaOH

/S-N^^S^VI

30-90%

1

V-.S

NR R

14

O2N

NR 1 R 2

H 2 O, DMSO

VY

60-90%

S"^g/"-CI

2

15

13

Improved conditions for the synthesis of benzo[6]thiophene-2-carboxylic acids 16 from the readily available (3-aryl-a-mercaptoacrylic acids 17 under microwave irradiation have been described. The products 16 could be further decarboxylated to the corresponding benzo[6]thiophenes under microwave conditions in quinoline <04TL9645>. R

vj\/5^^COOH

W/^ J)

R1

l2, DMEor1,4-dioxane

f T T

MW

SH

R2*~^

f V \ _ rCm O OH H

*- L [I S/

30-83%

o2"^^

17

16

Preparation of a series of substituted benzo[6]thiophen-2-ones 18 (separable mixtures of (E) and (Z) isomers) from the thiocarbamate 19 and aldehydes has been reported. The starting compound 19 was obtained by reaction of 2-methylthiophenol 20 with iV,yV-diethylcarbamoyl chloride <04H(63)1813>. R

a

Me

I.NaH, THF

^-^.Me

1.LDA.THF

2,CICONEt2>

(| ^ T y.

2. RCHO

SH

97%

^ ^ S ^ N E t ; ,

20

87-95%

^^

J \\T\=O

"

W^S

19

18

The trisubstituted thiophenes 21 were accessed by treatment of the intermediates 22 with ethyl 2-diazo-3-trimethylsilyloxy-3-butenoate 23 in the presence of Hg(OAc)2. The products 21 subsequently served as precursors for some thieno[3,2-Z>]pyridine derivatives <03JOC4867>. 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 <04S1633>.

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 <04OL3437>.

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 <04TL3405>. 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) <04TL5873>.

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 <04T7191>.

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 <04OL4179>. 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 <04AG(E)6474>.

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 <04JOM(689)65>.

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 <04EJO74>.

a CO2Me CO2Me

NIS

,

RCO2H(3equiv.)

CHCI3 35-98%

41

\

DBU

_ RO2Cs/3rCO2Me ^ ^ s CO2Me 42

r-y

CHCI3

J ^o 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 <04T1281>. 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 <04CC1772>.

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) <04TL4365>.

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 <04OL1617>.

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 <04SC3801>. The Gewald reaction has also been adapted to a soluble polymer support <04S3055>. Moreover, a solid phase synthesis of 2-substituted benzo[Z>]thiophenes using titanium(IV) benzylidenes (Schrock carbenes) has been reported <04JOC6145>. A series of 2,3-dihydrobenzo[6]thiophenes has been obtained by nickel catalyzed electrochemical cyclization of allyl 2-haloaryl sulfides <04SC3343>. Several thiophene derivatives have also been identified as products originating from cyclization of alkenylthioimidoyl radicals <04JOC2056>, or rhodium catalyzed decomposition of a-diazoketones bearing a cyclic dithioacetal <04JOC2899>. In addition, a new practical 10-step synthesis of (+)-biotin in 34% overall yield from L-cysteine has been developed <04CEJ6102>. 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 <04EJO2589>, 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) <04T275>. Other interesting achievements in this area include routes to the quinolinedione fused thiophene 58 <04JMC849>, and some thieno[2,3-6]benzothiopyran-4-one derivatives <04SC2159>. Naphtho[6]cyclopropene has been shown to participate in a cycloaddition process with trithiocarbonates to afford naphtho[2,3-c]thiophene derivatives <04H(62)773>. Finally, routes to thieno[2,3-c]pyridines <04S1935>, thieno[2,3-6]pyridines <04H(63)2199>, thieno[2,3-, and isoxazolo[3',4':4,5]thieno[2,3-6]pyridines <04CHE377> have been described.

5.1.3 REACTIONS OF THIOPHENES A potentially useful palladium-catalyzed C-H homocoupling of thiophenes in the presence of silver fluoride has been developed, and permits construction of 2,2'-bithiophenes from simple starting materials <04JA5074>. Oxidative homocoupling of A^TV-disubstituted 2aminothiophenes using for example iodine, leading to a series of 5,5'-diamino-2,2'bithiophenes has been reported <04T8213>, whereas oxidative copper mediated crosscoupling of the enol silyl ether 59 with thiophene 60 in wet acetonitrile has been shown to produce the difluoroketone 61 <04OL2733>. An interesting coupling reaction between 3,4ethylenedioxythiophene 7 and 1 -methylpyrrolidin-2-one catalyzed by Zr(OTf)4 under oxygen atmosphere leading predominantly to the 2-thienopyrrole derivative 62 has also been performed <04AG(E)4231>.

Transition metal catalyzed processes are useful tools for the synthesis of functionalized thiophenes. Thus for instance, a phosphine-free, palladium catalyzed coupling protocol for the synthesis of 2-arylbenzo[Z>]thiophenes from various 3-substituted benzo[6]thiophenes and aryl bromides or iodides has been reported <04T3221>. Likewise, 2,2'-bithiophenes have been 5,5'-diarylated directly with aryl bromides in the presence of Pd(OAc)2, bulky phosphine ligands and CS2CO3 <04T6757>. A series of electron-deficient and relatively electron-rich benzo[6]thienyl bromides have been shown to participate in palladium catalyzed amination reactions, as exemplified by the interesting conversion of 63 to the tetracyclic system 64 upon reaction with 2-aminopyridine 65 <04EJO3679>.

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

91

Moreover, Suzuki-Miyaura coupling reactions involving thiophene-2-boronic acid have been used for the preparation of thiophene-containing C3-symmetric polyaromatics <04EJO4003>, whereas benzo[d]thiophene-3-boronic acid has been coupled with a (4bromophenyl)acetylenic dehydroamino acid <04EJO3985>. An interesting application of thiophene-2-boronic acid 66 provided a route to fused benzo[6]thiophenes 67 [X = O, NTs, C(CO2Me)2] upon treatment with yne-propargylic carbonates 68 in the presence of [Pd(PPh3)4] <04CEJ5338>. An iterative strategy for the synthesis of oligothiophene derivatives based on Suzuki or Stille coupling reactions has been described <04HC121>, while Stille reactions have also been used for the preparation of donor-acceptor substituted oligothiophenes <04T4071>, or radial oligothienyl silanes <04TL3109>. Poorly soluble quinque- and sexithiophenes have been prepared by solution-phase microwave assisted chemistry based on Suzuki couplings <04JOC4821>.

A process for palladium-catalyzed cyanation of thiophene halides has been developed. Thus for example, 3,4-dibromothiophene 69 underwent efficient cyanation to the corresponding 3,4-dicyanothiophene 70 (91% conversion) <04S23>.

Metalated thiophene derivatives are extremely useful and versatile reagents for the synthesis of more complex thiophene containing systems. Thus for example, the interesting fused [l,4]dithiin 71 has been prepared by lithiation of 3-bromobenzo[6]thiophene 72 followed by reaction with SCI2 to furnish the sulfide 73, which could finally be converted to the target molecule. Likewise, an isomer differing in the orientation of the benzo[fr]thiophene units was prepared using similar methodology <03TL7943>. A related pentacyclic system, thieno[3,2-/:4,5-/']bis[l]benzothiophene was synthesized starting from 3-bromo-2lithiothiophene <04JOC2197>. In addition, it was established that metalation of 7bromobenzo[6]thiophene is accompanied by migration of Li to C-2, unless that position is blocked by a TIPS group <04SL1351>.

92

T. Janosik and J. Bergman

Metalation of 3,4-ethylenedioxythiophene 7, followed by transmetalation with Mg or Zn, and subsequent Ni- or Pd-catalyzed coupling, respectively, with various 1,4-dihalobenzenes provided a route to the corresponding bisthienyl substituted benzenes <04TL5637>. In an improved synthesis of tetrakis(2-thienyl)methane, treatment of tris(2-thienyl)methane with BuLi, followed by addition of 5-fluorothiophene-2-carbonitrile gave an intermediate which provided the target compound after hydrolysis and decarboxylation <04SC4037>. The interesting dithieno[3,2-6:2',3'-cf]phospholes 74 were obtained by treatment of 3,3'-dibromo2,2'-dithiophene 75 with BuLi, followed by introduction of suitable dichlorophosphines. Both compounds 74 displayed strong blue photoluminescence <04AG(E)6197>. Similar methodology has been employed for the synthesis of, for instance, the dithienosilole 76 <04OM5481>, and related benzo-derivatives <04OM5622>.

An elegant synthetic sequence relying on metalated thiophenes towards the system 77 has been developed. Thus conversion of 2,3-dibromothiophene 78 to the bisthiophene 79, followed by coupling with yet another thiophene unit gave the terthiophene 80, which was finally annulated to 77 <04OL273>. Lithiation strategy has also been employed in a synthesis of several derivatives of cyclopenta[2,\-b:3,4-b ']dithiophen-4-one <04BCJ1487>, and 2tropyliobenzo[£]thiophenes <04OBC 1413>.

Efficient application of various metalation techniques is also displayed in a synthesis of the [5]helicene 81, which was prepared via Negishi coupling of 4-bromo-2-octylthiophene 82 with the thiophene system 83 to provide compound 84, followed by construction of the final thiophene ring from the TMS-protected intermediate 85 <04SL177>. Similar techniques were employed for the asymmetric synthesis of similar extended systems, namely [7]helicenes O4JA15211>. A structurally similar thiophene based [7]helicene has also been prepared in enantiomerically pure form <04CEJ6531>. Moreover, azoniadithia[6]helicenes featuring thiophene units have been synthesized <04JHC443>.

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

93

An interesting, highly regioselective reaction of 2- or 3-sulfinylthiophenes with nucleophilic reagents has been disclosed. Thus for instance, treatment of 86 with the organotin reagent 87 in trifluoroacetic anhydride (TFAA) gave the thiophene 88 in a high yield <04OL3793>.

The reaction of 3,4-dinitrothiophenene 89 with Grignard reagents has been shown to give thienylphenols, as exemplified by the formation of 90. A mechanistic rationale was provided to account for this unusual transformation <04EJO3566>. Synthesis of a number of 2thienylphosphonates has been achieved by treatment of 2-chloro-3-nitrothiophenes with triethyl phosphite via a Michaelis-Arbuzov type reaction <04S668>.

In an intriguing dearomatizing transformation, the thiophenecarboxamide 91 underwent conversion to the fused azepine derivatives 92 upon treatment with LDA, followed by introduction of electrophiles. The mechanistic aspects of this, and some related reactions were also discussed <04CC2430>.

Thiophene, being aromatic, is very reluctant to participate in Diels-Alder reactions, even with rather strong dienophiles. In an intriguing study, it was however demonstrated that thiophene itself 60 does indeed add to maleic anhydride 93 under solvent free conditions at elevated pressure to provide the adduct 94. Similar reactions with maleic anhydrides were

94

T. Janosik and J. Bergman

found to give mixtures of exo and endo adducts in good yields <04AG(E)2015>. Nonconcerted addition reactions of a series of fused 2-vinylthiophenes with dimethyl acetylenedicarboxylate has also been studied and discussed in detail <04TL2189>. Moreover, Diels-Alder reactions of 5-isopropenyl-2,3-dihydrothiophene S^-dioxide leading to spirocyclic benzo[6]thiophene 1,1-dioxide derivatives have been studied <04RJO854>.

In an interesting reaction involving ring expansions of cyclobutenones based on hexatriene electrocyclizations, the lithiated species 95 underwent conversion to the fused thiophene derivative 96 upon treatment with the cyclobutenone 97 <04JA1624>.

A multi-step procedure for ring-expansion of 3-nitrobenzo[6]thiophene involving, among others, lithiation chemistry, to a series of diastereomeric 4-nitrothiochroman 5,5-dioxides has been reported <04T4967>. An unexpected ring-enlargement of a polycyclic thiophene to a macrocyclic anhydride involving several steps has been observed. This series of events include an initial S-oxidation to afford an S.S-dioxide, which then undergoes a ring-expansion via an insertion of oxygen similar to a Baeyer-Villiger reaction to an intermediate cyclic sulfonic ester, which can then in turn undergo further reactions <04T2433>. Thiophene-2,3-dicarboxaldehyde 98 has been converted to the benzo[6]thiophene-5,6dicarboxaldehyde 99, which was in turn treated with 1,4-cyclohexanedione under alkaline conditions to afford a mixture of the heptacyclic systems 100 and 101 <04OL3325>. In addition, similar smaller, angular anthrathiophenedione systems have been synthesized by treatment of (o-chloroaryl)acetylenic precursors withNa2S <04S2131>.

Di-2-thienyl carbonate 102, a new reagent for the esterification of carboxylic acids, has been developed and was prepared by treatment of 5//-thiophen-2-one 103 with triphosgene in the presence of a suitable base <04CL552>.

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

95

Thiophene-3-one 104 has been shown to undergo conversion to the benzo[6]thiophene derivatives 105 upon treatment with the pyran-2-ones 106 <04BMC1543>. A convenient transformation of tetrahydrothiophene-3-one to tetrahydrothiophene-3-one-l,l-dioxide has also been reported <04SC567>.

Since thiophene and some of its derivatives (e.g. dibenzothiophene) are common undesired components in crude oil or diesel causing severe emissions of SO* during combustion, studies on desulfurization of these aromatics are of considerable interest. Thus for example, elimination of sulfur from thiophenes has been achieved using the water soluble cluster [H4Ru4(C6H6)4]Cl2 under biphasic conditions <04CC204>, with NaOH in supercritical water at 400 °C <04CL330>, or using a molybdenum doped mesoporous silica in the presence of H2 <04CM2157>. A process for the removal of thiophene containing systems from fuel by oxidation to the corresponding S-dioxides employing H2O2 in the presence of the recoverable catalyst [(Ci8H37)2N+(CH3)2]3[PWi204o] has also been developed <04CEJ2277>. A hydrogenation catalyst highly resistant to poisoning by sulfur based on polymer incarcerated palladium, which enables conversion of benzo[6]thiophene to the corresponding 2,3-dihydro derivative, has been developed <04JOC2871>. It was demonstrated that dibenzothiophene 5-oxides undergo photolysis to provide, among other products, dibenzothiophene. These transformations were studied and discussed thoroughly <04JOC8177>. In addition, several large bicycloalkanes, namely bicyclo[10.10.10]dotriacontanes, have been prepared by desulfurization of thiophene precursors <04CL1018>. Other miscellaneous aspects of thiophene chemistry include synthesis of various coloured compounds by reactions of thiophene with aromatic 1,2-diketones under acidic conditions <04T9255>, application of iminophosphorane chemistry for the construction of thieno[2,3 or benzo[6]thieno[2,3-, synthesis of an interesting superphane containing a thiophene and one CpCostabilized cyclobutadiene unit <04OM1116>, and preparation of cyclopenta[6]thiophene r|5complexes of Mn, Cr, and Ru <04RJG105>. The thioindigo equivalent 107 was synthesized and underwent a retro-Diels-Alder reaction to provide thioindigo 108 as a single polymorph (P2i/c), differing from commercially available thioindigo samples, which display the space group P2\/n <04TL9083>.

96

T. Janosik and J. Bergman

The interesting biradicals 109 were generated from the thienosultines 110, and underwent addition to [60]fullerene under thermal conditions, with or without microwave irradiation, providing monoadducts along with bisadducts <04T10869>.

Finally, some examples of applications of thiophene-containing compounds in asymmetric synthesis should be mentioned, for instance diastereoselective synthesis of thieno[3',3':4,5]cyclopent[l,2-(/j[l,3]oxazolines as new ligands for copper-catalyzed asymmetric conjugate addition of diethylzinc to enones <04EJO4442>, development of new cyclopenta[6]thiophene-substituted alkyloxazolines as ligands in asymmetric palladiumcatalyzed allylic alkylation <04TA1043>, preparation of bis(oxazolinyl)thiophenes as ligands for Ru-catalyzed asymmetric cyclopropanation <04TL5649>, development of new chiral thiophene- and benzo[&]thiophene containing phosphines for asymmetric Heck reactions <04SL106> and asymmetric allylation of catechol <04SL1113>, and finally stereoselective preparation of 2,2-disubstituted tetrahydrothiophen-3-ones using asymmetric Michael reactions <04OL2421>. 5.1.4 NON-POLYMERIC THIOPHENE ORGANIC MATERIALS Photochromic thienyl- or benzo[6]thienyl containing ethenes continue to attract considerable attention in both synthetic and materials chemistry, and are highly interesting materials for applications in optoelectronic devices, such as memories, switches, and displays. The compounds 111 (R = Me or OMe) containing both thiophene and thiazole moieties were synthesized and subjected to studies regarding their photochromic properties, and underwent reversible transformation leading to the cyclic isomers 112 <04T6155>. Likewise, numerous other systems of this type have been prepared and studied, for example containing units such as chryso[Z>]thiophene <04T9863>, benzo[6]thiophenes substituted with oxycarbonyl related groups on a side chain attached to C-2 <04JOC8403>, 2,3'bi(benzo[/>]thiophene) <04CC1010>, thiophenes connected to phenolic Schiff bases <04JOC5037> or biphenyl-containing moieties <04AG(E)6346>, biphenyl based units providing mesomorphic properties <04JA15382>, and benzo[Z>]thiophenes incorporating complex ether containing substituents O4EJ0636, 04CEJ5243>. Systems based on 2,2'3,3"-terthiophene have been designed and investigated as molecular re-routers <04CC72>. Conformationally locked dithienyl ethylenes incorporating oxazole units have also been synthesized and studied with regard to their photochromic properties <04RJO79>.

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

97

In further applications, dithienylethene compounds have been tethered to (3-cyclodextrin for photocontrolled uptake and release of a porphyrin <04CEJ1114>, whereas a cationic dithienylethene derivative has been subjected to electrochemical reductive cyclization <04AG(E)2812>. A dithienylethene containing a 1,10-phenanthroline unit and a rhenium(I) complex thereof has also been prepared and studied <04JA12734>. Single-crystal organic field effect transistors based on the dithiophene-tetrathiafulvalene 113 have been studied and were shown to display unusually high hole mobility for an organic semiconductor not based on pentacene <04JA984>. The temperature dependence of the electrical properties of single-crystals of 113 has also been studied <04SM(146)265>. The properties of a series of some symmetrical donor-7i-donor (D-rc-D) chromophores <04JA13363>, as well as some donor-7t-acceptor (D-n-A) systems <04EJO3805> based on the dithienothiophene 114 have been investigated in detail. The acceptor-7i-acceptor (A-7t-A) system 115 has been prepared and was shown to exhibit considerable two-photon absorption and high fluorescence quantum yield <04OL2933>. A series of 2,3,4,5-tetrakis(4alkoxyphenylethynyl)thiophenes 116 has been constructed and studied focussing on their structure-mesomorphism relationship <04CM2379>. Thienyl end-capped 2,5(arylethynyl)thiophenes have been included in a study on the fluorescent properties of a group of related structures <04TL7061>. In addition, new fluorescent 2-(2',2'-bithienyl)-l,3benzothiazoles have been synthesized and evaluated <04TL2825>.

115 Ar= 2,4,6-trimethylphenyl

Further advances in the field of thiophene containing compounds for potential use in electronic or optical devices include synthesis of 117 together with a related system and their oriented assembly between two gold electrodes for control of electron transport <04AG(E)4471>, and synthesis and studies of the new chromophore 118, which displayed large molecular hyperpolarizability, useful for photonic switching at frequencies over 100 GHz <04JOC8239>. The donor-acceptor containing macrocycle 119 was prepared and evaluated as a fluorescence sensor for Ag(I) ions <04JOC1813>. In addition, the donoracceptor type diarylthiophene 120 was shown to display remarkably high photoluminescence. The liquid crystalline characteristics of this material, as well as a thiazole analogue thereof was also investigated <04OL2011>.

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5.1.5 THIOPHENE OLIGOMERS AND POLYMERS Both oligothiophenes and polythiophenes are important classes of compounds for construction of various electronic devices. Thus for example, a high-performance semiconductor for organic thin-film transistors, poly(3,3'"-dialkyl-quaterthiophene) 121, was prepared by FeCb induced polymerization of the corresponding quaterthiophene <04JA3378>. Likewise, organic thin field transistors have also been generated from a soluble sexithiophene containing thermally removable solubilizing groups <04JA1596>. Semiconductors with interesting properties have also been obtained from thin films of 122 <04CM4715>, and alternative polymers of thiophene and 4-alkylthiazoles <04CM4616>. It has been established that branched thiophene-based polymers exhibit increased field effect mobility compared to their linear counterparts <04SM(146)225>. Oligomers based on the dithieno[3,2-6:2',3'-cf]thiophene system 114 have been investigated as promising materials for organic field-effect transistor applications <04SM(146)251>. The crystal structures of a number of thiophene/phenylene co-oligomers structurally related to 122 have been determined and discussed <04CM237>. New low-gap thiophene containing regular copolymers, interesting materials for infrared electrochromic displays, have been prepared and studied, for example employing the system 123 as monomer <04CM3667>. Polymers based on some related systems containing one 2,3-disubstituted quinoxaline unit and two thiophene moieties were demonstrated to exhibit anion-specific changes in colour and conductivity <04T11163>. The new structurally interesting polymers 124 and 125 were prepared by Ullmann or Stille coupling methodology, respectively, but the initial studies revealed however only relatively low conductivity values <04OL3381>. Several materials for generation of functionalized molecular wires between nanogap electrodes have been devised, for example based on the complex 126 <04CEJ3331>. A study has also been devoted to the preparation and characterization, including X-ray crystallography and molecular orbital calculations, of 7i-stacking quinodimethane oligothiophenes containing three or four thiophene units <04JA15295>.

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The interesting dimer 127, as well as several related thieno[3,2-6]thiophenes and polymers thereof have been prepared and subjected to studies of their electrochemical properties <04MAC6306>. Linear ladder-type n-conjugated polymers consisting of fused thiophene systems have been prepared and studied in detail, in particular with regard to their electronic properties <04MAC1257>. A number of enantiomerically pure, chiral poly(3,4ethylenedioxythiophenes) of the general structure 128 have been described, along with a method to synthesize the requisite monomers <04CC926>. Optically active polyalkylthiophenes have also been prepared by polymerization of chiral, symmetrically substituted quinquethiophene units <04SM(l45)221>. Moreover, several poly(3,4ethylenedioxythiophene)-based polymers, for instance possessing perfluorohexylated sidechains, have been studied <04JFC(125)1441>, or composed from terthiophene-fullerene dyads <04OL4865>, while poly(3,4-ethylenedioxythiophene) derivatives featuring sulfonated side-chains have been designed as possible radioactive cation exchange materials <04SM(142)251>. Polythiophenes functionalized with side-chains containing Nimidazolinium units were prepared and used for the design of chemo- and biosensors for detection of e.g. oligonucleotides <04T11169>. During redox studies of the sulfur rich polymeric material 129, it was concluded that the l,2-dithiol-3-one ring is readily oxidized to the radical cation, followed by the expected oxidation of the thiophene ring <04CL1482>. Polymers have also been prepared from for instance the thieno[3,4-d]thiophene 130 <04CM5644>, as well as several related monomers featuring thiophene and cyanovinyl units <04JA16440>. In addition, an interesting peptide-oligothiophene conjugate containing a pentapeptide sequence inspired by silk has been described<04OBC3541>.

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A new method for photochemical polymerization of thiophenes in aqueous solution catalyzed by potassium dichromate and initiated by light has been disclosed <04CC2222>, whereas vapour phase polymerization of thiophene has been achieved using iron(III) sulfonates as oxidizing agents <04MAC5930>. Thiophene dendrimers have been constructed by Stille coupling of tetrabrominated 2,2'-bithiophene fragments and were demonstrated to form nanostructures on surfaces <04JA8735>, while dendrimer-encapsulated thiophene oligomers have been synthesized and investigated for conducting properties <04CL1154>. Several rather complex ferrocene-oligothiophene—fullerene triads were studied focussing on their photophysical properties <04JOC7183>. Additional developments in this field include, for instance, design of a,, thiophene oligomers containing a redox active hexaarylethane unit <04OL2523>, thiophene oligomers with azomethine groups displaying self-assembly and charge carrier mobility <04CM4765> and oligothiophene isocyanides for platinum-based molecular electronic applications <04JA11796>. 5.1.6 THIOPHENES IN MEDICINAL CHEMISTRY Numerous reports on biologically active thiophene derivatives have appeared during 2004. In an interesting study, the deaza analogue 131 of thiamin diphosphate possessing a thiophene ring instead of a thiazole was prepared and shown to inhibit thiamin diphosphate dependent enzymes <04OBC1732>. A series of thiophene-2-carboxylic acid derivatives, such as 3-sulfonamides <04BMCL793>, as well as the corresponding tertiary amides <04BMCL797>, have been prepared and studied as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Several structurally relatively simple arylthiophenes related to 4-(4-fluorophenyl)-2-methylthiothiophene-3-carbonitrile were found to display anthelmintic activity <04BMCL4037>, while compound 132 was identified as a potent IKK-2 inhibitor <04BMCL2817>. Some related 3-sulfamoyl thiophene-2carboxamides have been discovered to possess endothelin antagonistic effects <04JMC1969>, whereas a thiophene-2-sulfonamide based structure proved to be an AT2 receptor agonist in vivo <04JMC1536>. The anti-inflammatory activities of some 2-(4morpholino) substituted 3-arylthiophenes have also been investigated <04BMC4667>. A series of 2-amino-3-heteroaroylthiophenes was prepared and evaluated as potential allosteric enhancers at the human Ai receptor <04EJM855>. A new thiophene containing squalene epoxidase inhibitor was prepared and was shown to lower plasma cholesterol and triglyceride

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levels in dogs <04BMCL633>. The thiophene derivative 133, along with some related structures, was included in a study of compounds with dual COX/5-LOX inhibitory effects <04BMCL2559>. Moreover, (5)-4-(3-thienyl)phenyl-a-methylacetic acid has been prepared and subjected to in vivo, in vitro and theoretical docking studies involving COX-1 and COX2 protein structures <04BMCL979>. Various isomerically pure benzo[6]thienyl dehydrophenylalanines have been prepared using Suzuki cross-coupling, and were evaluated for antimicrobial activity .

Some further new developments in the area of biologically active fused thiophenes encompass synthesis and evaluation of the cytotoxic properties of lipophilic sulfonamide derivatives of benzo[6]thiophene-S,S-dioxide <04BMC963>, preparation of benzo[6]thienyloxy phenylpropanamines as dual inhibitors of serotonin and norephedrine uptake <04BMCL5395>, design and preparation of enantiopure imidazole tethered benzo[6]thiophenes as nonsteroidal Cn,20-lyase inhibitors <04BMC2251>, studies of new thieno[2,3-, and evaluation of 4,5,6,7-tetrahydrobenzo[£>]thiophene based compounds as retinoid X receptor a agonists <04JMC2010>. Some benzo[&]thieno[2,3-a]pyrrolo[3,4-c]carbazoles, for example 134, have been demonstrated to display antitumor activity in a prostate carcinoma xenograft tumor model <04JMC1609>. Thieno[2,3-6]carbazole derivatives have also been investigated as endothelin receptor antagonists <04BMCL1129>. The fused thiophene 135 was shown to exhibit promising antitubulin properties <04JMC1448>, whereas a detailed study was devoted to syntheses and structure—activity relationships of a series of thieno[3,2-&]azepine derivatives as arginine vasopressin antagonists <04JMC101>. In addition, a series of thienopyridines, in particular compound 136 was shown to display cytotoxic effects <04BMCL3411>. Finally, the 2,5-bis(thienyl)furan 137 was demonstrated to bind to p-53, and activate p-53 function in tumours, and may thus serve as a new anticancer lead compound <04NAT(M)1321>.

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5.1.7 SELENOPHENES AND TELLUROPHENES A limited number of reports on selenophene or tellurophene derivatives have appeared during the year. A general synthesis of polyhydroxylated thia- and selena heterocycles has been achieved by cyclization of, for example, ct,P-dibromoalditols. Thus, conversion of erythritol 138 to the dibromide 139, followed by annulation with Na2Se formed in situ afforded the tetrahydroselenophene 140 <04T2889>.

A new class of semiconductors for organic field-effect transistors (FET) has been developed and studied. Thus metalation of the 1,4-dibromobenzene derivative 141, followed by introduction of the appropriate chalcogens gave the fused systems 142, which displayed promising FET performances, in particular the selenophene derivative <04JA5084>.

The selenolo[2,3-6]selenophenes 143 were prepared by treatment of the selenophenes 144 with Na2Se and alkyl halides (Z1 and Z2 = electron withdrawing group). Likewise, a series of closely related selenolo[2,3-6]thiophenes could be obtained using a variation of this strategy <04S451>.

Treatment of a series of benzynes 145 with the 2-selenoxo-2//-pyridine derivatives 146 under various conditions has been shown to lead to formation of the benzo[6]seleno[2,36]pyridines 147 in modest yields <04JHC13>.

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The interesting dithione 148 underwent a reduction with sodium mediated by DMF, followed by alkylation with iodomethane to provide the 2,2'-biselenophene derivative 149 <04OL3039>. In addition, new telluranes, such as phosphonium salts containing [C^sTeLt]2ions, have been prepared, from the reactions of 1,1-diiodotetrahydrotellurophene with for example PPh3 <04JOM(689)194>. The deoxygenation and other photochemical processes involving aromatic selenoxides, for instance dibenzoselenophene-&-oxide, have been studied <04JA16058>. The selenophene containing amorphous molecular material 150 has been developed and displayed high hole drift mobility <04CL1266>. Other developments in this area include syntheses and detailed studies of selenium-containing azuliporphyrins <04JOC8851>, and 21-telluraporphyrins <04OM4513>.

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Five-membered ring systems: thiophenes and Se/Te analogues 04OM4513 04OM5481 04OM5622 04PS321 04RCB487 04RJG105 04RJO79 04RJO137 04RJO854 04S23 04S75 04S451 04S668 04S1633 04S1935 04S2131 04S3055 04SC567 04SC2159 04SC3343 04SC3801 04SC4037 04SL106 04SL177 04SL1113 04SL1351 04SM(142)251 04SM(145)221 04SM( 146)225 04SM(146)251 04SM(146)265 04T275 04T1281 04T2433 04T2889 04T3221 04T4071 04T4967 04T6085 04T6155 04T6757 04T7191 04T8213 04T9255 04T9863 04T10671 04T10869 04T11163

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Chapter 5.2 Five-membered ring systems: pyrroles and benzo derivatives Erin T. Pelkey Hobart and William Smith Colleges, Geneva, NY 14456 [email protected]

5.2.1 INTRODUCTION The synthesis and chemistry of pyrroles, indoles, and additional fused pyrrole ring systems reported during the past year (Jan-Dec 2004) are the subjects of this review. Pyrroles and indoles are amongst the most studied and reported heterocyclic ring systems due to their diverse biological activity and materials science applications. Page restrictions limit this review to selected advances. A number of specialized reviews covering aspects of pyrrole and structurally related fused heterocycles have appeared. The synthesis of texaphyrin conjugates <04PAC365>, pyrrole macrocycles <04AG(E)1918>, marine alkaloid natural products (variolins <04M615> and lamellarins <04M615, O4PHC1>), benzo[6]furoindoles <04CHE967>, and furocarbazoles <04H(63)2393> have been published. The synthesis and isolation of indole alkaloid natural products containing a non-rearranged monoterpenoid unit from the 2002 literature has been reviewed <04NPR278>. The preparation of pyrroles utilizing multicomponent coupling reactions has been highlighted <04AG(E)6238>. The synthesis and reactions of pyrrole oximes has been reviewed <04CHEl>. The utility of C-vinylpyrroIes as building blocks has been elaborated <04CR2481>. Part of a review detailed the use of the microwave irradiation in heterocylic synthesis includes pyrrole, indoles, and isatins <04H(63)903>. Finally, the biological activity of side-chain fluorinated indoles has been reviewed <04JFC501>. 5.2.2 SYNTHESIS OF PYRROLES During the past few years, the polyoxygenated 2,3,4-triarylpyrrole natural products known collectively as the lamellarins have been amongst the most thoroughly studied class of natural products. An interesting cyclocondensation reaction between imine 1 and nitroalkene ester 2 led to highly functionalized pyrrole ester 3, an intermediate which was converted to lamellarin L <04AG(E)866>. A similar reaction with a nitrocoumarin Michael acceptor proved to be less effective.

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Pyrrole-based anthranilic acid derivatives have been prepared utilizing a four step sequence starting from arylacetonitriles 4 <04T2267>. Condensation of the latter with ethyl formate followed by treatment with diethylaminomalonate hydrochloride (DEAM-HC1) led to enamine 6. Cyclization and transesterification then gave 3-aminopyrrole-2-carboxylate 7. The acidmediated cyclocondensation of methylaminoacetaldehyde dimethyl acetal with malonitrile provided a novel synthesis of 2-amino-3-cyanopyrroles, useful building blocks for the preparation of pyrrolo[2,3-.

A new method for nitrogen fixation involved the treatment of titanium tetraisopropoxide with lithium metal and trimethylsilyl chloride in the presence of a nitrogen atmosphere to give either a titanium-nitrogen complex and/or N(TMS)3 9 (proposed structures) <04BCJ1655>. This reagent was utilized to prepare pyrrole, indoles, and other nitrogen heterocycles. For example, treatment of preformed 9 with enol triflate 8 led to fused pyrrole 10.

Since discovery of the Paal-Knorr pyrrole synthesis in 1885, the cyclocondensation of primary amines and 1,4-diketones, it continues to be one of the most utilized methods for the preparation of pyrroles. A Paal-Knorr synthesis mediated by titanium tetraethoxide was utilized in a late step for the total syntheses of the pyrrole alkaloids funebrine 11 and funebral <04JOC1475>. Novel catalysts, additives, solvents have been investigated in association with the Paal-Knorr synthesis including imidazolium ionic liquids <04TL3417>, recyclizable bismuth triflate in an imidazolium ionic liquid <04TL5873>, iodine <04JOC213>, sulfated zirconium <04H(63)367>, and KSF and monmorollonite clay <04JOC213>. Metal-mediated reductive amination reactions of 1,4-dienones and the structurally related enals gave 2,5-diarylpyrroles <04T1625> and 2monosubstituted pyrroles <04SL137>, respectively.

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1,4-Diketones were prepared by a two step homologation of |3-ketoesters, and the former were cyclized into pyrroles under microwave irradiation <04OL389>. A solution-phase combinatorial approach to 1,2-disubstituted and 1,2,5-trisubstituted pyrroles was reported <04JCO893>. Treatment of ester 12 with excess vinyl magnesium bromide in the presence of copper cyanide led to the formation of homoallylic ketone 13. Wacker oxidation of the latter gave 1,4-diketone 14 which underwent a Paal-Knorr cyclization to give pyrrole 15. Ozonolysis of 13 and subsequent cylization gave the corresponding 1,2-disubstituted pyrroles.

Multicomponent reactions (MCRs) continue to provide attractive routes to highly functionalized pyrroles. Many MCR sequences involve cycloadditions as a key component. The palladium-catalyzed MCR involving imines 16, acid chlorides 17, and alkynes gave pyrroles 19 via a 1,3-dipolar cycloaddition between alkynes and Munchnones (l,3-oxazolium-5-oxides) <04JA468>. The latter were formed from palladium intermediate 18 by CO insertion, rearrangement, and intramolecular cyclization. The 1,3-cycloaddition of a Miinchnone was also utilized in a synthesis of pyrrole 20, a key intermediate utilized in the the preparation of atorvastatin (Lipitor®) <04BMCL129>. An MCR involving isocyanides, acetylenedicarboxylates, and maleimides led to the formation of 2-imidosubstituted pyrroles <04TL8409>. Finally, a MCR involved the thiazolium-catalyzed sila-Stetter reaction between acyl silane 21 and enone 22 leading to the formation 1,4-diketone intermediate 24 which underwent a Paal-Knorr cyclization to give poly-substituted pyrrole 25 <04OL2465>.

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Treatment of 26 with benzylamine under microwave irradiation led to the formation of 1,3oxazolidine 27 which subsequently rearranged to give the pyrrole 28. The serendipitous discovery of the latter reaction provides a novel domino process for the formation of pyrroles from acyclic enol-protected propargyl alcohols which are also be derived from a domino process, the double condensation of alkynoates with aldehydes <04JA8390>.

A titanium-promoted cyclization of 1,3-diketones with imines or oximes led to highly substituted pyrroles <04SL2239>. A nitroso group served as a novel source of nitrogen in a pyrrole synthesis. Treatment of l,4-bis(bromomagnesium)butadiene derivatives with nitrosobenzene (PhNO) gave N-phenylpyrroles <04CEJ3444>. The electrochemical dimerization of hydrazones derived from phenacyl bromides led to the formation of l-(A'-acylamino)-2,5-diarylpyrroles 29 <04T10787>.

Treatment of enone 30 with aluminum reagent 31 led to the formation of pyrrole 32 via a novel 1,2-rearrangement of a benzyl group followed by an intramolecular condensation <04TL9315>.

A titanium-catalyzed hydroamination of 1,4-diynes and 1,5-diynes produces 1,2,5trisubstituted pyrrroles in one synthetic step <04OL2957>. Treatment of 1,4-diyne 33 with titanium complex 34 led to the formation of pyrrole 35 via a hydroamination to an imino alkyne followed by an intramolecular 5-endo dig cyclization. Another transition metal-mediated pyrrole

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synthesis involved a ruthenium catalyst <04TL9245>. For example, treatment of enyne imine 36 with ruthenium catalyst 37 gave 1,2,3-trisubstituted pyrrole 38 via a metal-mediated 5-exo dig cyclization. A silver-catalyzed hydroamination reaction leading to 1,2,3,5-tetrasubstituted pyrroles from propargyl substituted enamines was reported <04TL6787>. An oxidative silverpromoted cyclization of a homopropargylamine led to the formation of dihydroindolizino|8,7bjindole <04SL1767>. Fused pyrroles have been prepared from 2-(bromoallyl)cyclohexanone by an anionic cyclization of the corresponding enamines intermediates <04TL9627>.

The domino alkynylation and subsequent cyclization of orf/io-bromo anilines derivatives represents an attractive method for appending a pyrrole ring onto an existing heteroaromatic framework. A copper-catalzyed variant of this reaction was utilized to prepare pyrrolo[2,3b]quinoxaline 39 <04SL287>. A related methodology involving a tandem palladium-catalyzed oxidative addition and amido cyclization onto an alkyne gave more complex pyrrolo|2,3fojquinoxalines 40 <04TL2431>. Palladium-catalyzed heteroannulation reactions leading to pyrrolo|2,3-6]pyrazines have also been published <04TL8087, 04TL8631>. With the development of new catalysts, ring closing metathesis (RCM) is becoming increasingly amenable to the preparation of 5-membered ring heterocycles including pyrroles. The aza-Baylis-Hilman reaction provides functional substrates that can be converted into pyrroles utilizing RCM as the key step <04JOC8372>. Allylation of the aza-Baylis-Hilman adduct 41 gave 42 which underwent a RCM reaction mediated by a Grubbs type-II catalyst leading to 3-pyrroline 43. Elimination of the SES (2-trimethyIsilylethylsulfonyl) protecting group gave pyrrole 44. A tandem RCM-dehydrogenation sequence transformed diallylamines into 1-substituted pyrroles <04TL8995>.

A three-step synthesis of cyclobutane-fused pyrrole 48 was accomplished <04EJO4667>. The 1,3-dipolar cycloaddition between aziridine 45 and cyclobutene 46 gave adduct 47. The latter was converted into 48 by saponification followed by an oxidative decarboxylation. Treatment of 48 with electrophiles led to ring opened products (i.e., 49). A palladium-catalyzed ring opening reaction of methyleneaziridines in the presence of acetylpyridines led to the formation of 2-(2pyridinyl)pyrroles <04JA13898>. 2,2'-Bipyrroles have been prepared by a cycloaddition between donor-acceptor cyclopropanes and 2-cyanopyrroles <04OL1057>.

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An interesting pyrrole synthesis involved a retro-Mannich reaction of tropinone derivatives <04EJO1397>. Two condensation approaches were developed for the synthesis of pyrrolo[2,3-i'lpyrroles 50 (pyrrolo-prolines) <04JOC4656>, novel fused proline derivatives <04JA14334>. Finally, a solid-phase approach to isoxazolinopyrroles 51 was reported <04JCO142>. The key step involved a Barton-Zard-type pyrrole synthesis. n

5.2.3 REACTIONS OF PYRROLES As a it-excessive heterocycle, pyrrole readily undergoes reactions with electrophiles. New methods continue to be developed to control the regiochemical outcome of pyrrole substitution reactions (N- vs. 2- vs. 3-substitution). The regioselective JV-alkylation, /V-acylation, and Nsulfonylation of pyrrole in ionic liquids was reported <04S1951>. Tetrabutylammonium iodide (TBAI) was found to assist the introduction of protecting groups onto electron deficient pyrroles <04TL5057>. For example, treatment of pyrrole ester 52 with methyl chloroformate and potassium carbonate in the presence of TBAI gave pyrrole carbamate 53. An improved method for the /V-amination of pyrroles involved monochloramine (NH2C1) <04JOC1368>. Treatment of pyrrole with a strong base followed by monochloramine gave N-aminopyrroles 54.

A copper-catalyzed A'-alkynylation reaction developed for amides was also applied to pyrroles. Therefore, treatment of pyrrole 55 with bromoalkyne 56 in the presence of copper sulfate and 1,10-phenanthroline gave A'-alkynylpyrrole 57 <04OLl 151>. A copper catalyzed Narylation reaction of indoles has also been demonstrated with pyrroles and other it-excessive nitrogen heterocycles <04JOC5578>.

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A novel /V-annelation provided access to pyrrolo[l,2-c]oxazoles and oxazolo[3,4-a]indoles. Specificially, treatment of acyl benzotriazole 58 with ketones in the presence of DBU led to the formation of pyrrolo[l,2-c]oxazoles 59 <04JOC9313>.

Treatment of A'-tosylpyrroles with carboxylic acids and trifluoroacetic anhydride led to the regioselective formation of 2-acylpyrroles <04TL9573>. A MCR involving pyrrole, Meldrum's acid, and isocyanides provided complex 2-acylpyrroles <04S989>. The condensation of 2phenylpyrrole 60 with alkynyl bromide 61 in the presence of aluminum oxide led to the formation of 2-alkynylpyrrole 63 <04TL6513>. Intermediate 62 was isolated and characterized by 'H NMR. This sequence can be thought of as a metal free, formal "Sonogashira coupling," although this reaction was not explored utilizing non-acyl alkyne derivatives. The addition of pyrroles 64 to nitroalkenes 65 in the presence of thiourea 66 gave alkylated pyrroles 67 <04SL2374>. The electrophilicity of the nitroalkene was presumably enhanced by hydrogen bonding interactions between the thiourea and the nitro group. The Michael addition of homochiral pyrroles to unsaturated esters gave diastereomeric adducts which could be separated by chromatography <04S2574>.

An annelation reaction of pyrroles leading to fused pyrroles 68 involved a rhodium-catalyzed decomposition of a-diazo-p-ketoesters <04T1505>.

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The intramolecular addition of pyrroles onto tethered Michael acceptors was investigated utilizing chiral auxiliaries and/or chiral catalysts. For example, treatment of chiral pyrrole 69 with boron trifluoride etherate proceeded with good diastereoselectivity (90% de) to give tetrahydroindolizidine 70 <04OBC157>. The asymmetric epoxidation of a,|3-unsaturated Nacylpyrroles was investigated <04JA7559>. A new synthesis of 2-substituted pyrroles involved magnesiation of N-phenylsulfonylindole 71 as the key step <04OL293>. Treatment of 71 with isopropylmagnesium chloride and a catalytic amount diisopropylamine followed by electrophiles provided 2-substituted pyrroles 72. Control experiments showed that diisopropylamine was required for the transformation, therefore, the magnesiation is most likely accomplished by a Mg-amide intermediate. A Kumada-type coupling process of the putative pyrrolylmagnesium provided access to 2arylpyrroles. The lithiation of 4-(l//-l-pyrrolyl)pyridine regioselectively provided intermediate aryllithium 73 <04JOC7914>.

Organometallic cross-coupling type reactions continue to serve as an important tool for the preparation of functionalized pyrroles. The palladium-catalyzed cross-coupling of pyrrole anions provided a new route to 2-arylpyrroles <04OL3981>. For example, treatment of pyrrolyl zinc chloride 74 with aryl halides in the presence of Buchwald's electron-rich phosphine 75 gave 2-arylpyrroles 76. A double cross-coupling reactions between a pyrrole-3-boronic acid and 1,2dihaloarenes provided (3-linked dipyrrole monomers <04T7141>. Palladium-catalyzed arylation <04JOC8668> and amination <04TL769> reactions of 3,4-dihydropyrrolo[l,2-a]pyrazines were reported. The preparation of protected pyrrole amino acid 77 involved a copper-catalyzed carbamidation reaction in a key step <04JOC8151>.

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Recent total syntheses of the lamellarins, 2,3,4-triarylpyrrole natural products, have showcased synthetic methodology involving palladium-catalyzed cross-coupling reactions. Three successive Suzuki coupling reactions were utilized to prepare lamellarin G trimethyl ether <04JOC2362>. Solid-phase total syntheses of lamellarins Q 83 and O have been developed <04T8659>. Negishi coupling between resin-bound iodide 78 and pyrrole-3-zincate 79 produced 80. Suzuki coupling of the latter with boronic acid 81 gave 82 which was converted into lamellarin Q 83. In addition, a Suzuki reaction involving a complex pyrrole-4-borate derivative was a central step in the preparation of dragmacidin F <04JA9552>.

5.2.4 PYRROLE NATURAL PRODUCTS AND MATERIALS A few structurally interesting pyrrole natural products have been isolated from marine sources during the previous year. Pyranigrin D 84, containing the novel pyrano[3,2-fo]pyrrole ring structure, was isolated from a Mediterranean marine sponge-derived fungus Aspergillus niger <04JNP1532>. Dipyrroloquinone zyzzyanone A 85 along with known pyrroloquinoline alkaloids were isolated from the Australian marine sponge Zyzzya fuliginosa <04TL7491>. 85 demonstrated moderate anti-cancer activity. Eight dimeric bromopyrrole-2-carboxamide alkaloids, nagelamides A-H, were isolated from marine sponge Agelas sp., and they demonstrated antibacterial activity <04JNP1262>. New bromopyrrole-2-carboxamide alkaloids, phakellins, were also isolated from Agelas sp. <04JNP1256>. The isolation <04T2517>, cytotoxicity, and synthesis <04TL2809> of novel pyrrole-2-carboxaldehydes, mycalazals, have been reported.

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The pyrrole nucleus is commonly found in biologically active lead compounds and designed analogs, and two out of many recently published examples will be mentioned here. The pyrrole core structures of roseophilin and prodigiosin have been studied as protein tyrosine phosphatase inhibitors <04CBC1575>. A new class of 2-vinylpyrroles, 6-pyrrolyl-2,4-dioxo-5-hexenoic acids, were found to be active HIV-1 integrase inhibitors <04BMCL1745>. As mentioned previously, the lamellarin natural products continue to be the focus of much study. The isolation, biological activity, and syntheses of the lamellarins have been reviewed <04M615, O4PHC1>. Analogues of lamellarin-D 86 have been evaluated as antitumor agents utilizing a topoisomerase I-mediated DNA cleavage assay <04BMC1697>. This study revealed a correlation between topoisomerase activity and cytotoxicity. The total syntheses of lamellarinK and L (via 3) <04AG(E)866>, lamellarins Q 83 and O <04T8659>, and lamellarin G trimethyl ether <04JOC2362> have been reported.

Many total syntheses of pyrrole natural products have been reported during the previous year. The most common targets were bromopyrrole-2-carboxamides. Two syntheses of the broadly biologically active marine alkaloid, sceptrin 87, were disclosed. The first involved an oxaquadricyclane rearrangement to set up the relative stereochemistry of the central cyclobutane ring <04JA3726>, while the second utilized a photocycloaddition and subsequent epimerization <04OL2369>. The total synthesis of rac-dibromophakellstatin 88 employed a novel vicinal syn diazidation reaction set up the cyclic urea moiety <04OL3881>. An intramolecular Michael addition of a pyrrole nitrogen onto a tethered chiral enone was the key step in a total synthesis of the antineoplastic (-)-agelastatin A 89 <04OL2615>. A total synthesis of the bromopyrrole alkaloid dispacamide A has also been reported <04JA10252>.

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Tribromination of A'-(triisopropylsilyl)pyrrole with NBS followed by TBAF deprotection provided a regioselective synthesis of 2,3,5-tribromopyrrole, an natural occurring antifeedant from the marine worm Saccoglossus kowalevskii <04JNP1929>. The total synthesis of manzacidin, a pyrrole-2-carboxylate ester with a dihydropyrimidine side chain, was achieved <04TL7197>. As mentioned previously, the total syntheses of the pyrrole2-carbinol natural products, funebrine 11 and funebral, were disclosed <04JOC1475>. The preparation of pyrrole macrocyles (i.e., porphyrins) continues to be an important area of research due to their interesting material science applications that include: molecular recognition, photoelectronic materials, biomedicine, and catalysis. 1-Acyldipyrromethanes and 1,9diacyldipyrromethanes are important building blocks for the rational synthesis of porphyrin materials. Boron-complexation <04JOC5354, 04JOC8356> and tin-complexation <04JOC765> strategies have been utilized to develop improved syntheses of these materials. One step selfassembly processes leading to pyrrole macrocycles has been subject of a review <04AG(E)1918>. A novel synthesis of porphyrins utilizing an ionic liquid was reported <04CC1902>. Artifical light-harvesting systems (artificial photosynthesis) that have been prepared and evaluated include a dodecameric porphyrin wheel <04JA4468> and porphyrinefullurene linked systems <04OBC1425>. Two examples of porphyrins containing external aromatic rings (expanded porphyrins) that have been synthesized include tetrabenzoporphyrins <04JOC522> and azuliporphyrin 90 <04TL5461>. The preparation of meso-substituted porphyrins <04T11435> and corroles <04JOC4159> has been further studied. Two new methods for the preparation of meso-formyl porphyrins (i.e., 91) that have been reported include the deprotection of cyclic acetals <04JOC5112> and the use of dithianes <04JA13634>. Potential shape-selective catalysts, meso-dendritic porphyrins, have been prepared <04H(63)505>. Finally, the preparation of N-coniused tetraphenylporphyrins <04JOC4571> and pentaphyrins <04AG(E)876, 04AG(E)2951> have been disclosed. CHO

The synthesis and molecular recognition properties of calixpyrroles and structurally related pyrrole-containing macrocycles have been investigated. A calix[4]pyrrole|2]carbazole 92 macrocycle showed a slight preference for the acetate anion compared to other carboxylate anions <04JA16073>. Dipyrromethane 93 showed a high sulfate-to-nitrate binding selectivity, potentially useful for the remediation of radioactive waste <04CC1276>. A terpyrrole analog of dipyrrolylquinoxaline (DPQ) has been prepared and evaluated as a colorimetric sensor for halides and dihydrogen phosphate anions <04T11283>. A chiral calix[41phyrin dimer was prepared that exhibited moderate enantiorecognition of malic acid enantiomers <04JOC8140>.

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93

A number of pyrromethene-BF2 complexes (BODIPY) analogs have been prepared and evaluated as luminescent probes including those functionalized with oligopyridines <04JOC2070>, terpyridines <04SL439>, indacenes <04JA3357>, and ethylenediamines (i.e., 94) <04CPB700>. 5.2.5 SYNTHESIS OF INDOLES New applications of the Fishcer indole synthesis, the acid-catalyzed cyclization of arylhydrazones, have been reported. A Fischer indole synthesis was utilized to prepare the indole-2-carboxylate fragment of the indole antibiotic, nosiheptide <04OBC701>. The reaction between phenylhydrazines and enol ethers afforded indoles as single regioisomers <04OL79>. For example, treatment of hydrazine 95 with dihydropyran in the presence of sulfuric acid gave indole-3-propanol 96. This reaction with the appropriate acylhydrazine and enol lactone provided a regioselective synthesis of the anti-inflammatory drug, indomethacin 97. A solidphase Fischer indole synthesis utilizing a resin-capture-release strategy was utilized to prepare a library of tyrosine kinase inhibitors in addition to 97 <04AG(E)224>. A Fischer indole synthesis employing M-Boc arylhydrazines was reported <04TL1857>. The Fischer indole synthesis was utilized to prepare pyrrolo[2,3-a]carbazoles 98, truncated analogs of indolo[2,3-a]carbazole <04JHC349>. An attempted Fischer cyclization approach to fascaplysin led unexpectedly to a benzo[c||3-carboline product <04TL1299>.

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Hydroamination reactions of alkynes provide an alternate route to arylhydrazones that can be utilized in the Fischer indole synthesis. Treatment of arylhydrazine 99 with alkyne 100 in the presence of catalyst system comprised of titanium tetrachloride and f-butylamine afforded arylhydrazone intermediate 101 which underwent a Fischer cyclization to give 1,2,3trisubstituted indole 102 as a single regioisomer <04TL9541>. A similar titanium-catalyzed hydroamination reaction was utilized to prepare tryptamine derivatives <04TL3123>.

New applications of well-established "reductive" name reaction indole syntheses have appeared during the past year. A microwave-accelerated Leimgruber-Batcho indole synthesis, the reductive cyclization of f5-dialkylamino-0-nitrostyrenes, was reported <04OBC160>. The Hemetsberger indole synthesis, the pyrolysis of a-azidocinnamates, was utilized as a key step in the preparation of the highly fluorescent pyreno[2,l-b|pyrrole 103 <04JOC6674>. This synthesis was also utilized in a second approach to the indole-2-carboxylate fragment of nosiheptide <04OBC701> and also in the synthesis of a pyrrolo[4',5':5,6]pyrido[3,4-b|indole derivative <04JHC531>. The modified Reissert indole synthesis involving the reductive cyclization of o-nitrophenyl methyl ketones was utilized to prepare 2-arylindole-6-carboxylates <04SL883>. This reaction was also utilized to prepare the novel KDR kinase inhibitor quinolin2(l//)-one 107 <04JOC7761>. Condensation of silyl-nitro compound 104 with quinoline-3carboxaldehyde 105 followed by oxidation gave ketone nitroketone 106. Reductive cyclization of 106 followed by hydrolysis gave 107. The Makosza indole synthesis, the reductive cyclization of vicarious nucleophilic sustitution (VNS) products, was utilized to prepare hydroxyindoles <04S3043> from o-nitrophenyl methyl nitriles. A related sequence involving a Bayer-type condensation of VNS products, o-aminonitrobenzyl ketones, was reported by Makosza <04T347>.

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A reductive cyciization of nitroester 108 produced oxindole 109 <04OL4957>. Compound 108 was prepared utilizing VNS three-component coupling reaction.

A modified Bartoli indole synthesis, the condensation of nitroarenes with a vinyl Grignard, was utilized to prepare a precursor to the pyrrolobenzoxazine natural product CJ-12662 <04JOC7875>. The carbolithiation of o-aminostyrenes provided a novel synthesis of 3-substituted indoles <04JOC7836>. Treatment of styrene 110 with an alkyllithium led to dilithiated products 111 which was trapped by DMF to give 2-hydroindoline intermediates 112. Loss of water from the latter then provided 3-substituted indoles 113.

Two separate reports of electrophilic 5-endo-dig iodocyclization reactions of oalkynylanilines leading to 3-iodoindoles were disclosed. Treatment of Sonogashira product 114 with iodine led to 3-iodoindole 115 <04TL539>. Similarly, treatment of Sonogashira product 116 with iodine afforded A'-methylindole 118 presumably by an iodocyclization to intermediate 117 followed by demethylation <04OL1037>.

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Metal-mediated electrophilic cyclizations of o-ethynylanilines leading to indoles have also been reported. For example, the gold(III)-catalyzed heteroannulation of bis-aniline 119 produced 2,2'-biindole 120 <04S610>. A similar heteroannulation reaction was reported utilizing copper triflate as the catalyst <04JOC1126>.

An indium-mediated carbometalation of o-iodoynamides 121 provided £-alkylideneoxindoles 123 via 122 <04OL2825>. Indium intermediate 122 could also be utilized in a palladiumcatalyzed cross-coupling reaction to give Z-alkylideneoxindoles. Metal-mediated heteroannulation reactions between o-haloanilines and alkynes provide a powerful route to indoles. A ferrocene-based bisphosphine ligand was utilized in the regioselective preparation of 2,3-disubstituted indoles <04OL4129>. For example, treatment of o-bromoaniline 124 and alkyne 125 with palladium acetate in the presence of bisphosphine 126 provided indole 127 (>99% regioselective). A palladium-catalyzed heteroannulation reaction was employed in the preparation of 2- and 3-trifluoromethylindoles <04CL314, 04JOC8258>, while a related heteroannulation sequence was investigated that exploited Pd-NaY zeolite catalysts <04TL693>. Another related reaction sequence involving trifluoroacetamidoaryl triflates was used to prepare 2-substituted C5-, C6-, and C7-nitroindoles <04T10983>. A tandem palladium/copper-mediated coupling/cyclization of o-iodobenzenesulfonamide 128 with

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propargyl alcohol provided indole-2-methanol 129 <04SL1965>. 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 <04OL2953>. A different type of onepot strategy involved a regioselective hydroamination/Heck reaction sequence that converted ochloroanilines into 3-aryl-2-alkylindoIes <04CC2824>.

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 <04AG(E)4526>. 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 <04SL907>, cyclopenta[fr]indol-l-ones <04HCA82>, and carbazol-4-ones <04HCA82>. An intramolecular Heck reaction of cyanoenamine 133 afforded 3-cyanoindole 134, a useful building block for the preparation of indole analogs of mycophenolic acid <04BMC2867>.

A copper-catalyzed tandem reaction between 2-alkynylarylideneanilines 135 and alcohols provided a novel route to 7V-(alkyloxybenzyl)indoles 136 <04TL35>. A stable tungsten carbene complex was isolated from a reaction involving 135 (R, = Me), f-butyl vinyl ether, and tungsten hexacarbonyl <04CL16>. 2,3-Disubstituted indoles were prepared by the cyclization of 2-

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alkenylimidoyl selanide radicals <04SL1905>. A tandem palladium-mediated cyclization/coupling reaction involving 1,1-dibromo-l-alkenes was reported <04TL907>. 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 <04JA10546>. 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 <04H(63)1765>. 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 <04OL3739>. 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) <04JOC2106>. A new milder method for converting nitrobiaryls into carbazoles was reported <04OL533>. 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.

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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 <04S2499>. 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 <04SL528> and 6-chlorohyellazole 155 <04SL2705>.

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 <04SL2394>. The yV-acylation of 5-substituted indoles utilized a DCC coupling reaction of benzoic acid derivatives <04S2653>. Thioglycolate proved to be an effective reagent for the deprotection of /V-tosylindoles <04TL599>.

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A regioselective Friedel-Crafts 3-acylation of indoles was reported that utilized diethyl aluminum chloride as a Lewis acid mediator <04S2277>. A facile, 3-cyanoacetylation of indoles has been reported <04S2760>. 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 <04OL819>. An intramolecular variation of this reaction afforded thioazepine 162. A vanadium catalyst has also been utilized to prepare 3-sulfenylindoles <04JOC7688>. Treatment of indoles with ammonium thiocyanate and iodine led to the formation of 3-thiocyanoindoles <04TL2951>.

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 <04SL944>. 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 <04TL3803>. 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 <04CC432, 04JOC1309>. 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 <04JOC7511>.

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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 <04OL711>. 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 <04OL4249>, spirotryprostatin B <04AG(E)5357>, and elocamine <04OL711>. Treatment of 3-substituted indoles 169 with r-butylisocyanate in the presence of boron trifluoride etherate produced indole-2-carboxamide 170 <04SL2806>. 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 <04OPP289>. 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 <04JOC2913>. 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 <04S895>, dypsprosium triflate in ionic liquids <04TL4567>, iodine <04T2051>, iron(lll) in ionic liquids <04EJO1584>, potassium hydrogen sulfate <04CL288>, and trichloro-l,3,5-triazine <04TL7729>. A solvent-free synthesis of trisindolylarylmethanes 173 utilized acid-washed montmorillonite clay <04SC1801>. Bisindolylalkanetriol 176 was prepared by treatment of indole with cyclic hemiacetal 175 in the presence of a clay catalyst

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<04TL3673>. A new synthesis of indole-substituted tetrahydrocarbazoles involved a rearrangement reaction of bisindolylalkanols promoted by diethylamino sulfur trifluoride (DAST) <04EJO2411>. Bisindolylarylethanes were prepared by combining indole with phenylacetylene in the presence of gallium(III) catalyst <04TL7577>. The Amerlyst 15catalyzed condensation of indoles with pyrazole-4-carboxaldehyde furnished bisindolylpyrazolylmethanes 174 <04TL5099>.

Three separate methods were developed for the synthesis of 2,3'-bisindolylmethanes 177 <04S1187>. 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 <04TL7273>.

An electrophilic annelation reaction was the key step in a synthesis of azepino[3,4-b|indole1,5-dione 179 <04EJO4606>. Intramolecular cyclization reactions of oxazolone-substituted indoles led to the formation of either p-carbolines or cyclopenta[b]indolones depending on the reaction conditions <04EJO1286>.

A novel preparation of fused indoles involved the platinum-catalzyed addition of indole to tethered alkenes <04JA3700>. 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 <04JA10250>. A palladium-catalyzed allylation of indoles with allyl carbonates furnished 3-alkylated indoles <04OL3199>. 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 <04SL1428>. 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 <04CC1502>. The synthesis of the p-carbolin-1-one analog 183 of pancratistain has been reported <04AG(E)5342>. A traceless solid-phase synthesis of carbolin-1-ones has been developed <04JCO855>. 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 <04JA10558>. 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 <04TL7103>. The preparation of cis- 1,3-disubstituted tetrahydro-p-carbolines has been achieved utilizing a m-specific Pictet-Spengler reaction <04EJO1887>.

The generation and reactivity of 2-indolylacyl radicals has been studied <04OL759, 04TL5605>. 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 <04T2147>. A zirconium-catalyzed oxidative coupling reaction between /V-methylindole 192 and Nmethylpyrrolidinone furnished 5-substituted pyrrolidinone 193 <04AG(E)4231>. 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 <04JA7450>. 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 <04OL2897>. 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 <04TL6549>. 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 <04T5315>. 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 <04OL2293>.

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 <04OL1665>. 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 <04OL3649>. 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 <04JOC6812>. 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 <04OL3>.

A regioselective palladium-catalyzed hydrodebromination of 4,6-dibromoindoles produced the corresponding 4-bromoindoIes <04JOC3336>. 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 <04OL3241>. 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 <04JOC3735>. The Diels-Alder reaction of ortho-carbazolequinones led to the formation of the corresponding benzo-fused carbazolequinones <04CPB1114>. A synthesis of benzothiopyrano[2,3-/?]indoles was accomplished by the cycloaddition of l,3-dihydroindole-2-thiones with benzyne dienophiles <04H(63)2785>.

Pummerer-like cyclization reactions were utilized to prepare spirocyclic oxindole derivatives <04OLl869, 04OL2849>. 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 <04OL2213>. 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) <04AG(E)1098> and the plakohypaphorines (iodinated tryptophan derivatives) <04EJO3227>. New photoprotective pigments related to scytonemin have been isolated from cyanobacteria <04JNP678>. Novel examples of familiar indole natural product classes that have been isolated include: an unnamed yohimbine alkaloid <04CPB359>, conodusarine (vobasine-iboga bisindole) <04H(63)845>, macrodasine A (spirocyclic macroline alkaloid) <04T3957>, and manzamine-related alkaloids <04JMC3512>. New oxindole natural products that have been identified include citrinadin A <04OL3087> 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) <04T10739>, mersicarpine 218 (azepine-fused indoline) <04TL5995>, jusbetonin (indolo[2,3fejquinoline) <04JNP461>, kopsifolines (methano-bridged hexacyclic monoterpene indoles) <04HCA991>, and angustilodine (oxepane-bridge pentacyclic indole) <04HCA366>. In an attempt to enhance the productivity of NGF-inhibitory carbazostatins, two new indolocarbazole alkaloids were produced and isolated, indolocarbazostatin C and D 219 <04JAN627>.

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 <04BMCL1703>. Novel bridged bis-7-azaindolylmaleimides proved to be selective glycogen synthase kinase-3p inhibitors <04BMC1239>. Simplified manzamine analogs demonstrated anti-cancer and anti-malarial activity <04BMCL5841>. A series of 2,5,6-trichloroindole nucleoside derivatives were investigated as antiviral agents <04JMC5753>. 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 <04OL3>, ergocryptine (lysergic acid derivative) <04JOC5993>, phenserine (physostigmine congener) <04JA14043>, yatakemycin (structurally related to CC-1065) <04JA8396>, and strychnine <04JA10246>. Halogenated indole natural products that have prepared include been prepared include arborescidine B 221 <04JOC1283>, dragmadicin F

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<04JA9552>, and perophoramidine 222 <04JA5068>. 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) <04TL6471>, dehydrovoachalotine (sarpagine alkaloid) <04TL3937>, fuchsiaefoline (sarpagine alkaloid) <04OL249>, gilbertine (uleine alkaloid) <04JA3534>, clavicipitic acid (ergot alkaloid) <04EJO1244>, vallesamidine <04T3273>, vincamajinine (ajmaline bisindole) <04JA1358>, and lapidilectine B 223 <04JOC9109>.

Finally, fused indole natural products that have been synthesized include: thienodolin (thieno|2,3-6]indole) <04EJO2589> and rutaecarpine (indoloquinazoline) <04TL997>. And lastly, in addition to previously mentioned examples, carbazole natural products that have been prepared include: hyellazole <04TL5411>, carbazomycin B <04T1513>, and carbazoquinocin C <04OL329>.

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138 04JOC1309 04JOC1368 04JOC1475 04JOC2070 04JOC2106 04JOC2362 04JOC2913 04JOC3336 04JOC3735 04JOC4159 04JOC4571 04JOC4656 04JOC5112 04JOC5354 04JOC5578 04JOC5993 04JOC6674 04JOC6812 04JOC7511 04JOC7688 04JOC7761 04JOC7836 04JOC7875 04JOC7914 04JOC8140 04JOC8151 04JOC8258 04JOC8356 04JOC8372 04JOC8668 04JOC9109 04JOC9313 04M615 04NPR278 04OBC157 04OBC160 04OBC701 04OBC1425 04OL3 04OL79 04OL249 04OL293

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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: <04H(63)2043>, <04JNP97>, <04JNP495>, <04JNP682>, <04JNP714>, <04JNP1147>, <04JNP1426>, <04JNP1396>, <04JNP1517>, <04OL2229>, <04P2101>, <04T4781>, and<04TL6891>. References on those naturally occurring compounds containing tetrahydrofuran or dihydrofuran skeletons whose biological activities were assessed are: <04EJO4239>, <04HCA1007>, <04JNP14>, <04JNP42>, <04JNP343>, , <04JNP767>, <04JNP772>, <04JNP990>, <04JNP1041>, <04JNP1455>, <04JNP1796>, <04JNP1804>,

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<04JOC3350>, <04OBC2131>, <04OL1593>, <04OL1661>, <04P969>, <04P2499>, <04T1229>, <04T6015>, and <04TL2989>, References on those furan-containing compounds whose biological activities were not mentioned are: <04HCA949>, <04JNP685>, <04JNP921>, <04JNP1859>, <04OL1841>, <04P127>, <04P377>, <04P2031>, <04P2051>, <04P2057>, <04P2833>, <04P2929>, <04P3075>, <04P3083>, and <04TL6997>. References of those naturally occurring compounds containing furan skeletons whose biological activities were assessed are: <04JNP1186>, <04JNP1483>, <04JNP1544>, <04JNP1947>, <04P387>, <04P2533>, <04T9991>, <04T10619>, <04TL591>, and <04TL2125>. References of those benzo|6|furan- or dihydrobenzo[b]furan-containing compounds whose biological activities were not mentioned are: <04H(63)1821>, <04H(63)1875>, <04H(63)2043>, <04H(63)2123>, <04HCA479>, <04HCA2346>, <04JNP932>, <04JNP1601>, <04JNP1859>, <04P207>, <04P221>, <04P427>, <04P439>, <04P921>, <04P1095>, and <04P3113>. References on those naturally occurring compounds containing benzo|&Jfuran or dihydrobenzo[b]furan skeletons whose biological activities were assessed are: <04H(63)879> and <04P3021>. 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 <04TL3877> as well as the mechanism of stereo- and regioselectivity <04JA2838> 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 <04AG(E)4364>. 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 <04AG(E)1998>. A related investigation using a cyano-substituted benzocyclobutene was also reported <04JOC7989>.

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 <04AG(E)5991>.

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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.)<04AG(E)615>.

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 <04AG(E)6517>.

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 <04TL4437>.

New Au(III)-pyridine-2-carboxylate complexes were developed to catalyze the intramolecular reaction between furan and acetylene to form phenols <04AE(G)6545>. 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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<04TL5023>, and carba-/3-L-mannopyranose derivatives <04JOC1625>. 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) <04CC1414>. 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 <04AG(E)6689>.

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 <04SCI495>.

In a formal total synthesis of (-)-secosyrin 1, Birch reduction and subsequent alkylation of the chiral furylamide provided the dihydrofuran with high diastereoselectivity <04OL465>.

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 <04OL79>.

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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 <04SL829>.

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 <04AG(E)3932>.

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 <04EJO2797>. 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 <04OL3617>. 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 <04OL3139>.

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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 <04SL2573>.

Synthetic applications of 8-oxabicycloL3.2.1Joct-6-en-3-one were reviewed <04AG(E)1935>. 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 <04AG(E)610>.

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 <04OL1625>.

An additional example of tandem ring opening/cross metathesis is shown in the scheme below <04OL3821>. 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 <04JOC8789>.

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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 <04JOC2i94>. The scope of enantioselective palladiumcatalyzed alkylative ring opening of oxabicyclic alkenes using organozinc reagents was reported <04JA1437>. 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 <04AG(E)3944>. 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 <04OL2833>.

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 <04TL795>.

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 <04SL2291>. A similar reaction using carbon tetrachloride and a catalytic amount of fer/-butylperoxy-Y3-indane was also reported <04TL3357>.

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 <04TL7581>.

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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 <04JOC1331>.

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 <04JOC4692>.

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 <04SL1375>. 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 <04AG(E)1998>. 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 <04AG(E)2020>. A modified synthesis of a chiral furan diol from D-glucal in 82% yield employing HC1O4 supported on silica gel was reported <04JOC6137>. 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 <04SL2484>. 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 <04OL1749>. An acid-catalyzed synthesis of 2,3,4-trisubstituted furans using substituted 1,4-diketones under microwave irradiation was recorded <04OL389>. 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 <04TL5689>.

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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 <04JNP1383>.

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 <04OL2733>.

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 <04OL3679>.

2,4-Furanophanes were synthesized from the palladium-catalyzed cyclization of 1 ,ndiallenyl diketones although the yields were low <04EJOC1923>.

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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 <04CEJ2078>. 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 <04AG(E)2280>.

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 <04OL3513>.

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 <04S865>.

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 <04S1359>.

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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 <04OL3793>.

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 <04JMC5816>.

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 <04TL6753>.

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 <04CC44>.

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An efficient and atom-economical Au-catalyzed poly substituted furan synthesis was reported <04JA11164>. 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 <04JA4118>. 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 <04T1913>.

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 <04JOC1738>.

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 <04JA9645>.

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-

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tetrasubstituted furans as well as 2,3,4-trisubstituted furans when aryl halides and triflate were used <04T4139>.

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 <04OL115>.

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 <04S2376>. A similar reaction using 2-furyl-2-oxoacetamide derivatives instead of aldehydes produced substituted furylfurans <04TL7099>.

An efficient formation of substituted furans under solvent-free, microwave irradiation conditions was reported <04SL1933>. 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 <04JOC1557>. 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 <04AG(E)1857>.

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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 <04S811>. Like before, Williamson cycloetherization continues to be one of the most popular and practical methods for preparing tetrahydrofurans <04AG(E)3175>, <04TL441>, <04TL1599>, <04HCA765>, <04JA13600>. An interesting example in this category involved the formation of substituted tetrahydrofuran derivatives upon treatment of oligomers of to-alkenyl iodoacetates with Grignard reagents <04JOC142>. The intramolecular opening of epoxides by hydroxy groups is also a very popular method to realize tetrahydrofurans <04TL351>, <04TL4193>, <04TL5163>, <04OL961>, <04T10651>, <04CEJ3467>, <04JA36>, <04JA15968>, <04EJO2707>. Another way in which tetrahydrofuran rings can be obtained is by electrophile-promoted cyclization of 4-pentenol derivatives. The electrophile can be mercuric salts <04TL1079>, <04OL893>; halogenating reagents <04SL65>, <04TL1717>, <04CJC377>, <04EJO1973>, <04EJO3799>, <04OL3059>; phenylselenium reagents <04TA405>, <04OLl 123>, <04TA1949>, <04EJO4567>, <04T9963> or a platinum catalyst <04JA9536>. A one-pot synthesis of 2,3,5-trisubstituted tetrahydrofurans by a double SakuraiHosomi reaction was reported and an example is shown below <04AG(E)1417>. Another procedure featuring the pivotal use of an O-alkylation route is also known <04Tl 15>.

Radical-mediated cyclization has also been employed in the synthesis of tetrahydrofurans <04TL2331>, <04TL7935>, <04JOC1844>, <04JOC2417>, <04EJO1740>, <04EJO2337>, <04OBC965>, <04OL1895>, <04OL1943>, <04T9283>, <04TL2223>. An application of the radical strategy was recently utilized in the synthesis towards entnocardione A <04JOC3282>.

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 <04JOC3368>, <04SL1437>, <04TL303>. Cycloaddition reactions of oxygen-tethered compounds were also used to construct oxygen-bridged heterocycles, in particular tetrahydrofurans. These methodologies include intramolecular nitronate cyclization <04OL2027>, <04SL1207>; intramolecular Diels-Alder cycloaddition <04JA10264>, <04SL1434>, <04JA5493>; intermolecular [4+3]

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oxocarbenium cycloaddition <04JA1642>; intermolecular [5+2] oxidopyrylium cycloaddition <04TL257>; intermolecular carbonyl ylide cycloaddition <04JOC1413>, <04HCA408> and intermolecular |3+2| carbonyl ylide cycloaddition <04JO8796>, <04CC822> <04HCA408>. With appropriate transformations, heterocycles such as acetals <04JA998>, <04JO1993>, <04JO3240>, <04OBC1145>, <04OL2063>; y-lactones <04HCA2100>; 2,3dihydrofuran <04JO1831> and 2,5-dihydrofuran <04TL2017> 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 <04JOC5143>; rhodium-catalyzed carbonylative | 2 + 2 + l | cycloaddition of 1,3-dienes, alkenes and CO <04JA2714>, <04JA5948>; palladium-catalyzed 1,2,7-triene cyclization/arylation cascade reactions <04OL4041>; intramolecular cyclization involving a copper carbenoid <04OL1773> and a one-pot three-component 1,3-dipolar procedure involving carbonyl ylides, aldehydes and dipolarophiles <04JOC4856>. The following scheme shows the reaction of a zirconacyclopentene with an aldehyde in the synthesis of a tetrahydrofuran derivative <04T1417>.

Aldehydes were utilized to react with a number of reagents, e.g., cyclic allylsiloxanes <04JOC6874>, dicobalthexacarbonyl complex of dimethyl 2-ethynylcyclopropane-l,ldicarboxylate <04CC2474> and an acylated bromooxazolidinone <04TL4457> to form complex tetrahydrofuran frameworks. The scheme below is an example to demonstrate the versatility of this approach <04OL3865>.

An O-alkylation procedure generated 2-methylenetetrahydrofuran skeletons in good yields, and an example is shown in the following scheme <04JOC6715>.

In the presence of I ^ ' E t j O , methylenecyclopropanes reacted with aldehydes to afford 3-methylenetetrahydrofurans <04OLl 175>. Using a catalytic amount of Zn(OTf)2 in EtjN, various alkylidene malonates react with propargyl alcohol to give 3methylenetetrahydrofurans <04OL2015>. Oxygen-tethered bromodienes were shown to provide 3-methylenetetrahydrofurans via a cascade palladium-catalyzed cyclizationcarbonylation reaction <04CC1232>. On the other hand, propargyl allyl ethers underwent a cycloisomerization reaction catalyzed by palladium reagents <04TL2155>, <04SL655>;

Five-membered ring systems: furans and benzofurans

157

rhodium reagents <04CC98> <04T4475>, <04AG(E)1860>, <04CC1134>, <04OL3699>, <04JA7875> and nickel reagents <04JA11162> to form 3-methylenetetrahydrofurans. Similarly, rhodium-catalyzed cycloisomerization of bis(propargyl) ethers also led to 3,4bis(methylene)tetrahydrofuran frameworks <04JA7875> 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 <04JA4859>. 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 <04TL1861>.

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 <04OL2877>.

epACJ-16,169 (40%)

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

Formation of dihydrofurocoumarins through palladium-catalyzed cascades and subsequent acid-catalyzed cyclization was also recorded <04T3359>. An unexpected formation of tetrasubstituted 2,3-dihydrofurans was reported through reactions between pketo polyfluoroalkanesulfones and aldehydes <04JOC6486>. 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 <04OBC806>.

158

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

2,5-Dihydrofurans can most conveniently be synthesized via ring-closing metathesis of bis(allyl) ethers <04TL2805>, <04TL5211>, <04JA12790>, <04JOC5770>, <04CC2506>. Substituted 2,3-butadienols were also utilized to form 2,5-dihydrofurans <04JA15970>, <04HCA1723>. 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 <04JOC2577>.

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 <04T1665>. A fully functionalized benzofuran was also utilized as a major building block in the total synthesis of kendomycin <04JA14720>. Benzofuran-based tetraols were also employed as key fragments in the synthesis of some helical molecules <04H(63)137>.

Two new classes of voltage-gated potassium channel Kvl.3 blockers were obtained by transformations of naturally occurring khellinone <04JMC2327>.

Five-membered ring systems: furans and benzofurans

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 <04OL3131>. Anodic oxidation of 2,3-dihydrobenzol61furan derivatives was also utilized to synthesize 2-fluoroand 2,3-difluoro-2,3-dihydrobenzo[6]furan derivatives <04JOC5302>.

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 <04OL3739>.

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 <04AG(E)6144>. Ionic liquid (fbmimJBF4) was found to be an effective solvent for the PdCl2-catalyzed intramolecular Heck reaction to realize benzofurans <04TL6235>. Another palladium-catalyzed intramolecular Heck reaction between vinyl triflate and benzo[£>]furan was utilized to construct the seven-membered ring based (-)-frondosin B <04T9675>.

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 <04TL911>.

160

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

o

•I

^sA

L

II II

R4

Ri

+

R5

W

Ag2CO3(2equiv)

\ /

AcO^^O^Ph j

r^V^

2\,3 ^ R3

c/V^O^Sh

R3 \ / 5 V^Cri I R4 " 2 R R1

dioxane-H2O(4:1) 100 °C, 24 h

O R

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 <04OL457>. The palladium-catalyzed intramolecular C-0 bond formation between aryl halides and enolates was employed to make 2,3-disubstituted benzo|b|furans <04OL4755>. 1. MeMgBr THF


0°C M e 0

2. Pd(PPh3)2CI2 (5 mol%)

^yBr

v

^ T > H

v

I

65°C,24h

n

1 ,

f

3. DMSO

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

<^-^L

f=\

• r £ V X \) ~

a

100°C, 24 h 80%

A library of 2-substituted furo[3,2-&lpyridines was made on solid support by K2CO3mediated sequential deprotection and cyclization <04OL1405>. The base-mediated furan formation was also applied to make 2-arylbenzo[b]furans, employing the coupling product generated from the ultra-fine nickel-catalyzed Sonogashira reaction of iodophenols with phenylacetylenes <04CC514>. Four 2,6-linked and 2,5-linked benzo|fc|furan trimers as organic electroluminescent materials were also prepared by the base-mediated cyclization of orr/io-hydroxyphenylene ethynylenes <04CEJ518>. 1. K 2 CO 3 18-Crown-6

r~\ Me W V-a. \=/

N=\ J—S AcO

DMF-H2O(19:1) 60 °C 2. AICI3 CH2CI2 25 °C 25%

M

^ \—* \=/

/r-^^^ o^\^

Five-membered ring systems: furans and benzofurans

161

A conformationally restricted 2,3-diarylbenzo[b]furan library was built up on solidphase by the palladium/bipyridy-catalyzed annulation of o-alkynyl phenols with aryl halides <04JOC2235>.

A number of 2,3-dihydrobenzo[6]furans can be made by the Ru-catalyzed olefinmetathesis approach in the presence of trimethylsilyl vinyl ether <04AG(E)4063>. The isovanillin derived benzo[£>]furan was also made by the olefin metathesis approach <04H(63)1771>.

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 <04T3941>. The same research group later published the SnCl4-mediated oxidative biaryl coupling reaction to build up the dinaphthanofuran framework <04T6295>. Silver(I) acetate was found to be an efficient agent to make the dimer of resveratrol in a high yield <04JOC2598>. Oxidation of phenol with PIFA was also applied to construct the framework of (-)-galanthamine <04AG(E)2661>.

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 <04JOC2637>.

162

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

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 <04T9615>. 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 <04TL6871>. A similar approach was also demonstrated by the same group to make spiro[pyrimidine-6,3'-2',3'-tetrahydrobenzofuran]-2,4-diones <04S1864>. 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 <04OBC585>. Moreover, a photoinduced fast tin-free reductive radical dehalogenation was found to be useful for the synthesis of 2,3-dihydrobenzo[>]furans<04JOC2037>.

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 <04T12231>. The Fries rearrangement was employed in the synthesis of benzo[£>lnaphtha[2,3-. [2,3]-Still-Wittig rearrangement was also utilized to make 2,3-disubstituted benzo[£>]furans from 2-stannane substituted benzol |furans <04T10921>.

2-Arylbenzo[£>]furans were synthesized by the [3,3]-sigmatropic rearrangement of oxime ethers <04OL1761>.

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 <04SL528>. An acid-catalyzed intramolecular cyclization to form the framework of furoquinoline alkaloids was also achieved from 3-oxiranylquinolines <04TL9483>. Furanoeremophilane sesquiterpenes were synthesized by acid-mediated furan ring formation from the corresponding phenolic a-ketone ethers <04CL136>. 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 <04T2843>. A ZnCl2-mediated benzo[6]furan formation was utilized to make benzo|&]furan-2-carboxylate from 3dimethylaminopropenoates <04TL2377>.

Five-membered ring systems: furans and benzofurans

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 <04JOC5322>.

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 <04OL4595>.

Coumestrol was synthesized by the condensation of a phenyl acetate with a benzoyl chloride, followed by demethylation and cyclization <04T1637>.

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 <04JOC7220>. A rhenium isobenzofuryl carbene complex was also synthesized recently <04OM4121>. 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

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

dimethyl acetylenedicarboxylate <04OM4121>.

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 <04HCA2364>. Bis(propargyl) ethers were converted to dihydrobenzo|c]furans through either a palladiumcatalyzed tandem reaction with arylboronic acids <04CEJ5338> or an iridium-catalyzed <04JA8382> [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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Five-membered ring systems: furans and benzofurans 04AG(E)4063 04AG(E)4364 04AG(E)5991 04AG(E)6144 04AG(E)6517 04AG(E)6545 04AG(E)6689 04CC44 04CC98 04CC514 04CC822 04CCH34 04CC1232 04CC1414 04CC2474 04CC2506 04CEJ518 04CEJ2078 04CEJ3467 04CEJ5338 04CJC377 04CL136 04EJO1741 04EJOC1923 04EJO1973 04EJO2337 04EJO2707 04EJO2797 04EJO3799 04EJO4239 04EJO4567 04H(63)137 04H(63)879 04H(63)1771 04H(63)1821 04H(63)1875 04H(63)2043 04H(63)2123 04HCA408 04HCA479 04HCA765 04HCA949 04HCA1007

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166 04HCA1711 04HCA2100 04HCA2346 04HCA2364 04JA36 04JA998 04JA1437 04JA1642 04JA2714 04JA2838 04JA4118 04JA4859 04JA5493 04JA5948 04JA7875 04JA8382 04JA9536 04JA9645 04JA10264 04JA11162 04JA11164 04JA12790 04JA13600 04.IA 14720 04JA15968 04JA15970 04JMC5816 04JNP14 04JNP42 04JNP94 04JNP343

04JNP389 04JNP495 04JNP682 04JNP685 04JNP714 04JNP767 04JNP772 04JNP921 04JNP932 04JNP990

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Five-membered ring systems: furans and benzofurans 04JNP1041 04JNP1147 04JNP1186 04JNP1383 04JNP1396 04JNP1426 04JNP1455 04JNP1483 04JNP1517 04JNP1544 04JNP1601 04JNP1796 04JNP1804 04JNP1859 04JNP1947 04JOC142 04JOCI331 04JOC1413 04JOC1557 04JOC1625 04JOC1738 04JOC1831 04JOC1845 04JOC1993 04JOC2037 04JOC2194 04JOC2235 04JOC2417 04JOC2577 04JOC2598 04JOC2637 04JOC3240 04JOC3282 04JOC3350

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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

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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

171

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 <04JHC109>. 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 <04TL1489>. Highly regioselective syntheses of 1,3,5-trisubstituted pyrazoles were prepared from acetylenic ketones and hydrazines <04S43>. Reactions of a-trifluoromethylated a-arylacetates 3 with excess hydrazines in refluxing dioxane afforded the corresponding 5-fluoropyrazolin-3-ones 4 <04T7943>. 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 <04TL8523>.

173

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

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 <04SC3281>. 5-(Substituted-amino)pyrazoles 11 were synthesized from (3-ketoamides 10 with hydrazines and Lawesson's reagent <04TL4265>. Diketooximes 12 reacted conveniently with excess hydrazine in ethanol to give 4-amino-3,5-disubstituted pyrazoles 13 <04TL2137>. (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 <04T901>. ?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 <04TL1769>. These trimethylsilylindazoles could also react with aryl aldehydes in the presence of cesium fluoride to give 3-(arylhydroxymethyl)indazoles in good to moderate yields <04S1183>. 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 <04CC104>. Reductive cyclization of o-nitroketoximes 24 in the presence of catalytic iron dimer in dioxane under a carbon monoxide atmosphere furnished 1//-indazoles 25 <04H(63)373>. Cyclization of hydrazones 26 in polyphosphoric acid (PPA) gave substituted indazoles 27 <04JHC601>. Efficient regiocontrolled synthesis of highly substituted and annulated indazoles from a-oxoketene dithioacetals has been reported <04T3457>.

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

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 <04TL5935>. 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 <04SL2299>.

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 <04TL6033>. The same results were obtained when aryl hydrazines were reacted with 2-formyl glycals under microwave irradiation <04TL8587>. Treatment of 3(3-aryl-3-oxopropenyl)chromen-4-ones with hydrazine yielded pyrazolyl-2-pyrazolines <04EJOC4672>. Intermolecular 1,3-dipolar cycloaddition of a-diazoarylacetates with alkynes in the presence of indium(III) chloride in water gave 3,5-disubstituted pyrazoles <04CC394>. 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 <04OL2193>.

Reaction of 5-trichloromethylpyrazoles 39 with various amines efficiently provided pyrazole-5-carboxamides 40 <04SC1915>. |3-Hydroxyethylpyrazoles were efficiently prepared from the regioselective ring opening of propylene and styrene oxide with various substituted pyrazoles <04TL5697>. Pyrazole-4-carboxaldehydes reacted with malonic acid to give 3-(4pyrazolyl)propenoic acids in high yields under microwave irradiation <04SC79>. Various nucleophilic aromatic substitutions on 5-chloropyrazoles 41 occurred readily to give 5substituted pyrazoles 42 in warm Af,./V*-dimethylformamide <04SC1541>. The photochemistry of trifluoromethyl substituted 1-methylpyrazoles has been reported <04JHC61>. 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 <04S2471>. 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 <04SL2303>.

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

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 <04JOC4433>.

^

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 <04S1744>. 1,3,5-Trisubstituted pyrazolines were aromatized to their corresponding pyrazoles with molecular oxygen in the presence of activated carbon <04S1015> or with trichloroisocyanuric acid as the oxidizing agent under solvent free conditions <04TL2181>. Clay-supported copper(II) nitrate (claycop) under ultrasound activation was found to be an ecofriendly reagent for the aromatization of various pyrazolines to pyrazoles <04TL4143>. 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 <04EJOC695>. L-Proline was an additive used in the copper-catalyzed 7V-arylation of pyrazole with aryl iodides <04SL128>. Copper(II) acetate-mediated TV-arylation with aryl boronic acids proceeded to form the N-2 substituted derivatives of 3-dimethylaminopropyloxypyrazoles <04JCO385>. Copper(I) iodide-catalyzed JV-arylations of various pyrazoles with aryl bromides and iodides were effectively performed in the presence of diamine ligands <04JOC5578>. 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 <04T933>. l//-Pyrazolo[3,4-6]pyridines 46 were obtained from copper(I) iodide-catalyzed cyclizations of 2-chloro-3-cyanopyridines with hydrazines <04TL2389>. Condensation of 2-pyrone with 3-aminopyrazolone led to a novel synthesis of pyrazolo[3,46]pyridines 47 <04SC2195>. 1-Substituted 4,5-diaminopyrazoles were useful precursors for the synthesis of pyrazolo[3,4-Z>]pyrazines 48 <04TL4105>. Intramolecular [3+2] nitrile oxide cycloadditions led to the synthesis of tetrahydroisoxazoloindazoles 49 <04TL4931>.

178

L. Yet

Intramolecular nitrilimine cycloadditions gave new pyrazolo[4,3-c]pyrrolizines 50 <04H(63)1423>. The syntheses of 5-substituted ethyl 3-oxo-2//-pyrazolo[4,3-c]pyridine-7carboxylates 51 <04H(63)609> and 5//-pyrazolo[4,3-c]quinolines 52 <04H(63)1883> have been described. Ring-closure reactions of 3-arylhydrazonoalkyl-quinolin-2-ones gave rise to 1-arylpyrazolo[4,3-c]quinolin-2-ones<04JHC681>.

A fully automated polymer-assisted synthesis of 1,5-biaryl pyrazoles has been reported <04JCO332>. 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 <04SC3521>.

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 <04S851>. 1,2Diaminoimidazoles 59 were obtained in good yields by reaction of l,2-diaza-l,3-butadienes 58 with cyanamide under solvent-free conditions <04SL549>. Thiazolium-catalyzed addition of the

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

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 <04OL843>. Reactions of a-amino nitriles 64 and isocyanates 65 provided 5-amino-2imidazolones 66 in moderate to good yields <04TL2677>. Routes to 4- and 5-nitro-lvinylimidazole have been disclosed <04JHC701>. iV-Malonylimidate 67 was activated with magnesium chloride in the presence of imine 68 to give imidazoline 69 <04JOC8537>. Flash vacuum pyrolysis of arylmethyl azides 70 gave 2,4-diazepentadienes 71 which upon further heating gave 2,4,5-triarylimidazoles 72 <04T6581>. 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 <04JOC5124>.

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 <04T5325>. 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 <04T9857>. 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 <04OL1681>. ./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 <04OL929>. O

"NHTS 78

R=Ar,Bn

Ts

'

79

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

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 <04OL4499>.

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 <04H(63)l 165>. 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 <04OL1453>. 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 <04H(63)87>.

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 <04JOC8829>. 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 <04T3967>.

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 <04H(63)41>. Copper(I) chloride-promoted intramolecular cyclizations of ./V-(2-aminoaryl)thioureas 101 provided a practical synthesis of 2-(7V-substituted)aminobenzimidazoles 102 <04TL7167>. A highly effective microwave-assisted fluorous Ugi and post-condensation reactions for benzimidazoles has been reported <04TL6757>. 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 <04SL1628>. Reactions of tetrahydrobenzimidazoles with dimethyldioxirane led to rearranged 5-imidazolone products <04OL735>. Multistep parallel synthesis of substituted 5-aminobenzimidazoles from l,5-difluoro-2,4-diaminobenzene in solution phase has been reported <04JCO811>. Substituted benzimidazoles underwent intermolecular coupling to alkenes at the C-2 position via rhodium-catalyzed C-H bond activation <04JOC7329>. 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 <04SC2245>. 1,2-Phenylenediamine reacted with aldehydes in the presence of ytterbium(III) triflate under solvent-free conditions <04SL1832> or in the presence of scandium triflate under an oxygen atmosphere to give substituted benzimidazoles <04H(63)2769>.

183

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

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 <04TL1869>. \Himidazole 108 is readily N-alkylated to 110 by a copper-catalyzed reaction with a-diazocarbonyl compounds 109 <04T9391>. 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 <04TL5529>. 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 <04TL5581>. l-(Alkyldithiocarbonyl)imidazoles 112 were prepared from imidazole 111 in the presence of carbon disulfide and alkyl halides <04S675>. 1. n-BuLi (2.2 equiv), THF, -30 JC

/T^ N

Br

2. (-BuNCO Bu

"" 105

R

<-BuHN.^#~ANHf-Bu °

f-BuHN.^/~ANHf-Bu

DMF, 6 0 G C

/T^N^'Y

3. NBS, MeCN

Pd(0), Et3N

h-Bu °

Y^N^iiC

reagents

°

106

\

9

Cu(acac)2

\ _

109 108

r=\

^NH 111

CS2,R-X

K3PO4, acetone1

N

Y 11

R = OEt,(CH2)2Ph,Ph,Ar

N

"-Bu ° 107

f=\ N

°

°

SR

^ Y

112

S

R = Me, /?-C4Hg, ally I, Bn, phthalimidyl

Several copper-catalyzed 7V-arylation reactions of imidazole have been published. The coupling of arylboronic acids with imidazole in the presence of binuclear bis-^-hydroxy copper (II) complexes in air has been carried out at ambient temperature without the need for base <04TL7659>. A variety of A'-arylimidazoles were prepared in excellent yields through the cross-coupling of arylboronic acids with imidazole in methanol or water with copper(I) chloride <04CC188>. Copper(II) oxide-coated nanoparticles were used catalytically in the Ullmann coupling of imidazole with various aryl chlorides with cesium carbonate in dimethyl sulfoxide <04CC778>.

184

L. Yet

Imidazolines could be dehydrogenated to imidazoles with potassium permanganate supported on silica gel in acetonitrile at ambient temperature <04TL8687>, with o-iodoxybenzoic acid in dimethyl sulfoxide at 45 °C <04JA5192> and with trichloroisocyanuric acid in the presence of DBU <04SL2803>. Several imidazole-containing reagents have been employed catalytically in various reactions. Boehringer-Ingelheim phosphinoimidazoline (BlPI)-type ligands 113 have been utilized in the control of chiral quaternary center creation in the intramolecular asymmetric Heck reaction <04JOC5187>. A new chiral benzimidazole-pyrrolidine ligand (BIP) 114 has been found to be a highly reactive chiral organocatalyst for the aldol reaction <04TL8035>. 7V-Acyl-7V-heterocyclic carbene palladacycle precursor 115 was found to have high turnover numbers in Suzuki coupling reactions <04TL3849>.

Several solid-phase syntheses of substituted imidazoles have been published. Resin-bound ureido acetals 116 were treated with trifluoroacetic acid to give disubstituted 1,3dihydroimidazol-2-ones 117 via intramolecular 7V-acyliminium cyclization <04SL2167>. Cleavage of resin-bound guanidinoamides 118 gave 1,5-disubstituted 2-(Nalkylamino)imidazolidin-4-ones 119 <04TL1267>. Solid-supported 5-aminopyrazoles 120 were cleaved with acetic acid in toluene to give functionalized imidazo[l,2-5]pyrazol-2-ones 121 <04TL1275>. Resin-bound 3-N, Ar-(dimethylamino)isocyanoacrylate 122 reacted with various amines to give imidazole-4-carboxylates 123 <04TL2219>. A small library of polyamineimidazole conjugates have been synthesized on SynPhase lanterns using amino alcohols and diamines as building blocks <04OL4711>. A novel intramolecular SwAr rearrangement of benzoimidazole-2-thiones was utilized as a template to prepare biheterocyclic indolebenzoimidazole derivatives on solid-phase <04OL4763>. A combinatorial approach to 2alkythioimidazocoumarins has been reported <04JCO604>. Polymer-supported [hydroxyl(sulfonyloxy)iodo]benzene reacted with ketones or alcohols followed by treatment with benzamidines or 2-aminopyridine to yield imidazoles and imidazo[l,2-a]pyridines, respectively <04S2673>. Polymer-bound esters were treated with 1,2-phenylenediamines in the presence of a Lewis acid to give benzimidazole cleavage products <04TL313>. Resin-bound 2aminobenzimidazoles underwent an unprecedented aza-Wittig/heterocyclization/substitution reaction sequence using halogenoalkyl isocyanates to give new tetracyclic benzimidazole systems <04JCO220>. A traceless solid-phase synthesis of substituted benzimidazolones has been reported <04JCO899>. A parallel solid-phase synthesis of 2-arylamino-6//-pyrano[2,3/|benzimidazole-6-ones has been published <04T8605>.

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

185

Many ring-fused imidazole derivatives have been reported. Disubstituted imidazo[4,5&]pyridine-2-ones 124 were prepared from 2-chloro-3-iodopyridine via two sequential palladium-catalyzed amination reactions followed by treatment with triphosgene <04JOC7752>. The first tandem double palladium-catalyzed aminations that led to the synthesis of dipyrido[l,2a:3',2'-. Regioslective synthesis of 6- and 7-substituted thiazolo[3,2-a]benzimidazoles 125 was achieved by crystallization-induced regioisomerization <04H(62)815>. Pyrrolo[3',4':3,4]pyrido[l,2-a]benzimidazoles 126 were prepared from cyclocondensation of 2benzimidazoleacetonitrile with ethyl 4-chloro-3-oxobutanoate followed by amination reactions <04S373>. 6-Arylbenzimidazo[l,2-c]quinazolines 127 were prepared under microwave irradiation and solvent-free conditions <04S436>. Reactions of acylbenzoic acids and 2-nitro-5chlorophenylhydrazine followed by amine addition, reduction and acidic cyclization gave benzo[4,5]imidazo[2,l-a]phthalazines 128 <04TL1407>. Novel pyrido[l\2':l,2]imidazo[5,4ii]-l,2,3-triazinones 129 were prepared from imidazo[l,2-a]pyridines <04JHC91>. Cyclocondensation of alkynyl(phenyl)iodonium salts and 2-aminopyridine provided a facile route to syntheses of 2-substituted-imidazo[l,2-a]pyridines 130 <04SC361>. Reactions of

186

L. Yet

hydrazides and malononitriles followed by intramolecular cyclodehydration gave imidazo[l,26]pyrazol-2-ones 131 <04TL619>. 1-Methylimidazole reacted smoothly with dialkyl acetylenedicarboxylates in the presence of isocyanates to produce an efficient one-pot synthesis of 7-oxo-l,7,8,8a-tetrahydroimidazo[l,2-a]pyrimidines 132 <04SL1086>.

5.4.4

1,2,3-TRIAZOLES AND RING-FUSED DERIVATIVES

Various phenacyl halides 133 reacted with excess tosyl hydrazine in refluxing methanol to provide 4-aryl-l-(p-toluenesulfonylamido)-l,2-3-triazoles 134 <04SC1175>. Addition of bromomagnesium acetylides 136 to aryl azides 135 led to the regioselective preparation of 1,5disubstituted-l,2,3-triazoles 137, which could be trapped with various electrophiles to form 1,4,5-trisubstituted 1,2,3-triazoles 138 <04OL1237>. Polytriazoles were employed as copper(I)stabilizing ligands in the synthesis of 1,2,3-triazoles <04OL2853>. Racemic 5-(4,5-substitutedl//-l,2,3-triazolyl)pipecolic acids 139 were obtained in racemic form from meso dimethyl-a,a'dibromoadipate <04TL8905>. The Baylis-Hillman adducts of 2-alkynylbenzaldehydes were employed in the synthesis of 5//-l,2,3-triazolo[4,3-a][2]benzazepines <04JHC613>.

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

187

1,3-Dipolar cycloadditions have been employed in the syntheses of various 1,2,3-triazoles. A one-pot procedure for the regiocontrolled synthesis of 2-allyl-l,2,3-triazoles 142 via the threecomponent coupling reaction of nonactivated alkynes 140, allyl carbonate (141), and trimethylsilyl azide via a Pd-Cu bimetallic catalyst has been developed while the combination of Pd(OAc)2-CuBr2-PPh3 promoted the formation of l-allyl-l,2,3-triazoles <04JOC2386>. Similarly, the four-component coupling reactions of silylacetylenes, allyl carbonates, and trimethylsilyl azide catalyzed by a Pd(0)-Cu(I) bimetallic catalyst led to trisubstituted 1,2,3triazoles <04TL689>. The [3+2] cycloaddition of nonactivated terminal alkynes and trimethylsilyl azide proceeded smoothly in the presence of copper catalyst and N,Ndimethylformamide and methanol to give the corresponding iV-unsubstituted 1,2,3-triazoles in good to high yields <04EJOC3789>. Condensation of enaminones 143 with mesyl azide gave l,4,5-trisubstituted-l,2,3-triazoles 144 <04SC369>. 1,3-Dipolar cycloaddition of tributyl(3,3,3trifluoro-1-propynyl)stannane 145 with phenyl azide gave the corresponsding 1,2,3-triazole 146, which was a useful building block for further functionalization <04TL7573>. Dipolar cycloadditions of azido ester 148 with electron-deficient alkynes 147 gave 1,4,5-trisubstituted 1,2,3-triazoles 149 under mild conditions in water <04TL3143>. Triazole-linked glycopeptides were obtained by Cu(I)-catalyzed cycloadditions of either azide-functionalized glycosides and acetylenic amino acids or acetylenic glycosides and azide-containing amino acids <04OL3123>. Two reports have been published which showed vitamin D analogues with 1,2,3-triazole side chains <04TL4619, 04TL4623>. 1,4-Disubstituted 1,2,3-triazoles 152 were obtained in excellent yields by a convenient one-pot procedure from a variety of aryl and alkyl halides 150 with alkynes 151 without isolation of potentially unstable organic azide intermediates <04OL3897>. Copper(I)-catalyzed 1,3-dipolar cycloaddition reaction of nonfluorescent 3azidocoumarins and terminal alkynes afforded intense fluorescent 1,2,3-triazole products <04OL4603>. Sodium azide reacted with diphenylvinylsulfonium triflate to give a 4-aryl-l,2,3triazole product <04H(63)2813>. TMSN3 Pd2dba3-CHCI3 R

— 140

H

+

^v/OCO2Me ' 141

CuC|

(PPh3)3 , P(OPh)3 EtOAc, 100'C

R

\ / \ N' L

142 II

188

L. Yet

Novel 1,2,3-triazolopyridylboronic acids and esters were prepared and were utilized in Suzuki-type reactions <04T4887>. Benzotriazole was regiospecifically substituted at the N-l position with alkyl halides or a-halogenated ketones in the absence of base in ionic liquid [Bmim][BF4] conditions <04H(63)1077>. Several benzotriazole-mediated processes have been reported. Benzotriazole was used to activate carboxylic acids in the presence of EDC/HC1 followed by reaction with amidoximes to generate oxime esters, which were in turn dehydrated to give 1,2,4-oxadiazoles <04SC1863>. Lithiated l-[(methylthio)methyl]-l//-benzonitrile reacted with various heteroaryl ketones to give 2-benzotriazolyl alcohols which were thermolyzed in the presence of zinc bromide to give o> methylthio ketones via a 1,2-shift rearrangement <04JOC4269>. Lithiated 1-(1benzotriazolylalkyl)benzotriazoles underwent additions to cyclic and acyclic ketones to give intermediate alcohols, which were then thermolyzed in the presence of zinc bromide to give onecarbon chain-extended or ring-expanded cc-benzotriazolyl ketones with excellent regioselectivity <04JOC303>. Bis(benzotriazolyl)methanethione reacted with various amines to yield 1(alky/arylthiocarbamoyl)benzotriazoles, which were stable isothiocyanate equivalents, in the

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

189

syntheses of di- and trisubstituted thioureas <04JOC2976>. (Benzotriazol-1yl)carboximidamides were employed for the preparation of polysubstituted acylguanidines and guanylureas <04JOC309>. A general and efficient synthesis of sulfonamides was reported from reactions of 7V-heterosulfonylbenzotriazoles with primary and secondary amines <04JOC1849>. Reactions of 5-[Ar-(benzotriazol-l-ylmethyl)amino]-3-fert-butyl-l-phenylpyrazole or 5-amino-4(benzotriazol-l-yl)-3-fert-butyl-l-phenylpyrazole with unactivated and electron-rich alkenes yielded hydropyrazolopyridines under solvent-free conditions <04T8839>. Polystyrene-sulfonyl hydrazide resins 153 reacted with various amines to give regiospecifically l,4-disubstituted-l,2,3-triazoles 154 via traceless cleavage reactions <04TL6129>. A library of peptidotriazoles were prepared by solid-phase peptide synthesis combined with a regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition between resinbound alkynes and protected amino azides <04JCO312>.

5.4.5

1,2,4- TRIAZOLES AND RING-FUSED DERIVATIVES

Syntheses of quaternary l-alkyl-3-perfluoroalkyl-4,5-dimethyl-l,2,4-triazolium iodides have led to the disclosure of a variety of new quaternary salts <04JOC1397>. Arylation of 3alkylthio-5-aryl-l,2,4-triazoles under basic conditions gave 5-alkylthio-l,3-diaryl-l,2,4-triazoles in moderate yields <04JHC201>. Acyl hydrazides 155 reacted with imidates 156 to yield 1,2,4triazoles 157 followed by Mitsunobu reactions with amino alcohols 158 to give regioisomeric 1,2,4-triazoles 159 and 160 in a parallel solution-phase synthesis fashion <04JCO35>.

159

160

An efficient one-pot, three-component synthesis of substituted 1,2,4-triazoles 164 has been reported from primary amines 161, dimethylamino acetals 162, and acyl hydrazides 163 <04OL2969>. 1,3-Benzoxazine 165 reacted with acyl hydrazides in refluxing methanol to give

190

L. Yet

1,2,4-triazoles 166 <04SC2655>. Photochemistry of some fluorinated oxadiazoles gave rise to mixtures of fluorinated 1,3,4-oxadiazoles and 1,2,4-triazoles <04JOC4108>. Diethoxyphosphinyl acetic acid hydrazide 168 was found to be a unique reagent for a convenient and efficient process to prepare fused [5,5]-, [5,6]-, and [5,7]-3-[(£)-2-(arylvinyi)]-l,2,4-triazoles 169 from aldehydes and alkoxyimines 167 <04TL1877>. New mono- and bipolar surfactants have been prepared from l,2,4-triazole-5-thiones <04SC4189>. Amines 170 were converted to 1-formyl semicarbazides 171 which were cyclized smoothly to 2,4-dihydro-3//-l,2,4-triazolin-3ones 172 with hexamethyldisilazane, bromotrimethylsilane, and a catalytic amount of ammonium sulfate <04OL4795>. S-Alkylated thioamides 173 were reacted with acyl hydrazides 174 to give 3,4,5-trisubstituted 4//-l,2,4-triazoles 175 in refluxing n-butanol <04EJOC3422>.

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

191

1,2,4-Triazolium salt 176 was a catalytically competent nucleophilic carbene used in the conversion of a-haloaldehydes into acylating agents <04JA9518>.

176 5.4.6

TETRAZOLES AND RING-FUSED DERIVATIVES

Microwave-assisted preparation of aryltetrazoleboronate esters 178 and 2,4-disubstituted-3(5-tetrazolyl)pyridines 180 were obtained, respectively, from benzonitriles 177 <04OL3265> and nicotinonitriles 179 <04TL2571> with trimethylsilyl azide and dibutyltin oxide. Tetrabutylammonium fluoride was an efficient catalyst for the [3 + 2] cycloaddition reaction of nitriles with trimethylsilyl azide under solvent-free conditions <04JOC2896>. 1-Substituted tetrazoles 182 were synthesized by a [3+2] cycloaddition between isocyanides 181 and trimethylsilyl azide in the presence of hydrochloric acid in methanol <04TL9435>.

CH 2 NH 2

pi 0 177

^

TMSN 3

H

Bu2SnO

pL

\ ^

R2

microwave

£

'

A.

178

TMSN 3 _

kl_

R-NC 181

I

Me

TMSN3

R2

Bu?SnO . microwave

179

R1

>
R

HCI, WleOH

.

Ri

M_CN

N-n

•

N'^ N

»N

R = Ar, f-Bu, CH2TMS, n-Bu

182

Several tetrazolyl ligands have found useful applications in several types of reactions. l-(2Iodophenyl)-l//-tetrazole 183 has been successfully employed as a ligand for the Pd(II)catalyzed Heck reaction <04TL4113>. l,3-Phenylene-bis-(l//)-tetrazole Pincer ligand 184 has been used successfully for the palladium-catalyzed Suzuki cross-coupling reactions of aryl halides with arylboronic acids <04SL2227>. 5-Pyrrolidin-2-yltetrazole 185 has been found to be a new, catalytic, and more soluble alternative to proline in an organocatalytic asymmetric Mannich-type reactions <04SL558> and as an asymmetric organocatalyst for the addition of ketones to nitroolefins <04CC1808>.

192

L. Yet

Several ring-fused tetrazole compounds have been reported. 2-Methyl-3-cyanopyridines were converted into their corresponding 2-azidomethyl derivatives, which underwent intramolecular cycloaddition reactions to give 3-(tetrazol-5-yl)pyridines 186 <04TL9127>. Fused tetrazole derivatives 187 were obtained via tandem cycloaddition and A'-allylation reactions <04JOC1346>. Expeditive synthesis of homochiral fused tetrazole piperazines 188 from |3-amino alcohols has been reported <04TL3725>. A novel Ugi-five-center-fourcomponent reaction (U-5C-4CR) of aldehydes, primary amines, trimethylsilyl azide and 2isocyanoethyl tosylate afforded tetrazolopiperazine type compounds <04TL6421>.

Resin-bound benzonitriles 189 were reacted with trimethylsilyl azide in the presence of dibutyltin oxide followed by acidic cleavage to give 5-biphenyl-2-yl-l//-tetrazoles 190 <04OL1143>. Resin-bound thioureas 191 reacted with sodium azide in the presence of mercury(II) chloride followed by acidic cleavage to give 5-aminotetrazoles 192 <04TL7787>.

5.4.7 04CC104 04CC188 04CC394

REFERENCES C.S. Cho, D.K, Lim, N.H. Heo, T.-J. Kim, S.C. Shim, Chem. Commun. 2004, 104. J.-B. Lan, L. Chen, X.-Q. Yu, J.-S. You, R.-G. Xie, Chem. Commun. 2004, 188. N. Jiang, C.-J. Li, Chem. Commun. 2004, 394.

Five-membered ring systems: with more than one N atom 04CC778 04CC1808 04CC2466 04EJOC695 04EJOC3422 04EJOC3789 04EJOC4672 04H(62)815 04H(63)41 04H(63)87 04H(63)373 04H(63)609 04H(63)1077 04H(63)l 165 04H(63)1423 04H(63)1883 04H(63)2769 04H(63)2813 04JA5192 04JA9518 04JCO35 04JCO220 04JCO312 04JCO332 04JCO385 04JCO604 04JCO811 04JCO899 04JHC61 04JHC91 04JHC109 04JHC201 04JHC601 04JHC613 04JHC681 04JHC701 04JOC303 04JOC309 04JOC1346 04JOC1397 04JOC1849 04JOC2386

193

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194 04JOC2896 04JOC2976 04JOC4108 04JOC4269 04JOC4433 04JOC5124 04JOC5187

04JOC5578 04JOC7329 04JOC7752 04JOC8537 04JOC8829 04OL735 04OL843 04OL929 04OL1143 04OL1237 04OL1453 04OL1681 04OL2193 04OL2853 04OL2969 04OL3123 04OL3265 04OL3897 04OL4499 04OL4603 04OL4711 04OL4763 04OL4795 04S43 04S1015 04S373 04S436 04S675 04S851 04S1183 04S1744 04S2471 04S2673 04SC79 04SC361 04SC369

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Five-membered ring systems: with more than one N atom 04SC1175 04SC1541 04SC1863 04SC1915

04SC2195 04SC2245 04SC2655 04SC3281 04SC3521 04SC4189 04SL1086 01SL128 04SL549 04SL558 04SL1628 04SL1832 04SL2167 04SL2227 04SL2299 04SL2303 04SL2803 04T901 04T933 04T3457 04T3967 04T4887 04T5325 04T6581 04T7943 04T8605 04T8839 04T9391 04T9857 04TL313 04TL619 04TL689 04TL1137 04TL1267 04TL1275 04TL1407

195

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196 04TL1489 04TL1769 04TL1869 04TL1877 04TL2137 04TL2181 04TL2219 04TL2389 04TL2571 04TL2677 04TL3143 04TL3725 04TL3849 04TL4105 04TL4113 04TL4143 04TL4265 04TL4619 04TL4623 04TL4931 04TL5529 04TL5581 04TL5697 04TL5935 04TL6033 04TL6129 04TL6421 04TL6757 04TL7167 04TL7573 04TL7659 04TL7679 04TL7787 04TL8035 04TL8523 04TL8587 04TL8687 04TL8905 04TL9127 04TL9435

L. Yet C D . Cox, M J . Breslin, B.J. Mariano, Tetrahedron Lett. 2004, 45, 1489. Y. Shoji, Y. Hari, T. Aoyama, Tetrahedron Lett. 2004, 45, 1769. A.G. Chittiboyina, C.R. Reddy, E.B. Watkins, M.A. Avery, Tetrahedron Lett. 2004, 45, 1869. F. Liu, D.C. Palmer, K.L. Sorgi, Tetrahedron Lett. 2004, 45, 1877. T. Majid, C.R. Hopkins, B. Pedgrift, N. Collar, Tetrahedron Lett. 2004, 45, 2137. M.A. Zolfigol, D. Azarifar, B. Maleki, Tetrahedron Lett. 2004, 45,2181. B. Henkel, Tetrahedron Lett. 2004, 45, 2219. G. Lavecchia, S. Berteina-Raboin, G. Guillaumet, Tetrahedron Lett. 2004, 45, 2389. I.V. Bliznets, A.A. Vasil'ev, S.V. Shorshnev, A.E. Stepanov, S.M. Lukyanov, Tetrahedron Lett. 2004, 45, 2571. B.W. Parcher, D.M. Erion, Q. Dang, Tetrahedron Lett. 2004, 45, 2677. Z. Li, T.S. Seo, J. Ju, Tetrahedron Lett. 2004, 45, 3143. F. Couty, F. Durrat, D. Prim, Tetrahedron Lett. 2004, 45, 3725. H. Palencia, F. Garcia-Jimenez, J.M. Takacs, Tetrahedron Lett. 2004, 45, 3849. T.-C. Chien, R.A. Smaldone, L.B. Townsend, Tetrahedron Lett. 2004, 45,4105. A.K. Gupta, C.H. Song, C.H. Oh, Tetrahedron Lett. 2004, 45,4113. S. Mallouk, K. Bougrin, H. Doua, R. Benhida, M. Soufiaoui, Tetrahedron Lett. 2004, 45, 4143. D.S. Dodd, R.L. Martinez, Tetrahedron Lett. 2004, 45, 4265. P.L. Suarez, Z. Gandara, G. Gomez, Y. Fall, Tetrahedron Lett. 2004, 45, 4619. B.-C. Suh, B. Jeon, G.H. Posner, S.M. Silverman, Tetrahedron Lett. 2004, 45, 4623. K.-H. Park, W.J. Marshall, Tetrahedron Lett. 2004, 45,4931. Y. He, Y. Chen, H. Du, L.A. Schmid, C.J. Lovely, Tetrahedron Lett. 2004, 45, 5529. S. Price, R. Bull, S. Cramp, S. Gardan, M. van den Heuvel, D. Neighbour, S.E. Osbourn, I.J.P. de Esch, C.L. Buenemann, Tetrahedron Lett. 2004, 45, 5581. V. Duprez, A. Heumann, Tetrahedron Lett. 2004, 45, 5697. N. Haddad, A. Salvagno, C. Busacca, Tetrahedron Lett. 2004, 45, 5935. J.S. Yadav, B.V.S. Reddy, M. Srinivas, A. Prabhakar, B. Jagadeesh, Tetrahedron Lett. 2004, 45, 6033. M.S. Raghavendra, Y. Lam, Tetrahedron Lett. 2004, 45, 6129. M. Umkehrer, J. Kolb, C. Burdack, G. Ross, W. Hiller, Tetrahedron Lett. 2004, 45, 6421. W. Zhang, P. Tempest, Tetrahedron Lett. 2004, 45, 6757. X.-j. Wang, L. Zhang, Y. Xu, D. Krishnamurthy, C.H. Senanayake, Tetrahedron Lett. 2004, 45, 7167. T. Hanamoto, Y. Hakoshima, M. Egashira, Tetrahedron Lett. 2004, 45, 7573. S.S. van Berkel, A.V.D. Hoogenband, J.W. Terpstra, M. Tromp, P.W.N.M. van Leeuwen, G.P.F. van Strijdonck, Tetrahedron Lett. 2004, 45, 7659. S.K. Singh, M.S. Reddy, S. Shivaramakrishna, D. Kavitha, R. Vasudev, J.M. Babu, A. Sivalakshmidevi, Y.K. Rao, Tetrahedron Lett. 2004, 45, 7679. Y. Yu, J.M. Ostresh, R.A. Houghten, Tetrahedron Lett. 2004, 45, 7787. E. Lacoste, Y. Landais, K. Schenk, J.-B. Verlhac, J.-M. Vincent, Tetrahedron Lett. 2004, 45, 8035. A. Guirado, B. Martiz, R. Andreu, Tetrahedron Lett. 2004, 45, 8523. J.S. Yadav, B.V.S. Reddy, G. Satheesh, P.N. Lakshmi, S.K. Kumar, A.C. Kunwar, Tetrahedron Lett. 2004, 45, 8587. I. Mohammadpoor-Baltork, M.A. Zolfigol, M. Abdollahi-Alibeik, Tetrahedron Lett. 2004, 45, 8687. F. Lenda, F. Guenoun, B. Tazi, N.B. Larbi, J. Martinez, F. Lamaty, Tetrahedron Lett. 2004, 45, 8905. I.V. Bliznets, S.V. Shorshnev, G.G. Aleksandrov, A.E. Stepanov, S.M. Lukyanov, Tetrahedron Lett. 2004, 45, 9127. T. Jin, S. Kamijo, Y. Yamamoto, Tetrahedron Lett. 2004, 45, 9435

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Chapter 5.5 Five-membered ring systems: with N and S (Se) atoms Yong-Jin Wu,a Upender Velaparthia and Bingwei V. Yangb Bristol Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492-7660, USA b Bristol Myers Squibb Company, PO Box 4000, Princeton, NJ 08543-4000, USA [email protected], [email protected] and [email protected] a

5.5.1

INTRODUCTION

The study of thiazoles has continued to flourish primarily due to their importance in both synthetic targets and drug candidates. The syntheses and reactions of 5-membered heterocyclic ring systems containing nitrogen and sulfur (or selenium) that have been reported during 2004 are the topic of this review. The importance of these Jt-rich heterocycles in medicinal chemistry and natural products is also covered. 5.5.2

THIAZOLES

5.5.2.1 Synthesis of Thiazoles and Fused Derivatives The use of thioamides and a-halocarbonyl compounds (Hantzsch reaction) is one of the most utilized methods for the preparation of thiazoles and several applications appeared during the past year O4JHC723; 04H(62)203; 04H(63)1083; 04TL7125; 04BMCL677>. This approach has been used in the synthetic studies of cytostatic peptides tubulysins <04OL4057> and thiopeptide antibiotic amythiamicin <04CC102>. The thiazolation of ccbromomethyl ketone 1 with thioamide 2 results in the formation of tri(thiazole) 3 as a potential precursor to macrocyclic antibiotic thiocilline I <04CL814>. Generation of the aiodocarbonyl component and condensation with thioamide in one pot has been described <04CPB634>. For example,

198

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

treatment of cyclohexanone with thiourea and iodine at 100 °C affords thiazole 4 in good yield. However, a mixture of regioisomers is obtained from unsymmetrical ketones An alternative to the Hantzsch reaction is the enamine approach by the procedure of Gewald and Kozikowski <04H(63)1555>. Thus, exposure of enamine 5 to elemental sulfur and subsequent addition of cyanamide give 6 in moderate yield. This procedure is applicable for large scale production of 6. Thiazoles can also be derived from 1,4-dicarbonyl compounds, which are available through N-H insertion reactions of rhodium carbenoids <04T3967>. For example, the dirhodium(II) carboxylate-catalyzed reaction of diazocarbonyl compound 7 in the presence of primary amide 8 results in the formation of a-acylaminoketone 9, which is converted into thiazole 10 by treatment with Lawesson's reagent. The cyclodehydration of |3-keto thioamide 11 to thiazole 12 is carried out with pyridine-buffered phosphorus oxychloride <04JA12897>.

Thiazoles can be readily prepared from thiazolines either by oxidation (e.g., 13 to 14) <04CEJ71> or by bromination-elimination protocol (e.g., 15 to 16) <04H(63)773>. The exclusive formation of thiazole-thiazoline 16 indicates that the C-4 acyl group of the thiazoline is essential for the formation of thiazoles under CBrCb/DBU conditions. In the case of the thiazoline Weinreb amide 17, the thiazole formation is carried out using CBrCVDBU (17 to 20) or through a novel base-induced transformation presumably via aziridone 18 (17 to 19) <04T12139>. Pr-/ O

Thiazole derivatives are obtained from ethyl 3-amino-3-acylhydrazinopropenoate 21 in good yields <04H(63)259>. Treatment of 21 with thiourea and bromine in acetic acid

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

199

furnishes 2-aminothiazole 24 via bromide 22, while 2-iminothiazole 26 is formed when sodium thiocyanate is used instead of thiourea.

2-Thiazolin-4-one derivative 29 in hydrazino-hydrazono tautomeric equilibrium is synthesized by cyclization of l,2-diaza-l,3-butadiene 27 with aryl thioamide 28. Subsequent hydrolytic removal of the NH-Boc-hydrazo protecting group provided 5-acetyl-4hydroxythiazole derivative 30a, which undergoes a-bromination to give a-bromomethyl ketone 30b. This bromide is used to prepare polyfunctionalized 4,5'-bithiazol-4'-ol derivatives via the Hantzsch thiazole synthesis <04SL2681>.

2-Arylthiazole 33 with a cyanoacetate moiety at C-4 is prepared via a novel cyclization from iminothiazine hydroperchlorate 31, readily available from the reaction of ethyl 2-cyano3,3-bis(methylthio)acrylate and phenylthioamide <04H(63)2319>. Treatment of 31 with phenacyl bromide and triethylamine in methanol generates 33, which is converted to the thiazolo[5,4-c]pyridine 34 under acidic conditions.

Two new methodologies have been developed for the preparation of 2-arylthiazoles 35 from 2-aminothiophenol and aryl aldehydes: One uses ionic liquid, l-pentyl-3methylimidazolium bromide ([pmlmJBr), under microwave conditions <04CL274>; the other involves catalytic amount of scandium triflate in the presence of oxygen <04H(62)197>. The 2-aminobenzothiazole 37 is prepared by means of copper- and palladium-catalyzed intramolecular C-S bond formation <04CC446>. With respect to the 7-nitro-2aminobenzothiazole 40, a one step synthesis has been developed (38 to 40) <04TL9373>.

200

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

The synthesis of halogenated 2(3//)-benzothiazolethiones 44 is carried out using orthoselective nucleophilic aromatic substitution reaction of polyhaloanilines 41 with potassium O-ethyl xanthate 42 <04JOC7371>. ~

CT \^SH

NCS


£S

Culor

- ,f r y . (Y'i ^ f r s > - -

or Sc(OTf)3, 02 V ^ ^ S 35

KNCO K

U

2° 3

^^N^NHR 36 H

[ITYVNHR1 |

NO2 38

88-97% \ S ^ N 37

61-98% u ^ v v

II

[

NO2 39

V - NHR

N02 40 H

R

f T

\ ^ ^ x 41 X = CI, Br, F

+

A KS^"OEt 42

R

0Et

— - fT /

—-

\#^-s^4

15-99%

L

S

43

J

R

T

i >=s

\ j ^ 44

S

A series of 3-benzylthiazolo[3,2-a]benzimidazoles 47 are prepared from 2-mercaptopropargyl benzimidazole 45 with various aryl iodides via palladium-copper-catalyzed Sonogashira coupling followed by heterocyclization <04TL5747>. A regioselective synthesis of 6- and 7-substituted thiazolo[3,2-a]benzimidazole derivatives from 2mercaptobenz-imidazole has been reported <04H(62)815>. Treatment of 48 with methyl formylchloroacetate in DMF at 65 °C generates 49, which is converted to 50 upon exposure to cone, sulfuric acid. Compound 49 undergoes isomerization with hydrochloric acid to give 51, which is dehydrated to furnish 52.

201

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

The synthesis of benzothiazolo pyrimidinone 55 involves a regioselective [4+2] cycloaddition of benzothiazolo fused l,3-diazabuta-l,3-diene 53 with phenylketene <04T4315>. Diene 53 is readily prepared from the condensation of l,3-diazabuta-l,3-diene with 2-aminothiophenol. Condensation of the stable Hantzsch reaction intermediate 56 with 1,2-phenylenediamine 57 in refluxing acetic acid furnishes thiazolo[3,4-a]quinoxalin-4-one 59 <04H(63)1783>. Intermediate 56 is available from the Hantzsch reaction of methyl phenylchloropyruvate with 7V,./V-diphenylthiourea. PhCH2COCI Ph

Ph

Ph^N

Et3NJ

Ph NH

NVN

N

_

I J ^ 53

Ph H

PhNVNx_

rf

S-J^A

"

^ ^

®^O L

54

NPh

MeO,C OH o- X Ph

/=^

A « Ph'

„

N H

2

NH2

"*\JL PhHN ^ S

HOAc

-MeOH L ^ L L H L

56

Ph

"I

^V^V°

ph

W _

^ ^

T

"

Ph

^k^°

-

N

?3%

VN\_

\)

J

55

—

-i PhN Ph

-PhNH2

-^Q Tv

K^NX0 H

J

58

59

5.5.2.2 Synthesis of Thiazolines As described previously, thiazolines are versatile intermediates to thiazoles. In addition, thiazoline rings are structural motifs found in numerous natural products. Among a variety of methods for the construction of thiazolines, the cyclodehydration protocol is perhaps most popular. Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) is used as the cyclodehydrating agent for the conversion of (3-hydroxy thioamide 60 to the bis(thiazoline) 15 <04H(63)773>. A more recent protocol for the cyclodehydration of (3-hydroxy thioamides to thiazolines involves pyridine-buffered phosphorus oxychloride as exemplified by the formation of 62 from 61 <04JA12897>. MeO2C

J

°kH D««°- CO2Me

H rOH F3C-JNH 1 60

S

68%

OHS

c^j-s^ „ S

15

r> '

N

N

61

p°C'3'

s

ph

" 93% —' Cr* N

62

In the total synthesis of cyclic peptide natural products bistratamides E and J, the thiazoline moiety of 13 is formed from the trityl protected cysteine 63 by a nucleophilic attack of the cysteine thiol group on the phosphorus-activated amide carbonyl group of the preceding residue (see 64) <04CEJ71>. The titanium tetrachloride catalyzed cyclodehydration of a vinyl substituted amido thiol 65 is utilized to assemble the thiazole portion of kalkitoxin 66, a cytotoxic metabolite of cyanobacterium Lyngbya majuscula <04OBC2092>. An alternative synthesis of kalkitoxin 66 involves the Wipf s oxazolinethiazoline conversion as the key step <04T6859>. Thus, the oxazoline formation is carried

202

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

out from 67 by (diethylamino)sulfur trifluoride (DAST), and treatment of the resulting oxazoline 68 with hydrogen sulfide led to ring-opening to give the thioamide 69, which is recyclized to afford kalkitoxin. Pr-/

O

ph3

N

HN-^Y V^OAIIyl Fmoc O ^

T

p0

["

rSH

II

f H

L TiCI4

65

O

fr

, ~ \

DAST

66 (kalkitoxin) Me

1

pr-j

0

^ , ' FmocHN-V^-^OAIIyl _ _ HN^N-^OAIIyl 89o/o (Tf0)ph3pt0^J Fmoc S J

63

o

Pr-'

0

Me

64

13

J

s

rOH

H2Si

||

|

Et3N

? " ^ v S>

69

68

M;e

DAST| 81%

R= B A ^ N V ^ \ ^ V > ^ < O M'e Me

OH RANA^ o

H

67

5.5.2.3 Synthesis of 2-Methylene- and 2-Imino-thiazolidine Derivatives 2-Alkylidene-4-(hydroxymethyl)thiazolidine 74 is prepared from a one-pot cyclization of dilithiated benzylnitrile 70 with phenylisothiocyanate 71 and epibromohydrin <04SL2200>. The formation of 74 can be rationalized by attack of the dianion of 70 onto the central carbon atom of 71 to give the dianionic intermediate 72, S-alkylation and subsequent epoxide opening of 73. The cyclization proceeds with good regio- and is-diastereoselectivity (EIZ = 5:1). A similar cyclization is utilized to prepare 2-alkylidenethiazolidine-4,5-dione 76 <04SL1963>. Again, good regio- and £/Z-diastereoselectivity is observed. The good EIZdiastereoselectivity is attributed to the steric repulsion of the phenyl groups. °H

O

Ph

Y-N

CN

^ ~ -

Lg^^ph

PKCH2CN B

41-94%

Ph-N=C=S

28-58%

*"

0J^S^"^Ph

76 i

I n-BuLi

|

j (2.2 equiv.) h

1

S7JN C L ^S^^PhJ "

ON ' ^ c N

71

|

p h

CIC(O)CO2Et

+

74

^

n.BuLi(22equiv);

r

f

Ph

^ es^h 72

I

| r

2uffi

Ph

"

_ _ Wfr CN O-S^^Ph L

°

75

uffl

J

A regioselective synthesis of 3-(heteroaryl)-iminothiazolidin-4-ones is based on the cyclization of unsymmetrical thioureas with bromoacetate in the absence of base <04TL1907>. For example, thioureas 77a/b are treated with 1.0 equiv. ethyl bromoacetate in acetonitrile at 80 °C to give 79a/b in good yields. The high regioselectivity in these cyclizations presumably results from the intramolecular hydrogen bonding as depicted in

203

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

78a/b. With respect to the 2-unsubstituted imino-4-thiazolidinones, a one-pot threecomponent synthesis from aldehydes has been developed <04TL4449>. For example, treatment of benzaldehyde with chloroform and DBU followed by addition of aqueous solution of thiourea and sodium hydroxidegives thiazolidinone 83 in moderate yield. The formation of 83 presumably involves gem-dichlorooxirane intermediate 81 under basic conditions and subsequent ring opening by thiourea to give 82.

T

S

•

\=N®

kMAMHR N NHR 77a/b

N^S

k

-

.?-*

^ 78a/b

DBU,CHCI3; thiourea, NaOH, -

phCHo ! ^ ^ _

L A

80% (79a) 85% (79b)

a:R = Et

N S b: R = p-Meo-Bn J>—/ ° 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 <04SL1643>. 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 <04OL3083>. 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 <04OL3083>. 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
Me

°^

\

-

fr^^snBua MeO^O M e 9 4

N

jT^-OT, 92

Tfo >{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-<-OTBS

M e

^

S

Q, 9l3

M e

It should be noted that the 4-bromo-2-thiazolyl lithium reagent used in the total synthesis of cystothiazole B 96b is unstable at 0 °C or higher. The alternative reagent is 2-thiazolyl magnesium 97, which is stable at ambient temperature <04SL131>. This reagent is readily prepared from 2,4-dibromothiazole 89 using a regioselective bromine-magnesium exchange. Addition of 97 with nitrile 98 yields an intermediate imine, which is directly reduced with sodium borohydride to afford amine 99. Boc protection of the free amine in 99, brominemetal exchange of 100 into the corresponding zinc compound, followed by a regioselective Negishi cross-coupling with 2,4-dibromothiazole 89 furnish bis(thiazole) 101. This compound could serve as a building block for the synthesis of thiazolyl peptide GE2270 <04SL131>. Br

Br

v

V-N

^PTMOB^

S^Br

v

1-

V-N

NcAOTBS

^s-^MqBr 97 Br^^. T N S—'/ >-N

// X\\

Ph

1

^S' ^S'OTBS 101 NHBoc

l"h 98

2.NaBH4,62%

B I

^M

X

Ph

flZ^

S ^ T OTBS NH2g9

Boc2O I 94% ' 1.ZnCI2, (-BuLi Br Ph 2.89, [PdCI2(PPh3)2] V N

-"

I! \- ^L

75%

\ S -^^^OTBS 100 NHBoc

The halogen dance reaction on thiazoles has been elegantly applied to the total synthesis of the pyridine-thiazole-containing natural product WS75624 B <04JOC2381>. Treatment of 2-bromothiazole with 2.2 equiv. LDA at -78 °C in the presence of 1 equiv. TESC1 results in the formation of 2-thiazolyl lithium 105, which undergoes copper(I)-catalyzed coupling reaction with allylic tosylate 106 to give 107. The remarkable generation of 2-thiazolyl lithium 105 likely proceeds via intermediates 102,103 and 104. Presumably, the first equiv. LDA deprotonates 2-bromothiazole at the more acidic 5-position to produce 5-lithio-2-

205

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

bromothiazole 102, which is trapped with TESC1 to give 5-triethylsilyl-2-bromothiazole 103. This compound is deprotonated by the second equiv. LDA to generate the substituted 4lithothiazole 104, which undergoes a 1,3-halogen dance reaction to furnish 105. Bromide 1 0 7 is converted into tributylstannylthiazole 108, and Stille coupling of 108 with iodopyridine 109 provides pyridyl thiazole 110, which is converted to WS75624 B in three steps. LDA (2.2 equiv), r

N

TESCI

Br-f 1 $

i

N

Br-< 1 s

lithiate 5-position [

r

„

LiJ

[

-f R-('T

Ar

4

r

-P osition

N

[

103

S^TES

I

t i nnt\ N-^SnBu3 f-BuLi, (106), N-^Br Pd(PPh3)4 R _ ^ / Y Bu3SnCI R - < / T ,Cul

53%

S-^TES 108

-

-,

104

r {

S^TES 110

Li

Br-^ T

S-^TESj

102

N

, lithiate

_ _ Br-^ 1

S^TES 107

halogen dance

Br

N

Li-
42%

S"SES

105

l3steps

OMe

HQ

s

^

Me-^^^\^\>UM/

^

QTIPS

Ar

(/.pr)2N

R= Me^^^^^^X.

N

/

A r =

}—( V-OMe O N=<

WS75624B

tf

The intermolecular coupling of unactivated alkenes to thiazoles using Rh(I) catalyst provides an easy entry into substituted thiazoles <04JOC7329>. The optimized conditions involve HCl«PCy3 (Cy = cyclohexyl) and HCl#P-/-Bu2Et as additives for this reaction. For example, three 2-substituted 4,5-dimethylthiazoles 111-113 are prepared from 4,5dimethylthiazole via C-H bond activation. Chiral thiazole substituted aziridines are prepared in a diastereoselective fashion by adding lithiated (a-chloroalkyl)thiazoles to chiral imines <04T1175>. For example, treatment of racemic thiazole 1 1 5 with LDA and chiral imine 1 1 4 provides 116 in high diastereoselectivity. Me

R

V-N S

= /

^ f c ^ ^ lutidinium chloride

Me

\-N

OMe Me

Ph RJ

MeX :K R

s ^

111(99%), R = Bu-f 112(93%), R = CO2Bu-f 113(59%), R = CN

1 \ h "1 1 /4 "

H

OMe

VN

Ph

C[

H5 S ^ LDA

> 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 <04TL69>. 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

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

/ 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 <04JOC5023; 04SL1711; 04TL3629>. 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 <04TL3629>.

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,
O ^ ^ ^ NaBH 4> 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 <04OL23>. Thiazolidinethione reagent 127, pseudoenantiomeric to 125, is also found to be effective in diastereoselective asymmetric aldol reactions, thus obviating the expensive D?ert-leucine <04OL3139>. 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 <04SL1371>. Thiazolidinethione auxiliaries can be cleaved under various conditions, but a recent protocol using benzyl alcohol and catalytic amount of DMAP deserves to be mentioned <04JOC6141>. 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 ^e

Bn 131

93%

f^e ^e 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 <04H(62)217>. 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 <04TL6579>. 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 ^O 3 Na

137

Bn

^N' | 139 CN

Thiazolyl thioglycosides such as 140 are used as glycosyl donors <04AG(E)3069>. 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 <04OL4515>. 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-^O 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

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

acylsilanes (R'C(O)SiX3) to unsaturated esters and ketones 149 using thiazolium salt 146 (Sila-Stetter reaction) <04JA2314> and a ROMP gel-supported thiazolium iodide 147 for parallel Stetter reactions <04OL3377>. 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 <04ASC1097>. 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^V^OEt Me 155 (a/if/)

OH O +

X X Ph^^^OEt 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 <04TA3433> and 158 and 159 for palladium-catalyzed asymmetric allylic alkylation <04T9263, 04S221>. However, these ligands generally provide moderate enantioselectivity.

209

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

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

^Et 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 <04JMC1605>, BMS-387032 <04JMC1719>, AG-7352 <04JMC2097>, (£)-9,10-dehydro-dEpoB <04JA10913>, tetomilast <04DF1003>, 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.

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

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 <04OL3401>, macrocyclic antibiotics thiocilline I <04CL814> and sulfomycin I <04CL72>, cytostatic peptide tubulysin D <04OL4057> and thiopeptide antibiotic amythiamicin A <04CC102> 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 <04OL3083>, antitumor agent epothilone C <04CEJ2529>, neurotoxin kalkitoxin O4T6859; 04OBC2092>, antihypertensive agent WS75624B <04JOC2381>, cytotoxic antibiotics tenuecyclamides AD <04OL2627>, bistratamides E and J <04CEJ71>. 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 <04AG(E)5087; 5092>. 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.

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

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

<( T "- / - f M Me O

HN-^°

O

AJ

1 /

v J Me^OH

thiostrepton

Me

NH

V o

\— pr-/

)_Me \_oAc Me

K T

tubulysin D

ISOTHIAZOLES

5.5.3.1 Synthesis of Isothiazoles by Ring-formation The most frequently used methods for construction of isothiazole (and its partially or completely saturated analogs) consist of cyclization of compounds containing preformed NC-C-C-S fragments. The S-N bond connection is usually accomplished via either nucleophilic attack of an amine on oxidized sulfur or attack of a sulfide nucleophile onto oxidized nitrogen. Only a few examples were reported in 2004 on methodology development for the syntheses of isothiazoles. Isothiazolinones 161 are conveniently prepared from dithiodibenzamides 160 upon treatment with O-methylhydroxylamine hydrochloride <04S1585>. Formation of 161 probably involves amination of sulfur in 162 by Omethylhydroxylamine to give sulfenamide 163 which cyclizes to 161. 4-Cyanoisothiazoles 166 are obtained from thiones 165 by oxidative cyclization with hydrogen peroxide in good to excellent yields <04SC2681>.

212

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

R

R

O^NH

HN

MeONH2«HCI,

O

p

n

J

EtCN

r

O

f

H

->

f

U

fT^T^^HR J

X X X - *639^7%^ f y > - C x NHR — L^ is

U

U

"

160 R = alkyl, aryl.

I '

R1 NC X > T O Lawesson's R ^ N H 2 reagent

H2N-OMe

>, 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 <04JOC843; 04T4709>. 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 <04SC471>. 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 = ^e,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

^O y*

Me^Ar

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 <04OL727>. 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

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

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 <04TL3305>. 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 <04JOC1401>. 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 <04AG(E)2001>. 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.

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

214 M

\<.Me

M e

M e

O O "B" J

B %' Ph 1RCHO(187), f| " N _ ^ toluene, 80 'C ^ Me 2. aq. NaHCO3

+

CN 185

S y Et

62%

18S°

x--"

. ® s ' Ph T >g—( Me N ^

INaOH, H2O, acetone 2 a HCI ^

° H NBn2 ° 8 8

I

^

^

L

191

e

e

OH NBn2 °

J 189

((-)-methyl dihydropalustramate)

Palladium(II)-promoted alkenylation involving a-bromo sulfonamide has been utilized to construct the bridgehead bicyclic sultam 193 <04OL 1313>. Treatment of 192 with palladium acetate in DMF containing K2CO3, tri-2-furylphosphine and 4A molecular sieves at 100 °C furnishes 193. Subsequent bromination with NBS and elimination with DBU give rise to conjugated diene 194. When irradiated at 350 nM, 194 is isomerized via a two-photon process to the structurally novel spiro heterocycle 198. Pd(OAc)2 K2CO3

/-V BrCH2SO2N

1 192

h^,350nm,

T

P(2-Furylj3, DMF,' 4

A'MS, 100'C

K 0

~S"N^_/

67% (plus 5% 194)

^ N ^ 1

r

1.NBS,

H S

°

rrrN^ n

K

CHCI3 f58%)

Hpx

2. DBU (60%) ^

O^-N^

193

°

T

H ^N

194 H

1

r\,.H

S5T 7 ^ — I P - ^ P J2->><> ,? =o O

L

195

,?«o O

J

196

.?-o L O

J

197

s^o 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 <04S20; 04TA3869> and the oxime ether groups <04JOC1415>, conjugate addition reactions <04OBC749; 04T1293; 04TA793>, [2+2] cycloaddition <04AG(E)610>, [4+2] cycloaddition <04S87>, hydrogenation of alkenes <04TA3979>, oxidative cyclization of 1,6dienes <04TL7269> and electrochemical carboxylation of a-bromo carboxylic acid derivatives <04JOC487>. 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 <04OL893>. 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

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

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 <04T4807>. 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 <04T9997>. 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-< '"S^O 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<-

Me MeO ys_ /V V

204(endo)

P

202

n

Me^,Me

W>

-\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)

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

216

^ffip

(T^"0

MgBr2

1 ~^r-

N'

5 steps

CNJ A

212

[

^-"

V

N

R=

^ U Me

214

V-/V

o^o'

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 <04S1739>. 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 <04BMCL909> and HIV replication inhibitors <04ACC201>, benzoisothiazole into selective 5HTID antagonist/serotonin reuptake inhibitor 221 <04BMCL2469>, and benzosultam into cyclooxygenase-2 (COX-2) inhibitor 222 <04BMCL499>. 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 <04JMC2981>.

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" <04MI274>. 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 <04RJOC99>.

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 <04RJOC818>.

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 <04OBC2870>. 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) <04BMCL3401>, and 238, a potent and selective antagonist of adenosine A2a receptor <04JMC4291>. CF 3

NH 2

Et

S 237

S

S

\A^N,

J 238

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

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 <04MI277>. 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 <04HAC175>.

*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 <04PAC1691>. 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 <04S2975>.

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 <04BMC4221>, selective allosteric modulators of human adenosine A3 receptors <04JMC663>, and inhibitors of cysteine protease cathepsin K <04JMC588; 04JMC5057>. 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 <04JHC955>. 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

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

^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 <^y''S\l'

S-N 252

Vinyl-substituted 1,2,5-thiadiazole 255, a potential precursor to bis(l,2,5-thiadiazole) ligand 256 for coordination polymerization, is derived from methionine amide 253 via heterocyclization and oxidative elimination. However, attempts to perform the olefin metathesis were not successful <04TL5441>. MeS

NH2d

l T >

2

Py, 90 °C;

MeS

v^-,

PhNSO

N

CH3CO3H;

V > KOBu-f

253

N'

N

^ V \

254

"«!

_*_ V ^ V %

255

256

The 1,2,5-Thiadiazole moiety has been incorporated into several biologically active compounds, including inhibitors of human leukocyte elastase O4ABB191; 04BMC589>, gonadotropin releasing hormone (GnRH) <04BMCL5599>, and neuropeptide Yi receptor (NPY) <04BMC507>. 5.5.4.4 1,3,4-Thiadiazoles The chemistry of 1,3,4-thiadiazole has been recently reviewed <04MI405>. The 2substituted 1,3,4-thiadiazoles 258 are formed by the reactions of thiohydrazides 257 with DMF and diethyl chlorophosphate. This cyclodehydrating agent is superior to several commonly used ones such as ethyl orthoformate, ethyl formate or even phosphorus oxychloride for this type of cyclization <04S17>. Reaction of/7-tolualdehyde hydrazone 259 with disulfur dichloride in the presence of DBU gives 2,5-di(p-tolyl)-1,3,4-thiadiazole 260 <04S1929>. S ArHN. A

I I I 257

(EtO)2P(O)CI, DMF

60-90% '

ArHN

N- N . x 1 ?

V^

S

258

NH2 S2CI2,DBU, N CH2CI2

P - ™ ^^ T ^ 259

li \

-r ,

P-TOI^^P-TO, 260

The aza-Wittig reaction is used twice in the preparation of bicyclic 1,3,4-thiadiazoles <04S1067>. Thus the isothiocyanates 262, obtained from aza-Wittig reactions of vinyliminophosphoranes 261 with sulphur disulfide, react with hydrazine to give 3-amino-2thioxo-4-imidazoidinones 264. Exposure of 264 to triphenylphosphine, hexachloroethane and triethylamine produces iminophosphoranes 265, which are treated with aromatic isocyanates to give bicyclic 1,3,4-thiadiazoles 267. Presumably, the conversion of 265 to 267 involves initial aza-Wittig reaction between 265 and an isocyanate to give a carbodiimide 266 as a reactive intermediate, which undergoes ring closure across the mercapto group to give 267<04S1067>.

220

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

r CO2Et

cs2

.CO2Et

NH2NH2

CO2Et /-<

I

NHN

H2

264 PPh3, Et3N, I CI3CCCI3 J 7 2 " 8 5 / °

R 1 ,R 2 = aryl

o R1

\\ NH2 _ ^ N "

-BOH

kN-Ni^R21

r

N^^S

48-64% L

H'"^

267

K -N=PPh3

J

S

H

266

265

A parallel solid-phase synthesis of l,3,4-thiadiazolium-2-aminides involves trimethylsilyl chloride mediated cyclization of resin bound aldehydes 269 and 1,4,-disubstituted thiosemicarbazides 268 <04JCO746>. Two additional combinatorial approaches have been developed to prepare focused libraries of 1,3,4-thiadiazoles O4T8627; 04BBR1053>. 1,3,4Thiadiazoles 273 are prepared by condensation of triazole 271 with various carboxylic acids 272 in the presence of phosphorus oxychloride <04IJHC69>. H

^

P^nK

RCHO(269), (

TMSCI

R

-v/Sx

TY-QH

JJ

268

RCO2H (272),

^o^

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 <04BMC6l3>. 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 <04RJOC1047>.

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

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 <04S1257; 04H(63)2243; 04JHC517>, including a general facile synthesis of 2,5diarylheteropentalenes via Suzuki coupling of bromo-1,3,4-thiadiazole <04TL7157>, and an one-pot diastereoselective synthesis of new chiral spiro- 1,3,4-thiadiazole from (IR)thiocamphor <04JHC731>. The 1,3,4-Thiadiazole moiety is incorporated into thiosugar nucleosides as anti-HIV and human cytomegallovirus (HCMV) agents <04NNN1739>, into crown ethers <04JHC419>, and into macroheterocyclic compounds <04RJGC1031>. 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) <04JMC5593>, and selective PDE7 inhibitors <04BMCL4607; 04BMCL4615>. 5.5.5

SELENAZOLES AND SELENODIAZOLES

The chemistry of selenazoles is reviewed in a book <04MI777>. 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 <04S875>. 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 <04S233>.

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

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

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 <04SL329>.

[>=< 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 <04JHC955>. 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 <04JHC1023>.

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

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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

Y. Zhang, A. Phillips, T. Sammakia, Org. Lett. 2004, 6, 23. S. Hirano, R. Tanaka, H. Urabe, F. Sato, Org. Lett. 2004, 6, 727. G. Nguyen, P. Perlmutter, MX. Rose, F. Vounatsos, Org. Lett. 2004, 6, 893. L.A. Paquette, W.R.S. Barton, J.C. Gallucci, Org. Lett. 2004, 6, 1313. S. You, S. Deechongkit, J. Kelly, Org. Lett. 2004, 6, 2627. J. Shao, J. Panek, Org. Lett. 2004, 6, 3083. Y. Zhang, T. Sammakia, Org. Lett. 2004, 6, 3139. A. Barrett, A. Love, L. Tedeschi, Org. Lett. 2004, 6, 3317. M. Bagley, X. Xiong, Org. Lett. 2004, 6, 3401. P. Wipf, T. Takada, M. Rishel, Org. Lett. 2004, 6,4057. P. Pomsuriyasak, U.Gangadharmath, N. Rath, A. Demchenko, Org. Lett. 2004, 6, 4515. N.N. Makhova, I.V. Ovchinnikov, A.S. Kulikov, S.I. Moltov, E.L. Baryshnikova, Pure Appl. Chem. 2004, 76, 1691. A. Piskala, A. Vachalkova, M. Masojidkova, K. Horvathova, Z. Ovesna, V. Paces, L. Novotny, Pharmazie 2004, 59, 756. A.A. El-Barbary, A.Z. Abou-El-Ezz, A.A. Abdel-Kader, M. El-Daly, C. Nielsen, Phosphorous Sulfur and Silicon 2004, 179, 1497. M.A. Kulikov, Y.G. Vorobev, G.R. Berezina, V.A. Stepaninko, Russian Journal of General Chemistry 2004, 74, 1031. O.B. Flekhter, E.V. Tretyakova, N.I. Medvedeva, L.A. Baltinax, F.Z. Galin, G.A. Tolstikov, V.A. Bakulev, Russian Journal of Organic Chemistry 2004, 40, 99. M.L. Vasileva, M.V. Mukhacheva, N.P. Belskaya, V.A. Bakulev, R.J. Anderson, P.V. Groundwater, Russian Journal of Organic Chemistry 2004, -^0, 818. R.I. Vaskevich, Y.L. Zborovskii, V.I. Staninets, A.N. Chernega, Russian Journal of Organic Chemistry 2004, 40, 1047. V.N. Yarovenko, A.V. Shirokov, I.V. Zavarzin, O.N. Krupinova, A.V.Ignatenko, Synthesis 2004, 17. T. Bauer, J. Gajewiak, Synthesis 2004,20. M. Kosior, M. Asztemborska, J. Jurczak, Synthesis 2004, 87. B. Fu, D. Du, Q. Xia, Synthesis 2004,221. M. Koketsu, T. Mio, H. Ishihara, Synthesis 2004, 233. K. Geisler, W.D. Pfeiffer, A. Kunzler, H.Below, E. Bulka, P. Langer, Synthesis 2004, 875. M.W. Ding, B.Q. Fu, L. Cheng, Synthesis 2004, 1067. Z. Ge, J. Cui, Y. Wang, T. Cheng, R. Li, Synthesis 2004, 1257 S. Tomohumi, T. Toshiyuki, G. Yasuo, S. Isao, S. Masao, Synthesis 2004, 1585. A. Khazaei, A.A. Manesh, Synthesis 2004, 1739. K. Okuma, K. Nagakura, Y. Nakajima, K. Kubo, K. Shioji, Synthesis 2004, 1929. B. Zaleska, B. Trzewik, E. Stodolak, J. Grochowski, P. Serda, Synthesis, 2004, 2975. Z. Liu, T. Toyoshi, Y. Takeuchi, Synth. Commun. 2004, 34,471. M. Mishra, S.K.D. Dutta Chowdhury, K.K. Mahalanabis, Synth. Commun. 2004, 34, 2681. N. Shah, C. Tran, F. Lee, P. Chen, D. Norris, C. Sawyers, Science 2004, 305, 399. A. Spieb, G. Heckmann, T. Bach, Synlett2004, 131. X. Huang, W.L. Chen, H.W. Zhou, Synlett 2004, 329. M. Crimmins, J. She, Synlett2004, 1371. O. Attanasi, G. Carvoli, P. Filippone, F. Perrulli, S. Santeusanio, A. Serri, Synlett 2004, 1643. A. Dondoni, B. Richichi, A. Marra, D. Perrone, Synlett 2004, 1711. U. Albrecht, P. Langer, Synlett 2004, 1963. U. Albrecht, P .Langer, Synlett 2004, 2200. A. Arcadi, O. Attanasi, P. Filippone, F. Perrulli, E. Rossi, S. Santeusanio, Synlett 2004, 2681. M. Ojika, T. Watanabe, J. Qi, T. Tanino, Y. Sakagami, Tetrahedron 2004, 60, 187. L. Vitis, S. Florio, C. Granito, L. Ronzini, L. Troisi, V. Capriati, R. Luisi, T. Pilati, Tetrahedron 2004, 60, 1175. A. Kakuuchi, T. Takeo, Y. Hanzawa, Tetrahedron 2004, 60, 1293. J. Davies, P. Kane, C. Moody, Tetrahedron 2004, 60, 3967. S. Jayakumar, P. Singh, M. Mahajan, Tetrahedron 2004, 60, 4315. A.N. Van Nhien, L. Dominguez, C. Tomassi, M.R. Torres, C. Len, D. Postel, J. MarcoContelles, Tetrahedron 2004, 60, 4709. I. Kudyba, J. Raczko, Z. Ur-Lipkowska, J. Jurczak, Tetrahedron 2004, 60, 4807. F.Yokokawa, T.Asano, T.Okino, W.Gerwick, T.Shioiri, Tetrahedron 2004, 60, 6859.

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

Y.-J. Wu, U. Velaparthi andB.V. Yang J. Pernerstorfer, M.Brands, H. Schirok, B.S. Ludwig, E. Woltering, Tetrahedron 2004, 60, 8627. I. Abrunhosa, L. Delain-Bioton, A. Gaumont, M. Gulea, S. Masson, Tetrahedron 2004, 60, 9263. O. Tamura, A. Kanoh, M.Yamashita, H. Ishibashi, Tetrahedron 2004, 60, 9997. G. Mislin, A. Burger, M. Abdallah, Tetrahedron 2004, 60, 12139. G.P. Reid, W.B. Kieron, D.J. Robins, Tetrahedron Asymmetry 2004, 15, 793. S. Lu, D. Du, S. Zhang, J. Xu, Tetrahedron: Asymmetry 2004, 15, 3433. K. Kiegiel, T. Balakier, P. Kwiatkowski, J. Jurczak, Tetrahedron: Asymmetry 2004, / J, 3869. S. Jawaid, L.J. Farrugia, D.J. Robins, Tetrahedron: Asymmetry 2004, 15, 3979 A.R.L. Cecil, R.C.D. Brown, Tetrahedron Lett. 2004, 45, 7269. T. Yamane, H. Mitsudera, T. Shundoh, Tetrahedron Lett. 2004, 45, 69. D. Laurent, Q. Gao, D. Wu, M. Serrano-Wu, Tetrahedron Lett. 2004, 45, 1907. D. Steinhuebel, M. Palucki, D. Askin, U. Dolling, Tetrahedron Lett. 2004, 45, 3305. G. Busscher, F. Rutjes, F. Delft, Tetrahedron Lett. 2004, 45, 3629. J. Blanchet, J. Zhu, Tetrahedron Lett. 2004, 45, 4449. D.M. Philipp, R. Muller, W.A. Goddard, K.A. Abboud, M.J. Mullins, R.V. Snelgrove, P.S. Athey, Tetrahedron Lett. 2004, 45, 5441. M. Heravi, A. keivanloo, M. Rahimizadeh, M. Bakavoli, M. Ghassemzadeh, Tetrahedron Lett. 2004, 45, 5747. M. Seki, M. Hatsuda, S.Yoshida, Tetrahedron Lett. 2004, 45, 6579. M. Popsavin, L. Torovic, V. Kojic, G. Bodganovic, V. Popsavin, Tetrahedron Lett. 2004, 45, 7125. P. Vachal, L.M. Toth, Tetrahedron Lett. 2004, 45, 7157. S. Huang, P. Connolly, Tetrahedron Lett. 2004, 45, 9373.

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 <04EJO2002>. 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 <03MI842>, Nb2O5 or NbCl5 <03MI245>, Cr salen <04OM924>, Co(II) salen/DMAP <04CC1622>, A1C1 salen complexes <03MI317, 04MI31> and either Co(III) <04TL2023> or Sn(IV) porphyrins <04T6105>. Kinetic resolution occurs upon reaction of racemic epoxypropene with CO 2 mediated by a Co salen catalyst to give chiral dioxolanones <04JA3732>. 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 <04SL2013>. A variety of substituted epoxy ketones 5 rearrange to the benzodioxoles 6 upon treatment with Bu4N+ CN~ in CH2C12 or KI in acetone <04T3825>. 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 <04SL1195>.

R1

R

.O

O^P

.CL,SPh

°-\

1— 'V C J - c P o

R2

3

1 n

Rr^^V

CX— 5

4

2

n

R

r<^N-°v

OCO> 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 <04SL1561> while Ru-catalysed cyclisation of 2-allyloxyethanol gives 10 <04SL1203>. 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 <04WOP5276> and a range of tricyclic compounds 12 have been prepared from the corresponding cyclohexanetriol <04T5077>. 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 <04OL3071>. 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 <04TL6485>.

There have again been many new developments involving chiral dioxolanes. Enzymatic kinetic resolution of 16 has been achieved using an amidohydrolase <04WOP3001> and an erroneous [a D ] value for 17 has been corrected <04TA289>. Convenient preparation of bis(dioxolanones) 18 from tartaric acid and aldehydes has been described <04TA803> and addition of mandelic acid-derived chiral dioxolanone anions to substituted [3-nitrostyrenes to give products 19 has been examined <04T165>. A range of salts 20 have been evaluated as asymmetric phase-transfer catalysts for alkylation and Michael addition of a protected glycine anion equivalent <04T7743> and the difluorodioxole analogue of BINAP 21 has been prepared <04S326>. Dioxolane-containing P/N ligands such as 22 have also been introduced for asymmetric catalysis <04JOC5060>.

Cyclopropanation of the corresponding vinyldioxolane has been used to prepare compound 23 useful for pyrethrin synthesis <04T7637> and addition of Ph 2 P-SiMe 3 to the corresponding dioxolane aldehyde gives 24 <04TL6955>. The preparation and reactions of alkene-containing dioxolanes have been reported <04JGU256> and a calorimetric and theoretical study of benzodioxoles has appeared <04OBC908>. The X-ray structure of dioxolane 25 has been

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

229

reported <04MI612>. The oxa-Pictet Spengler rearrangement of aryldioxolanes 26 gives products 27 <04TL411>. Protection of a-hydroxy acids with hexafluoroacetone to give 28 has been reported <04S1821> and carbonyl compounds can be protected as the fiuorous dioxolanes 29 <04T8341>. The hydrolysis of 2,2-disubstituted dioxolanes can be accomplished under mild conditions using erbium triflate in wet acetonitrile <04S496>. 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 <04H(63)l>.

Ring-opening of dioxolanes with organoaluminium compounds has been examined <04SL647, 04JGU903> and stereoselective TiCl4-promoted nucleophilic ring-opening of chiral dioxolanes has also been reported <04S3005>. A new anionic ring contraction of dioxolanes to give oxetanes is exemplified by conversion of 33 into 34 upon treatment with ?-BuLi <04SL651>. Stereoselective side-chain fluorination of sulfur-containing dioxolanes has been reported <04JOC1276> 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 <04JOC1531>. There have been various studies on the preparation and synthetic utility of 4-alkylidene-l,3-dioxolan-2-ones <04S1399> including their preparation from propargyl alcohols either using Na2CO3 as the CO2 source <03JFC(123)57> or by reaction with CO2 in an ionic liquid <04JOC391>. Their reactivity with hydrazines has also been examined <03CHE1057>. The 1,2-migration of Br or I in lithiated benzodioxoles has been exploited synthetically <04EJO64> and addition of diazomethane and methyl diazoacetate to the double bond of levoglucosenone 36 has been reported <03MI337>. Resolution of glycerol monoacetonide has been achieved using the inclusion complex with a TADDOL derivative <03MC125> and the cyclohexadienyltitanium TADDOL compound 37 reacts with aldehydes to give products 38 in good d.e. and e.e. <04AG(E)313>. TADDOL promoted asymmetric Michael addition of diethyl malonate has been used in amino acid synthesis <04ARK(iii)132> and a further report on bicyclic amino acid derivatives such as 39 has appeared <04T2583>. Bis(dioxolanes) such as 40 have been used as components of liquid crystal displays <03GEP10222166> and benzodioxoles such as 41 have been evaluated as cannabinoid receptor antagonists to tackle obesity <04WOP13120>. 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" <04EJO2002>, AIC13 supported on silica <03SC4253>, aqueous HBr <04ARK(xiv)110>, scandium chloride <04S828>, praseodymium triflate <04S2837> or silica-supported polyphosphoric acid <04SL2307> and compound 42 can be used as an odourless equivalent of ethanedithiol in such reactions <04SL999>. 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 <04SL659>. Theoretical and experimental studies on the cycloaddition of thiocarbonyl ylides to thiocarbonyl compounds to give 1,3-dithiolanes have appeared <03CEJ2245, 03CEJ2256, 03JA14425>. Enzymatic oxidation of benzodithioles to give chiral monosulfoxides has been examined <04T549> and ferrocene-containing benzodithioles 43 have been prepared <04SM(140)95>. 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 <04JOM(689)885>. A novel

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

231

metal templating effect allows the coupling process in complex 46 to give 47 upon treatment with Ar3NSbCl6 followed by Na2S2O4 <04CC212>. A two-step method for conversion of iminooxathiolium salts 48 (Ad = 1-adamantyl) into iminodithiolanes 49 has been reported <03JOU1806> and electrophilic aromatic substitution using the sulfenyl chlorides 50 has been described <04EJO1455>. Naphthocyclopropene 51 reacts with the dithiolethione 52 in an apparent 2JI + 2a process to give the spiro product 53 <04H(62)773> and the formation and structure of benzotris(dithioles) 54 have been reported <04CC1758>.

An improved synthesis of l,3-diselenole-2-thione and its coupling to form tetraselenafulvalenes have been patented <04JAP262839, 04JAP262840>. 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 <03SRl>, TTF-based organic conductors <04BCJ43, 04CRV4891>, organic conductors with unusual band fillings <04CRV4947>, new trends in Jt-electron donors <04CRV5057>, synthesis of non-symmetrically substituted TTFs , highly functionalised TTFs <04CRV5151>, conducting organic radical salts with organic and organometallic anions <04CRV5203>, single-component molecular metals with extended TTF dithiolate ligands <04CRV5243>, materials based on bis(ethylenedithio)tetraselenafulvalene <04CRV5265> and bis(ethylenedithio)tetrathiafulvalene <04CRV5289> and its trihalide derivatives <04CRV5347>, hydrogen bonding in TTF-based conductors <04CRV5379> and magnetic TTF-based charge transfer complexes <04CRV5449>. Studies on new substituted TTFs include fluoroaryl TTFs <03CHE760>, pyridine and pyrazine-containing TTFs <03CR657, 03TL9275>, silicon substituted TTFs in a silica-based hybrid organic/inorganic material <04CC396>, 1,3,4-oxadiazole functionalised TTFs as electrochromic materials <04CC578> and TTF cation radical dimers within the cavity of curcurbit[8]uril <04CC806>. TTF oxazoline phosphines such as 55 have been used as redox-

232

R.A. Aitken

active chiral ligands <04CC1384> and TTFs such as 56 with long alkylthiol substituents have been designed to form self-assembled monolayers on a gold surface <04JMAC81>. The diamide 57 has been found to form "microwires" <04SM(146)273>, amide derivatives 58 have been prepared <04TL5103> and the amide 59 undergoes an unusual 2+2 cycloaddition in the crystal <04CC1538>. The synthesis and properties of compound 60 have been reported <03MI1916>. A purely organic molecular metal has been formed from 2-imidazolyl-TTF and pchloranil <04AG(E)6343> and a variety of push-pull donor-acceptor alkenes have been evaluated as non-linear optical materials <03OL3143, 04ARK(iv)32>. Fluorescence switching of a dianthryl-TTF has been observed <04OL1209> and a variety of new radical salts of BEDTTTF 61 <04CC18,04SM(140)9,04SM(144)51> as well as its dimethyl analogue <04CC2454> and dehydro derivative <04SM( 140) 171> have been investigated. Metallic conductivity down to 2 K has been observed for a salt of formula (62)6K2(BW12O40) <04AG(E)3022> and the metalinsulator phase transition for (63)2 PF6 has been examined <04AG(E)3670>. An important new donor 64 has been prepared <04CC1590>. The complex (65)4Hg3 8 3 9I8 is an ambient pressure superconductor with Tc 8.1 K <04SM(140)151> and new conductors based on lanthanide complexes of this donor have also been investigated <04SM(l43)221>.

The properties of the dithieno-TTF 66 have been examined (04SM(146)265> and pyrrole-fused TTFs 67 <04S2555> and 68 <04H(63)1577> have been prepared. The new furoand thieno-BEDT-TTF derivatives 69 have been prepared <04JMAC2822> 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 <04OBC1685>. A number of new donors of structure 73 have been prepared <04S1315> and compounds 74 (n = 5-8) have been examined <04SM(144)89>. The area of bi-TTF, bis (TTF) and oligomeric TTF compounds has been reviewed <04CRV5085> and new examples of this type include the 1,4-diphosphinine 75 <04CC2794>, tris-fused TTFs <04SM(141)307>, TTF-fused dehydroannulenes <04CC2042>, extended dimeric and trimeric TTFs <04OL1569, 04JOC4492> and acetylenic extended TTF analogues <04SL2818>. Reviews of TTF-containing cyclophanes and cage molecules <04CRV5115> 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 <04SL2785> and K-10 montmorillonite has been used for the same reaction where it shows selectivity for aldehydes over ketones <04SL1592>. The compound 76 has been used to introduce a mercapto acid unit into peptide analogues <04S1088> and the diastereoselectivity of addition of the anion of 77 to carbonyl compounds has been examined <03JHC979>.

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 <04JOC3672>. 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 <03JHC1071, 03TL395>. Diastereoselectuve hydrolysis of ysultones 82 to give products including homotaurine derivatives has been examined <04S590,

04S2910>. 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 <04AG(E)1268>.

234 5.6.6

R.A. Aitken THREE HETEROATOMS

A series of spiro 1,2,4-trioxolanes 84 have been prepared <04JOC6470> and evaluated as antimalarials <04USP186168>. The spiro 1,2,4-oxadithiolane 85 reacts with £-cyclooctene to afford the corresponding thiirane together with Ph2C=S and the cyclobutanedione <03AG(E)4O12>. Treatment of sulfines with Lawesson's reagent has been used to obtain 1,2,4trithiolanes such as 86 and 87 <04BCJ187> and oxidation of the latter to the corresponding mono- and disulfoxide and sulfone has been investigated <04JOC1695>.

5.6.7

REFERENCES

03CEJ2245 03CEJ2256 03CHE760

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236 04MI165 04MI612 04OBC908 04OBC1685 04OL1209 04OL1569 04OL3071 04OM924 04S326 04S496 04S590 04S828 04S1088 04S1315 04S1399 04S1821 04S2555 04S2837 04S2910 04S3005 04SL647 04SL651 04SL659 04SL999 04SL1195 04SL1203 04SL1561 04SL1592 04SL2013 04SL2307 04SL2785 04SL2818 04SM( 140)9 04SM(140)95 04SM(140)151 04SM(140)171 04SM(141)307 04SM(143)221 04SM( 144)51 04SM(144)89 04SM(146)265 04SM(146)273 04T165 04T549 04T2583 04T3825 04T5077 04T6105

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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 <05JA210>. 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

Five-membered ring systems: with O & N atoms

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 <04T1671>. 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 <04TL3421>. 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


HN^Y I R2 N

r

POCI,

Y ° Et3N

HN^V ' 2 J, R

„

1 Ph 1 Ph

<J 9

^ r^ 5 ^ a N

^ O - O H = Wang resin

CeH

NaOCI < U - o ^ ^ ^ rt 3d ' R20,C/>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 <04JOC1470>. 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 <04TL2277>.

A r - ^ V ^ - ^

R2OBn Ri^^^O

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

NHBoc ^s^v.«. ^fCO 2 Me

BnoV^A-^=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 <04OL2929>. 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 <04JMC4881>. 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 <04SL2815>.

/~~^ 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 / ^Ar

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 <04SL1949>. 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

Five-membered ring systems: with O & N atoms

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 <04S401>.

^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 <04TL4935>. 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 <04JOC7013>. 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%) <04JA5367>. 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%) <04JCO142>. 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 <04TL7347>.

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% <04TA3079>. 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 <04SL1949>.

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 <04T6453>. RO^S^S

BnO-'V O 49

NH2OH HCI R O ^ V * O H EWB0H

BHO'-SON

p-TsOH

9H

CH2CI2,rt

/^V<

80-83%

HO O ' 92-95% 50 R = 2',3',4',6'-tetra-O-benzyl-a-D-galactopyranosyl R = 2',3',4',6'-tetra-O-benzyl-|3-D-glucopyranosyl

B n

r-^ O

.N

° 51

Matsugy and Curran applied the new separation technique of reverse fluorous solid-phase extraction (r-fspe) to the purification of the fluorous-tagged isoxazolines 53. Compounds 53 were synthesized through a two-step sequence consisting of allylation of perfluoroalkyl iodides 52 with an excess of allyl stannane, followed by reaction of the crude allyl perfluoroalkanes with benzonitrile oxide generated in situ from an excess of benzaldehyde oxime under oxidative conditions. At the end, the isoxazolines 53 were easily separated from the complex reaction mixtures by column chromatography on standard silica gel eluting with a mixture of perfluorohexanes (FC-72) and Et2O. The fluorous liquid-phase selectively eluted the fluorous-tagged fractions from the column while all the 'non-tagged' compounds were retained on the polar solid phase <04OL2717>. 1)

<

^ \ ^ S n B u 3 ( 2 equiv), AIBN (cat)

2) PhCH=NOH (6 equiv), NaOCI (excess) 52

3) r-fspe [SiO2, FC-72/Et2O (3/1)]

\ j T ^ R i °53

R^ Yield C7F16 62% C8F17 68% (CF3)2CF(CF2)6 63% Ciop21

55%

C12F25

48%

Isoxazolines were converted to 1,3-amino alcohols by polymethylhydrosiloxane (PMHS)-Pd(OH)2/C. When the reduction was performed in the presence of di-^-butyl dicarbonate [(Boc)2O], TV-Boc protected compounds were directly achieved. For example, NBoc aminols 55 were synthesized from the corresponding isoxazolines 54 in one step and in 78-88% yields <04SL1303>. R

5.7.3

l ^—y "O 54

Pd

R2

<0H'2/C R1 R2 PMHS, BoczO Y ^ f R1 = Ph, 4-MeOC6H4, Et, /-Pr; R2 = CO2Et BocHN 0 H EtOH 50 °C * R1 = Ph, 4-MeOC6H4,/-Pr; R2 = Ph dr ='ca. 2:1 55 78-88%

ISOXAZOLIDINES

The 1,3-DC of nitrones and olefins is a powerful and versatile method for preparing

244

F.M. Cordero andD. Giomi

polysubstituted isoxazolidines which are useful synthetic intermediates. During the last year, this reaction has been employed as a key step in the total synthesis of a variety of products of biological interest including natural substances and related unnatural compounds. The most popular approach to enantiopure isoxazolidines is still based on the use of optically active nitrones and/or dipolarophiles usually derived from the natural chiral pool. For example, the alkaloid (-)-funebrine <04JOC1475>, and the nitrogenated disaccharide analogues 57 <04TL4835>; 58 <04TL4237> and 59 <04TL4123> were prepared via the 1,3-DC of sugar derived nitrones with suitable alkenes followed by elaboration of the primary cycloadducts.

One of the metabolites of nicotine, the (3'i?,5'S)-3'-hydroxycotinine (+)-63 was synthesized starting from L-gulose-derived nitrone 60 and (25)-Ar-(acryloyl)bornane-10,2sultam 6 1 . The matched pair of reagents 60 and 61 afforded isoxazolidine 62 with high selectivity (62:other isomers = 9.3:1), whereas the corresponding mismatched pair 60 and ent-6l yielded a complex mixture of isomers <04T9997>. The enantiopure y-hydroxy-aamino acids 65 were prepared starting from the imidazolone-derived nitrone 64 <04OL1653>.

Some new combinations of chiral ligands with different Lewis acids have been lately evaluated in catalytic asymmetric 1,3-DC reactions of nitrones. When the complex derived from copper(II) triflate and bis(oxazoline) 72 was used as chiral catalyst in the cycloaddition of nitrone 66 and crotonate 68, both endo and exo isomers were obtained with very high enantioselectivities (7:3 dr; > 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 <04TL9581>. 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

Five-membered ring systems: with O & N atoms

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) <04JA718>. 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 <04OL1677>.

246

F.M. Cordero and D. Giomi

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 <04OL675; 04TL4061>. The chiral complexes 79/Zn(II) <04OL675> and {(r|5"C5Me5)Rh[(.K)-l,2-bis(diphenylphosphmo) propane](H2O)}(SbF6)2 80 <04JA2716> 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 <04OL675>. 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 <04SL1569>. 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 <04ZOR186>.

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%) <04EJO2205; 04EJO4158>. Under analogous reaction conditions, tricyclic isoxazolidines 85c afforded the |3homoprolines 87, probably by ring opening and #-acylation of the primary carbapenam intermediates 86c <04EJO2205>. The chemistry of spirocyclopropane isoxazolidines 85 as versatile precursors of different azaheterocycles has been reviewed <04M649>.

247

Five-membered ring systems: with O & N atoms

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 <04TL8375>. 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 <04OL2027>. 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 - [^Oj 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 <04EJO2321>.

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 <04T11995; 04T8991; 04SLl>. Moreover, many studies are still focused on the synthetic strategies to access the antitumor marine natural product diazonamide A. In particular, a

248

F.M. Cordero and D. Giomi

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 <04JA10162; 04JA10174>. 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 <04CC2712>. 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 <04OL4391>. 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 <04OL3593>.

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 <^N

CICH2CH2CI 60 °C, 1 h

ill l|l

103

P R1 = Ph, Ar; R ^ = H Cat _ ° Ru-Rif" R = Me,m,Ph,Ar ^ - ^ S M e

i0mol%AuCI 3

O

R 2

L

R

80 °C, 18 h 20-88%

V N R

H o R2

104 J

105

R1 = H I

[ J~\ "

I

1

^O^R

~ '

L 106 R

N2

NH ^ 103

+


R

h2(OAc)4 (cat)

H R^N

o <s*^ R i CICH2CH2CI, reflux 107 13-82%

°

O

R2

^ R

1

R2 pph 3 , | 2 , NEt3

N

R'^0'^-R1

23-80%

10g

1

- /

109 2

R = H, Alk, Ar, Het R = Me, Ar R = CO2Me, CO2Et, Ph

A convenient route to polysubstituted oxazoles was developed through a variation on the Robinson-Gabriel synthesis in which the key 1,4-dicarbonyl compounds were obtained by a rhodium carbene N-H insertion reaction. Dirhodium tetraacetate catalysed reaction of primary amides 103 and diazocarbonyl compounds 107 gave a-acylaminoketones 108, which were converted into 109 by cyclodehydration using the Wipf and Miller protocol <04T3967>. A truncated Passerini reaction between various aldehydes or ketones and a-alkyl-aisocyanoacetamides in toluene at 70 °C in the presence of LiBr afforded 2,4,5-trisubstituted oxazoles in satisfactory yields (38-98%). For instance, stereoselective nucleophilic addition of 110 to TV.vV-dibenzylphenylalanal 111 led predominantly to the anti-adduct 112 (dr = 9:1) which was smoothly converted after acidic hydrolysis of the oxazole ring into the dipeptide 113, containing an a-hydroxy-P-amino acid (norstatine) component <04T4879>.

cN

O

ph

Ph

y V + y HO ^

y Ph

NBn, 110

111

toluene 70 °C

OH

Ph

W-o NBn2N^/ \ 112 64%

^-Ph

OH

O

^FA_ y - y N y v THF/H2O, rt _ S M ' ^ ^ O NK2- —|"IN—\/

M D

NBn2O

k

113

86%

Ph

249

Five-membered ring systems: with O & N atoms

A novel oxazole building block, 4-bromomethyl-2-chlorooxazole, has been synthesised and exploited in palladium-catalysed cross-coupling reactions to give a range of 2,4disubstituted oxazoles in satisfactory yields <04TL3797>. The synthesis of previously inaccessible 2-amino-4-benzyloxazoles has also been reported <04TL867>. Microwave-assisted reactions of 5-amino-4-hydroxy-3(2//)-pyridazinone 114 with various carboxylic acid derivatives allowed a convenient and versatile approach to substituted 1,3oxazolo[4,5-. An intramolecular DA reaction of the oxazole-olefin 116, obtained through a highly stereoselective route starting from L-tryptophan methyl ester, was the key step in the total synthesis of Rauwolfia alkaloids, as norsuaveoline 118 <04TL6471>.

o HO 1 H

RC 2H

°

H3P 4

°

° V ^ N H NMP

-

15 20min

"

N

o « A

^

O s~J~°

O_XNH

I^K/^\

"•

/^NVW^^I

DBN £ J " \ N R \ J

" \e1% Et

TFAH

117R = L

0 °C 88%

The solid-phase assembly of heterocyclic amino acids provided a very efficient route towards thiazole- and oxazole-containing macrolactams and allowed the total synthesis of different diastereoisomers of tenuecyclamides A-D <04OL2627>. 4-Arylidene-2-phenyl-5(4//)-oxazolones (azlactones) 121 were prepared via Erlenmeyer synthesis from aromatic aldehydes 119 and hippuric acid 120 employing calcium acetate under solvent-free conditions with microwaves irradiation <04TL425>. O X

ArCHO + P f r " N

H

119

122 Ar-^^^OCO2Me 123

^

CO2H

Ac2O/Ca(OAc)2

120

_ ^

)=/

Mo(CO)3C7H810% HMDS, THF, 65 °C

Ar = Ph, 3-thienyl, 2-BrC6H4, 2,4-(MeO)2C6H3

*•

mw, 300W 70-99%

Ar^s/P T~\

N O y 121 P h

H

"/^? r

J ^=74941

NaOH EtOH-H2O 60 C °

from 89 to > 99% ee

/v^ Ar

77-86/o

R = Me, n-Bu, /-Bu, ;-Pr, allyl, c-Hex, Ph

The first example of using 5-alkyl-2-phenyl-5//-oxazol-4-ones (oxalactimes) 122 as nucleophiles in Mo-catalysed asymmetric allylic alkylation with allyl carbonates 123 was reported. This strategy allowed the facile asymmetric synthesis of a-hydroxy amides 125, through ring-opening of intermediates 124 isolated as major regio- and diastereoisomers with high enantioselectivity <04JA1944>. The intramolecular Pauson-Khand reaction of 2-oxazolone derivatives with a suitable alkyne appendage gave exclusively tricyclic oxazolidinones in quite satisfactory yields.

250

F.M. Cordero and D. Giomi

Starting from oxazolone 126, the first total synthesis of (±)-8a-hydroxystreptazolone 128 was achieved in a highly stereoselective manner through the key intermediate 127 <04JOC1803>. Efficient and selective deprotection methods for iV-protected 2(3//)-benzoxazolones have been reported <04T10321>. TBDPSO

TBDPSO

N^> \ o' rT u

5.7.5

I '

V^OH

TBDPSO

— «N-1>. H 2.TMAN0, MS 4 A 1±L O toluene,-10 °C o

126

*»

\&O

N'tV-H J-^-O O

127 51%

128 48%

OXAZOLINES

Compounds containing chiral oxazolines have become one of the most successful, versatile, and commonly used classes of ligands for asymmetric catalysis and the development of new species is then pursued with great interest <04CRV4151>.

R2?1

rKu'°bZ /X^Vo

^M'CbZ

^ ^

™

AA.O

1MsCI NEt

'

3

J ^

R1

C

= H;R2 = /-Pr

SS,T.ECA

EDC, HOBt CH2CI2,

K

yP^2

°^R 132 74-80%

f~\

«

R = Me,/-Pr,f-Bu, Ph, Bn

134^ R1

= H, Me, Ph

H N

R1 2

^ T j ^ R ° 131 48-61%

O^

0

133

'

CH 2 CI 2 ,0°C^rt / 1 ^ N

2

Ri ]n,Jk.2.Pd/C, H2 NH rt ~\ EtOH.rt 129 1 130 64-94% ^ O H 2 R = H; R = Me, /-Pr, f-Bu

^ ^0 H

N

O^

«^<2

2

P^™ 135 58-99%

Condensation of Cbz-protected amino acid 129 with enantiomerically pure amino alcohols afforded |3-hydroxyamides 130, which were converted into a new class of C\ symmetric chiral 2-azanorbornane-oxazoline ligands 131 <04T3393>; analogously, starting from proline, new pyrrolidine-oxazolines 133 were synthesised in satisfactory yields <04T3405>. Such new ligands were evaluated in the transfer hydrogenation of acetophenone with different metal complexes. Further functionalization of 2-azanorbornane-oxazolines 131 with chlorodiphenylphosphine led to a novel class of chiral phosphinooxazolines 132 and their cationic iridium complexes were found to induce high enantioselectivities (66-90% ee) in the asymmetric hydrogenation of acyclic aromatic ./V-arylimines <04OL3825>. This reaction was also studied using Ir-complexes with other chiral phosphinooxazolines in ionic liquid/carbon dioxide media to assess the potential of this methodology for multiphase catalysis <04JA16142>. (SySerine methyl ester and a range of carboxylic acids RCO2H (R = metallocenes, 1adamantyl, phenyl) were readily transformed in three steps and 58-92% yields into 4hydroxyalkyloxazoline N,0 ligands 134, which were converted into the corresponding phosphinite-oxazoline N,P ligands 135 by treatment with Ph^PCl under basic conditions. These new ligands were screened in the addition of diethylzinc to benzaldehyde (up to 75%

Five-membered ring systems: with O & N atoms

251

ee) and in the palladium-catalysed allylic alkylation of allyl acetates with dimethyl malonate (48-96% ee), respectively <04TA653>. Novel N,0 ligands 136, derived from tartaric acid, were synthesised in moderate to good yields <04EJO1820>. Ph

R

Ph

l

\ / OMe R-° 136 R= Me, ;-Pr, Ph

o ° 137

Wtene reflux R1 = ,-Pr f-Bu

IBuLi.TMEDA

w

, ,

\ 2. XPR2 R1 0 "C—rt Ri 138 17-58% X = Cl, Br 13929-62% R = Ph, o-Tol

Condensation of hydroxy acid 137 with homochiral amino alcohols, in refluxing xylene with azeotropic removal of water, led to oxazolinyl alcohols 138. Subsequent reaction with the appropriate chloro- or bromophosphine afforded phosphinites 139 (SimplePHOX) <04OL2023>. Starting from readily available enantiopure phenyl glycinol and carboxylic acids a new class of conformationally rigid phosphino-oxazoline ligands 140 was synthesised <04OL513>. Iridium complexes with 139 and 140 proved to be very efficient catalysts for asymmetric hydrogenation of unfunctionalized and functionalized olefins (up to 99% ee). New optically active phosphino-benzyloxazolines 141 <04TA2189> and P-stereogenic N-P ligands 142 <04TL603> were prepared and applied to asymmetric Heck reactions and Pdcatalyzed allylic substitutions of malonate to allyl acetates, respectively, with high enantioselectivities. The latter application (with up to 99% ee) was also reported for a new class of phosphino-oxazoline ligands containing a heterocyclic backbone (HetPHOX) such as benzothiophene derivatives 143 O4TA2235; 04SL106>.

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 <04TA1043; 04EJO4442>. New chiral N-S 5-ferrocenyl-oxazolines have also been prepared from enantiomerically pure ferrocenyl cyanohydrins <04TAl 133>. 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 <04TA219>, 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 <04OL4399>.

252

F.M. Cordero and D. Giomi

New chiral oxazolinylcarbene-rhodium complexes 149 proved to be efficient catalysts for asymmetric hydrosilylation of dialkyl ketones with diphenylsilane (77-95% ee) <04AG(E)1014>. 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) <04TA119>, 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) <04TL2121>. 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 <04OL4097>. 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 <04CC1616>. 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 <04JOC3121>. 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 <04TA3693>. Novel tridentate ligands 156 with a diphenylamine backbone were also reported <04TA3433>. Enantiopure Box and Pybox ligands continue to show interesting applications in many kinds of asymmetric reactions, such as Ir-catalyzed <04OL4631> and Pd-catalyzed allylic alkylation <04TA3195>, DA <04EJO3057; 04OL4387>, hetero Diels-Alder (HAD) <04JOC7198>, 1,3-DC <04TL9581>, and cyclopropanation in ionic liquids <04TA77>. 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 <04OL4231>.

253

Five-membered ring systems: with O & N atoms

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 <04AG(E)1685>. The use of a new, insoluble polystyrene-bound Box ligand (IPB-BOX) was also described with good activity (85-95% ee) <04TA3233>. 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 <04AG(E)490>. 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 ^ifT^^^

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 <04TL8027>. 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 <04OL1685>.

254

F.M. Cordero and D. Giomi

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

^eO^O'^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 <04JOC8537>.

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 <04EJO677>. 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 <04TA387>.

The Garner aldehyde 177, a synthetically important compound employed for instance to synthesize (25)-homopentafluorophenylalanine 179 in 57% overall yield through oxazolineolefin 178 <04JOC5468>, 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 <04JOC5439>. 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

Five-membered ring systems: with O & N atoms

255

asymmetric alkylation <04TL3651>. 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 <04JOC7906>. 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 <04OL1741>. 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 <04OL4881>.

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 <04OL2709>.

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 <04JOC4192>.

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 <04JOC3990>. 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 <04TL7715>. 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 <04JOC3240>. 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 <04SL49>. 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 <04OL641>. / = ^

GrubbslM0% ^

I—( O

N ^ ^ ^

82%

O 202 R1^^

° Y

TMSCI

R2

N

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

T H F

'°^

R2^NA^O™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

ArANA^OH 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

Five-membered ring systems: with O & N atoms

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 <04TL3257>.

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^^O^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 <04TL3895>.

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-^O-s^Ar

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 <04TL7157>. The photochemical behaviour of some fluorinated 1,2,4-oxadiazoles has been investigated recently 04JOC4108; 04JFC165>.

5.7.8

REFERENCES

04AG(E)490 04AG(E)1014 04AG(E)1685 04CC1128 04CC1616 04CC2712 04CRV4151 04EJO677 04EJO1820 04EJO2205 04EJO2321 04EJO3057 04EJO4158 04EJO4442

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258 04JA718 04JA1944 04JA2716 04JA5367 04JA10162 04JA10174 04JA12888 04JA12897 04JA16142 04JCO142 04JFC165 04JMC4881 04JOC811 04JOC1470 04JOC1475 04JOC1803 04JOC3121 04JOC3240 04JOC3990 04JOC4108 04JOC4192 04JOC5439 04JOC5468 04JOC7013 04JOC7198 04JOC7906 04JOC8537 04M649 04OL513 04OL641 04OL675 04OL1653 04OL1677 04OL1685 04OL1741 04OL2023 04OL2027 04OL2627 04OL2709 04OL2717 04OL2929 04OL3593 04OL3825 04OL4097 04OL4231 04OL4387 04OL4391 04OL4399 04OL4631 04OL4881 04S401 04SL1 04SL49

F.M. Cordero and D. Giomi M.P. Sibi, Z. Ma, C.P. Jasperse, J. Am. Chem. Soc. 2004,126, 718. B.M. Trost, K. Dogra, M. Branzini, J. Am. Chem. Soc. 2004, 126, 1944. D. Carmora, M.P. Lamata, F. Viguri, R. Rodriguez, L.A. Oro, A.I. Balana, F.J. Lahoz, T. Tejero, P. Merino, S. Franco, I. Montesa, J. Am. Chem. Soc. 2004, 126, 2716. M.P. Sibi, K. Itoh, C.P. Jasperse, J. Am. Chem. Soc. 2004, 126, 5367. K.C. Nicolaou, S.A. Snyder, X. Huang, K.B. Simonsen, A.E. Koumbis, A. Bigot, J. Am. Chem. Soc. 2004, 126, 10162. K.C. Nicolaou, S.A. Snyder, N. Giuseppone, X. Huang, M. Bella, M.V. Reddy, P. Bheema Rao, A.E. Koumbis, P. Giannakakou, A. O'Brate, J. Am. Chem. Soc. 2004, 126, 10174. K.C. Nicolaou, D.Y.-K. Chen, X. Huang, T. Ling, M. Bella, S.A. Snyder, J. Am. Chem. Soc. 2004,126, 12888. K.C. Nicolaou, J. Hao, M.V. Reddy, P. Bheema Rao, G. Rassias, S.A. Snyder, X. Huang, D.Y.-K. Chen, W.E. Brenzovich, N. Giuseppone, P. Giannakakou, A. O'Brate, J. Am. Chem. Soc. 2004, 126, 12897. M. Solinas, A. Pfaltz, P.G. Cozzi, W. Leitner, J. Am. Chem. Soc. 2004, 126, 16142. S.H. Hwang, M.M. Olmstead, M.J. Kurth, J. Comb. Chem. 2004, 6, 142. S. Buscemi, A. Pace, I. Pibiri, N. Vivona, T. Caronna, J. Fluorine Chem.2004, 125, 165. L. Di Nunno, P. Vitale, A. Scilimati, S. Tacconelli, P. Patrignani, J. Med. Chem. 2004, 47, 4881. A.R. Katritzky, C. Cai, K. Suzuki, S.K. Singh, J. Org. Chem. 2004, 69, 811. C. Quan, M. Kurth, J. Org. Chem. 2004, 69, 1470. O. Tamura, N. lyama, H. Ishibashi, J. Org. Chem. 2004, 69, 1475. I. Nomura, C. Mukai, J. Org. Chem. 2004, 69, 1803. J. Bayardon, D. Sinou, J. Org. Chem. 2004, 69, 3121. G. Jalce, M. Seek, X. Franck, R. Hocquemiller, B. Figadere, J. Org. Chem. 2004, 69, 3240. Y. Wu, Y.-Q. Yang, Q. Hu, J. Org. Chem. 2004, 69, 3990. A. Pace, I. Pibiri, S. Buscemi, N. Vivona, J. Org. Chem. 2004, 69, 4108. C. Gaulon, R. Dhal, T. Chapin, V. Maisonneuve, G. Dujardin, J. Org. Chem. 2004, 69, 4192. A.J. Wills, M. Cano, S. Balasubramanian, J. Org. Chem. 2004, 69, 5439. I.R. Babu, E.K. Hamill, K. Kumar, J. Org. Chem. 2004, 69, 5468. A. Pena-Gallego, J. Rodriguez-Otero, E.M. Cabaleiro-Lago, J. Org. Chem. 2004, 69, 7013. A. Bayer, M.M. Endeshaw, O.R. Gautun, J. Org. Chem. 2004, 69, 7198. M. Shen, C. Li, J. Org. Chem. 2004, 69, 7906. R.K. Bowman, J.S. Johnson, J. Org. Chem. 2004, 69, 8537. F.M. Cordero, F. De Sarlo, A. Brandi, Monatsh. Chem. 2004,135, 649. D. Liu, W. Tang, X. Zhang, Org. Lett. 2004, 6, 513. F. Gosselin, A. Roy, P.D. O'-Shea, C.-Y. Chen, R.P. Volante, Org. Lett. 2004, 6, 641. M. Shirahase, S. Kanemasa, Y. Oderaotoshi, Org. Lett. 2004, 6, 675. S.W. Baldwin, A. Long, Org. Lett. 2004, 6, 1653. Z.-Z. Huang, Y.-B. Kang, J. Zhou, M.-C. Ye, Y. Tang, Org. Lett. 2004, 6, 1677. S.H. Wiedemann, R.G. Bergman, J.A. Eman, Org. Lett. 2004, 6, 1685. G.R. Cook, B.C. Maity, R. Kargbo, Org. Lett. 2004, 6, 1741. S.P. Smidt, F. Menges, A. Pfaltz, Org. Lett. 2004, 6, 2023. P.-Y. Roger, A.-C. Durand, J. Rodriguez, J.-P. Dulcere, Org. Lett. 2004, 6, 2027. S.L. You, S. Deechongkit, J.W. Kelly, Org. Lett. 2004, 6, 2627. S. Suga, Y. Kageyama, G. Babu, K. Itami, J-i, Yoshida, Org. Lett. 2004, 6, 2709. M. Matsugi, D.P. Curran, Org. Lett. 2004, 6, 2717. A. Dondoni, P.P. Giovannini, A. Massi, Org. Lett. 2004, 6, 2929. P. Wipf, Y. Aoyama, T.E. Benedum, Org. Lett. 2004, 6, 3593. A. Trifonova, J.S. Diesel, C.J. Chapman, P.J. Andersson, Org. Lett. 2004, 6, 3825. J.C.-D. Le, B. L. Pagenkopf, Org. Lett. 2004, 6,4097. P.R. Andreana, C.C. Liu, S.L. Schreiber, Org. Lett. 2004, 6,4231. H. Usuda, A. Kuramochi, M. Kanai, M. Shibasaki, Org. Lett. 2004, 6, 4387. A.S.K. Hashmi, J.P. Weyrauch, W. Frey, J.W. Bats, Org. Lett. 2004, 6, 4391. X.-L.Hou, N. Sun, Org. Lett. 2004, 6, 4399. H. Miyabe, A. Matsumura, K. Moriyama, Y. Takemoto, Org. Lett. 2004, 6, 4631. X. Xu, S.R.S.S. Kotti, J. Liu, J.F. Cannon, A.D. Headley, G. Li, Org. Lett. 2004, 6,4881. A. Barbero, F.J. Pulido, Synthesis 2004,401. P.M. Fresneda, P. Molina, Synlett 2004, 1. A.S. Davis, N.J. Gates, K.B. Lindsay, M. Tang, S.G. Pyne, Synlett 2004, 49.

Five-membered ring systems: with O & N atoms 04SL106 04SL1303 04SL1569 04SL1949 04SL2815 04T1671 04T3393 04T3405 04T3967 04T4879 04T6453 04T8991 04T9997 04T10321 04T11995 04TA77 04TA119 04TA219 04TA387 04TA653 04TA1043 04TA1133 04TA2189 04TA2235 04TA3079 04TA3195 04TA3233 04TA3433 04TA3693 04TL425 04TL603 04TL867 04TL2121 04TL2277 04TL3257 04TL3421 04TL3651 04TL3797 04TL3895 04TL4061 04TL4123 04TL4237 04TL4693 04TL4835 04TL4935 04TL6471 04TL7157 04TL7347

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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 <04EJO235> and the second describes the use of chiral pyridine JV-oxides as ligands for asymmetric catalysis <04TA1373>. Additional reviews on the chemistry of pyridines published in 2004 include Henry's review on de novo synthesis of pyridines <04T6043> and Lavilla's review on the chemistry of dihydropyridines and pyridinium salts <04CORC715>. 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 <04T5069>. 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 <04CEJ4283>. 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 <04OL2059>.

Baldwin et al. examined an interesting pyridine cyclization in a new synthesis of pyrazolo[4,3-c]pyridine core 8 <04T933>. 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

Six-membered ring systems: pyridines and benzo derivatives

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 <04S1349>. 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 <04TL4911>. 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 <04BMC3987>. 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 <04TL6471; 04H2845>. 1,2,4-Triazines were used by Branowska in reaction with cyclic enamines to prepare two new classes of 2,2'-bipyridines <04T6021>. 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 <04CC508> 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.

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

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 <04T8893>. Deniaud et al. has investigated diazadienium iodide 15 as an aza-diene moiety in the synthesis of pyridines <04TL9557>. 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 <04SL1309>. 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 <04T8633>. This method utilizes a CH-acidic substrate 19, dimethylformamide dimethylacetal (DMF-DMA) and diverse active methylene nitriles 20 as building blocks.

Six-membered ring systems: pyridines and benzo derivatives

I

R1^O

+

I

MW

^O^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 <04TL6121>. 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 <04JMC3180; 04JMC2688; 04JMC254; 04JMC3163>. Zolfigol et al. has developed a mild solvent free modification to this synthesis with improved yields <04SL827>. 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 <04TL9011>. Dondoni et al. utilized a one-pot thermal Hantzsch reaction for the synthesis of highly functionalized |3pyridylalanines 23 as shown in Scheme 9 <04TL2311>. 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 <04JMC1575; 04JMC4277; 04BMCL4511>, 3halopyridines <04OL3; 04JMC4588> and 4-halopyridines <04BMCL4603> are used frequently by medicinal chemists in the preparation of innovative biologically active molecules. Likewise 3-pyridyl boronates <04OPRD955> 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, <04EJO1891> as shown in Scheme 10. O O o ^Y^O^ Pd(PPh3)4 f^y^O^ ^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 <04SC3227> and other biologically active compounds <04JMC2453>. Palladium catalyzed carbonylation reactions have been improved for chloropyridines <04OL2097; 04H411> and examined in cobalt-catalyzed cross-coupling reactions <04CL1240>. Maes developed a unique elaboration of Buchwald chemistry <04CC2466>. 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 <04SC759>.

a

1

Pd(OAc) 2

|^J*^

ci+ ^rANH2

BINAPorXANTPHOS %

CS2C 3

°

|/5V'N\V_

^r/V^A

toluene, reflux, 17 h

24

25

\=~/

26

Scheme 11

Six-membered ring systems: pyridines and benzo derivatives

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 <04CEJ5607>. 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 <04TL4257> 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 <04T6113> and 2,4-disubstituted pyridines <04S2614>. 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 <04EJO1018> 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 <04TL7873; 04TL6697>. 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 <04OL4905>.

268

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

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 <04SL2319>. 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 <04JOC6766>. 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 <04OL4109>. Yamamoto et al. used the chelation

269

Six-membered ring systems: pyridines and benzo derivatives

of the 2-nitrosopyridine to promote the catalytic and highly enantio and diastereoselective nitroso Diels-Alder reaction <04JA4128>. 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 <04OL3695>, 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 <04BMCL3893; 04BMCL3993; 04OL2373; 04BMCL2401; 04AG(E)366; 04JA10389; 04JOC8723>. Extensions of this chemistry encompass a multi-component coupling reaction to give propargylic amines <04TL2607>. Wolf et al. has demonstrated that the Sonogashira coupling can be accomplished in water under an air atmosphere <04OBC2161>. 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 <04SL182>. 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 <04CL1298>. Likewise compound 42 can be prepared from the respective benzyl sulfone and pyridine-2-carboxaldhyde. rf^i

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 <04OL3671> 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 <04T11843> and Builla has accomplished an intermolecular addition of a heteroaryl radical onto an aromatic solvent <04T6217>. BOYS

CI^N^V"

DLp,DCE

'

C ! - W

J^o

R

) n

!

CIANAN;>n

J^o

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 <04TL1803>. 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 <04JMC6691>. 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 <04T429>.

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

Six-membered ring systems: pyridines and benzo derivatives

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 <04OL3517> 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 <04TL3401>. 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 <04OL4579>. Moreover, Taddei has prepared a polymer-supported Mukaiyama reagent with a spacer between the resin and the pyridine ring, compound 51, <04JOC9316>. 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 <04JMC6025>; here the molecule is built on the resin and is then cleaved off in a Zincke reaction to generate the pyridinium salt.

272

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

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 <04TL1557>. Moreover, Wu has reported the reaction of pyridinium halides with 2,2-difluorovinyl tosylate in the presence of base to yield monofluorinated indolizines <04T5487> 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 <04TL4281>. Zhong and co-workers performed this oxidation with trichloroisocyanuric acid in the presence of acetic acid and sodium acetate in acetonitrile/water <04SC247>. 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 <04SC3197>. Pyridine A'-oxides have also been used in the presence of a ruthenium catalyst for oxidation of alkanes <04CC798; 04OBC1013> and terminal alkenes to give the unexpected "Wacker type oxidation" <04AG(E)4950>.

273

Six-membered ring systems: pyridines and benzo derivatives

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 <04CC290>.

6.1.3

QUINOLINES

Synthetic approaches to the construction of pyrrolo[3,2-c]quinoline systems were compiled in a review by Nyerges <04H1685>. 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 <04JHC423> 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 <04TL6029>. 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

^OH

NH 2

LRu/HT-N, O2

2.

[f^I^I

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

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

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 <04S63>. 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 <04OL2433>.

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 <04TL8879>.

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 <04TL9037>. 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

Six-membered ring systems: pyridines and benzo derivatives

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 <04TL5473>. 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 <04BCJ1505>. Radical chemistry previously investigated by Naito and coworkers led to a formal synthesis of Martinelline <04TL3481>. 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 <04SC109>.

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 <04OL2361>. One-pot Diels-Alder reactions mediated by FeCl3-NaI <04TL3507> or sulfamic acid <04S69; 04S949> 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 <04SL1175>. 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 <04OL4913>.

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

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

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 <04CL590; 04SL1219>, 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 <04CL1206>. Notably, Piatnitski and coworkers reported that the reaction of (2-trifluoromethyl)aniline 73 with esters of arylacetic acids produced 4-fluorinated quinolinones 74 <04OL4061>.

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

^A^/^

., ., ^^^Si,

T

*"

2

"I ^V^i

]

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 <04SL2827>. In another report, tetrahydroquinolines were also produced via a [Cp*IrCl2J2 catalyzed transfer hydrogenation reaction using 2-propanol as a hydrogen source <04TL3215>. Various methods for the functionalization of quinolines were also investigated. Hydroxylated heteroarenes were reacted with acetylene in the presence of SnCU and an amine <04H1839>. 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 <04CL1316>. 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 <04EJO1008>. The reaction of l-methyl-3,6,8-trinitroquinoline with enamines was performed for the synthesis of 4-acylmethylquionlones <04CPB1334>. 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 <04CC2124>. R-i

EtO^O 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 <04JCO54>. 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 <04TL2251>. 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 <04JCC768>. 6.1.4

ISOQUINOLINES

A review by Chrzanowska and Rozwadowska <04CRV3341> 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

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

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 <04TL7339>. 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 <04T1611>. 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 <04S1446>.

S ^i~ 5 mol %

„

-

KC

.

2 °3

80

f

I

—x

1

°W d Q

~
50%

V ^ I ^ N I / L

lf^%

V ^ O ^

79 Scheme 35 One-pot metal-catalyzed reaction sequences were also studied for the synthesis of isoquinolines. Tetrahydroisoquinolines were formed in moderate yields using a Pd(OAc)/tri-2furylphosphine catalyzed one pot 3-bond formation consisting of metal mediated oalkylation/alkenylation and an intramolecular aza-Michael reaction <04TL6903> shown in Scheme 36. I

(\

k^

NHCbz +

(^

Br

+

J

Pd(OAc)2/TFP Cs

—

CO 2 Me

^ ^ ^ 1

2 C °3 .

k

K->^

[^—(

^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 <04OL3155>. <04TL417>.

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 O^i r T ^ T ^ v ^ ? R 2

f<^i MeOH 1 I n \X k/ ^ 83-90% R3f ] J T Pd(OAc)2 ^

Ri-NC ^ ^ N H

OR2

0

HN

^

pc

^Ri

|| 82 Scheme 37

2

y3

1

I

o T

H N

- R I

1 3

3

A ^ O

80-92% R {rJJ 84

Catalyzed cyclization reactions for the synthesis of isoquinolines were the focus of various reports. 4-Aryl-l,2,3,4-tetrahydroquionlines were synthesized in good yield via a quinone methide mediated cyclization in the presence of zinc chloride <04TL7487>. The intramolecular radical cyclization of oc,|3-unsaturated amides 85 was reported for the synthesis of isoquinoline analogs 86. In this study cc-unsubstiuted acrylamides afforded 6-exo products exclusively. On the other hand, substrates bearing an a-chlorine (X = Cl) substituent provided the 1-endo benzazepine derivatives <04TL2335>.

o ^ • Y ^ Y ^ N ^ T ^

lL^

2

D

R X

Bu3SnH

AIBN *" X

85

=

R1

N/5*Y^N'R2

I^ok^s.

H

48-55%

I 86

Scheme 38 The synthesis of Amaryllidaceae alkaloids siculine, oxocrinine and peicrinine was reported using a key phenyliodine(III) bis(trifluoroacetate)-mediated intramolecular p-p 'diphenol coupling reaction of norbelladine derivatives followed by an intramolecular Michael addition <04T4901>. An alternative approach to isoquinoline derivatives was reported by Chang and coworkers. In this report the benzene nucleus is installed via an intramolecular electrophilic cyclization of 3,4-disubstituted lactams 87 to provide 3,4-dihydrobenzo[g]isoquinoline-l(2/f)one 88 and 3,4-dihydroisoquinoline-l(2/f)-one 89 derivatives in good yields <04TL10637>.

280

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

R

VvVBn

UU

*-9 / s v^r^N- Bn

\\ Ts R-\T

Ti

HC1

0^NJ

HCI

" ^UU 89 DDQ I '

Bn 87

0

Ra-k^A^ 1

O

o

DDQ

R2-kA^k^

88

Scheme 39 A three-step synthesis of lOb-substituted-hexahydropyrroloisoquinolines from Z-tartaric acid was achieved using an acid-catalyzed C-C bond forming reaction via an JV-acyliminium ion. This approach offers the desired products with moderate to good stereoselectivity. The selectivity of the reaction was dependent on the size of the substituent introduced during the generation of the acyliminium functionality <04TL6011>. A three-step domino reaction mediated by AlMe3, illustrated in Scheme 40, was reported for the synthesis of the skeleton of Erythrina and B-homoerythrina alkaloids 90. The reaction is believed to proceed via an Nacyliminium ion and a metalated amide <04AG(E)5391>.

l^J

R O ^ ^

79 . 89 o /o

90

ff

|_

'"

W^' n

Scheme 40 In a study on the activation of macrocyclic enediynes by transannular cyclization it was found that the deprotection of the sulfonamide group of ketone 91 triggered the formation of aminol 92 which readily provided the isoquinoline derivative 93 via a Bergman cyclization reaction <04AG(E)132>.

281

Six-membered ring systems: pyridines and benzo derivatives

N

[f^f

"^

PhSH, K2CO3

y ^ ^ ^

O

I

92

HN

O

^^jfC^/

93

H

° —'

HO

Scheme 41 The acid catalyzed cyclization of 2-acylphenylacetonitriles 94 was investigated using strong acidic conditions. It was found that the use of Amberlyst ion exchange resins, such as A-15 and A-XN1010 in place of sulfuric or methanesulfonic acid provided 1-substituted 2//-isoquinolin-3ones 95 (Scheme 42) in improved yields <04JHC979>. r^j^CN

\^S^°

Amberlyst

95%

94

^y^yP

k^y NH 95

Scheme 42 Methods for the synthesis of isoquinolines using solid-phase supports were also described in the literature. The solid supported synthesis of tetrahydroisoquinolines using a Pictet-Spengler reaction was performed using (4-hydroxyphenyl)sulfide resin (Marshall linker) <04JCO487; 04JCO564>. Tetrahydroisoquinolines were also formed on solid support using a BischlerNapieralski cyclization reaction <04TL8323>.

6.1.3.2 Reactions of Isoquinolines The alkylation of isoquinolines with diethyl malonate mediated by LiCl was reported. This reaction was found to proceed in the absence of Pd catalysts to give dihydroisoquionline derivatives in good yield <04T19049>. An alternative method for the allylation of isoquinolines was developed using indium and allyl bromides to provide allyldihydroisoquinolines in the presence of phenyl chloroformate. This approach circumvents the formation of benzoisoquinuclidine byproducts observed in the allylation reaction of activated isoquinolines with allylsilanes <04OBC2170>. Oxidative and reductive conditions were investigated for the radical cyclizations to isoquionline systems as shown in Scheme 43. For example, isoquinoline 96 was reacted with iron sulfate and hydrogen peroxide (Fenton-type conditions) or n-

282

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

BirjSnH/AIBN to give the desired tricyclic framework 97 and 98 in moderate and good yields, respectively <04L2855>. ^W^Y—
^^Y -yf o

X

""Bu3SnH f j ^ r ^ S AIBN

88% 98

N

^ ^ y

V" R

i V

FeS

°4 7H2O [ j ^ V ^ l

H2O2, DMSO'

^y

N v

o

o

n = 1 , R = H , X = Br

28%

(^

Mr

97

96

Scheme 43 l-( Alky lidene)-l,2,3,4-tetrahydro-./V-(trichloroacetyl)isoquinolines 99 were shown to undergo oxidative cyclization with migration of the trihalogenomethyl group in the presence of lead tetraacetate to provide the corresponding oxazoloisoquinolinone derivatives 100 in good yields <04HCA690>. Rv

"[f^T~^

cc| coci

3

^"v^1^^

R"^R

LTA

R1

V^I/XI

R^R

ClaC^o R R 100

99

Scheme 44 The degradation of 2,2-dimethylisoquinolinium iodides 101 was carried out for the synthesis of phenanthrene alkaloids. Hoffmann elimination of the quaternary ammonium salt gave a stilbene intermediate 102 (Scheme 45), which was used as substrate for a photochemical electrocyclization to afford phenanthrene derivatives 103 in moderate to good yields <04TL4171>.

ir^T R—

rr^r R—

'e

102

I

101

hv, U, O2

^°

\

ill 103

Scheme 45

Y% R—

283

Six-membered ring systems: pyridines and benzo derivatives

A catalytic enantioselective alkynylation of tetrahydroisoquinoline 104 was carried out using CuOTf (Scheme 46). The relatively high enantioselectivity observed for tetrahydroisoquinoline 105 is attributed to a combination of steric effects and possible coordination of the oxygen of the methoxy substituent to copper <04OL4997>. 10 mol % Cu OTf

[f^V^

||

15mol%L

|

f-BuOOH

\_J

f^Y^

^v^v^N-v1X'^1

T

V^/

jf

J

61%, 74%ee 105

Scheme 46

6.1.5

PIPERIDINES

A comprehensive review article on the synthesis of piperidines by Buffat was published in 2004. The review covers many different methodologies applicable to simple piperidines and complex natural products. Pertinent literature through early 2003 is included <04T1701>. A review on the history, chemistry, and biology of the alkaloids from Lobelia inflate by Felpin and Lebreton includes useful information on the synthesis of piperidine alkaloids, with an emphasis on asymmetric methods <04T10127>. 6.1.5.1 Preparations of Piperidines Much effort has been devoted to the application of olefin metathesis to the synthesis of piperidines. Some of this work was outlined as part of a review by Deiters and Martin on ringclosing metathesis (RCM) in the synthesis of oxa- and azacycles <04CRV2199>. Shown below in Schemes 47 and 48 are reactions involving diverse precursors using one of the ruthenium catalysts "Ru" developed by Grubbs and others and always producing a piperidine product. The choice of a particular "Ru" is important in these examples. Diester 106 was prepared as an intermediate for constrained analogs of aminomalonic acid <04TL9607>. A similar RCM reaction was used in the preparation of 107, which was then elaborated to a phenylalanine mimetic constrained in a proline-like conformation <04OBC2365>.

284

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

PCM, 25 °C

^ k^NAc EtOOC

f^\ L^NAc

*"

COOEt

EtOOC

COOEt 106

k

N A CO 2 Me Ph^O

benZene ref UX

'

'

V^CO2Me Ph^O 107

Scheme 47 A chiral 1,6-diene 108 provided the azaspirocycle 109, an intermediate for the total synthesis of pinnaic acid <04SL2295>. A careful choice of catalyst, solvent, and temperature permitted the highly diastereoselective tandem RCM conversion of a tetraene 110 to the azaspirocycle 111 <04T8869>. The key conversion in a synthesis of (-)-allosedamine 112 entailed the extrusion of ethyl acrylate in an RCM reaction as shown <04TL1919> in Scheme 48. A similar RCM reaction involving the extrusion of styrene was used in a total synthesis of some potent polyhydroxylated piperidine glycosidase inhibitors <04JOC1497>. Spirolactams were prepared by RCM of appropriate 6-alkenyl-6-(3-butenyl)-2-piperidones <04T5613>. iV-acryloyl derivatives of substituted (3-butenyl)amines readily undergo RCM reactions to give 6-substituted 5,6-dihydropyridin-2-ones <04JOC6305; 04OL493; 04JCO684>.

TBSCL^LJc^^*" ^^ N '•, Ph^ \

C^\ iH

"Ru"

r~"i T

toluene, 80 °C

N Ph^

^
rs_

DCM,40°C,

^^I'-^N-fl F 3 COC'

"

110

OTS?AC ^ f^^Ph

Jr\ //

109

^ t V ^ .RU"

J B02C^

X ^^

108

5

f\ "

TBSO —

'Ku" toluene, reflux •

" ^ 111

f^l OAc N-WSh

k

Ts H

^ k

- * «•

OH N^T"Ph Me

H

112

Scheme 48 Additional applications of olefin metathesis shown below in Scheme 49 and 50 are indicative of the extent to which the olefmic moieties in the primary products may be transformed to complex piperidine-containing molecules, such as polyhydroxylated indolizidine alkaloids and

Six-membered ring systems: pyridines and benzo derivatives

285

iminosugars. A synthesis of (-)-swainsonine 113 used a ring rearrangement metathesis (RRM) reaction of substrate 114 as the key step to provide the tetrahydropyridine 115 <04JOC7284>. A RCM reaction of 116 provided 117, which was converted to 118 by catalytic OsO4 in high overall yield <04TL761>. HO A c

-

N

^ ^

"Ru"

BnO J L a i B S W

H

^C

/~~\

°™, 4CTC C M ^ H2C=CH2

114 EtO

TBSO

^

^ " ^ S

B n O ^ ^

H O ^ - ^

115

2 c - N ^^v5^X ^ ^

"Ru" DCM,40°C

113

TBSO., ^ 5 . [ |

0TBS

•

CO2Et

116

OH HO,,^L,OH [ | CO2Et

117

118

Scheme 49 The /V-allyllactam 119 was converted by RCM to 120, which on catalytic osmylation provided the polyhydroxylated indolizidine 121 <04OBC3128>. An analog 122 of the iminosugar siastatin B was prepared from the tetrahydropyridine 123. The relative configuration of the substitiuents in the latter were defined by the RCM reaction precursor 124 derived from a 2-azetidinone <04SL2776>. H OTBS

N

^\ 119

TBSO^^oH

,,D „

H?TBS

—* y

120

Dc;40OCTBSO^^

v^, 124

Boc 123

H?

——

H

^ N ^° H 121 OH

TBSO^J Boc 122

Scheme 50 Sequential RRM and cross metathesis (CM) reactions were used in a carefully-designed step in a synthesis of (-)-lasubine 125. The cyclopentenone 126 undergoes RRM to provide the intermediate 127, which reacts with 128 in a CM to provide the intermediate 129 <04T9629>.

286

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

o

r

f >

I

"Ru"

^

PCM. 40-C

\/~^/N-Boc

I

II

.

^ N ^ - ^ /

B

°C

<^"^Y \

127 L

126

^ - O M e

J

\

CiH J L JJ

M e O ^ ^

128

^ Boc

125

^^^ B /, 129

^

OMe

Scheme 51 A CM reaction of the allylic alcohol derivative 130 and the enone 131 provided the acyclic precursor 132 for the synthesis of (+)-carpamic acid 133 . ™

S 0

V^^ T

+

^NHCbz

"Ru" 9 toluene, 80 » c T M S O ^ / ^ > 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 <04S3047> and 136 into 137 <04T6437> 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

Six-membered ring systems: pyridines and benzo derivatives

287

<04JOC3139>. The reaction of a sulfonamidomesylate 140 with K2CO3/DMF gave the azasugar-type intermediate 141 <04JMC1930>. 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 <04TL987>. 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 <04JOC2229>. 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 <04HCA2712>.

I LH C \_J -mC02Me l7\-NHBn

6

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

Scheme 56

288

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

"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 <04TL8065> (Scheme 57). {^/r~~Y^<^

BnNH 21

/^Y^^

[-Lores

^O-^OTBS

1

144 Scheme 57

A method which uses a primary amine - diol pair in iV-heterocyclization has been developed. It features the catalytic activity of an iridium complex bearing pentamethylcyclopentadienyl (Cp*) ligands, and produces only water as a byproduct. The method was used in the two-step asymmetric synthesis of (5)-2-phenylpiperidine 145 from (7?)-phenylethylamine 146 <04OL3525>. NH 2 1

cat [Cp*lrCI 2 ] 2

^^Ph

KOAc

146 +

...

^ ^

[ J _ ^

toluene 100 X

*"

pn'

N

[ J Ph' N

^ 145

HO^^'^^OH Scheme 58

Ring formations by reactions of a 7V-nucleophile on carbonyl groups or their equivalents are shown in Scheme 59, 60 and 61. The most familiar application, reductive amination, was used in the synthesis of azasugar derivative 147 from a diol precursor as shown in Scheme 59 <04TL5751>. NHCbz

^ T 0O>^^SDH

/—>.

1.NalO4 2. NaBH3CN r

/^-Q °''-f^S 147

^—S

Cbz

Scheme 59 A key step in the synthesis of optically pure 5-hydroxypipecolic acid derivatives was effected by PTSA-DMF in refluxing toluene to give 148 <04OL4941>. A similar acid-catalyzed ring closure of a hemiacetal gave 149 <04JOC1872>.

289

Six-membered ring systems: pyridines and benzo derivatives

J

H0

-^\

ff^l

f

PTSA-DMF II. JL

HN^^CO2Me

toluene

—-

Cbz

f

i

n

Cbz R

1

R^^N^-COjH

148

_

OH

iV^JL,Ph

PPTS/THFi

T

R2^J

Ri

R

k

.

OH

y~^A^^Ph

2-(T T

O^OH NHBoc

O^Y 149 Scheme 60

Boc

The aza-Achmatowicz oxidation of (2-furylcarbinyl)amines continues to be a valuable method for the preparation of highly-substituted piperidines. The methoxy group in 150, prepared as shown in Scheme 61, underwent displacement reactions to provide useful carbon substituents, for example as a route to racemic azimic acid 151 <04OL4029>. Treatment of 152 with mCPBA/DCM gave 153, presumably with maintenance of chiral integrity <04JOC2892>.

F \ ^ ^ M e 2.(MeO)3CH-catBF3| 0

<*^f 1

]LT

MeO ' N

_ ^ Me

r>' HO2C(H2C)5"

150

)=/

mCPBA/DCM L

NHTs

N

Me

151

1

II ,i.H UH

152

153

Scheme 61 In Scheme 62 are shown recently developed cyclization reactions of JV-nucleophiles on olefmic electrophiles to give piperidines. In an iodolactamization method, chiral 154 gave 155 in 90% yield and 97% de. <04JOC7906>. A tandem Heck-allylic substitution reaction served to convert 156 to 157 with modest diastereoselectivity. A proposed intermediate is the allylic palladium species 158 <04T9687>. An amidomercuration reaction of similar olefinic substrates to give 2,6-dialkylpiperidines has been reported <04OL3067>.

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

290

" > f M ,LHi '-CP H

O

^

2.l 2 ,

0A

- S ^

THF

/ ^'\-°

154 r

r^Y

MUT NHTs

igand

156

155 -l

Ts

H

C r e ^

ACN

Me

T~

Ts i ,_.

Pd(OAc)2 +

/

;

Me |_

s^^s

158

L rt

PdBr

J

157

Scheme 62 Lactamization of suitable 5-aminoacyl derivatives, to give 2-piperidones, continues to be employed in diverse situations (Scheme 63). Acylation of Meldrum's acid with TV-protected |3aminoacids, followed by thermolysis of the resultant Af-protected 5-amino-|3-ketoacid, gave dioxopiperidines 159 <04JOC130>. The key step in a chiral synthesis of (+)-febrifugine was the reductive deamination-recyclization of proline derivative 160 to give 161 <04TL6221>. Formal addition of ammonia to 162 gave the epimeric mixture 163 in fair yield <04JOC1872>. Lithium (S)-iV-benzyl-/V-a-methylbenzamide was used as a chirality source in a synthesis of 6-substituted 2-piperidones, which featured a lactamization reaction <04OBC1387>. O Boc, NH O

;M«

Jl

E c DcM 2 ^ rr 1.Meldrum's Acid

[

°*N * Boc

159 TBSO

A|

TBSO

H

H

160 o

161

Ph V ~ \

Q

NH4QH-NH4CI/Me0H

^/^°^Ph

H

162

163 Scheme 63 Aza-cycloaddition reactions, especially of the [4+2]- type, continue to be of interest for the synthesis of piperidines in various oxidation states. Danishevsky's diene 164 and N-

291

Six-membered ring systems: pyridines and benzo derivatives

functionalized imines gave 4-piperidone derivatives (Scheme 64). The ethyl glyoxylate-derived imine 165 reacted with 164 in the presence of a (S^-BINOL-zinc complex to give 166 after hydrolysis, with moderate to high enantioselectivity <04SL711>. iV-Phosphorylarylimines 167 were used in a study with 164 and various Lewis acid catalysts. Whereas Cu(OTf)2 gave the best chemical yield of racemic 168, the (5)-BIN0L-zinc complex was the only system able to effect an asymmetric (77% ee) result <04SL708>. The aza-cycloaddition of 164 with JV-arylimincs in supercritical CO2 has been studied <04T6163>. CO2Et

.. Me

OTMS

N

M e O ^ ^

^^^OMe

Y l

164

XJ °

^JT\

BINOL-metal complex

165

EtO2C^^O 166 E t

N -PO 3 Et 2 Ar

J

2°3

P

-

N

1.164/DCM ,

^

Ar^^O

2. TFA/DCM

167

168

Scheme 64 In a route to meso-2,6-diaryl-4-piperidones, a diene partner 169 was reacted with Ar-matched yV-allylimine 170 in the presence of Cu(OTf)2 in THF to give, after hydrolysis, 171 with generally high yield and de >99% <04TL4357> (Scheme 65). A [4+2] cycloaddition of |3,yunsaturated a-bromoketenes 172 and imines 173 was studied in detail. Some of the 2-piperidone adducts underwent reaction with allylamine to give aziridines with 99% de. For example, 174 afforded 175 in 85% yield <04T5031>.

„

Ph

Ar^-^y

+

1

J

+

170

PCM

^N--

P h

O 172

[

171

^

\

J

Ar'^^O

Ph

(

X 1

Cu(OTf)2/THF

f

169

r^

j

173

174

Ph

^l

^N>-Ph

allylamine v

O

Ph

175

Scheme 65 The structures of l-aza-2-siloxydienes 176, prepared by silylation of a,|3-unsaturated amides, were rigorously proven. A study of the Lewis acid-catalyzed reactions of 176 with simple dienophiles showed that the [4+2] cycloaddition products 177 did form, along with several

292

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

byproducts <04S2222>. Hydrazone derivatives 178 have been used in aza-[4+2] cycloadditions with very reactive dienophiles to provide allyl boronate intermediates, which can be trapped with aldehydes to afford highly functionalized piperidines. Some of these were transformed to (-)methyl palustramate 179 and similar compounds <04AG(E)2001; 04JOC8429>. f> CO2Me ^vXO2Me

TBSoAj

+

f

TBSOTf/DCE

J^^]

Ph

Ph

176

177

'

OH

178

179 Scheme 66

Inverse electron-demand cycloadditions of N-sulfonyl vinylimines and allenamides, exemplified by the formation of 180 from 181 and 182, have been examined. The synthetic limitations, mechanistic issues, and stereochemistry of the process have been addressed <04T7629>. Fulvenes have been used as dienophiles with N-sulfonyl vinylimines to synthesize the [l]pyrindine system <04OL3453> and in a formal [6+3] cycloaddition with an appropriate 2//-azirine to give the [2]pyrindine system <04TL1663>. V" N V_

SO2Ph

J*

+

X

^ ^ / ^

f ».

181

PhSo/^N

ACN,50°C

,,N

N

>-

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 <04OBC2270> (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

Six-membered ring systems: pyridines and benzo derivatives

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^N^O Me 186

Scheme 69

A second 5-exo-trig cyclization of an intermediate occurred with the enamide 187 to give 188 <04T8181>. 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 <04CC1422>. Ph i%.

J l Jsv Ph^N^O R

Ph R = 3-butenyl ^

^oc

^

Ph

toluene, A

w^N^O ^—'

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 <04BMCL2147>.

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

294 OBn B n

r

N

°^v

HO^^N;

, >

R0H

\ ^

DIAD ,

BnO. / W

192

RONA^OBn

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 <04JOC3226>. Intramolecular alkylation was used to covert chiral enaminone 199 to 200, a key intermediate in the total synthesis of lepadin alkaloids <04AG(E)4222>. OH

<


J^^

O

PCC/DCM t

i

r-R

j^Y^-R i

Ts 197

Ts 198

A V T B S TEA-N3, , r V Y 0 1 6 3 kANX..

DMF.110-C KJL X...

H

H

199

200

Scheme 72 Dieckmann cyclization of diester 201 gave the 3-piperidone derivatives 202, aseco ergoline derivative <04JMC5620>. A stepwise [3+3] annulation was effected by sodium hydride to give glutarimide 203, which was found to be a valuable intermediate for piperidine syntheses <04T10223>.

295

Six-membered ring systems: pyridines and benzo derivatives o AxO 2 Et

.CO2B

f| /-CO 2 Et Jj 1 ^J^,N.Me LiHMDS/THF ^ - ^ Y Me 201

0

1

202

1

^H

NaH/THF

EtcAo

J

"

T

O^N^O

R

R

203 Scheme 73 Simple access to piperidines is available in many cases through the reduction of pyridine derivatives (Scheme 74). Recent preparations of 2- and 4- arylmethylpiperidines 204 entailed the addition of aryl Grignard reagents to the requisite aldehydes to give the arylcarbinols 205, followed by a designed sequential hydrogenolysis and ring saturation <04EJO3623>. In a preparation of 4-arylpiperidines 206, aryl Grignard reagent addition to the requisite acylpyridinium salts afforded the dihydropyridines 207, which were hydrogenated selectively in the presence of Wilkinson's catalyst .

f\cHO k

N^

ArMgX,

if^L/0"

H

k

HCI-EtOH

N^Ar

^ 2 5 °C

205

CI^^^CN

T

if^l L

II JL 207

60 °C,

^N^^Ar

RhCI(TPP)4

(^ |j

-I

Ar

204

Jl A 206

Scheme 74 6.1.5.2 Reactions of Piperidines An important area of research in piperidine chemistry involves the synthesis and modification of chiral compounds of general structure 208 derived from (R)- and (S)- phenylglycinol (Scheme 75). The chiral cyanopiperidine 209 was oxidized by permanganate to the lactam 210. Further non-racemizing transformations included chemoselective hydrogenation to 211 and formation of lactone 212 on acid treatment <04EJO4823>.

296

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

208

OXN1CN \^

_J<MnO^_ 0 X N X C N

y

acetone-H2 Ph

'" RaNi/THFJ

2 09

O

j

H e / ™ 210

MVK

\HCI/EtOH

ji

\

cfV 213

>h 211 .-

r>

Ph ^o

—'.

_^MgBr |

215

HC/

O

>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 <04JOC3836>. 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 <04OLl 139>. 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 <04TL4903>.

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 HO^A^OBn

1-PhSeBr

3. OsO4-Ba(CIO3)2

o^N^o

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 <04T5433>. Reduction of advanced intermediate 226 with LAH, followed by hydrogenolysis and deketalization gave 1-deoxy-D-gulonojirimycin 227 <04TL5355>.

1

X

°

~ ^ N ^ ° \ 2. PTSA

P°

I

1

h J 3 ^et°ne-H?O ^ N ^ S

Ph

4. LAH 222

224

^,.CO2Me

1BH3/THF

rX»k^\J O

N

N Ph

o

^,--^OH

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

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

phosphorus ligands. The resulting zinc enolates can be trapped with electrophiles, for example with acetaldehyde to give, after oxidation, 229 with 94% ee <04CC1244>. 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 <04TL5271>. 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 <04T9757>.

V/0-B^N^ ^ 6 Cbz

ArBr <°)

,

Pd

230

] | O^N^ Bn

Ar'Nr 6bz 231

1. LiHMDS, ZnCI2 IHE . 2 ArBr pd - (°)

232

" Y ^ O^"N^ Bn 233

Scheme 79 6.1.6

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Six-membered ring systems: pyridines and benzo derivatives 04OL3 04OL493 04OL1139 04OL2059 04OL2097 04OL2361 04OL2373 04OL2433 04OL3067 04OL3155 04OL3453 04OL3517 04OL3525 04OL3553 04OL3671 04OL3695 04OL4029 04OL4061 04OL4109 04OL4579 04OL4905 04OL4913 04OL4941 04OL4997 04OPRD955 04S63 04S69 04S949 04S1349 04S1446 04S1619 04S2222 04S2614 04S3047 04SC109 04SC247 04SC759 04SC3197 04SC3227 04SL182 04SL708 04SL711 04SL811 04SL827 04SL1175 04SL1219 04SL1309 04SL1711 04SL2295 04SL2319 04SL2776 04SL2827 04TA1373

301

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302 04T429 04T933 04T1557 04T1611 04T1701 04T2311 04T4901 04T5031 04T5069 04T5433 04T5487 04T5613 04T6021 04T6043 04T6113 04T6163 04T6217 04T6437 04T7629 04T8181 04T8633 04T8869 04T8893 04T9629 04T9687 04T9757 04T10127 04T10223 04T10637 04T11367 04T11639 04T11843 04T11869 04TL417 04TL761 04TL987 04TL1167 04TL1663 04TL1803 04TL1919 04TL2251 04TL2335 04TL2607 04TL2855 04TL3215 04TL3401

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa T.C. Govaerts, I.A. Vogels, F. Compernolle, G.J. Hoornaert, Tetrahedron 2004, 60,429. L. Commeiras, S.C. Woodcock, J.E. Baldwin, R.M. Adlington, A.R. Cowley, P.J. Wilkinson, Tetrahedron 2004, 60, 933. F. Delattre, P. Woisel, G. Surpateanu, M. Bria, F. Cazier, P. Decock, Tetrahedron 2004, 60, 1557. T. Harayama, A. Hori, H. Abe, Y. Takeuchi, Tetrahedron 2004, 60, 1611. M.G.P. Buffat, Tetrahedron 2004, 60, 1701. A. Dondoni, A. Massi, E. Minghini, V. Bertolasi, Tetrahedron 2004, 60, 2311. S. Kodama, H. Takita, T. Kajimoto, K. Nishide, M. Node, Tetrahedron 2004, 60, 4901. G. Cardillo, S. Fabbroni, L. Gentilucci, R. Perciaccante, F. Piccinelli, A. Tolomelli, Tetrahedron 2004,60,5031. A.D. Thomas, K.N.N. Josemin, C.V. Asokan, Tetrahedron 2004, 60, 5069. C. Agami, L. Dechoux, S. Hebbe, C. Menard, Tetrahedron 2004, 6(9,5433. X. Fang, Y.-M. Wu, J. Deng, S.-W. Wang, Tetrahedron 2004, 60, 5487. M.A. Brimble, M. Trzoss, Tetrahedron 2004, 60, 5613. D. Branowska, Tetrahedron 2004, 60, 6021. G.D. Henry, Tetrahedron 2004, 60, 6043. S. Saitton, J. Kihlberg, K. Luthman, Tetrahedron 2004, 60, 6113. M. Shi, S.-C. Cui, Q.-J. Li, Tetrahedron 2004, 60, 6163. A. Nunez, A. Sanchez, C. Burgos, J. Alvarez-Builla, Tetrahedron 2004, 60, 6217. G. Lesma, S. Crippa, B. Danieli, D. Passarella, A. Sacchetti, A. Silvani, A. Virdis, Tetrahedron 2004, 60, 6437. C.R. Berry, R.P. Hsung, Tetrahedron 2004, 60, 7629. J. Flisinska-Luczak, S. Lesniak, R.B. Nazarski, Tetrahedron 2004, 60, 8181. N.Y. Gorobets, B.H. Yousefi, F. Belaj, CO. Kappe, Tetrahedron 2004, 60, 8633. R.A.J Wybrow, A.S. Edwards, N.G. Stevenson, H. Adams, C. Johnstone, J.P.A Harrity, Tetrahedron 2004, 60, 8869. S.P. Stanforth, B. Tarbit, M.D. Watson, Tetrahedron 2004, 60, 8893. M. Zaja, S. Blechert, Tetrahedron 2004, 60 , 9629. E.W. Dijk, L. Panella, P. Pinho, R. Naasz, A. Meetsma, A.J. Minnaard, B.L. Feringa, Tetrahedron 2004, 60, 9687. A. de Filippis, D.G. Pardo, J. Cossy, Tetrahedron 2004, 60 , 9757. F.-X. Felpin, J. Lebreton, Tetrahedron 2004, 60, 10127. B.-F. Chen, M.-R. Tasi, C.-Y. Yang, J.-K. Chang, N.-C. Chang, Tetrahedron 2004, 60, 10223. M.-R. Tsai, T.-C. Hung, B.-F. Chen, C.-C. Cheng, N.-C. Chang, Tetrahedron 2004, 60, 10637. G.N. Boice, C.G. Savarin, J.A. Murry, K. Conrad, L. Matty, E.G. Corley, J.H. Smitrovich, D. Hughes, Tetrahedron 2004, 60, 11367. K. Kobayashi, K. Yoneda, K. Miyamoto, O. Morikawa, H. Konishi, Tetrahedron Lett. 2004, 60, 11639. A. Sanchez, A. Nunez, J. Alvarez-Builla, C. Burgos, Tetrahedron 2004, 60, 11843. F. Cottet, M. Schlosser, Tetrahedron 2004, 60, 11869. V. Gracias, J.D. Moore, S.W. Djuric, Tetrahedron Lett. 2004,45,417. F. Chevallier, I. Beaudet, E. Le Grognec, L. Toupet, J.-P. Quintard, Tetrahedron Lett. 2004, 45, 761. M.S. Bodas, P.K.Upadhyay, P. Kumar, Tetrahedron Lett. 2004, 45, 987. S. Randl, S. Blechert, Tetrahedron Lett. 2004, 45, 1167. B.-C. Hong, A.K. Gupta, M.-F. Wu, J.-H. Liao, Tetrahedron Lett. 2004, 45, 1663. M. Adib, H. Yavari, M. Mollahosseini, Tetrahedron Lett. 2004, 45, 1803. S. Raghavan, A. Rajender, Tetrahedron Lett. 2004, 45, 1919. S. Arseniyadis, A. Wagner, C. Mioskowski, Tetrahedron Lett. 2004, 45, 2251. A. Kamimura, Y. Taguchi, Tetrahedron Lett. 2004, 45, 2355. N. Olivi, P. Spruyt, J.-F. Peyrat, M. Alami, J.-D. Brion, Tetrahedron Lett. 2004, 45, 2607. Y.M. Osornio, L.D. Miranda, R. Cruz-Almanza, J.M. Muchowski, Tetrahedron Lett. 2004, 45, 2855. K.-I. Fujita, C. Kitatsuji, S. Furukawa, R. Yamaguchi, Tetrahedron Lett. 2004, 45, 3215. E. Convers, H. Tye, M. Whittaker, Tetrahedron Lett. 2004, 45, 3401.

Six-membered ring systems: pyridines and benzo derivatives 04TL3481 04TL3507 04TL4171 04TL4257 04TL4281 04TL4357 04TL4903 04TL4911 04TL5271 04TL5355 04TL5473 04TL5751 04TL6011 04TL6029 04TL6121 04TL6221 04TL6471 04TL6697 04TL6903 04TL7339 04TL7487 04TL7873 04TL8065 04TL8323 04TL8879 04TL9011 04TL9037 04TL9049 04TL9557 04TL9607

303

Y. Takeda, T. Nakabayashi, A. Shirai, D. Fukumoto, T. Kiguchi, T. Naito, Tetrahedron Lett. 2004,45,3481. A. Kamal, B.R. Prasad, A.V. Ramana, A.H. Babu, K.S. Reddy, Tetrahedron Lett. 2004, 45, 3507. S.V. Kini, M.M.V. Ramana, Tetrahedron Lett. 2004, 45, 4171. C.S. Li, D.D. Dixon, Tetrahedron Lett. 2004, 45,4257. V.B. Sharma, S.L. Jain, B. Sain, Tetrahedron Lett. 2004, 45, 4281. A.B. Garcia, C. Valdes, M.-P. Cabal, Tetrahedron Lett. 2004, 45, 4357. J. Xie, T. Guveli, S. Hebbe, L. Dechoux, Tetrahedron Lett. 2004, 45, 4903. S.C. Collet, J.-F. Remi, C. Cariou, S. Laib, A.Y. Guingant, N. Quang Vu, G. Dujardin, Tetrahedron Lett. 2004, 45,4911. A. Ferrali, A. Guarna, F. Lo Galbo, E.G. Occhiato, Tetrahedron Lett. 2004, 45, 5271. M. Amat, M. Huguet, N. Llor, O. Bassas, A.M. Gomez, J. Bosch, J. Badia, L. Baldoma, J. Aguilar, Tetrahedron Lett. 2004, 45, 5355. A.V. Ivachtchenko, A.V. Khvat V.V. Kobak, V.M. Kysil, C.T. Williams, Tetrahedron Lett. 2004, 45, 5473. T.-L. Shih, W.-S. Kuo, Y.-L. Lin, Tetrahedron Lett. 2004, 45, 5751. D. Mostowicz, R. Wqjcik, G. Dolega, Z. Kaluza, Tetrahedron Lett. 2004, ¥5,6011. K. Motokura, T. Mizugaki, K. Ebitani, K. Kaneda, Tetrahedron Lett. 2004, 45, 6029. X. Xiong, M.C. Bagley, K. Chapaneri, Tetrahedron Lett. 2004, 45, 6121. M. Katoh, R. Matsune, H. Nagase, T. Honda, Tetrahedron Lett. 2004, 45,6221. M. Ohba, I. Natsutani, T. Sakuma, Tetrahedron Lett. 2004, 45, 6471. H. Awad, F. Mongin, F. Trecourt, G. Queguiner, F. Marsais, F. Blanco, B. Abarca, R. Ballesteros, Tetrahedron Lett. 2004, 45, 6697. R. Ferraccioli, D. Carenzi, M. Catellani, Tetrahedron Lett. 2004, 45, 6903. M Ohtaka, H. Nakamura, Y. Yamamoto, Tetrahedron Lett. 2004, 45, 7339. B.C. Raju, P. Neelakantan, U.T. Bhalerao, Tetrahedron Lett. 2004, 45, 7487. H. Awad, F. Mongin, F. Trecourt, G. Queguiner, F. Marsais, Tetrahedron Lett. 2004, 45, 7873. J. Igarashi, H. Ishiwata, Y. Kobayashi, Tetrahedron Lett. 2004, 45, 8065. M.-S. Chern, W.-R. Li, Tetrahedron Lett, 2004, 45, 8323. C. Macleod, C.A. Austin, D.W. Hamprecht, R.C. Hartley, Tetrahedron Lett. 2004, 45, 8879. N. Tewari, N. Dwivedi, R.P. Tripathi, Tetrahedron Lett. 2004, 45, 9011. W. Uchikawa, C. Matsuno, S. Okamoto, Tetrahedron Lett. 2004, 45, 9037. Y.M. Chang, Y.S. Park, S.H. Lee, CM. Yoon, Tetrahedron Lett. 2004, 45, 9049. A. Robin, K. Julienne, J.C. Meslin, D. Deniaud, Tetrahedron Lett. 2004, 45, 9557. S. Kotha, K. Singh, Tetrahedron Lett. 2004, 45, 9607.

304

Chapter 6.2 Six-membered ring systems: diazines and benzo derivatives

Michael P. Groziak California State University East Bay, Hayward, CA, USA [email protected]

6.2.1 INTRODUCTION The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine remain central to a great many chemical and biological investigations. Progress on the syntheses and reactions of these heterocycles, and their continued use as intermediates toward broader goals was abundant. Many studies relied on solid-phase, microwave irradiation, or metal-assisted approaches. Also, more progress of an Xray, computational, spectroscopic, natural product, and biological nature was made. These have been grouped together as much as possible.

6.2.2 REVIEWS AND GENERAL STUDIES One review of a synthetic nature covered new routes to pyridazino-fused ring systems <04SL1123>. In addition to this, there were two reviews focusing on specific medicinal applications of some diazines. One covered the design, synthesis and SAR of 5-[(l-substituted) alkyl (or vinyl)J pyrimidine nucleosides as potential inhibitors of herpes viruses <04MI2749>, and the other described 4-thiophenoxy-N-(3,4,5-trialkoxyphenyl)pyrimidine-2-amines as potent and selective inhibitors of the T-cell p561ck tyrosine kinase <04MI747>. Several general reports covered more than one type of diazine. For example, Cu(II) complexes of a diverse set of alkoxy diazine ligands were prepared, and their magnetic properties investigated. X-ray crystal structure determinations of many of these were included <04IC4278>. New sulfinylcinnolines, quinoxalines, quinazolines, and phthalazines were prepared from appropriate halobenzodiazines. These were converted to sulfanyl benzodiazines, which in turn

305

Six-membered ring systems: diazines and benzo derivatives

were oxidized with mCPBA to the corresponding sulfoxides <04T7983>. When quaternized at Nl with alkyl and polyfluoroalkyl halides, the diazines pyrazine, pyridazine, and pyrimidine underwent anion metathesis with other salts to afford new ionic liquid materials <04S1072>. An acid-promoted direct C-C coupling of 1,3-diazines with calix[4)arene, benzo-12-crown-4, and l,5-bis(2,6-dimethylphenoxy)-3-oxapentane to give compounds like 1 was described <04ARK6>, and substituted 1,2-diazines 2 were shown to condense with alkylidenecyclopropanes 3 in a Pd-catalyzed intermolecular l3+2"|cycloaddition reaction, giving 5azaindolizines 4 <04JOC3202>. Finally, a microwave-assisted condensation synthesis of thiaand oxadiazines was developed <04IJH283>.

f*i

+ArH

° ^ H i s -3C0-

N

B

Ar

=/^^o^o. I T

J

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1

R

O->

rtf^

2

3

""

R

N

^ ^ ^ - ; ^j 4 ^-'

6.2.3 PYRIDAZINES AND BENZO DERIVATIVES The tautomeric and conformational equilibria, and pKa values of seventeen pyridazines were studied by semi-empirical AMI COSMO calculations in aqueous solution, and the results were compared to experimental data <04TC221>. Two diaryl derivatives of ethyl [(4-cyano-6-methyl3,8-dioxo-2,3,5,6,7,8-hexahydropyridol3,4-c]pyridazin-6-yl)hydrazono]acetate were characterized rather thoroughly by 'H, C, and !5N NMR spectral and X-ray crystallographic methods <04HEC35>. Pyridazinedione-based enediynes 5 were prepared and their chemical reactivity to give 6 and their crystal structures were determined <04JOC6927>. Also of a purely heterocyclic nature were the X-ray crystal structure reports of 2,3,4,6-tetraphenyI-2//-pyrazolo[3,4-d|pyridazin-7(6/f)-one 7 <04AX(E)807> and three 5//-indeno|l,2-c]pyridazin-5-ones, type-B monoamine oxidase inhibitors <04AX(C)623>.

O 5

5

Ph

6

Ph 7

Focusing on metal complexes, an ionic hydrazinium Mg(II) complex with pyridazine-3,6dicarboxylate ligands was characterized by X-ray <04JCC917>, as was carena-poly[mercury(II)di-lu-bromo-,u-pyridazine-K2A'.-./V'| <04AX(E)753>, cafena-poly[mercury(II)-di-1u-chloro-^-pyridazine-f^/V.-iV'] <04AX(E)751>, diaqua-fran.s-bis(pyridazine-3-carboxylato-K2O,A')zinc(II) 8 <04AX(E)1481>, and polyr[(pyridazine-KjV)copper(I)]-lu3-thiocyanato-K3A'.S:5] <04AX(C)153>. Mixed-metal (Mn/Cu, Fe/Cu, Ni/Cu) pyridazine-linked cryptates were obtained by a one-pot

306

M.P. Groziak

two-step method <04EJI2570>. Finally, X-ray crystallographic and solid-phase 13C and 15N NMR spectroscopic analyses of Zn(II), Cd(II), Hg(II) chloride complexes with pyridazine were reported <04JMS143>.

6.2.3.1 Syntheses Condensation approaches to the synthesis of pyridazines were popular. For instance, pyridazino[4,5-/][l,3,5]triazepine 10 was among the compounds accessed via condensation of 6,7-dicyano-l,3,5-triazepine-2(lW),4(3//,5W)-dione 9 with amines <04ARK71>. Treatment with (EtO)3CH gave tetracycle 11. 3(2H)-Oxo-, 3-mercapto-, and 3-aminopyridazines were condensed with /V-phthaloyl- or 7V-tosyl-amino acids using DCC to obtain amino acid-pyridazine conjugates <04IJC629>. A new one-pot synthesis of pyridazino[l,4Joxazin-3-ones relied upon the condensation of A'-substituted 2-chloroacetamides with 5-chloro-6-hydroxypyridazin-6-one followed by rearrangement of the intermediate spiro-aminoketals <04SC1399>. Condensation of 7-acylbenzoxazinones with glyoxylic acid followed by cyclization with NH2NH2 gave 6-(2,2dimethyl-3,4-dihydro-3-oxo-l,4(2W)-benzoxazin-7-yl)pyridazin-3-ones <04OPP292>. Cyclocondensation of ethyl a-(3-carbamoyl-4,5,6,7-tetrahydrobenzo[fc]thiophen-2-ylhydrazono)acetate with active methylene compounds generated polyfunctional pyridazines <04HAC300>, and unsaturated pyridazinones were obtained in good overall yield via DDQ oxidation of dihydrofurans followed by condensation of the resulting tetronic acids with hydrazine <04EJO2797>.

3,5-Disubstituted pyridazines 13 were prepared from p-hydroxy-y-ketoaldehydes 12 and NH2NH2 <04JOC1380>, and treatment of 3-chloro-5,6-diphenylpyridazine-4-carbonitrile with KSCN gave the corresponding isothiocyanate, which underwent cyclization with arylamines to give new pyrimido[4,5-c]pyridazines <04M45>. 5H-Pyridazino[4,5-b]indoles and their benzofuran analogs were prepared via an intramolecular Heck-type ring closure <04T2283>. 2-Aryl4a-methyl-10-oxo-4-phenyl-2,4a,5,10-tetrahydropyridazino[4,3-iilquinoline-3-carboxylic acids were prepared via [4+2] cycioaddition of phenylpropiolic acid to aryidiazonium nitrates derived from dihydroquinolin-4-ones <04TL8423>. A microwave-assisted preparation of 1,3-oxazolo-

Six-membered ring systems: diazines and benzo derivatives

307

[4,5-, as was a procedure for the preparation of [l,4]pyridazinooxazine[3,4-a]tetrahydroisoquinolines from pyridazino[4,5-£>][l,4]oxazines, based on reduction and stereoselective Pictet-Spengler cyclization <04T3763>. New pyridazine-based purinyl-homo-carbonucleosides were obtained from l,4-diphenyl-5,8-dihydro-5,8methanophthalazine <04S2855>.

Chirality was an important aspect in some pyridazine syntheses. Optically active 3-carbamoyll,6-dimethylpyrimido|4,5-cjpyridazine-5,7(l/y,6/f)-dione 14a and related compounds 14b,c were obtained from the corresponding ethyl esters. Several of them were characterized by UV/Vis and electrochemical methods <04H(63)1393>. An (/?)-4,5-dihydro-5-methylpyridazin3(2f/)-one bearing a pyrazolopyridine ring was synthesized in high optical yield in four steps from (7?)-2-chloropropionyl chloride by a chiral-pool method <04S1554>, and enantiomerically pure, partly saturated (i?S)-[(lS)-isoborneol-10-sulfinyl]-substituted cinnolines, benzo[/|cinnolines, and [l,2,4]triazolo[l,2-a]pyridazines like 15 were accessed via Diels-Alder cycloadditions <04ARK79>.

6.2.3.2 Reactions The reactivity of pyridazines in Pd-catalyzed reactions was of interest. For example, the Heck alkenylation at C5 of 6-phenyl-3(2//)-pyridazinones was investigated, with the aim of suppressing production of 4-phenyl-6-substituted-2-phthalazinone byproducts <04TL3459>. In another study, the reactivity of 5-iodopyridazin-3(2f/)-ones in Pd-catalyzed reactions was investigated to develop an efficient route to 2,5-disubstituted pyridazin-3(2//)-ones <04T12177>. Other pyridazine syntheses relied on condensation approaches. Benzo[g]pyridazino|l,2-£>]phthalazine-6,13-diones 16 and 17 related to certain anthracyclinones were obtained by cycloaddition of 1,3-dienes to benzo|g]phthalazine-l,4-dione <04H(63)1299>, and pyridazine Cnucleosides synthesized by [4+2] cyclocondensation of alkynyl C-nucleosides with substituted tetrazines afforded, upon extrusion of a nitrogen atom, pyrrole C-nucleosides in good yields

308

M.P. Groziak

<04TL1031>. The reaction of 3-diazopyrazoloL3,4-c]pyridazine 18 with aromatic amines, naphthols, and active methylene compounds like malononitrile, affording 19, was investigated <04H(63)l 143>, and pyridazin-3(2//)-ones were found to be efficiently N-arylated using Pb(OAc)4/ZnCl2 in C6H6 or C6H5C1 or QH 5 Br <04TL8781>.

6.2.3.3 Applications There were some interesting non-medicinal applications of pyridazines revealed. The fused pyridazines l,2,3,6,7,8-hexahydrocinnolino|5,4,3-cde]cinnoline and its 2,2,7,7-tetramethyl derivative were prepared as rigid multidentate ligands for designing and fine-tuning the structure of hybrid organic/inorganic frameworks <04JCS(D)l 153>. The use of 4,5-dichloro-2-[(4nitrophenyl)sulfonyl|pyridazin-3(2f/)-one 20 in the presence of base permitted the esterification of aliphatic and aromatic carboxylic acids to proceed in excellent yield <04BKC501>. A conformationally constrained pyridazinone PNA-monomer for recognition of thymine in PNADNA triple-helix structures <04BMCL1551>.

Pyridazines continued to play a central role in the construction of new biologically active compounds. Six [6-(5-methyl-3-phenylpyrazole-l-yl)-3(2//)-pyridazinone-2-yllacetic acid amides like 21 were prepared as analgesic and anti-inflammatory compounds <04AP7>, 5substituted-6-phenyl-3(2H)-pyridazinones 22 were prepared as antiplatelet drugs <04BMCL321>, and 6-(substituted aryl)-2,3,4,5-tetrahydro-3-pyridazinones were prepared as anticonvulsants <04MI303>. There were two reports on 6-aryl-6f/-pyrroloI3,4-, and one on 2,3-diaryl-pyrazolo[l,5-£>]pyridazines as potent and selective cyclooxygenase-2 (COX-2) inhibitors <04BMCL5445>. Pyrrole-substituted aryl pyridazinones and phthalazinones were prepared via a Paal-Knorr route and evaluated as antihypertensives <04EJM1089>. A less lipophilic series of imidazo[l,2-b]pyridazines were investigated as potent

Six-membered ring systems: diazines and benzo derivatives

309

and selective cyclin-dependent kinase (CDK2) inhibitors <04BMCL2249>, and /V-phenyl-4pyrazolo[ 1,5-6]pyridazin-3-ylpyrimidin-2-amines were prepared as inhibitors of glycogen synthase kinase 3 (GSK3) and also CDK-2/CDK-4 <04JMC4716>.

Pyridazino|3',4':3,4]pyrazolo[5,l-c|-l,2,4-triazines were developed as antimicrobials <04BMCL5013>, pyridazino|4,3-6]indoles were developed as antituberculosis agents and MAO inhibitors <04JMC3455>, and pyridazinylpiperazines were examined as vanilloid receptor 1 (VR1) antagonists <04BMCL5513>. Substituted pyridazino[3,4-£]|l,5|benzoxazepin-5(6//)ones were investigated as multidrug-resistance modulating agents <04JMC4627>, and newly synthesized orally bioavailable pyridazinyl oxime ethers 23 were shown to be as potent as pirodavir, a capsid-binding chemoprophylaxis compound for the common cold <04AAC1766>. 4,5-Dihydro-3(2//)-pyridazinones structurally related to nonpeptide angiotensin II receptor antagonists were prepared <04SC783>, and finally, the mechanism of action of pyridazine analogues like 24 on protein tyrosine phosphatase IB (PTPIB) was shown to be related to the generation of H2O2 which oxidizes an active site Cys residue of this enzyme <04BMCL891>.

6.2.4 PYRIMIDINES AND BENZO DERIVATIVES A few reports centered on the structural aspects of pyrimidines. The hydrogen bonding and tautomerism of a macrocycle containing 2-thio-4-aminopyrimidine and 6-methyluracil groups was examined by IR, UV and quantum chemical studies . Two sets of 2-|/V-aryl-2oxo-2-arylethanehydrazonoyl]-6-methyl-4(3//)-pyrimidinones were prepared via coupling of 2(arylmethylene)-l,2-dihydro-6-methyl-4(3//)-pyrimidinones with diazotized anilines, and spectroscopic analysis revealed that they exist predominantly in their hydrazone tautomeric form <04T3051>. X-ray crystallography continued to expand our knowledge of the solid state structures of pyrimidines. The crystal structure of 4-amino-5-(2-hydroxy-4,4-dimethyl-6-oxocyclohexenylmethyl)-l-methyl-2-(methylsulfanyl)pyrimidin-6(l/f)-one 25 revealed H-bonded chains in JIstacked pairs <04AX(C)191>. 4,6-Diphenyl-2-pyrimidinylamine 26, a natural product isolated

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from Justicia secunda (Acanthaceae), existed as H-bonded dimers <04AX(C)229>. Pyrimidinecontaining linear molecules 27a-c based on the structure of l,4-bis(phenylethynyl)benzene were investigated by X-ray crystallography <04JOC8038>, as were racemic 5-(4-chlorophenyl)-2methoxyindenoLr,2':2,3]pyrido[5,6-fif|pyrirnidine-4,6(3//,5//)-dione 28 and (5^S,5aS/?,10b5/?)10b-hydroxy-2-methoxy-5-(4-methoxyphenyl)-5a,10b-dihydroindeno|r,2':2,3]pyrido[5,6-d]pyrimidine-4,6(3//,5//)-dione 29 <04AX(C)ol86>. Both of the latter compounds, obtained as 1:1 adducts with DMF, revealed chains of rings generated by N-H«#«O and C-H"»;rc(arene) hydrogen bonds.

Solid state structures of the ethyl esters of 2-(2,4-dichlorobenzylidene)-7-methyl-3-oxo-5phenyl-2,3-dihydro-5/y-thiazolo[3,2-a]pyrimidine-6-carboxylic acid 30 <04AX(E)344> and ethyl 5-(2,6-dichlorophenyl)-7-methyl-2-(l-naphthylmethylene)-3-oxo-2,3-dihydro-5f/-thiazolo[3,2-aJpyrimidine-6-carboxylate X <04AX(E)464> determined, as were those of (2£)-2-(2,4dichlorobenzylidene)-6,7-dihydro-2tf-thiazolo[3,2-a]pyrimidin-3(5//)-one 31 <04AX(E)1334>, the novel condensed pyrano[4',3':4,5]thienol3,2-e]triazolo[3,4-fr]pyrimidine l,7,7-trimethyl-6,7dihydro-9//-pyrano[41,3':4,5]thieno[3,2-e]triazolo[3,4-fe]pyrimidin-5-one 32 <04CHE79>, 1ethyl-5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)pyrimidine-2(lW)-thione 33 <04AX(E)l 123>, 2-[(l,3-benzodioxol-5-yl)methylene]-6,7-dihydro-5//-thiazolo[3,2-a|pyrimidin-3-one 34 <04AX(E)339>, and 3-nitroso-2-phenylimidazo[ l,2-a]pyrimidine 35 <04AX(E)l 131>.

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4-Arnino-2-chloro-5-nitro-6-(propylamino)pyrimidine 36 <04AX(E)1260>, 3-amino-2methyl-5,6,7,8-tetrahydro-l-benzothieno[2,3-rflpyrimidin-4(3W)-one 37 <04AX(E)1239>, 6amino-5,5-diisopropyl-5W-pyrimidine-2,4-dione hemihydrate 38 <04AX(E)1739>, and 7-(4methylphenyl)pyrazolo[l,5-a]pyrimidine-3-carbonitrile 39 <04AX(E)1294> were all characterized by X-ray. We now have solid-state structures of two oxidizing agents based on tropylium ions annulated with 2,4-dimethylfuro[2,3-, pyrimidine-based cations (2Z)-2-(hydroximino)-3-methoxy-3-phenyl-2,3dihydro-l//-imidazo[l,2-a]pyrimidin-4-ium perchlorate 42 <04AX(E)1719> and 4-hydroxy-6methyl-2-(sulfonatoethylsulfanyl)pyrimidin-l-ium monohydrate 43 <04AX(E)376>.

Crystal structures of pyrimidine-based organometallic compounds included the adduct of bis(2,2'-biimidazole)copper(II) perchlorate with 4,7-dihydro-l,2,4-triazolo[l,5-a]pyrimidine-7one <04MI549>, a new complex of HgBr2 and pyrimidine-2-thione, namely, (pyrimidine-2-thionato-;rf>)(pyrirnidinium-2-thionato-KS)rnercury(II) tetrabromomercurate(II) 44 <04AX(C)44>, and chloro|pyrimidine-2(l//)-thione-K:5]bis(triphenylphosphine-K:/))copper(I) 45 <04AX(E)776> and dimethyl-(4-trifluoromethylpyrimidine-2-thionate)thallium(III). This latter organometallic species exists as a polymeric chain with the Tl(III) coordinated with two N and two S atoms from different ligands <04JOM557>. Solid-state structures of benzyltrimethylammonium tris(pyrimidine-2-thiolato-K;2A',S)nickelate(II) 46 <04AX(E)566>, tetra-^-acetato-/^O:O'-bis|(2-

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benzylidene-6,7-dihydro-5//-thiazolo[3,2-a]pyrimidin-3-one-K-./V)cobalt(II)l <04AX(E)703>, and bis[bis(pyrimidin-2-yl-K/V)amine](dicyanamido-KA'7)(trifluoromethanesulfonato-K:O)copper(II) ethanol hemisolvate 47 <04AX(C)51>, and a new copper(I) halide pyrimidine-containing coordination polymer <04EJI2868> are also now available.

6.2.4.1 Syntheses Condensation routes to pyrimidines remained popular. Triazolo|4,3-a]pyrimidines were obtained via cyclocondensation of hydrazonoyl halides and pyrimidine-2-thione <04HAC107>, and 1-substituted 2-amino-3-cyanopyrroles, precursors to 5,6-unsubstituted pyrrolo[2,3-^]pyrimidines, were prepared via acid-catalyzed condensation of /V-substituted aminoacetaldehyde dimethyl acetals and malononitrile <04OL2857>. 4-Substituted aryl-6-(2,4-dialkoxyphenyl)l,2,4-triazolol4,3-a]pyrimidines, 4-substituted-aryl-6-(2,4-dialkoxyphenyl)-tetrazolo| 1,5-a)pyrimidines, and 4-substituted-aryl-6-(2,4-dialkoxyphenyl)pyrimido|2,l-c][ l,2,4|triazepines were prepared from the corresponding 2-hydrazinopyrimidines by cyclocondensation with appropriate reagents <04IJC667>. 5- or 7-Trifluoromethyl-l,2,3,4-tetrahydropyrido|2,3-d]pyrimidine-2,4-diones were prepared from 6-aminouracils. For example, 6-amino-l,3dimethyluracil and 4,4,4-trifluoro-l-phenyl-l,3-butanedione gave l,3-dimethyl-7-phenyl-5(trifluoromethyl)pyrido[2,3-finpyrimidine-2,4(l//,3W)-dione<04JHC525>. An efficient cyclocondensation route to 6-aryl-l-methyl-3-n-propyl-6,7-dihydro-lWpyrazolo[4,3-of]pyrimidin-7-ones was developed <04OPP92>, and 2-substituted 5,6,7,8tetrahydrobenzothieno[2,3-of]pyrimidin-4(3W)-ones were obtained via condensation of carbodiimides with aryl isocyanates <04S75>. New condensed pyrimidines were obtained from 2-(3,4-dihydro-4-oxo-2-quinazolinyl)acetonitriles <04S2659>, thiazolo[4,5-c]pyrido[l,2-a]pyrimidines were obtained by condensation of arylidenethiazolidinones and 2-aminopyridine <04IJC909>, and substituted 2-oxo-2//-benzopyrano[2,3-d]pyrimidines with promising optical properties were obtained via condensation of /V-ethoxycarbonyl-3-cyano-7(diethylamino)iminocoumarin with amines <04SC3553>. Aryl-substituted 1,2,5,6tetrahydropyrimidines 48-49 were prepared via cyclocondensation of a,(3-unsaturated ketones,

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carbonyl compounds, and NH3. 'H NMR (COSY, NOESY) was used to determine the stereochemical features of these products <04CCC897>.

The use of microwave acceleration in pyrimidine syntheses continued to grow. A microwaveassisted synthesis of 7-amino-6-cyano-5-aryl-5//-pyrano[2,3-d]pyrimidine-2,4(lH,3//)-diones from arylidenemalononitriles and barbituric acid was developed <04SC1295>, as was one of thieno|3,2-rf]pyrimidin-4-ylamines and quinazolin-4-ylamines 50 from formamidines <04OL4775>. A solid-state, microwave-assisted synthesis of oxazino[4,5-rf]-, pyrano[2,3-, and a microwave-assisted condensation of dialdehydes with active methylene compounds was found to be a rapid method for generating bifunctional pyrimidines <04BMCL1533>. Solventless microwave-assisted chemistry is a rapidly growing area of investigation as well. In this category, syntheses of pyrimido|4,5-d|pyrimidines and pyrido[2,3-tf|pyrimidines <04SL1179>, pyrano[2,3-rf]pyrimidines and pyrido[2,3-dlpyrimidines <04SL283>, and dihydropyrimidin-2(l//)-ones <04SL235> were reported. Many of these were three component reactions.

Palladium-catalyzed reactions were also used extensively in the synthesis of new pyrimidines. 4/y-Pyrrolo[2,3,4-Je]pyrimido[5',4':5,6][l,3|diazepino[l,7-alindole, a member of a new heterocyclic ring system, was obtained along a route starting with the Pd-catalyzed coupling of methyl 5-amino-4-halo-7-methyl-2-methylthiopyrroIo[2,3-. A 5-alkoxypyrido[3,4-d|pyrimidin-4(3/f)-one was synthesized via Pd-catalyzed amination of a bromopyridine, followed by directed orr/zo-metalation/carboxylation <04TL3733>. Eight new 4,5-di(hetero)arylquinazolines were obtained via metalation and Pdcatalyzed coupling approaches <04T5373>, and stereo-defined alkenyl-substituted pyrimidines were obtained via Suzuki-Miyaura cross-coupling of chloropyrimidines with alkenylboronic acids. With 2,4-dichloropyrimidine and 2,4,6-trichloropyrimidine, the reaction occurred at C4 before it occurred at C2 <04SC3773>. Finally, a very interesting mechanically induced solidstate preparation of disubstituted pyridine/pyrimidine ferrocenyl complexes via Suzuki coupling of l,l'-ferrocenediboronic acid was reported. This procedure involved grinding the Pd catalyst with KF/A12O3 or KOH/AI2O3 and adding the reactants together with a few drops of MeOH. An X-ray crystal structure of one of the mixed-ligand complexes was obtained <04OM2810>.

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A good number of ring closure syntheses of pyrimidines appeared last year. 5,6-Disubstituted pyrimidinones and pyrimidinediones like 51a,b were accessed by treating thiouronium salts with P-ketoesters <04ARK349>, 2-(trihalomethyl)-3,4-dihydrothieno[2,3-, and some 2-substituted-l,3,4-thiadiazolo[2,3-/>]-6,7,8,9-tetrahydrobenzoU?]thieno[3,2-e]pyrimidine-5(4H)-ones were prepared via cyclization of 3-amino-2-mercapto5,6,7,8-tetrahydrobenzo[6]thieno[2,3-d]pyrimidin-4(3//)-one with Cl donors <04IJH347>. 3Aryl-2-phenyl-5-prop-2-ynylsulfanyl-3H-pyrimidin-4-ones were synthesized and shown to undergo transformation to new thieno[3,2-cf]pyrimidin-4-ones via thio-Claisen rearrangement <04TL6075>. Partially hydrogenated [l,2,4]triazolo[4,5-a]pyrimidine-4-ones 54 and 55 were obtained via cyclization of 2-arylidenehydrazino-6-methyl-4-pyrimidones 53 <04ARK243>, and l,2,4-triazolo|4,3-a]pyrimidines of the thiadiazoline and selenadiazoline classes were obtained via cycloaddition of hydrazonoyl halides to ethyl 6-methyl-2-methylthio-3,4-dihydropyrimidine5-carboxylate in the presence of KSCN or KSeCN <04PS601>. Benzothiazolo-fused pyrimidinones were obtained by regioselective [4+2] cycloadditions of yV-benzothiazoI-2-yl-/V'arylbenzamidines and ketenes <04T4315>, and cyclization of enamide esters with primary amines gave 3-substituted 3f/-pyrimidin-4-ones 56 in good yield <04OL1013>. A tandem Michael-addition/cyclization route to pyrido[2,3-, and l,3-dimethyl-5,10-methanocycloundeca[4,51furo[2,3-d]pyrimidin-2,4(l,3//)dionylium tetrafluoroborate 57 was prepared from dimethylbarbituric acid. By spectral data and MO calculations, the positive charge was found to be localized largely at Cl 1 <04JOC9184>.

A 5-alkoxypyrido[4,3-if]pyrimidin-4(3f/)-one has been synthesized via a selective A'-oxidation followed by a regioselective Meisenheimer N-oxide rearrangement <04TL3737>. 1,2,3,4,5,6,7,8Octahydroquinazolinediones and 3,4-dihydro-l//-indeno[l,2-rf]pyrimidine-2,5-diones were obtained by a modified Biginelli synthetic route <04IJC135>. A series of l//-pyrazolo[3,4-rf]-

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pyrimidin-4(5W)-ones were prepared via a tandem aza-Wittig reaction, and many were found to be antibacterial <04JHC393>. Substituted thieno[2,3-. 2,4,6-Trisubstituted pyrimidines 58 were obtained from a-chloro oxime ethers and Grignard reagents <04CL122>, and 6-substituted 7-aryl-5,6dihydropyrido|2,3-d]pyrimidine(l//,3//)-2,4-diones were obtained from dihydropyridopyrimidine(l//,3//)-2,4-diones and Vilsmeier reagents <04T11511>. The first general synthesis of functionalized pyrido[2,3-/6,5-/']di[l,2,4]triazolo[4,3-a]pyrimidin-5(l//)-ones was reported. Thirteen examples were prepared in a two-step procedure starting with pyridodipyrimidinones and hydrazonoyl chlorides <04M211>.

One-pot syntheses of pyrimidines demonstrated just how efficiently these heterocycles can be constructed. 2,6-Diaryl-4-polyfluoroalkylpyrimidines were obtained by a simple one-pot reaction of 2-polyfluoroalkylchromones and benzamidine or guanidine <04S942>, and a highly efficient one-pot three-component synthesis of dialkyl l-methyl-7-oxo-l,7,8,8a-tetrahydroimidazo|l,2-a|pyrimidine-5,6-dicarboxylates from 1-methylimidazole, dialkyl acetylenedicarboxylates, and isocyanates was developed <04SL1086>. A one-pot synthesis of dialkyl 2-oxo-l,9a-dihydro-2//pyrido[l,2-aJpyrimidine-3,4-dicarboxylates from pyridines and dialkyl acetylenedicarboxylates in the presence of isocyanates was developed <04TL1803>, as was a one-pot synthesis of pyrido[2,3-. 4-Phenylpyrido[l,2-a]pyrimidinium salts were obtained from the reaction of 3-aryl-3-chloropropeniminium salts with aminopyridines in EtOH <04ZN(B)424>, and expedient routes to all three monobrominated and all three dibrominated isomers of 4-(trifluoromethyl)pyrimidine were developed <04EJO3714>. A general route to 4-methoxypyridopyrimidines involved selective lithiation/functionalization of the pyridine ring <04T6353>, and a general route to pyridopyrimidin-4(3f/)-ones involved the first regioselective metalation/functionalization of 2-aminopyridinecarboxylic acids <04T4107>. Pyrido[2,3-d]pyrimidines were obtained from 2-amino-3-cyano-4-trifluoromethyl-6-substituted pyridines <04SC4463>, and 6-alkoxy(aryloxy)-l,5-dihydropyrazolo-[3,4-d]pyrimidin-4-ones were obtained by base-catalyzed condensation of ethyl 3-methylthio-l-phenyl-5-{[(triphenyl-X5phosphanylidene)methane]amino}-l//-pyrazoIe-4-carboxyIate with alcohols <04HEC197>. A synthesis of 6-(2-hydroxy-3-chloro-5-(hydroxymethyl)phenyl)-4-aryl/heteryl-3,4-dihydro-2(l/f)pyrimidinethiones was reported <04MI403>, ribofuranosides of 4-amino-5,7-disubstituted pyrido[2,3-, and pyrrolidine- and perhydroazepine-fused 5-benzoylamino-4-oxo-2pyrimidinethiones like 59 were obtained by the reaction of oxazolones with isothiocyanates <04CHE127>. Amino- and thiopyrimidine derivatives of 2-(l,3-disubstituted pyrazolyl)chromones were prepared as PDE(IV) inhibitors <04JHC541>, and pyrrole and pyrrolidine derivatives of pyrimidine like l-(2-pyrimidinyl)pyrrole were prepared as antibacterials of plant pathogens <04JHC343>.

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New pyrido[3',2':4,5]thieno|3,2-rf]pyrimidines were obtained from 5-acetyl-3-amino-4-aryl-6methylthieno[2,3-fc]pyridine-2-carboxamides <04PS513>, pyrazolo[4,3-e]-l,2,4-triazolo[l,5-c|pyrimidines were among the new heterocycles obtained from 5-amino-4-imino-l(2)-substitutedl(2/f)-4,5-dihydropyrazolo[3,4-, and pyrido[l,2-a]pyrimidin-2-ones 60, 2//-quinolizin-2-ones, pyrido[l,2-a]quinolin-3-ones, and thiazolo[3,2-a]pyrimidin-7-ones were generated from l-benzotriazolyl-2-propynones <04ARK52>. Condensed tetrazolo|l,5-c|and triazolo[4,3-cjpyrimidines like 61a,b were obtained from 2-amino-3-cyano-7,7-dimethyl7,8-dihydro-5W-pyrano-|4,3-/?lpyridine <04CHE75>, /V,/V'-bis(2-pyrimidinyl)benzenedicarboxamides were prepared from 2-aminopyrimidine and aroyl chlorides <04SC3061>, and pyrimidine-containing 3-aminobutenolides were prepared starting from Calkoxycarbonyl isoxazolidines <04T6593>. A resin catch and release strategy for making a combinatorial array of 2,4,5-trisubstituted pyrimidines 62 was developed <04JCO105>, and multigram quantities of a novel pyrimidinone were obtained from CF3CN generated in situ in a most convenient manner from CF3CONH2 and (CF3CO)2O/pyridine <04SC903>.

The reaction of 4-bromobenzaldehyde with substituted acetophenones and urea gave arylsubstituted pyrimidin-2-ones 63 or hexahydro-l//,8//-pyrimido[4,5-d]pyrimidin-2,7-diones 64, depending on the nature of the acetophenone substituent and the solvent <04CHE194>. Two new approaches to 2,4-dialkylamino-substituted 6,7-dihydro-5//-benzocyclohepta[l,2-d]pyrimidines were developed, one based on the reaction of substituted cyanamides and the enol triflate of 1benzosuberone, and the other based on nucleophilic displacements at C2 and C4 of

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benzocycloheptapyrimidines <04T5475>. A preparation of spiro[furo[2,3-d]pyrimidinejpyrimidines via bromination of dibarbiturates was reported, and an X-ray crystal structure of one product was obtained <04SC3915>.

6.2.4.2 Reactions A solventless microwave assisted SNAr-type amination of halopyrimidines by pyrrolidine and piperidine without the use of a transition metal catalyst was developed <04TL757>. A simple method for pivalamide group hydrolysis in 2-pivalamido-3//-pyrimidin-4-ones or fused 2pivalamido-3//-pyrimidin-4-ones was developed using Fe(NO3)3 in MeOH <04TL5643>. 2Amino-4,6-diarylpyrimidines were condensed with indole-3-carbaldehydes to give 2-(2',5'substituted indolideneamino-3'-yl)-4,6-diarylpyrimidines <04IJH275>. 10-Methyl-4-phenyl-6,7dihydro-5W-benzo[6,7]cyclohepta[. A study of the reactions of quinolizine- and pyridino[l,2-a]pyrimidine-3-diazonium tetrafluoroborates with aliphatic amines revealed that A'-alkyl-iV'-heteroaryltriazenes are produced when 2° amines are used, while picolinic acid A'-alkylcarboxamides are produced when 1° ones are employed <04ZN(B)380>. Halogen-metal exchange of 4-iodo-6-phenylthieno[2,3-. Substituted 3-alkenylpyrazolo[l,5-a|pyrimidines were obtained from 3-iodopyrazolo|l,5-a]pyrimidines via a Heck cross-coupling reaction <04S2329>. The enantioselective addition of (iPr)2Zn to pyrimidine-5-carbaldehyde gave up to 97% ee of chiral 67 via asymmetric autocatalysis initiated by chiral ephedrine immobilized on SiO2 <04BCJ1587>, and diastereoselective electrophilic amination of chiral 1benzoyl-2,3,5,6-tetrahydro-3-methyl-2-(l-methylethyl)pyrimidin-4(l/f)-one was key to the asymmetric synthesis of a-substituted a,|3-diaminopropanoic acids <04HCA1016>. The Michael addition reaction of pyrimidinediones and acrylates was found to be catalyzed enzymatically by B. subtilis alkaline protease in DMSO solution <04S671>.

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Regioselective AIBN-initiated aryl radical cyclization of 6-(2'-bromophenoxymethyl)-l,3dimethyluracils provided access to pyrimidine-annelated spiro heterocycles through a 5-exo ring closure reaction <04S1864>. The stereoselectivity and regioselectivity of nucleophilic ring opening in 3-phenylisoxazolo[2,3-a]pyrimidines 69 to give 70 or 71 was investigated, and unexpected dimerizations and ring transformations like that giving 68 were uncovered <04JOC4966>. Experimental evidence for pyrimidine ring-opening during nitrosative guanine deamination was gathered by studying the cyclization reactions of a 5-cyanoamino-4imidazolecarboxamide 72 to give 73 and/or 74 <04JA2274>. 2-Thiopyrimidine nucleosides were found to undergo efficient desulfurization upon treatment with rra«s-2-(phenylsulfonyl)-3phenyloxaziridine <04TL6729>. This transformation involves oxidation of the 2-thiocarbonyl group to a sulfur oxyacid, followed by elimination of SO2. The microwave-assisted ring opening of epoxides with pyrimidine nucleobases provided a rapid entry into C-nucleosides <04S583>.

6.2.4.3 Applications Some applications of pyrimidines focused on organometallic derivatives. The host-guest chemistry of heterotopic metallacalix[n]arenes (n=3,4,6) containing ethylenediaminePd(II), 4,7phenanthroline, and 2-pyrimidinolate bridges was investigated <04JCS(D)2780>, and a singlecrystal magnetic study on guest-tunable weak low-temperature ferromagnets [M{N(CN)2}2(pyrimidine)](guest) 75 (M = Fe, Co) was conducted <04BCJ1125>. Extended coordination frameworks of Zn(II) and Ni(II) and the pyrimidin-4-olate ligand obtained by solid state reactions were characterized by spectroscopic, thermal, and magnetic measurements and by ab initio XRPD <04IC473>. Multinuclear NMR spectroscopy was used to investigate the

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solution structures of antitumor Pt(II) complexes of 5,7-disubstituted-l,2,4-triazolo[l,5-<2]pyrimidines <04JIB167>.

Other applications involved photon adsorption or emission. An FTIR spectroscopic study of the adsorption of pyrimidine on loughlinite was conducted to characterize the surface interaction <04JMS147>, and new mono-, poly-, and macrocyclic mesoionic pyrimidinium-olates were prepared and their propensity toward photochemical rearrangement to bis(P-lactam) derivatives was studied <04T10011>. Sequential nucleophilic addition of aryl anions to 2methylthiopyrimidine 76 followed by DDQ oxidation gave 4-aryl-2-methylthiopyrimidines, then 4,6-diaryl-2-methylthiopyrimidines, and then 2,4,6-triarylpyrimidines 77. Some of these compounds showed interesting fluorescent properties like solvatofluorochromism <04JA15396>. Naphthalene-anthracene assemblies linked by a 2-ureido-4(l/f)-pyrimidinone binding module were prepared for fluorescence studies <04TL6807>.

Racemic 2-hydroxy-4- and 2-hydroxy-5-(hydroxymethyl)cyclohexane pyrimidine Cnucleoside analogues of 4-thiouracil, cytosine, and uracil like 78 were reported <04CCC918>, and 3'-3'-phosphodiester-linked pyrimidine oligonucleotides containing an acridine moiety were prepared for alternate-strand triple helix formation <04EJO2331>. Indolo- and pyrrolopyrimidines 79 and 80 were shown to bind to DNA via intercalation, with their side chains positioned along the minor groove <04ARK263>. Self-complementary /V.^V'-disubstituted 4,6diaminopyrimidin-2(lf/)-ones were shown to self-assemble in organic solvents, giving a linear supramolecular polymer network via DDArAAD hydrogen-bonding <04CC1114>. The Nalkylation of 4-aminopyrimidine by a tetrahydro-3-aza-cyclopropa|c]inden-5-one 81 —* 82 was used in a quantum chemical study as a model reaction of the pharmacophore of duocarmycins. Carbonyl oxygen protonation of the model cyclohexadienone was proposed to be important to DNA alkylation by the duocarmycins <04BKC69>.

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As for medicinal applications, some pyrimidines were prepared as potential antiviral agents. Among them were 2,4-diamino-5-cyano-6-[2-(phosphonomethoxy)ethoxy]pyrirnidines 83a,b <04BMC3197>, imidazo[l,2-c]pyrimidine base-modified nucleoside mimetics 84a-c and 85a-c <04BMC4245>, (Z)- and (£)-[2-fluoro-2-(hydroxyrnethyl)cyclopropylidene]methylpyrimidines <04JMC6964>, (Z)- and (E)-2,2-[bis(hydroxymethyl)cyclopropylidene]methylpyrimidines <04JMC566>, and 2-[2-(3,5-dimethylphenoxy)ethylthio]pyrimidin-4(3//)-ones 86 obtained by S-alkylation of 2-thiouracils with l-bromo-2-(3,5-dimethylphenoxy)ethane <04CHE37>. Modified acyclic purine and pyrimidine nucleosides like 87 were prepared as potential substrates of herpes simplex virus type-1 thymidine kinase (HSV1-TK) <04CJC513>. Other pyrimidines were prepared as cyclin-dependent kinase (CDK) inhibitors. Among these were 2-anilino-4-(l//pyrrol-3-yl)pyrimidines <04BMCL4237>, l-aryl-4,5-dihydro-l//-pyrazolo[3,4-rf]pyrimidin-4ones as inhibitors of CDK-4 and CDK-2 <04JMC5894>, and 2-anilino-4-(thiazol-5yl)pyrimidines as inhibitors of CDK-2 and CDK-9 <04JMC1662>. X-ray crystal structures of four of the latter type of compounds were obtained. Still other enzyme-inhibiting pyrimidines were reported. Among those inhibiting dihydrofolate reductase (DHFR) were 2,4-diamino-5(2',5'-substituted benzyl)pyrimidines <04JMC1475>, 2,4-diamino-5-methyl-6-substitutedpyrrolo[2,3-rf]pyrimidines <04JMC3689>, benzoyl ring-halogenated 2-amino-6-methyl-3,4dihydro-4-oxo-5-substituted thiobenzoyl-7//-pyrrolo[2,3-, threecarbon-bridged 5-substituted furo[2,3-<^]pyrimidines and 6-substituted pyrrolo[2,3-d]pyrimidines <04JMC6893>, and new pyrrolo[2,3-d]pyrimidines and thienoL2,3-c/Jpyrimidines <04JHC787>. 4-Acylamino-6-arylfuro[2,3-d]pyrimidines were prepared as glycogen synthase kinase-3 (GSK3|3) inhibitors <04BMCL3907>, 5-alkyl-2-[(aryl and alkyloxylcarbonylmethyl)thio]-6-(lnaphthylmethyl)pyrimidin-4(3/f)-ones were prepared as HIV-RT inhibitors <04BMCL3173>, antiproliferative pyrazolo[3,4-rfjpyrimidines were prepared as inhibitors of Src phosphorylation <04BMCL2511>, and furol2,3-dlpyrimidines and oxazolo[5,4-rf]pyrimidines were prepared as inhibitors of receptor tyrosine kinases like VEGFR2 (vascular endothelial growth factor receptor 2, KDR) and EGFR (epidermal growth factor receptor) <04HCA956>. A cell-based reporter assay was used to identify new classes of antifungal pyrimidines 88a-c and 89a,b acting against

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Candida albicans presumably by inhibiting lanosterol demethylase <04AAC313>, octahydroimidazol l,2-a]pyridine and octahydro-2//-pyrido[l,2-ajpyrimidine bicyclic diazasugars like 90 were prepared as glycosidase inhibitors <04BMC4039>, and a study of mimics of 4-anilinoquinazoline inhibitors of EGFR tyrosine kinase revealed a structural requirement for the pyrimidine ring <04BMCL2299>.

Pyrimidines were also prepared as receptor antagonists. Those acting at the corticotropinreleasing factor- (CRF) receptor included 3-(2-pyridyl)pyrazolo[l,5-a]pyrimidines <04BMCL3943>, 3-phenylpyrazolo[l,5-a]pyrimidines <04BMCL3669>, and 3-pyridylpyrazolo[l,5-a]pyrimidines <04JMC4787>. 2,4,6-Trisubstituted pyrimidines were prepared as adenosine A, receptor antagonists <04JMC6529>, fused l,2,4-triazolo[l,5-c]pyrimidines were found to act as human adenosine A3 receptor ligands <04BMCL2443>, and 5-(tryptophylamino)l,3-dioxoperhydropyrido[l,2-c]pyrimidines were prepared as cholecystokinin (CCK) receptor antagonists <04JMC5318>. Fused bicyclic pyrazolo[l,5-alpyrimidines were prepared as estrogen receptor (ER) antagonists <04JMC5872>, pyrimidine-based non-steroidal estrogens selective for ER-|3 were synthesized <04BMCL5835>, and pyrazolo[l,5-a]pyrimidine was used as a novel scaffold for building estrogen receptor ligands <04BMCL5681>. Optimization efforts produced l-|(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-{2-methoxy-l(/?)-4-(trifluoromethyl)phenyl}ethyl-3(S)-methyl-l-piperazinyl]-4-methylpiperidine as a potent CCR5 antagonist for HIV-1 inhibition <04JMC2405>, and pyrimidine methyl anilines were developed as selective potentiators for the metabotropic glutamate 2 (mGlu2) receptor <04BMCL5071>.

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Antiproliferative pyrimidines included 4-amino-6-methylthio-lW-pyrazolo(3,4-rf]pyrimidines substituted at Nl with a 2-chloro-2-phenylethyl group <04EJM153>, new l-aryl-4-amino-l//pyrazolo|3,4-rf]pyrimidines <04EJM939>, pyrazoloL3,4-rf]pyrimidines <04JMC1595>, and cytotoxic 5-substituted 2-cyanoimino-4-imidazodinones and 2-cyanoimino-4-pyrimidinones . Pyrimido[5,4-d]pyrimidines were developed as modulators of antimetabolite antitumor agents <04JMC4905>. A Ru(III) complex containing the ligand 5,7dimethyl[l,2,4]triazolo|l,5-a]pyrimidine as an antimetastatic agent <04JMC1110>. Schiffs bases formed from 2-aminopyrimidine and aryl aldehydes were cyclized with thiolactic acid and thioglycolic acid to generate new pyrimidines with potential antibacterial and antifungal properties <04MI411>. Pyrimido[4,5-d/]pyrimidine-2,5-diones were the subject of a QSAR study seeking to optimize antimicrobial activity <04BMCL4185>, and pyrazolo[3,4-d]pyrimidines were the subject of another SAR study designed to develop novel enterovirus inhibitors <04BMCL2519>. Terpenyl pyrimidines were examined as antileishmanial agents <04EJM969>, and transition metal complexes of disodium 2-thio-4,6-pyrimidinedione dithiocarbamate and disodium 5,5-diethyl-2,4,6-pyrimidinetrione dithiocarbamate were synthesized, characterized, and evaluated for antimicrobial activity <04PJC645>. A PhI(OAc)2-mediated synthesis of 3aryl/heteroaryl-5,7-dimethyl-l,2,4-triazolo[4,3-alpyrimidines was used to access new antibacterial agents <04EJM1073>. (4,6-Diaryl-2-thioxo-l,2,3,4-tetrahydropyrimidin-5-yl)acetic acids obtained from (3aroylpropionic acids were studied as anti-inflammatory agents <04BMCL1733>, 5-alkyl and 5arylisoxazolo[4,5-djpyrimidinones 91a-g, 92, and 93 from 4-amino-3-oxo-isoxazolidine-5carboxylic acid amides showed anxiolytic activity <04BMC265>, 5//-[l]benzopyrano[4,3-d]pyrimidines 94 were synthesized as antiplatelet/analgesic agents <04BMC553>, and new 2substituted-3-arylpyrido[2,3-d]pyrimidinones 97 were prepared from 9 5 via 9 6 as anticonvulsants <04BMC5711>. 4-Imino-3,5,7-trisubstituted pyrido[2,3- and substituted benzylamino-6-(trifluoromethyl)pyrimidin-4(l//)ones were designed to be selective human A-FABP inhibitors <04BMCL4449>.

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6.2.5 PYRAZINES AND BENZO DERIVATIVES A total synthesis of the pyrazine alkaloid Botryllazine B from the red ascidian Botryllus leachi was accomplished, and a previously proposed structure was shown to be correct <04M333>. Also in the natural product arena, six new polyhydroxy-p-terphenyl pyrazinediol dioxide conjugates 98a-c and 99a-c related to sarcodonin were isolated from the fruiting bodies of the basidiomycete Sarcodon leucopus <04EJO592>.

A new unsolvated form of pyrazine-2,3-dicarboxylic acid 100 was subjected to X-ray crystallography <04AX(E)1305>, as was an orthorhombic polymorph of N,N'-b\s(2pyridylmethyl)pyrazine-2,3-dicarboxamide 101 <04AX(E)210> and two triclinic polymorphs of 2,3,5,6-tetrakis(naphthalen-2-ylsulfanylmethyl)pyrazine 102 <04AX(C)152>. Crystal structures of pyrazino-tetracyanonaphthoquinodimethanes revealed a butterfly-shaped sterically deformed geometry <04T1997>, and structures of frani-2-(2-phenylethenyl)pyrazine 103 <04AX(E)1255> and 3-phenyl derivatives of tetrafluorobenzo- and pyrazino[2,3-e](l,2,4|thiadiazines 104 were determined <04JOC2551>.

In a comprehensive characterization, the IR, 'H/13C/l95Pt NMR spectral, and X-ray crystal structures of cis- and frawj-Pt(R2SO)(pyrazine)Cl2 105a,b were investigated <04CJC649>. Other

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pyrazine-containing organometallic compounds characterized by X-ray included a Ca(II) complex with pyrazine-2,3-dicarboxylate ligands <04JCC1151> and one with pyrazine-2,6dicarboxylate ligands <04JCC167>, a dinuclear Co(II) complex containing pyrazine as a bridging ligand <04JMS193>, a La(III) complex with pyrazine-2-carboxylate ligands <04JCC97>, a ZnI2-pyrazine adduct polymer <04JMS69>, and an unusual heptanuclear complex of Zn(II) and pyrazine <04JCS(D)3840>. Binuclear Al complexes with bridging nitrogen donors including pyrazine were described <04JCS(D)3689>, as were bis|fran5-2-(2phenylethenyl)pyrazin-4-ium]tetrachlorozincate 106 <04AX(E)1208>, diaqua-bis(pyridine-2,6dicarboxylato-0,,/V,O')-(i«2-pyrazino)dicopper(II) dihydrate <04ZK137>, and a macrocyclic binuclear copper(II) complex of A',Ar'-bis(pyridin-2-ylmethyl)pyrazine-2,3-dicarboxamide <04AX(E)177>.

A neutral macrocyclic binuclear Cu(II) complex of deprotonated A',A''-bis(pyridin-2ylmethyl)pyrazine-2,3-dicarboxamide <04AX(E)180>, a mononuclear Co(III) complex of N,N'bis(pyridin-2-ylmethyl)pyrazine-2,3-dicarboxamide 107 <04AX(E)174>, and mono-, di- and trinuclear 2,3,5,6-tetrakis(2-pyridyl)pyrazine-containing Cu(II) complexes <04JCS(D)3997> were all solved crystallographically. Solid-state structures of jit-pyrazine-K^/V.Wbisfdiiodomercury(II)] 108 <04AX(E)749>, tetraaqua-^2-pyrazine-Zn(II) squarate <04ZK33>, tetraaqua-bis(pyridine-2,6-dicarboxyIato-O,N,O')-((U2-pyrazino)dinickel(II) <04ZK139>, N,N'bis[l-(pyrazin-2-yl)ethylidene]hydrazine <04AX(C)507>, and self-assembled diorgano-Sn(IV) compounds containing 2-pyrazinecarboxylic acid <04JCS(D)1832> were also reported. Finally, there were several polymeric organometallic pyrazine-based structures determined. Among these were poly[[dibromomercury(II)]-di-lit-pyrazine-(f'MA''] <04AX(E)747>, polymeric aqua(nitratoK2O,O')(l,10-phenanthroline-K2A',A'')(2,3-pyrazinedicarboxylato-K2A',O)Eu(III) monohydrate 109 <04AX(C)ml86>, polymeric bis(hydrogen pyrazine-2,3-dicarboxylato)Cu(II) <04AX(E)647>, and poly[Hg(II)-di-/i-chloro-/*-pyrazine-K2AWV'] 110 <04AX(E)744>.

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6.2.5.1 Syntheses Some synthetic approaches to pyrazines relied on metal-assisted reactions. A synthesis of 6substituted 5f/-pyrrolo[2,3-6]pyrazines via Pd-catalyzed heteroannulation from N-(3chloropyrazin-2-yl)methanesulfonamide and alkynes was developed <04TL8087>, and 3- and 5substituted 2(l//)-pyrazinones were prepared by Suzuki and Heck reactions using 3,5-dichloro2(l/f)-pyrazinones <04TL1885>. An improved synthesis of 6-substituted-5//-pyrrolo|2,3-£>Jpyrazines via microwave-assisted Pd-catalyzed heteroannulation was developed <04TL8631>, and the reaction of a-diazo-|3-keto esters with Boc amino acid amides in the presence of a Rh catalyst gave, after air oxidation, pyrazin-6-ones 111, which were then converted into tetrasubstituted pyrazines 112 <04OL4627>.

A pyrrolo[4,5-ft]indole was shown to undergo a Schmidt reaction to give a pyrazino|5,6-b]indole <04PJC837>. 6-Phenylpyrazinoisoquinolinediones and their corresponding thieno analogs were prepared via a diastereoselective Pictet Spengler-type reaction of O,7V-amidoacetals <04T6319>. A one-pot tandem aza-Wittig heterocumulene-mediated annulation approach generated pyrazino[5",6":4,5;3"2":4',5']dithieno[3,2-rf:3',2'-£/1)dipyrimidine-4,8(3f/,9«)-diones, members of a new pentaheterocyclic system <04T275>. l-Imino-2,3-dihydro-lH-pyrazino[2,l-&|quinazolin-5-ones were prepared from 4,5-dichloro1,2,3-dithiazolium chloride <04TL3097>, and 1-substituted pyrazolo[3,4-fc]pyrazines were prepared by the reaction of in situ generated 1-substituted 4,5-diaminopyrazoles with glyoxal <04TL4105>. A concise synthesis of lf/-pyrazin-2-ones from Boc-protected amino acids was reported. These were converted into 2-aminopyrazines via their triflates <04SL2031>. A one-pot 1,4-addition/lactamization/aromatic substitution approach to 2,3,4a,5-tetrahydro-lWpyrazino| l,2-a]quinoline-4,6-diones was developed <04SL2165>, as was a potentially biomimetic route to nonsymmetric pyrazines from enaminoketones and a-hydroxyketones

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<04SL1414>. Octahydropyrazino|l,2-a]pyrazine was obtained in an efficient manner from 1,3dichloro-2-propanol and an yV-tosylated diethylenetriamine, and the X-ray crystal structure of this fused pyrazine was obtained <04SC845>. Finally, functionalized quinoxalines and pyrazines were prepared via a microwave-assisted reaction of aryl/heteraryl 1,2-diamines and common 1,2diketone precursors. The formation of polymeric byproducts was suppressed <04TL4873>.

6.2.5.2 Reactions A method for using deuterated ammonium formate for the synthesis of highly deuterated pyrazines and other heterocycles was developed <04TL8889>. The influence of N2-substitution in the 1-alkylation of (4S)-alkyl-2,4-dihydro-l//-pyrazino[2,l-fr]quinazoline-3,6-diones was investigated <04TA3045>. Trifluoroacetylation of l-methyl-3,4-dihydropyrrolo[l,2-a]pyrazines occurred at the Me group to give 113, whereas acetylation of 3,4-dihydropyrrolo[l,2-a]pyrazines gave only A'-acetyl-substituted products <04CHE351>. Finally, electrophilic ring acylation of dipyrrolo[l,2-a:2',l'-c]pyrazines 114 and 5,6-dihydrodipyrrolo|l,2-a:2',l'-c]pyrazines gave ester, nitrile, and amide derivatives of dipyrrolo[l,2-a:2',l'-c|pyrazines <04CHE436>.

6.2.5.3 Applications The applications available for pyrazine-based compounds are extremely diverse. The unprecedented pH-dependent bimodal chemiluminescence of 2-methyl-6-phenyl-8-(4-substituted phenyl)-imidazo[l,2-alpyrazin-3(7//)-ones 115a,b induced by superoxide anion in aqueous phosphate buffer reveals these compounds to be useful as pH indicators/superoxide anion probes <04H(63)759>. 2,8-Diphenylimidazoll,2-a]pyrazin-3(7H)-ones were developed which can act as visible indicators of the proton donor ability of solvents <04TL8531>. Pyrazino[2,3-g]quinoxalines 116a-d and a related 1,2,5-thiadiazole-fused quinoxaline 117 were shown to have a good electron affinity and emit fluorescence near the red-green-blue (RGB) regions of the visible spectrum <04H(63)2207>, and metal-ion complexes of imidazo[l,2-a]pyrazin-3(7/f)-ones were observed to exhibit changes in absorption spectra depending on the identity of the metal ion (Li, Mg, Ca, Ba, Sc, La), suggesting that these complexes can be used as indicators of Lewis acidity <04TL1065>.

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A new Pd complex, l,2-bis(2'-pyrazineethynyl)benzene Pd(II) dichloride, was prepared, characterized, and shown to catalyze Suzuki coupling reactions <04SC1499>. New metal complexes of tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazine were found to exhibit both linear and nonlinear optical (NLO) properties <04IC8637>. Mixed valence [2,3,5,6-tetrakis(2pyridyl)pyrazine]-bridged diruthenium complexes were prepared and characterized <04IC5128>, and lanthanide(III)/actinide(III) differentiation was observed in the coordination of pyrazine to tris(cyclopentadienyl) complexes of cerium and uranium. The cerium complex reacts with pyrazine to give Lewis base adducts, but the uranium one is oxidized by the pyrazine ligand <04EJI1996>. The photochemical and photophysical properties of a Ru(II)-(pyrazine)-Re(I)containing dyad were determined <04OM5967>, and the thermal and light induced spin transition in Fe(II) complexes of 2,6-di(3-methylpyrazol-l-yl)pyrazine were investigated <04JCS(D)65>. Using the new semiflexible substituted pyrazine ligand pyrazine-2,3dicarboxylic acid bis|(pyridin-2-ylmethyl)amide, Cu(II) and Ni(II) complexes with multiple anion encapsulation and antiferromagnetic properties were prepared. These complexes were characterized by X-ray crystallography <04IC1021>. The bistability and phase transition properties of the molecular radical l,3,2-dithiazolo[4,5-b|pyrazin-2-yl 118 were also investigated by X-ray crystallography <04JA14692>, and the new electron-deficient macrocycle te?ra&/s-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazine was prepared in two steps from l,2-di(2-pyridyl)ethanedione and 2,3-diaminomaleonitrile for a study of its electrochemical properties <04IC8626>. Starting from 13C-glycine, the 13C-labeled versions of pyrazinone thrombin inhibitors were prepared for use in structure elucidation of key metabolites of these orally bioavailable compounds <04HCA674>, and nucleosides featuring the 6aminopyrazin-2(lW)-one nucleobase are under development for an exploration of expanding the genetic alphabet <04HCA1299>.

b

N 118

In medicinal applications, l,2,3,4-tetrahydropyrazino[l,2-a]indoles were of interest as highaffinity selective imidazoline receptor ligands <04BMCL1003>, 3,4-dihydro-l//-pyrido[2,3-£>]pyrazin-2-ones as corticotropin-releasing factor-1 (CRF 1) receptor antagonists <04JMC5783>, 3,6-bis[2',6'-dimethyl-L-tyrosyl-NH(CH2)n]-2(l//)-pyrazinones as (x-opioid receptor agonists <04JMC2599>, anilino 5-azaimidazoquinoxalines as antiinflammatory agents <04JMC4517>, and pyrazinones as mast cell tryptase inhibitors <04BMCL4819>. Mixed-ligand metal complexes of pyrazinamide and isoniazid were prepared and tested for antibacterial properties <04MI409> and pyrazine-containing thiazolines and thiazolidinones like 119 were developed as antimicrobial agents <04BMC2151>. Pyrrolo[l,2-a]quinoxalines, bispyrrolo[l,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[l,2-a]pyrazines, and bispyrrolo[l,2-a]thieno[3,2-e]pyrazines were developed as antimalarials <04JMC1997>, and of fifty-five multi-drug pyrazinamide (120) resistant Mycobacterium tuberculosis clinical isolates examined, all but three were shown to be pyrazinamidase (PZase) negative <04AAC2736>.

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R N I ^N

f^-K N

OCH 2 CONHN^ j I

S-^ 119

S

N

ffj

V

N

^

NHz

120

R = alkyl, aryl; R1 = 4-Br, 4-CI, 4-F, 4=MeO, 4-HO

6.2.6 REFERENCES 04AAC313 04AAC1766 04AAC2736 04AP7

E.T. Buurman, A.E. Blodgett, K.G. Hull, D. Carcanague, Antimicrob. Agents Chemother. 2004, 48, 313. D.L. Barnard, V.D. Hubbard, D.F. Smee, R.W. Sidwell, K.G.W. Watson, S.P.T. Tucker, P.A.R. Reece, Antimicrob. Agents Chemother. 2004, 48, 1766. I. Portugal, L. Barreiro, J. Moniz-Pereira, L. Brum, Antimicrob. Agents Chemother. 2004,48, 2736. E. Banoglu, C. Akoglu, S. Uenlue, E. Kuepeli, E. Yesilada, M.F. Sahin, Arch. Pharm. (Weinheim, Ger.) 2004, 337,1.

04ARK6 04ARK52 04ARK71 04ARK79 04ARK243 04ARK263

N.A. Itsikson, D.G. Beresnev, G.L. Rusinov, O.N. Chupakhin, Arkivoc 2004, 12, 6. A.R. Katritzky, J.W. Rogers, R.M. Witek, S.K. Nair, Arkivoc 2004, 8, 52. H.H. Abdel-Razik, Arkivoc 2004, /, 71. M.C. Aversa, A. Barattucci, P. Bonaccorsi, F. Caruso, P. Giannetto, Arkivoc 2004, /, 79. L. Szilagyi, T.Z. Illyes, Z. Gyoergydeak, G. Szabo, A. Karacsony, Arkivoc 2004, 7, 243. A. Lauria, P. Diana, P. Barraja, A. Montalbano, G. Dattolo, G. Cirrincione, A.M. Almerico, Arkivoc 2004, 5, 263. 04ARK349 M.c. Parlato, C. Mugnaini, M.L. Renzulli, F. Corelli, M. Botta, Arkivoc 2004, 5, 349. 04AX(C)44 D. Matkovic-Calogovic, D. Mrvos-Sermek, Z. Popovic, Z. Soldin, Ada Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, C60, m44. 04AX(C)51 H. Kooijman, A.L. Spek, G.A. van Albada, P. Gamez, J. Reedijk, Ada Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, C60, m51. 04AX(C)152 J. Pacifico, H. Stoeckli-Evans, Ada Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, C60, ol52. 04AX(C)153 C. Naether, I. Jess, Ada Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, C60, ml53. 04AX(C)ol86 J.N. Low, J. Cobo, C. Cisneros, J. Quiroga, C. Glidewell, Ada Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, C60, ol86. 04AX(C)ml86 M.L. Hu, J.X. Yuan, F. Chen, Q. Shi, Ada Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, C60, ml86. 04AX(C)191 J.N. Low, J. Cobo, S. Cruz, J. Quiroga, C. Glidewell, Ada Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, C60, ol91. 04AX(C)229 J.F. Gallagher, S. Goswami, B. Chatterjee, S. Jana, K. Dutta, Ada Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, C60, o229. 04AX(C)507 A. Senguel, N. Karadayi, O. Bueyuekguengoer, Ada Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, C60, o507. 04AX(C)623 R. Frederick, B. Norberg, F. Durant, F. Ooms, J. Wouters, Ada Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, C60, o623. 04AX(E)174 D.S. Cati, H. Stoeckli-Evans, Ada Crystallogr., Sect. E: Struct. Rep. Online 2004, £60, ml 74. 04AX(E)177 D.S. Cati, H. Stoeckli-Evans, Ada Crystallogr., Sect. E: Struct. Rep. Online 2004, E60, ml77. 04AX(E)180 D.S. Cati, H. Stoeckli-Evans, Ada Crystallogr., Sect. E: Struct. Rep. Online 2004, £60, ml80. 04AX(E)210 D.S. Cati, H. Stoeckli-Evans, Ada Crystallogr., Sect. E: Struct. Rep. Online 2004, £60, o210. 04AX(E)339 Z.P. Liang, Ada Crystallogr., Sect. E: Struct. Rep. Online 2004, E60, o339. 04AX(E)344 X.G. Liu, Y.Q. Feng, X.F. Li, Z.P. Liang, Ada Crystallogr., Sect. E: Struct. Rep. Online 2004, E60, o344. 04AX(E)376 D.E. Lynch, I. McClenaghan, Ada Crystallogr., Sect. E: Struct. Rep. Online 2004, £60, 0376.

Six-membered ring systems: diazines and benzo derivatives 04AX(E)464 04AX(E)566 04AX(E)647 04AX(E)703 04AX(E)744 04AX(E)747 04AX(E)749 04AX(E)751 04AX(E)753 04AX(E)776 04AX(E)807 04AX(E)1123 04AX(E)l 131 04AX(E)1208 04AX(E)1239 04AX(E)1255 04AX(E)1260 04AX(E)1294 04AX(E)1305 04AX(E) 1334 04AX(E)1481 04AX(E)1719 04AX(E)1739 04BCJ1125 04BCJ1587 04BKC69 04BKC501 04BMC265 04BMC553 04BMC2151 04BMC3197 04BMC4039 04BMC4245 04BMC5711 04BMCL321

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04JMC4627 04JMC4716 04JMC4787 04JMC4905 04JMC5318 04JMC5783

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334 04JMS143 04JMS147 04JMS193 04JOC1380 04JOC2551 04JOC3202 04JOC4732 04JOC4966 04JOC6927 04JOC8038 04JOC9184 04JOM557 04M45 04M211 04M333 04MI303 04MI403 04M1409 04MI411 04MI549 04MI747 04M12749 04OL1013 04OL1991 04OL2857 04OL4627 04OL4775 04OM2810 04OM5967 04OPP92 04OPP292 04PJC645 04PJC837 04PS345 04PS513 04PS601 04RJO397 04S75 04S583 04S671 04S942 04S1072 04S1554 04S1864

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Six-membered ring systems: diazines and benzo derivatives 04S2329 04S2659 04S2855 04SC783 04SC845 04SC903 04SC1295 04SC1399 04SC1499 04SC3061 04SC3553 04SC3773 04SC3915 04SC4331 04SC4463 04SL235 04SL283 04SL1086 04SL1123 04SL1179 04SL1414 04SL2031 04SL2165 04SL2327 04T275 04T1997 04T2283 04T3051 04T3763 04T4107 04T4315 04T5093 04T5373 04T5475 04T6319 04T6353 04T6593 04T7983 04T10011 04T11511 04T12177 04TA3045

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336 04TC221 04TL757 04TL1031 04TL1065 04TL1803 04TL1885 04TL2405 04TL3097 04TL3459 04TL3733 04TL3737 04TL4105 04TL4693 04TL4873 04TL5643 04TL6075 04TL6729 04TL6807 04TL8087 04TL8423 04TL8531 04TL8631 04TL8781 04TL8889 04ZK33 04ZK137 04ZK139 04ZN(B)380 04ZN(B)424

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Chapter 6.3 Triazines, tetrazines and fused ring polyaza systems Carmen Ochoa, Pilar Goya and Cristina Gomez de la Oliva Instituto de Quimica Medica (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain e-mail: [email protected], [email protected]

6.3.1

TRIAZINES

This year the number of reports dealing with triazines has considerably decreased compared with 2003. Due to the fact that many applications of compounds bearing the triazine moiety have been reported, we have divided section 6.3.1 in two parts: synthesis and reactivity and then applications. 6.3.1.1 Synthesis and reactivity The first examples of the synthesis and structural characterization of boron-containing 1,2,4triazines have been reported <04TL3249>. Cleavage of the pyrrolidine ring in 5-nitroisatin 3semicarbazone and subsequent cyclization of the semicarbazone moiety afforded 5-(2-amino-5nitrophenyl)-2,3,4,5-tetrahydro-l,2,4-triazine-3,5-dione <04JHC633>. An easy access to 3- or 5heteroarylamino-l,2,4-triazines by Sj^Ar, S N H and palladium-catalyzed A'-heteroarylation reactions has been described <04JOC7809>. Regioselectivity of nucleophilic attack in the reaction of 1,2,4-triazine 4-oxides 1 with some C-nucleophiles, such as 2 (among others), to give piperidinetrione derivatives 3 has been achieved <04KGS1060>.

Preparation of 5-amino-6-oxo-l,6-dihydro-l,2,4-triazine-3-carboxylic acid derivatives and the synthesis of compound libraries thereof have been reported <04TL2791>. Intramolecular inverse electron demand Diels-Alder reactions of imidazoles with 1,2,4-triazines have been described as a new route to obtain l,2,3,4-tetrahydro-l,5-naphthyridines and related heterocycles

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<04JOC7171>. Intramolecular cycloaddition/retro-cycloaddition reactions applied to 1,2,4triazines have been used to obtain unsymmetrical 2,2'-bipyridine and 2-benzofuropyrazin-2ylpyrimidine analogues <04T6021>. A tethered imine-enamine methodology has been developed for the direct conversion of 1,2,4-triazines into highly substituted pyridines via the inverse electron demand Diels-Alder reaction <04CC508>. A one-pot reaction cascade from 3(ethoxycarbonyl)-5-phenyl-l,2,4-triazine 4, cyclobutanone and secondary amines 5 yielded functionalized 4,5-dihydroazocines 7 through dihydropyridines 6 <04TL8607>.

NHR 1 R 2 = pyrrolidine, morpholine, 4-(carbo-f-butyloxy)piperazine, cyclopropylamine, diethylamine

Cyclocondensation between l,2-dihydroquinoxalin-2-ones and l,2,4-triazine-3,5-dione derivatives involves the carbonyl group of the 1,2,4-triazinedione and not the carbonyl group of the quinoxalinones <04JHC597>. New examples of the synthesis of pyridine and 2,2'bipyridine derivatives from a variety of substituted 1,2,4-triazines through Diels-Alder reactions have been described <04T8893>. Zirconacyclopentanes reacted with isocyanates 8 to give trimerization products such as isocyanurate 9 <04T1393>.

Five bis(isocyanuric)acid dimers have been prepared and characterized <04T6385>. Treatment of methoxyribosyltriazinone 10 with hydrazine afforded 4-hydrazino-l-|3-Dribofuranosyl-l,3,5-triazin-2-one 11 which rearranged rapidly to the isomeric 5ribosylureidotriazole 12 <04CCC905>.

Microwave-assisted synthesis of new 2-isoxazolyl-l,3,5-triazin-2-ones by condensation of isoxazolylureas, aqueous formaldehyde and primary amines has been described <04IJC(B)1784>. Microwave-assisted synthesis of fluorinated hexahydro 1,3,5-triazine

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339

derivatives in aqueous medium has been achieved and l,2,4-triazolo|3,4-a]ll,3,51triazines were also prepared by one-pot reaction of in situ synthesized triazinyl hydrazine <04SC1141>. Reaction of titanocene precursors with 1,3,5-triazine leads, by way of selective C-C coupling, to the formation of polynuclear titanium compounds <04AG(E)1583>. One-pot preparation of triazinyl amide 16 via a sequential SftAr substitution and oxidation has been achieved by using diethylaminoacetonitrile 14 as amide synthon. An important advantage of this process is that the oxidation of intermediate 15 to the amide occurs under mild conditions <04JOC1360>.

Triflic anhydride has been found to be an efficient agent for the cyclotrimerization of dialkylcyanamides to give 2,4,6-trisubstituted-l,3,5-triazines under mild conditions <04S503>. A convenient method for the preparation of new derivatives of 1,3,5-triazine under solvent free conditions using nucleophilic reactions on cyanuric chloride has been reported <04H1867>. An efficient one-pot synthesis of a novel class of 2,4,6-tris(arylchalcogeno)-l,3,5-triazines (sulfur, selenium and tellurium) has been developed by reaction of 2,4,6-trichloro-l,3,5-triazine with the corresponding arylchalcogenide anions <04TL6453>. A novel safety catch method for orthogonal synthesis of highly pure trisubstituted 1,3,5-triazines, using a polymer support not acid-labile, has been described. Due to the polymer support property, this strategy was uniquely applied to the synthesis of a library of acid sensitive triazines <04JCO474>. Microwave assisted parallel synthesis of a library of seventeen aryl dihydrotriazines 19-35 has been successfully achieved from dicyandiamide 17 and acetone 18. This method decreased reaction time from an average of 22 hours to 35 minutes comparing to conventional parallel synthesis <04JCO504>.

2,4-Diamino-l,3»5-triazines have been prepared by reaction of dicyandiamide with nitriles under microwave irradiation. This method can be considered as a green procedure due to the reduction in the use of solvents during synthesis and purification <04NJC952>. Sharpless asymmetric dihydroxylation ligands have been synthesized using a 1,3,5-triazine spacer group between two chirai moieties. This new ligand may be an economic alternative to current systems for the asymmetric dihydroxylation of alkenes <04TL8527>.

340

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

Coupling reactions of organoboronic acids with 2,4,6-trichloro-l,3,5-triazine have been investigated <04MI941>. 1,3,5-Trihydroxyisocyanuric acid (THICA) has been prepared by an efficient method from O-benzylhydroxyamine and diphenyl carbonate <04TL8277>. A novel class of multifunctional and multinucleate chalcogen (selenium and tellurium) containing derivatives 38 has been developed based on sequential chloride substitution of 2,4,6-trichloro1,3,5-triazine 37 with chalcogen-bearing amines 36 <04TL8941>.

6.3.1.2 Applications Dimeric 2,2'-bipyridylruthenium(II) complexes containing 2,3-bis(l,2,4-triazin-3-yl)-4,4'bipyridine have been synthesized as bridging ligands <04EJI2277>. Characterization and photochemical studies of some copper complexes of Schiff bases derived from 3-hydrazino-6methyl-l,2,4-triazin-5-one have been described <04SRI1069>. Enhanced 2-photon properties of tri-branched styryl derivatives based on 1,3,5-triazine have been found <04CL470>. Several novel phosphinoxide ligands have been obtained based on molecular scaffolds such as 1,3,5triazine. These compounds form highly luminiscent complexes with Eu(III) and Tb(III) <04MI61>. A new photoluminiscent poly(arylene ethylene) containing 1,3,5-triazine units has been reported <04MI795>. Structure of liquid crystals in the series of 2,4,6-tristyryl-1,3,5triazines (39, 40) has been described <04T6765>.

Star-shaped compounds having a 1,3,5-triazine core and stilbenoid arms have been prepared. These compounds form nematic discotic systems <04T6881>. Discotic liquid crystalline

Triazines, tetrazines and fused ring polyaza systems

341

materials containing a 1,3,5-triazine core for potential nonlinear optical applications have been achieved . Molecular structures featuring two or three triolefinic 15-membered macrocycles containing 2,4-dichloro-1,3,5-triazine moieties form complexes of palladium(O) and platinum(O) <04OM2533>. A family of tridentate ligands based on a 2-aryl-4,6-di-(2-pyridyl)1,3,5-triazine motif and their ruthenium complexes have been prepared. The luminiscence properties and redox behavior of these complexes have been studied <04CEJ3640>. Synthesis and characterization of metal-containing multicomponent hydrogen-bonded rosette assemblies bearing 1,3,5-triazine arms have been described <04MI441>. 2,4,6-Tris(/?bromotetrafluorophenoxy)-l,3,5-triazine forms channel inclusions with the solvents p-xylene and p-chlorotoluene, showing a stoichiometry of 2: 1 (host: guest) <04NJC393>. Derivatives of pentaerythrityl tetraphenyl ether incorporating four diamino-l,3,5-triazine groups form highly porous networks and define significant interconnected channels for the inclusion of guests <04JOC1776>. Synthesis of various monomers modified with triphenyl-1,3,5-triazine side groups as electron transport moieties has been reported <MI1633>. 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 <04AG(E)1255, 04CC2108>. Characterization and application of triazine based polyfluorinated triquaternary liquid salts, as solvents in rhodium(I) catalyzed hydroformylation of 1-octene, have been reported <04OM783>. 2-Chloro-4,6bisl(heptadecafluorononyl)oxy)-1,3,5-triazine has been used as a condensation reagent to obtain di- and tripeptides <04S80>. Dihydro-l,2,4-triazine derivatives have been described as antimalarials due to their ability to inhibit multiple mutants of Plasmodium falciparum dihydrofolate reductase <04JMC673>. Analgesic and antinflammatory activities of some 1,2,4-triazine derivatives have been described <04AF42>. 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 <04EJM535>. 1,2,4-Triazine TV-oxide derivatives have been studied as potential hypoxic cytoxins <04AP247>, <04AP271>. Sulfonamides incorporating 1,2,4-triazine moieties have been studied as inhibitors of cytosolic/tumor-associated carbonic anhydrase isoenzymes I, II and IX <04BMCL5427>. A series of diamino-l,3,5-triazines 41 have been identified as novel 5-HT7 receptor antagonists <04BMCL4245>. New 4,6-disubstituted 2-alkyl-l,3,5-triazines 42 and 43 showed interesting anticancer properties in different tumor cell lines <04JMC4649>. R1

Me y_)

N^N

"

x

41 1

X = H, F, R =H, F, Me, NH2, NMe2 R2 = (CHjkPh, (CH2)3Ph, (CH^OPh, 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

VW^OH 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 <04BCJ569>. Hemolysis and cytotoxicity activities of six dendrimers based on melamine have been evaluated. None of them showed acute in vivo toxicity <04JA10044>. 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 <04JMC600>. 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 <04JA3185>. Simple synthetic routes to 1,3,5-triazinyl-dithiocarbamate derivatives which exhibit antimicrobial and antitubercular activities have been reported <04UC(B)378>. Substituted chalcones and pyrazolines bearing a 1,3,5-triazine moiety have been synthesized and screened for antibacterial activity <04IJC(B)1580>.

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 <04NJC387>. 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 <04OL1397>.

Electropolymerization of a verdazylthiophene derivative has been carried out to give solid materials with a high concentration of radical spins <04MI55>. 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 <04T1991>. 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 <04JCR(S)408>. 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 <04OL2889>.

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<*SJ

NO,

+

N

N

'

HCI/MeOH

Na Me

H2N^NH2

°

1

V" R

Y ~N \L_4'

R = nitroguanyl, 3,5-dimethyl-1 -pyrazolyl

Me 48

49

50

6.3.2.2 Applications Several verdazyl radical and diradicals containing pyridine based multitopic coordination sites have been described as paramagnetic analogues of oligopyridine metallosupramolecular building blocks <04OL1887>. Fiftyfive 1,2,4,5-tetrazines including hexahydro-, 1,6-dihydro-, 1,4-dihydro-, 1,2-dihydro- and aromatic derivatives have been prepared as antitumor agents <04BMCLl 177>. 6.3.3

POLYAZA HEXACYCLES CONTAINING OTHER HETEROATOMS

The number of azaheterocycles containing phosphorus which appear in the literature, mainly phosphazene derivatives, is increasing year to year.

6.3.3.1 Cyclotriphosphazenes Synthesis and polymerization of multifunctional cyclotriphosphazenes have been described <04PS961>. A series of new nongeminal cyclophosphazenes 52 has been prepared via deprotonation-substitution reactions at the methyl groups of both cis and trans isomers of cyclotriphosphazene 51 with different electrophilic reagents <04PS817>. P

HN^OPn

Me

Ph

K Me

Ph

.

M e

/ > 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 <04POL979>. Synthesis of a bridged fluorophenoxycyclotriphophazene has been described <04JCR(S)156>. 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 .

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

Thioacylation reactions for the surface functionalization of dendrimers containing a phosphazene core have been described <04OL1309>. 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 <04CL932>. 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 <04POL1027>. Chirality in cyclotriphosphazenes with one stereogenic center has been studied <04ICC842>. 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 <04OL2109>. A dendritic cyclotriphosphazene derivative bearing hexaxis(alkylazobenzene) substituents has been described as a photosensitive trigger <04H1563>. 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 <04ICC657>. 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 <04PS845>. Reversible skeletal substitutions in diverse heterophosphazenes bearing B, As and Al atoms have been studied <04PS845>. 6.3.3.3 Tetrazaphosphorines A new method to obtain tetrazaphosphorine derivatives 57 by phosphodihydrazides 56 with A'-acylimidates 55 has been described <04PS365>.

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 <04AP81>. 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 <04JCR(S)174>. Synthesis of new 8-aryl-l,2,4-triazolo[l,5-. The synthesis of triazolotriazine 59 by a cyclization reaction of A'-aminotriazole 58 and triethyl orthoformate has been achieved <04KGS130>.

MeHN

J \

CH 0Et)

< * .

NH 2

X^SMe Me'

58

^ 59

The synthesis of pyrazolo[5,l-c]|l,2,4]triazines from (2-cyano-l-oxo-lH-inden-3-yl) acetonitrile has been studied <04JCR(S)687>. Synthesis of imidazo[l,2-£>][l,2,4|triazines from 1,2-diaminoimidazoles, which were obtained under solvent free conditions, has been reported <04SL549>. 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 <04KGS1844>. 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 <04H1829>. 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 <04PS1469>. NH 2 S

^N^O

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 <04MI127>. Synthesis of trifluoromethyl substituted dihydrotetrazolopyrimidines and tetrahydrotetrazolopyrimidines <04KGS71> and other triazolo- and tetrazolopyrimidines have been described <04IJC(B)667>. An expeditive synthesis of homochiral fused triazole- and tetrazole-piperazines from [5-amino alcohols has been reported <04TL3725>. 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 <04TL6421>.

346

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

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 <04PS601>. Synthesis of perfluoroalkyl[l,2,4]triazolo[l,3]thiazinones has been reported <04JGU472>. 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 <04IJC(B)385>. 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 <04TL4233>.

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 <04JOC3230>. Preparation of new 6,9-disubstituted 2-phenyladenines under conditions compatible with the use of thiomethyl resin for solid phase synthesis has been reported <04JHC575>. 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 <04JOU1649>. A simple and practical synthesis of 7- and 9-alkylated guanines starting from guanosine has been developed <04S2026>. 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 <04ZN(B)802>. Synthesis of 6-enaminopurine derivatives from 5-amino-4cyanoformimidoylimidazoles has been reported <04OBC2340>. Copper-mediated coupling of aminopurines with arylboronic acids has been explored and iV-arylated purines have been obtained <04TL195>. Reductive Heck reaction of 6-halopurines has been studied. Alkenylation of 9-benzyl-6-halopurines did not proceed under conventional Heck conditions <04TL273>. Reactions of 8-5//-purines with glycidol have been studied <04JGU624>. 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 <04OPP121>. Multigram scale syntheses of the important 8-styrylxanthine A2a adenosine receptor antagonists MSX-2, MXS-3 and KW6002 have been accomplished <04JOC3308>. A new and practical method for the synthesis of 1- and 1,3-disubstituted xanthines has been developed <04OL2237>. 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 <04H1673>. 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 <04TL2321>. An efficient conversion of 6-cyanopurines into 6alkoxyformimidoylpurines has been developed <04OBC1019>. Synthesis of diverse purine libraries has been optimized by a microwave assisted method using minivials <04JCO171>. An efficient one pot three component synthesis of 7-oxo-l,7,8,8a-tetrahydroimidazo[l,2alpyrimidines has been described <04SL1086>. 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 <04H1629>. 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-
348

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

carbomethoxypyrazole 77, to give amine 78, and subsequent cyclization with arylamines and triethyl orthoformate <04OPP92>. Me MeOzC.N^

MeOH

_)M, O2N

Me MeO 2 C^.N^

Ni/H 2 ^

>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 <04JHC393>. 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

N^il 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 <04TL6633>. A novel synthesis of pyrazolo[3,4bjpyridines by condensation of 2-pyrone with 3-aminopyrazolone has been described <04SC2195>.

6.3.4.2 Applications Pyrazolo[l,5-. Piperazine derivatives of l,2,4-triazolo[l,5-a][l,3,5ltriazine 86 and 87 exhibited potent and selective activity as adenosine A2a receptor antagonists <04JMC4291>,

Triazines, tetrazines and fused ring polyaza systems

349

<04BMCL4835>. Following these studies on adenosine A2a receptor antagonists a comparison of l,2,4-triazolo[l,5-a][l,3,5]triazine and l,2,4-triazolo[l,5-c|pyrimidine cores was carried out <04BMCL4831>. Me \

NH2

C(Me)3

NH 2

N-7

R Ar 85

86

87

Pyrazolo[l,5-c][l,3>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 <04MI1898>. 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 <04JMC4054>. Disubstituted A^-cyclopentyladenine analogues behaved as neutral antagonists with high affinity for adenosine Ai receptor <04BMC139>. 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 <04JMC4741>. 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 <04BJP1059>. Identification of new purine derivatives as inhibitors of phosphodiesterase 7 has been reported <04BMCL2955>. Synthesis and evaluation of 2substituted 8-hydroxyadenines 88 - 91 as potent interferon inducers with improved oral bioavailabilities have been carried out <04BMC1091>. Some 9-benzyI-8-hydroxy-2-(2hydroxyethylthio)adenine derivatives 92 have been described as prodrugs with potent interferon inducing agents in monkeys <04CPB466>. 2-Substituted O-6-cyclohexylmethylguanines 93 showed potent inhibitory activity of cyclin-dependent kinase-1 and kinase-2 <04JMC3710>. 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—<

J £ VOCO2R ROCO2CH2S^N

^

)

N^N RK^\(

92 93 R = ci, NMe2, NHaryl

Guanine derivatives connected to pyrene with methylene spacers exhibited exciplex emission in highly polar solvents. This fact opens up a novel approach to the synthesis of fluorescent nucleic bases <04CC824>. Diverse thio analogues of purine have been prepared as anti-Mycobacterium tuberculosis agents. Two of them, 9-(ethylcarboxymethyl)-6-(decylthio)-9//-purine and 9(ethylcarboxymethyl)-6-(dodecylthio)-9f/-purine proved to be particularly active <04JMC273>.

350

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

Pyrazolopyridine derivatives have been reported as new orally active phosphodiesterase 4 (PDE 4 ) inhibitors with therapeutic potential <04BMCL29>, <04BMC4089>, <04CPB1098>. Phosphodiesterase 5 (PDE5) inhibitory activity of new sildenafil 94 (viagra) analogues 95-97 containing a phosphonate group at the 5'-sulfonamide moiety of the phenyl ring has been evaluated <04BMCL2099>.

A series of pyrazolo[3,4-af]pyrimidines has been described as a novel class of potent enterovirus inhibitors <04BMCL2519>. Novel 1,4,6-trisubstituted pyrazolo|3,4-rflpyrimidines have been reported as in vitro potent inhibitors of breast cancer cells 8701-BC <04JMC1595>. A pyrazolo[l,5-fl]pyrimidine scaffold has been examined as a novel core structure for estrogen receptor ligands <04BMCL5681>. A novel series of [l-(l//-benzimidazol-7-yl)-l//pyrazoloL3/W]pyrimidin-4-yl]arylhydrazones has been described as GSK-3 inhibitors with improved cellular activity <04BMC2127>. A new series of 2,3-diaryl-pyrazolo[l,5bjpyridazines showed activity as potent and selective cyclooxygenase-2 inhibitors <04BMCL5445>. 2,4-Diamino-5-methyl-6-substituted-pyrrolo[2,3-. Synthesis of 7-deazaguanines as potential inhibitors of guanosine triphosphate cyclohydrolase has been reported <04T943>.

6.3.5

FUSED [6]+[6] POLYAZA SYSTEMS

6.3.5.1 Synthesis and reactivity The reaction of 3-chloro-l,5-diarylformazan98 with 3-amino-2-thiouracils 99 provided easy access to the synthesis of 3-arylazo derivatives of pyrimido[l,2-b][l,2,4,5]tetrazinone derivatives 100 <04JCR(S)399>.

Synthesis of 3-substituted 6-arylbenzo[. Gas-phase thermolysis of thieno[3,2-e][l,2,4]triazines yielded benzonitrile, isothiazole, pyrimidine, [ 1 ]benzothieno[2,3-^]pyrimidine and thieno[3,2rf]thiazole derivatives. These products were separated by HPLC and column chromatography and characterized using GCMS, LCMS, 'H, 13C-NMR and 2D NMR spectroscopy

Triazines, tetrazines and fused ring polyaza systems

351

<04T9121>. A one-pot condensation-substitution reaction of 6-carbethoxy-5-chloro-3cyclopentyl-l,2,4-triazine 102 with a urea derivative 101 yielded the isofervenulin analogue 103 <04JHC637>.

A practical synthesis of 2//-pyrimido[4,5-e][l,2,4]triazin-3-ylidenecyanamides 106 has been developed. The key step is the coupling reaction of an aryldiazonium salt with l-cyano-3-(2,6dioxo-l,2,3,6-tetrahydropyrimidin-4-ylamino)-2-methylisothiourea 105, obtained from uracil 104, followed by an intramolecular cyclization <04TL9319>.

/: dimethyl W-cyanodithioimidocarbonate, K2CO3, DMF, 130 °C 5 h; //: ArN2+, DMSO, 0 °C to r.t., 1 h.

A methanopterin analogue, l-allyl-6-(mesitylamino)rnethyl-7-methyl-3-phenylpteridine, has been synthesized using nucleophilic substitution of 2,3-dicyano-5-hydroxymethyl-6methylpyrazine with allylamine <04JCR(S)648>. Regioselectivity in S N H reactions of some 3-nitro-l,5-naphthyridines with chloromethylphenyl sulfone have been studied <04CJC567>. The synthesis and redox ability of optically active 3-carbamoyl-l,6-dimethylpyrimido[4,5-c]pyridazin-5,7-dione and related pyrimido-annulated pyridine analogues have been described <04H1393>. Two examples of a metallation and functionalization of the pyridine moiety in pyridopyrimidine derivatives have been reported <04TL3733, 04T4107>. Functionalization of 4-methoxypyridopyrimidines via a metallation reaction provided an efficient process to access new substituted pyridopyrimidines <04T6353>. A three-step parallel solid-phase synthesis of 2-acetylamino-4//-azino[l,2x]pyrimidin-4-ones has been reported <04JCO356>. Synthesis of trifluoromethylated pyrido[2,3-. The synthetic strategy towards a 5-alkoxypyrido[4,3-c?]pyrimidin-4(3//)-one 114 has been described using a selective N-oxidation and subsequent regioselective Meisenheimer ./V-oxide

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rearrangement as key steps. The seven steps neccessary to obtain 114 are outlined below <04TL3737>.

An easy microwave-induced one-pot synthesis of novel pyrido[2,3-fif]pyrimidines and pyrimido[4,5-. A general microwave assisted protocol to give quinoxalines and pyridopyrazines in excellent yields (69-99%) from common 1,2-diketone intermediates has been described <04TL4873>. Synthesis and reactions of novel pyrimido[4,5-c]pyridazine derivatives have been described <04M45>. One pot synthesis of oxazino[4,5-rf|-, pyrano[2,3-<^]-, and pyrido[2,3-.

6.3.5.2 Applications New 3-0-substituted pyrimido[2,3-e]Ll,2,31triazin-4(3//)-one hexafluorophosphate salts have been shown to be useful peptide coupling additives <04JOC54>. A series of novel 1,2,4benzotriazine 1,4-dioxides (BTO) 115 has been synthesized as potent analogues of hypoxia selective cytotoxin tirapazamine. BTOs bearing a positive charge showed increased hypoxic cytotoxicity (1.5-56 fold) compared to tirapazamine <04JMC475>.

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A new 2-carbamoylpteridine that inhibits mycobacterial FtsZ has been described <04BMCL3161>. Nematocide activity of S-glycopyranosyl-ej-diarylthiolumazines has been investigated <04BMC4431>. 2-Amino-O-4-benzylpteridine derivatives have been reported as potent inactivators of 0-6-alkylguanine-DNA alkyltransferase <04JMC3887>. New 2,4diaminopteridine derivatives have been studied as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii and Mycobacterium avium dihydrofolate reductase <04JMC2475>. Biological evaluation of pteridines 116 and pyrazolopyrimidines 117 as adenosine kinase inhibitors has been carried out. 4-Amino substituted pteridines were generally less active than the corresponding 5- and 6-substituted pyridopyrimidines selected as standard <04BMCL4165>.

n= 0,2,3,4; R = H, Ph

Synthesis and antimicrobial activity of new 7,8-diaminopyrido[3,4-cf]pyridazin-3-one derivatives have been described <04IJC(B)1314>. Synthetic studies on azaisoquinoline derivatives with multidrug-resistance (MDR) modulating activity have been carried out <04H75>. 6.3.6

MISCELLANEOUS FUSED RING POLYAZA SYSTEMS

6.3.6.1 Synthesis and reactivity The reactivity of l,3,6,8-tetraazatricyclo[4.4.1.1]dodecane 118 (TATD) in basic media to give l,3,6,8-tetraazatricyclo[4.3.1.1|undecane 119 (TATU) has been studied. When ammonium hydroxide or ammonia gas was used only 12% of 119 was obtained. Better results were obtained by using ammonium fluoride as base <04TL7563>.

Synthesis of l,2,4-triazino[5,6-£>]indole-3-thiols from isatin, 2-chloroisatin and /V-benzylisatin have been carried out using microwave irradiation in order to accelerate each reaction step <04SL723>. Reaction of 3-benzylindole-2-carbohydrazides 122 and triethyl orthoformate in a polar solvent like DMF yielded only 10-benzyl-l,2-dihydro-l-oxo-l,2,4-triazino[4,5-a]indoles 121 while on reaction with triethyl orthoacetate it afforded also the oxadiazolylindole derivatives 122 <04JHC7>.

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Synthesis of thiazolo[3',272,3][l,2,4]triazino[5,6-b]indoles has been reported <04IJC(B)1585>. Different functionalizations of l,2,4-triazino[5,6-£]indoles have been carried out <04JCR(S)183>. Reaction of 3-diazopyrazolo[3,4-c]pyridazine with reactive methylene compounds yielded condensed 1,2,4-triazine derivatives . New tetracyclic benzimidazole systems containing the 1,3,5-triazine ring have been synthesized by an efficient one-pot procedure in the solid phase from resin-bound benzimidazoles <04JCO220>. Thermolysis of methyl l-methyleneamino-4,5-dioxo-4,5-dihydro-lf/-pyrrole-2-carboxylates 123 led to substituted dimethyl 3,9-dioxo-l,5,7,ll-tetrahydro-l//,7//-dipyrazolo[ l,2-a:l',2'rf][l,2,4,5]tetrazine-l,7-dicarboxylatesl24<04T5319>.

A rapid and convenient synthesis of novel l-imino-2,3-dihydro-lf/-pyrazino|2,lblquinazolin-5-ones has been reported <04TL3097>. Synthesis of new pyrazolo|4,3elll,2,4]triazolo[l,5-c]pyrimidines and related compounds has been described <04T5093>. A novel pentaheterocyclic ring system of l,2,4-triazolo|2'',376',r]pyrimido[4',572,3]pyrido[l,2ajbenzimidazole has been described <04JHC281>. A base-catalyzed method to convert \Hpyrazole-4-carboxamides into tri-fused heterocyclic systems containing two classes of pyrazolotriazolopyrimidine framework has been developed <04JCR(S)50>. Synthesis of functionalized derivatives of pyridotriazolopyrimidinones has been described <04M211>. Various 4-substituted dihydropyridopyrazines have been synthesized by palladium-mediated cross-coupling reactions from the corresponding 4-iodo or 4-bromo derivatives <04TL2343>. Synthesis of 6,9-disubstituted cyclohepta[i']pyrimidoL5,4-cfJpyrrole-8(6/f))10(9/f)-diones has been accomplished by a ring opening and ring closure sequence from 9-substituted cyclohepta[&]pyrimido[5,4-. A general method for the synthesis of novel mesoionic 2-amino-7-aryl-4-oxo-2,4,5,8-tetrahydro[ 1,2,3 ]triazolo[5,l.

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6.3.6.2 Applications A series of tricyclic dihydropyridopyrazolones and dihydropyridoisoxazolones have been described as novel KATP channel openers <04BMC1895>. Tricyclic oxazolo|2,3-/]purinediones have been tested as adenosine receptor ligands. They showed mainly adenosine A2 receptor affinity and selectivity <04BMC4895>. Development of structure activity relationships of imidazoguanines allowed the discovery of a potent and selective series of phosphodiesterase 5 inhibitors 131 for treatment of erectile dysfunction <04BMCL1291>.

l,2,4-Triazolo[4,3-a|quinoxalin-l-one has been described as a scaffold to develop new potent and selective human A3 adenosine receptor antagonists <04JMC3580>. The design and synthesis of novel imidazo[l,2-a]quinoxalines as PDE4 inhibitors have been reported <04BMC1129>. Biological evaluation of novel 4-alkylarnino-l-hydroxymethylimidazo[l,2a]quinoxalines as novel adenosine A\ receptor antagonists has been carried out <04BMC4701>. The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-l,2,4triazolo[3,4-a]phthalazines as GABAatx5 inverse agonists has been reported <04JMC3642>.

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New l//,3//-pyrimido[2,l-/]purine-2>4-dione derivatives have been evaluated in vitro for their affinity for 5-HTi a , 5HT2a and D-2 receptors <04JMC2659>. A series of analogues containing the imidazo[4,5-e][l,2,5]triazepine ring resulted in competitive inhibitors of mammalian adenosine-deaminase <04JMC1044>. Structure-Activity relationships of 4-cycloalkylaminol,2,4-triazolo[4,3-<2|quinoxalin-l-one derivatives as Ai and A3 adenosine receptor antagonists have been studied <04AP35>. A series of 1-substituted 2-methyl-l//-imidazo[4,5-g]phthalazine-4,5-diones have shown cytotoxic activity against several human tumor cell lines <04BMC3683>. 6,11-Dihydropyridazo[2,3-ft]phenazine-6,ll-dione and 6,ll-dihydropyridoI2,3-fc]phenazine-6,ll-dione have been reported as new anticancer drugs <04BMC1623>. The cytotoxic activity of new quinazolino-|3-carbolin-5-one derivatives has been evaluated <04BMC1991>. The cytotoxic and DNA-binding properties of mono-dihydrodipyridopyrazines and bis-dihydrodipyridopyrazines have been studied <04JMC978>.

6.3.7

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04JMC3689 04JMC3710

S.I. Radchenko, E.V. Ratsino, Russ. J. Gen. Chem. 2004, 74, 624. S.J. Maddirala, V.S. Gokak, L.D. Basanagoudar, J. Heterocycl. Chem. 2004, 41,1. N.M. Elvvan, J. Heterocycl. Chem. 2004, 41, 281. H.Q. Wang, Z.J. Liu, L.M. Yang, M.W. Ding, /. Heterocycl. Chem. 2004, 41, 393. M. Takahashi, H. Nagaoka, K. Inoue, J. Heterocycl. Chem. 2004, 41, 525. G.A. Biagi, I. Giorgi, O. Livi, F. Pacchini, V. Scartoni, O.L. Salemi, J. Heterocycl. Chem. 2004,47,575. R. Buchtik, J. Hlavac, J. Sluka, P. Frycak, J. Heterocycl. Chem. 2004, 41, 597. J. Hlavac, M. Sourai, P. Hradil, I. Frisova, J. Slouka, J. Heterocycl. Chem. 2004, 41, 633. A. Bach, X.L. Jiang, J. McKenna, K. Prasad, O. Repic, W.C. Shieh, J. Heterocycl. Chem. 2004,47,637. A.K. Pathak, V. Pathak, L.E. Seitz, W.J. Suling, R.C. Reynolds, J. Med. Chem. 2004, 47, 273. M.P. Hay, F.B. Prugin, S.A. Gamage, H.D.S. Liyanage, M.S. Kovacs, A.V. Patterson, W.R. Wilson, J.M. Brown, W.A. Denny, J. Med. Chem. 2004, 47, 475. A.L. Rodriguez, A. Tamrazi, M.L. Collins, J.A. Katzeneilenbogen, J. Med. Chem. 2004, 47, 600. S. Kamchonwongpaisan, R. Quarrell, N. Charoenetakul, R. Poinsinet, T. Vilaivan, J. Vanichtanankul, B. Tamchompoo, B. Siravvaraporm, G. Lowe, Y. Yuthavong, J. Med. Chem. 2004, 47, 673. S. Blanchard, I. Rodriguez, C. Tardy, B. Baldeyrou, C. Bailly, P. Colson, C. Houssier, S. Leonce, L. Kraus-Berthier, B. Pfeiffer, P. Renard, A. Pierre, P. Caubere, G. Guillaumet, J. Med. Chem. 2004, 47, 978. A. Reayi, R.S. Hosmane, J. Med. Chem. 2004, 47, 1044. F. Carro, A. Pucci, A. Naldini, S. Schenone, O. Bruno, A. Ranise, F. Bondavalli, C. Brullo, P. Fossa, G. Menozzi, L. Mosti, F. Manetti, M. Botta, J. Med. Chem. 2004, 47, 1595. A. Rosowsky, H.N. Fu, D.C.M. Chan, S.F. Queener, J. Med. Chem. 2004, 47, 2475. S. Jurczyk, M. Kolaczowski, E. Maryniak, P. Zajdel, M. Pawlowski, E. Tatarczynska, A. Klodzinska, E. Chojnacka-Wojcik, A.J. Bojarski, S. Charakchieva-Minol, B. Duszynska, G. Nowak, D. Maciag, J. Med. Chem. 2004, 47, 2659. V. Colotta, D. Catarzi, F. Varano, F.R. Calabri, O. Lenzi, G. Filacchioni, C. Martini, L. Trincavelli, F. Deflorian, S. Moro, J. Med. Chem. 2004, 47, 3580. L.J. Street, F. Stemfeld, R.A. Jelley, A.J. Reeve, R.W. Cariing, K.W. Moore, R.M. McKeman, B. Sohal, S. Cook, A. Pike, G.R. Dawson, F.A. Bromidge, K.A. Wafford, G.R. Seabrook, S.A. Thompson, G. Marshall, G.V. Pillai, J.L. Castro, J.R. Atack, A.M. MacLeod, J. Med. Chem. 2004, 47, 3642. A. Gangiee, X. Lin, S.F. Queener, J. Med. Chem. 2004, 47, 3689. l.R. Hardcastle, C.E. Arris, J. Bently, F.T. Boyle, Y.H. Chen, N.J. Curtin, J.A. Endicott, A.E. Gibson, B.T. Golding, R.J. Griffin, P. Jewsbury, J. Menyerol, V, Mesguiche, D.R.

Triazines, tetrazines and fused ring polyaza systems

04JMC3887 04JMC4054 04JMC4291 04JMC4649 04JMC4741 04JMC5829 04JOC54 04JOC1360 04JOC1776 04JOC1890 04JOC3230 04JOC3308 04JOC7171 04JOC7809 04JOU85 04JOU1649 04KGS71

359

Newell, M.E.M. Noble, DJ. Pratt, L.Z. Wang H.J. Whitfield, J. Med. Chem. 2004, 47, 3710. M.E. Nelson, N.A. Loktionova, A.E. Pegg, R.C. Moschel, J. Med. Chem. 2004, 47, 3887. J.T. Hunt, T. Mitt, R. Borzillen, J. Gullo-Brown, J. Fargnoli, B. Fink, W.C. Han, S. Mortillo, G. Vite, B. Wautlet, T. Wong, C.A. Yu, X.P. Zheng, R. Bhide, J. Med. Chem. 2004, 47, 4054. C.B. Vu, B. Peng, G. Kumaravel, G. Smits, X.W. Jin, D. Phadke, T. Engber, C. Huang, J. Reilly, S. Tarn, D. Grant, G. Hetu, L.Q. Chen, J.B. Zhang, R.C. Petter, J. Med. Chem. 2004,47, 4291. R. Menicagli, S. Samaritani, G. Signore, F. Vaglini, L.D. Via, J. Med. Chem. 2004, 47, 4M9. R.A. Hartz, K.K. Nanda, C.L. Ingalls, V.T. Ahuja, T.F. Molski, G. Zhang, H. Wong, Y. Peng, M. Kelley, N.J. Lodge, R. Zaczek, P.J. Gilligan, G.L. Trainor, J. Med. Chem. 2004, 47, 4741. M.S. Chambers, J.R. Atack, R.W. Carting, N. Collinson, S.M. Cook, G.R. Dawson, P. Ferris, S.C. Hobbs, D. O'Connor, G. Marshall, W. Reycroft, A.M. MacLeod, J. Med. Chem. 2004, 47, 5829. L.A. Carpino, J.S. Xia, A. El-Faham, J. Org. Chem. 2004, 69, 54. Z. Zhang, Z. Yin, J.F. Kadow, N.A. Meanwell, T. Wang, J. Org. Chem. 2004, 69, 1360. D. Laliberte, T. Maris, J.D. Wuest, J. Org. Chem. 2004, 69, 1776. N.S. Kumar, K.P. Kumar, K.V.P.P. Kumar, P. Kommana, J.J. Vittal, K.C.K. Svvamy, J. Org. Chem. 2004, 69, 1890. H.Z. He, L. Llauger, N. Rosen, G. Chiosis, J. Org. Chem. 2004, 69, 3230. J. Hockemeyer, J.C. Burbiel, C.E. Muller, J. Org. Chem. 2004, 69, 3308. B.R. Lahue, S.-M. Lo, Z.-K. Wan, G.H.C. Woo, J.K. Snyder, J. Org. Chem. 2004, 69, 7171. E. Gamier, J. Audoux, E. Pasquinet, F. Suzenet, D. Poullain, B. Lebret, G. Guillaumet, J. Org. Chem. 2004, 69, 7809. V.L. Rusinov, G.V. Zyryanov, I.N. Egorov, E.N. Ulomskii, G.G. Aleksandrov, O.N. Chupakhin, Russ. J. Org. Chem. 2004, 40, 85. A. Yahay-Zadeh, Russ. J. Org. Chem. 2004, 40, 1649. S.M. Desenko, E.S. Nenajdenko, O.V. Shishkin, S.V. Shishkina, Khim. Geterotsikl. Soedin.

2004, 71. 04KGS130 04KGS1060 04KGSI844 04M45 04M211 04MI55 04MI61 04MI127 04MI441 04MI795 04MI941 04MI1633 04MI1898 04NJC387 04NJC393 04NJC418 04NJC952

L. Labanauskas, V. Bucinskaite, D. Bucyte, A. Brukstus, Khim. Geterotsikl. Soedin. 2004, 130. D.N. Kozhevnikov, A.M. Prokhorov, V.L. Rusinov, O.N. Chupakin, Khim. Geterotsikl. Soedin. 2004, 1060. V.N. Britsun, l.M. Bazavova, A.N. Esipenko, M.O. Loynskii, Khim. Geterotsikl. Soedin. 2004, 1844. M.I.A. Moneam, Monatsh. Chem. 2004, 735, 45. M.A.N. Mosselhi, M.A. Abdallah, T.A. Farghaly, A.S. Shawali, Monatsh. Chem. 2004, 735,211. M. Hmyene, A. Hakam, H. Naarmann, E. Dormann, Ann. Chim.-Sci. Mat. 2004, 29, 55. M. Pietraszkirwicz, A. Klonkowski, K. Staniszewski, J. Karpiuk, S. Bianketti, O. Pietraszkiewicz, J. Incl. Phenom. Macrocyclic Chem. 2004, 49, 61. B. Golankiewicz, P. Januszczyk, J. Zeldler, M. Popenda, Nucleosides Nucleotides 2004, 23, 127. H.J. vanManen, V. Paraschiv, J.J. Garci'a-L6pez, H. Schonherr, S. Zapotoczny, G.J. Vancso, M. Crego-Calama, D.N. Reinhoudt, Nano Lett. 2004, 4, 441. Q. Fang, T. Yamamoto, Macromol. Chem. Physics 2004, 205, 795. J.Q. Tan, J.H. Chang, M.Z. Deng, Chin. J. Chem. 2004, 22, 941 M. Behi, R. Zentel, Macromol. Chem. Physics 2004, 205, 1633. C.B. Vicentini, D. Mares, A. Tartari, M. Manfrini, G. Fortani, J. Agr. Food Chem. 2004, 52, 1898. P. Audebert, S. Sadki, F. Miomandre, G. Clavier, M.C. Vernieres, M. Saoud, P. Hapiot, New J. Chem. 2004, 28, 387. K. Reichenbacher, H.I. Suss, H. Stoeckli-Evans, S. Bracco, P. Sozzani, E. Weber, J. Hulliger, New J. Chem. 2004, 28, 393. V. Vicente, A. Fruchier, M. Taillefer, C. Combes-Chamalet, I.J. Scovven, F. Plenat, H.J. Cristau, New J. Chem. 2004, 28, 418. A. Diaz-Ortiz, J. Elguero, C. Foces-Foces, A de la Hoz, A. Moreno, M.D. Mateo, A. SanchezMigallon, G. Valiente, New J. Chem. 2004, 28, 952.

360 04OBC1019 04OBC2340 04OL1309 04OL1397 04OL1887 04OL2109 04OL2237 04OL2889 04OM783 04OM2533 04OPP92 04OPP121 04POL979 04POL1027 04PS365 04PS601 04PS817 04PS839 04PS845 04PS961 04PS1469 04S80 04S503 04S2026 04SC1141 04SC2195 04SL549 04SL723 04SL1086 04SL1179 04SRI1069 04T459 04T943 04T1393 04T1991 04T4107 04T5093 04T5319 04T5367 04T6021 04T6353 04T6385 04T6765 04T6881 04T8893 04T9121 04TL195

C. Ochoa, P. Goya and C. Gómez de la Oliva M.A. Carvalho, T.M. Esteves, M.F. Proenca, B.L. Booth, Org. Biomol. Chem. 2004, 2, 1019. M.A. Carvalho, M.E.A. Zaki, Y. Alvares, M.F. Proenca, B.L. Booth, Org. Biomol. Chem. 2004, 2, 2340. P. Marchand, L. Griffe, A.M. Caminade, J.P. Majoral, M. Destarac, F. Leising, Org. Lett. 2004,6, 1309. Y. Morita, S. Nishida, T. Kobayashi, K. Fukui, K. Sato, D. Shiomi, T. Takui, K. Nakasuji, Org. Lett. 2004, 6, 1397. R.G. Hicks, B.D. Koivisto, M.T. Lemaire, Org. Lett. 2004, 6, 1887. A. Kanibolotsky, S. Roquet, M. Cariou, P. Leriche, CO. Turrin, R. Bettignies, A.M. Caminade, J.P. Majoral, V. Khodorkovsky, A. Gorgues, Org. Lett. 2004, 6, 2109. I.A. Zavialov, V.H. Dahanukar, H. Nguyen, C. Orr, D.R. Andrews, Org. Lett. 2004, 6, 2237. D.E. Chavez, M.A. Hiskey, R.D. Gilardi, Org. Lett. 2004, 6, 2889. B.A. Omotowa, J.M. Shreeve, Organometallics 2004, 22, 783. J. Masllorens, A. Roglans, M. Moreno-Mafias, T. Parella, Organometallics 2004, 22, 2533. N.R. Reddy, G.M. Reddy, P.P. Reddy, Org. Prep. Proced. Int. 2004, 36, 92. M. Abdul-Ghani, S.N. Khattab, A.M. El-Massry, A. El-Faham, A. Amer, Org. Prep. Proced. Int. 2004,36, 121. N.S. Kumar, K.C.K. Swamy, Polyhedron 2004, 23, 979. C. Dfaz, M. Barbosa, Z. Godoy, Polyhedron 2004, 23, 1027. A. Rekik, F. Chabchoub, A. Belhadjamor, M. Salem, Phosphorus Sulfur 2004, 179, 365. A.O. Abdelhamid, B.A.M. Abdel-Wahab, A.A. Atoom, Phosphorus Sulfur 2004, 179, 601. P. Wisian-Neilson, J. H. Jung, S.K. Potluri, C.E. Mauldin, H.M. Zhang, Phosphorus Sulfur 2004, 179, 817. Z. Zak, J. Taraba, Phosphorus Sulfur 2004, 179, 839. E. Rivard, A.R. McWilliams, A.J. Lough, I. Manners, Phosphorus Sulfur 2004, 179, 845. L.H. Cong, C.W. Allen, Phosphorus Sulfur 2004,179, 961. M.M. Heravi, N. Ramezanian, M.M. Sadeghi, M. Ghassemzadeh, Phosphorus Sulfur 2004, 179, 1469. M.W. Markowicz, R. Dembiski, Synthesis 2004, 80. A. Herrera, R. Martfnez-Alvarez, P. Ramiro, M. Chioua, R. Chioua, Synthesis 2004, 503. G. Kalayanov, S. Jaksa, T. Scarcia, J. Kobe, Synthesis 2004, 2026. A. Dandia, K. Arya, M. Sati, Synth. Commun. 2004, 34, 1141. S. Fadel.Y. Hajbi, E.M. Rakib, M. Khouili, M.D. Pujol, G. Guillaumet, Synth. Commun. 2004, 34, 2195. O.A. Attanasi, L. De Crescentini, G. Favi, P. Filippone, F.F. Mantellini, S. Santeusanio, Synlett 2004, 549. E.S.H. El Ashry, E.S. Ramadan, H.M.A. Hamid, M. Hagar, Synlett 2004, 723. M. Adib, M. Pollahosseini, H. Yavari, M.H. Bijanzadeh, Synlett 2004, 1086. M. Gohain, D. Prajapati, B.J. Gogoi, J.S. Sandhu, Synlett 2004, 1179. A.H. Osman, M.S. Saleh, S.M. Mahmoud, Synth. React. Inorg. Met-Org. 2004, 34, 1069. S. Naya, Y. Lida, M. Nitta, Tetrahedron 2004, 60, 459. C.L. Gibson, S. La Rosa, K. Ohta, P.H. Boyle, F. Leurquin, A. Lemacon, C.J. Suckling, Tetrahedron 2004, 60, 943. Y.Z. Li, H. Matsumura, M. Yamanaka, T. Takahashi, Tetrahedron 2004, 60, 1393. J. Farago, Z. Novak, G. Schlosser, A. Csampai, A. Kotschy, Tetrahedron 2004, 60, 1991. J. Audoux, N. Pie, A. Turck, G. Queguiner, Tetrahedron 2004, 60, 4107. P.G. Baraldi, H. El-Kashef, A.R. Farghaly, P. Vanelle, F. Fruttarolo, Tetrahedron 2004, 60, 5093. N.A. Lisowskaya, A.N. Maslivets, Z.G. Aliev, Tetrahedron 2004, 60, 5319. E.A. Saveleva, Y.A. Rozin, M.I. Kodess, L. Van Meervelt, W. Dehaen, Y.Y. Morzherin, V.A. Bakulev, Tetrahedron 2004, 60, 5367. D. Branowska, Tetrahedron 2004, 60, 6021. J. Audoux, N. Pie, A. Turck, G. Queguiner, Tetrahedron 2004, 60, 6353. M.J. Plater, J.P. Siclair, S. Aiken, T. Gelbrich, M.B. Hursthouse, Tetrahedron 2004, 60, 6385. H.C. Hoist, T. Pakula, H. Meier, Tetrahedron 2004, 60, 6765. H. Meier, M. Lehmann, H.C. Hoist, D. Schvvoppe, Tetrahedron 2004, 60, 6881. S.P. Stanforth, B. Tarbit, M.D. Watson, Tetrahedron 2004, 60, 8893. Y.A. Ibrahim, N.A. Al-Avvadi, M.R. Ibrahim, Tetrahedron 2004, 60, 9121. R.A. Joshi, P.S. Patil, M. Muthukrishnan, C.V. Ramana, M.K. Gurjar, Tetrahedron Lett. 2004, 45, 195.

Triazines, tetrazines and fused ring polyaza systems 04TL273 04TL553 04TL1019 04TL2321 04TL2343 04TL2405 04TL279I 04TL3097 04TL3249 04TL3725 04TL3733 04TL3737 04TL4233 04TL4873 04TL6421 04TL6453 04TL6633 04TL7563 04TL8277 04TL8527 04TL8607 04TL8941 04TL9319 04ZN(B)802

361

T. Tobrman, D. Dvorak, Tetrahedron Lett. 2004,45, 273. J.M. Chezal, E. Moreau, N. Desbois, Y. Blanche, O. Chavignon, J.C. Teulade, Tetrahedron Lett. 2004, 45, 553. H. Lee, D. Kim, H.K. Lee, W.F. Qiu, N.K. Oh, W.C. Zin, K. Kim, Tetrahedron Lett. 2004, 45, 1019. S. Tandel, I. Biznets, K. Ebinger, Y.A. Ma, D. Bhumralkar, M. Thiruvazhi, Tetrahedron Lett. 2004,45, 2321 I. Grig-Alexa, A.L. Finaru, L. Ivan, P. Caubere, G. Guillaumet, Tetrahedron Lett. 2004, 45, 2343 I. Devi, H.N. Borah, PJ. Bhuyan, Tetrahedron Lett. 2004, 45, 2405. R. Gambert, C. Kuratli, R.E. Martfn, Tetrahedron Lett. 2004, 45, 2791. M.D. Pereira, F.R. Alexandre, V. Thiery, T. Besson, Tetrahedron Lett. 2004, 45, 3097. Y. Azev, E. Lork, T. Duelcks, D. Gabel, Tetrahedron Lett. 2004, 45, 3249. F. Couty, F. Durrant, D. Prim, Tetrahedron Lett. 2004, 45, 3725. A.P. Dishington, P.D, Johnson, J.G. Kettle, Tetrahedron Lett. 2004, 45, 3733. E.J. Williams, P.W. Kenny, J.G. Kettle, P.G. Mwashimba, Tetrahedron Lett. 2004, 45, 3737. B.T. Utenova, L.L. Gundersen, Tetrahedron Lett. 2004,45, 4233. Z.J. Zhao, D.D. Wisnoski, S.E. Wolkenberg, W.H. Leister, Y. Wang, C.W. Lindsley, Tetrahedron Lett. 2004, 45, 4873. M. Umkehrer, J. Kolb, C. Burdack, G. Ross W. Hiller, Tetrahedron Lett. 2004, 45, 6421. A. Nayek, S. Banerjee, S. Sinha, S. Ghos, Tetrahedron Lett. 2004, 45, 6453. G. Lavecchia, S. Berteina-Raboin, G. Guillaumet, Tetrahedron Lett. 2004,45, 6633. A. Rivera, M.E. Nunez, M.S. Morales-Ri'os, P. Joseph-Nathan, Tetrahedron Lett. 2004, 45, 7563. N. Hirai, T. Kagayama, Y. Tatsukavva, S. Sakaguchi, Y. Ishii, Tetrahedron Lett. 2004, 45, 8277. C.A. McNamara, F. King, M. Bradley, Tetrahedron Lett. 2004, 45, 8527. S.A. Raw, R.J.K. Taylor, Tetrahedron Lett. 2004,45, 8607. M.D. Milton, N. Kumar, S.S. Sokhi, S. Singh, M. Maheshvvari, J.D. Singh, M. Asnani, R.J. Butcher, Tetrahedron Lett. 2004,45, 8941. I.Y. Lee, S.Y. Kim, J.Y. Lee, C.-M. Yu, D.H. Lee, Y.-D. Gong, Tetrahedron Lett. 2004, 45, 9319. C. Barth, O. Seitz, H. Kunz, Z. Naturforsch. (B) 2004, 59, 802.

362

Chapter 6.4 Six-membered ring systems: with O and/or S atoms

John D. Hep worth James Robinson Ltd., Huddersfield, UK Email: [email protected] B. Mark Heron

Department of Colour and Polymer Chemistry University of Leeds, Leeds, UK Email: [email protected]

6.4.1

Introduction

Interest continues in marine polycyclic ether toxins and recent advances in the synthesis of these ethers have been discussed <04BCJ2129, 04SL1851>. Notable is the Japanese work on ciguatoxin O4ACR961, 04JOC2797, 04OL751, 04SL577, 04SL603, 04T8375, 04TL4795, 04TL7011>. Progress on azaspiracid <04AG(E)4312, 04CC2138, 04H(63)885, 04OL4159, 04TL351>, brevetoxin O4TL29, 04TL5243>, other toxins from mussels <04EJO2533, 04OBC3573> and prymnesins <04OL1501, 04OL4311> has been reported. Synthesis of complex marine macrolides such as the spongistatins O40L3637, 04SL2281>, bryostatins O4BCJ875, 04OL4045> and halochondrin B <04JA7770> has attracted attention. Syntheses of the lamellarins, marine products which contain a coumarin unit, have been published <04AG(E)866, 04JOC2362, 04PHC1, 04T8669> and total syntheses of pinnatoxin A <04AG(E)6505> and lasonolide A <04S1102> have been achieved. Approaches to the synthesis of the puffer fish toxin, tetrodotoxin, have been reviewed <04AG(E)5572>. A total synthesis of the complex plant-derived 1-0-methyllateriflorone has been reported involving a Claisen - Diels-Alder (DA) cascade and an intramolecular Michael addition in which carboxylate functions as the nucleophile <04JA5493>. Reviews of the uses of coumarins in polymers <04CRV3059>, heterocycle-substituted chromones <04H(63)2875>, 1,4-benzodioxins <04SL2449>, syntheses from dehydroacetic acid <04H(63)1193> and the hetero DA (hDA) approach to oxathiins have been published. Several general reviews include examples relevant to this chapter: carbonylation of alkynes <04T5499>; Claisen rearrangement <04CRV2939>; 1,3-dicarbonyl compounds in synthesis <04EJO4957>; electrolytic fluorination <04T1435>; halo- and seleno-lactonisation <04T5273>; o-halobenzoyl chlorides in heterocyclic synthesis <04RCB1137>; microwaveinduced syntheses <04H(63)903>; organic materials and devices <04CM4389, 04CRV5057>; oxidative spiroacetalisations <04S2767>; the Pummerer reaction

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

363

<04CRV2401>; radical cyclisations <04H(63)1903, 04T6239> and ring-closing metathesis (RCM) O4CRV2199, 04CRV2239, 04OBC8>. 6.4.2

HETEROCYCLES CONTAINING ONE OXYGEN ATOM

6.4.2.1

Pyrans

The silylated diynols 1 undergo a Ru-catalysed double ring closure to a cyclopenta[c]pyran in aqueous acetone. The exact nature of the product depends on the amount of water in the reaction mixture; when an excess of water is present the 2//-pyran is obtained together with about 5% of the dihydropyran. The latter is produced exclusively when only 5 equivalents of water are used. The reaction is successful with various tethers and with a variety of propargyl alcohol units and the silyl function can be manipulated to give access to functionalised pyrans <04OL4235>.

MeO2C x ^ / X ^

M e 0 2 C

^^/

MeO2yY^

0H

MeO2C N —EEE^TMS

T TMS

T TMS

Reagents: (i) 10% [CpRu(MeCN)3]PF6, Me2CO, 5 eq. H2O, 60 °C (99%); (ii) 5% [CpRu(MeCN)3]PF6, 40 vol. % H2O, Me2CO, 60 °C, (94%)

Alkylidenecyclopropyl ketones 2, accessible by the Rh-catalysed cyclopropanation of allenes with a-diazo ketones, afford 4//-pyrans through a Pd-catalysed cycloisomerisation. In one instance, where the substrate lacked a hydrogen atom on the alkylidene moiety, a 2//-pyran was obtained <04JA9645>. 4//-Pyrans fused to medium to large rings result from the reaction of enynals with DMAD via a Pd-catalysed tandem cyclisation - ring expansion <04S1409>. R

\

>° < \L

J-R1 H 2

5 mol%

, w.

PdCI2(MeCN)2 Me2CO RT ' wie2ou, m

r ^ v R 1 JI R

i^

0

2

CHO

DMAD

/ X—\ ^ \

CatPd( AC)2

((CY ° Wr, V °\ k A s , cat. cyclooctadiene \s?K^R

>\

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 <04OBC28>. 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 <04JA1310>. 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 <04JOC1548>.

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 <04T8043>.

T°^o0^

O^-O-^O

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 <04JOC3408>. 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 <04JA9544>. 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 <04AG(E)4788>.

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) <04SL2618>. 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 <04TL3373>. 9 A

O^/ ^T

OH

Ar^O

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 <04S87, 04SL1755>. 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 <04S1150>. 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 <04CL848>. 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) <04CEJ4341>. X

OHC^N. ,, 0

(\ /Tro^O

+ +

/

^ <W"°^

°YK-°

c.

o

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

S.T /

0

l^Jli^O"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^\ YV^O ^"\^J \J / 15

, f T l ™ 69% l

v^S0^~0Me

366

J.D. Hepworth and B.M. Heron

Chiral Al-salen complexes enable pyranoquinolines to be obtained with high diastereoselectivity by an inverse electron demand DA reaction between dihydropyran and benzylidene aniline <04BMCL2035>. 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 <04S69> and sulfamic acid is also a suitable catalyst for the Pechmann synthesis of coumarins <04SL1909>. 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) <04EJO372>. Malonates with a pendant hydroxy group undergo a Mn-catalysed radical cyclisation offering a route to tetrahydropyrans linked to a carbocycle 16 <04OBC965>. A tandem radical cyclisation also provides a route to tricyclic molecules, e.g. 17, from enynes and diynes derived from methylcyclopentenones <04TL7225>. 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 <04TL5505> and a stereoselective solid-phase synthesis of 6,6-spiroketals has been reported in which aldol reactions of boron enolates are the key feature <04AG(E)3195>. Spiro orthoesters are accessible from thiophenyl ketene acetals and diols (Scheme 5) <04SL2013>. 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 <04OBCl 145>.

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-^O^O-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 <04JOC4701>. Ph3P, / P h 3 Pd

a

, T R1^E=-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 <04JA9186>. A variety of 2-substituted 2//-chromenes can be obtained from the facile reaction of 2-hydroxybenzaldehydes with vinylboronic acids in ionic liquid solvents <04SL2194>. 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 <04S1783>. In like manner, cz's-fused furopyranopyran derivatives have been obtained from sugar aldehydes <04TL3493>.

f^Y°H°+ U. J k ^ ^ O H

+

f^ R

B(OH)2 BmimBF.

^V^)

(PhCH2)2NH

ks J<~J^n

g^2^

^Y°^t° f^l kJ-^O^O

^ - ^ O R 9 examples, 87 - 94% BmimBF 4 = butylmethylimidazolium BF4

T

T

O^^,O / \ H 20

T

fl ° R VK^l I

||

I

o^V^O^O I 1^ z ^^ = 21

The naturally occurring (+)-calanolide A 21, R = «-Pr, and (+)-inophyllum B 21, R = Ph, are of interest in that the molecules possess chromene, coumarin and chromanol systems. Total syntheses of them start from a coumarin and generate the chromanone unit through an intramolecular Michael addition which under (-)-quinine catalysis affords cis and trans benzodipyrans with 97% and 52% ee, respectively. The chromene moiety is constructed using the phenylboronic acid assisted reaction with senecioaldehyde. Reduction of the chromanone to the chromanol completes the sequence <04JOC2760>. The reaction of m- and p-substituted phenols with the tetrone 22, readily obtained from ninhydrin and 1,3-indanedione, leads to highly substituted 4//-chromenes <04T10197>.

J.D. Hepworth and B.M. Heron

368 / ^

^~S

VV°

r\

HO

^/\ 3

n

A > 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 <04T449>. 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^^Ar

? 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 -^<\

EtO2C 26

\

A significant study of the synthesis of chiral chromans by the Pd-catalysed intramolecular asymmetric allylic alkylation of readily available phenol allyl carbonates has established the optimum conditions for this highly efficient method and demonstrated its value by the total syntheses of (+)-clusifoliol and (-)-siccanin (Scheme 6) <04JA11966>. A biomimetic enantioselective synthesis of (-)-siccanin also features this approach to the chroman moiety <04JA12565>.

R

r^N

oc 2Me JU R

^i^Y^ ° 0H

CCV

R

*^

r^N

.OCO2Me

V ^ T

0 H 8 examples, 62-100%, 7 3 - 9 5 % ee Reagents: (i) 2 mol% Pd2(dba)3, CHCI3, 6 mol% (R,R)-ligand, AcOH, CH2CI2, RT; (ii) 2 mol% Pd2(dba)3, CHCI3, 6 mol% (S,S)-ligand, AcOH, CH2CI2, RT Scheme 6

A carbocationic intermediate is probably involved in the Pd- and Pt-catalysed cyclisations of dienylphenols. Reduction of the initial products affords fused chromans with a trans ring junction (Scheme 7) <04AG(E)3459, 04T7405>. A similar enantioselective polycyclisation has been performed using a chiral Sn complex by which total syntheses of (-)-chromazonarol and (+)-8-ep/-puupehedione have been achieved .

369

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

The insertion of allenes into a stable oxapalladacycle yields chromans. Monosubstituted electron-rich allenes afford the 2,3-disubstituted 4-methylene derivative with high regiocontrol and complete diastereocontrol, whereas those containing an electronwithdrawing group give the 2-substituted 4-(£)-ylidene compound (Scheme 8) <04JOC8266>.

[ T T rH r**VPd £ ^ ° ^ % U^>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 <04JA7460>. 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 <04OL3191>. R1

/^A ^

« «_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 <04JOC9196, 04SL1101>. A tandem R.CM - DA sequence applied to enynes derived from 1-iodophenol leads to 4-vinylchromans 31 <04JOC2084> and a hDA between phloroglucinol and citronellal features in a synthesis of the antimalarial Machaeriols A and B <04TL1689>.

370

J.D. Hepworth and B.M. Heron

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) <04JA13596> 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 <04TL9369>. 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 <04TL2293> and iodonium species catalyse the intramolecular arylation of alkenes which yields iodo-substituted chromans 33 <04JA3416>. 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 <04SL45>

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 <04EJO1261>. 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) <04OL1581>.

371

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

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 <04JOC468>. ^^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 <04EJO574>. Annulation of alcohols to the latter reactants yields the isochroman exclusively under catalysis by Cul <04JOC5139> and the Pd-catalysed insertion of isonitriles into 2-(2-bromophenyl)ethanols affords isochromans 36 <04TL6995>. R2R3

CR 1 CO 2 R 4

[^Y^OH 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^-^O 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 <04T2629>. This methodology features in the first synthesis of ventiloquinone J 37 and in syntheses of related quinones <04EJO4416, 04S1601>. 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 <04AJC329, 04TL6147>. A Michael addition is used to generate the isochroman ring of a pyranonaphthoquinone isolated from Streptomyces sp. <04TL939>.

372

J.D. Hepworth and B.M. Heron

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 <04TL411>. /\^Br

Br OH

XX n ^^yy«^r R1

6.4.2.4

TiCI

Ph

R2

Ph

< r^A" ^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 <04JOC1432>. 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 <04JOC536>. 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 <04JA7458>.

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

"" /-^IlXoH Br3Aue^3

^^V^R^ J

J^ , UK 7 examples, 64 - 80%

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

373

Interest continues in the potential value of flavylium salts in read-write systems <04CEJ1519>, as photochromic materials <04NJC1221> and as photosensitisers in photodynamic therapy <04JMC3897>. 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 <04T7431>. 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 <04NJC153>. 10mol%Ni(COD)2 MeO2C / — = ~ R

MeO^A

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) <04AG(E)5369>. 4-Chloropyran-2ones have been obtained from acetonide-protected 4,5-dihydroxy-2-chloroglycidic esters by treatment with MgCk <04TL6299>, 4-aroyl derivatives from mandelic acid and 1,2-diaroylethenes <04TL8583> and 4-formylpyran-2-ones from the monoacetal of but-2yndial <04TL9197>. 1,3-Diketones react with readily available (chlorocarbonyl)phenyl ketene to provide a facile synthesis of 5-acylpyran-2-ones 42 <04T5931> and arylpropanones afford 5-aryl-4-oxo-4//-pyran-3-carboxaldehydes in a Vilsmeier-Haack reaction <04T5069>. 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) <04TL5857>. The DA reaction between 3-benzoylaminopyranones and alkynes is a source of highly substituted anilines <04JOC3190> and 3-phenylamino derivatives provide a-amino acid esters following addition of electron-deficient dienophiles <04TL1683>. In the solid state, benzophenones efficiently photocycloadd to the 5,6-bond of pyran-2-ones to give oxetanes e.g. 43 <04H(63)1541>. 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) <04SL2197>.

374 9

Br

J.D. Hepworth and B.M. Heron

-*^~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 <04JOC8413> and when applied to salicylaldehyde and cyclohexenone a tetrahydroxanthen-1-one results possibly via a domino Michael addition and intramolecular aldol condensation <04AG(E) 115>. Synthesis of dihydropyranones from ketones using the hDA reaction has been reviewed <04EJO2093>. Enantioselective syntheses of dihydropyran-4-ones from aldehydes by this route can be achieved using chiral Rh catalysts <04AG(E)2665, 04SL2425> and Ti complexes <04SL1772>. Their synthesis from hindered a-ketoesters and Danishefsky's diene has been optimised using a high throughput screening approach <04TA1987>. 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 <04CEJ5964>. 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 <04JOC839>. CO^R1 ^ R2 CuX-2,85°C »- A , f ^ ^ <, n 10 examples

R2

V X

MeCN, H2O

I

I 70-81% O'^O

0

0

^ JL ^ 11 ^ \ ^ ^ > 44

8 mol% cat. 8 JL CHCI on2u2 ' | l| MI ? h

reflux Scheme 17

92%

"^^"^^^ph

The HF-induced translactonisation of oxetan-2-ones derived by a [2+2] cycloaddition of a silylketene with p-silyloxyaldehydes produces 5,6-dihydropyran-2-ones and has been used in the syntheses of goniothalamin and (-)-massoialactone <04T1659>. Other approaches to (+)-goniothalamin are based on RCM of the butenyl acrylate 44 following an enzymatic resolution (Scheme 17) <04T521, 04TL83>. RCM methodology has been used to synthesise 4,4-difluoromassoialactone <04TL9479>. The asymmetry in 5-hydroxy-5,6-dihydropyran-2-ones, which form the basis of the phomopsolides, is derived from the Noyori asymmetric hydrogenation of a furyl ketone. The resulting furyl alcohol is then stereoselectively transformed into the pyranone <04TL1005>.

375

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

A general route to 2,3-dihydropyran-4-ones is based on the Pd-mediated oxidative cyclisation of (3-hydroxyenones; given the correct conditions there is no evidence of Michael addition products. The cyclisation occurs without racemisation (Scheme 18) <04OL91>.

OHO r-~\^v

Ph

\

fi j r y

^\^0^K

n J

100% conversion

^ ^

Ph

Scheme 18

6.4.2.6

o ^K

pdci2, cm, o2

o

H

nucteophi|e(Nu)

r y 1

T jl 'lactone method | J R^^^R

R T J

^HO^^Nt

Coumarins

The Pd-catalysed reaction of phenols with propynoic acids offers an atom-economic and green route to coumarins. Although the reaction with propynoic acid itself is not regioselective, 3-phenylpropynoic acid gives a single product from /w-substituted phenols <04S1466>. The synthesis of coumarins both from alkynes, CO and iodophenols and by the reaction of phenols with propiolic esters is facilitated by Co/Rh nanoparticles <04SL2541>. The value of naphtho[2,l-6]coumarins in the atroposelective synthesis of axially chiral biaryls, the so-called 'lactone method,' has been discussed with emphasis on an approach to chiral phosphineamines O4T4349, 04T6335>. Several coumarins have been assembled from biphenyl precursors. Treatment of 2-hydroxybiphenyls with BCh provides the boroxarenes 45 which undergo a Pd-catalysed carbonylation to give excellent yields of benzo[c]coumarins <04JOC5147>. Super bases abstract both the ortho proton and the hydroxyl proton from 2,2'-dihydroxybiphenyls and carboxylation then affords the [l]benzopyrano[5,4,3:cfi?e][l]benzopyrandione 46 <04EJO1014>. HO

O

>~°\ /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

(^O2,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^


hexanes, 70°C

\=(

80-100%

L L P+

ron.BuU.KOlf

"•-.

\J

6 examples

o

^

1

"

I

f*??Yn

I

f Bu

I X

(i)

M2C2?nK'

^^^k,

. XT

1

HO^^<^O^O (ii)DMF0Ayik A Cl

r

,

/ U V _ / 48

reflux 1

Q

< V ^ 28% V

-J

The benzonaphthopyranone system 47, the basic structure of the gilvocarcins, has been assembled in one step using a Hauser-Kraus annulation. The key feature is the incorporation of a suitably placed ester function in the Michael acceptor which generates the lactone ring. Thus, isobenzofuranones and esters of ethyl cinnamate form the tetracycle directly in high yields. Methyl 6-methylcoumarin-5-carboxylate behaves in an identical manner providing a total synthesis of the pentacycle chartarin <04TL7895>.

376

J.D. Hepworth and B.M. Heron

Cycloalka[6]pyrano[2,3-/j]coumarins are formed when the chloroethylidene derivative 48, produced by the reaction of cycloalkanols with thionyl chloride, reacts with a 7-hydroxycoumarin <04H(63)1637>. The photochemical [2+2]cycloaddition of alkenes to coumarins provides a mixture of the exo- and e«c/o-cyclobuta[c]coumarins. Treatment with CH2=SOMe2 opens both the lactone and cyclobutane rings and both diastereomers are considered to give the same quinone methide from which a single dibenzofuran-4-ol stereoisomer results <04SL1897>. 4-Hydroxycoumarin behaves as a nucleophile towards the Tc-allylPd(II) species generated from allene and various iodo compounds in a three-component cascade. The C-allyl substituted products readily cyclise to dihydrofurocoumarins (Scheme 19) <04T3359>. OH

O--V"Ar

OH

^ y \ 5mol%Pd(PPh3)4 ^ X ^ A r + II l_ II I || Arl, Cs2CO3, MeCN f IT T 0 k ! v ^ ^ 0 ^ * 0 65 °C = i^ O^^O

TFA CHCI3, RT

10 examples, 62 - 97% Scheme 19 O

O

OMe MeO

^yHy |

^ ^ \

P

y

N=

I

-= fT^°

n-BuLi

THF,-30°C

L 1

A

MeO J

R R 5 examples, 53 - 75%

5 examples, 54 - 7 1 %

M

e

H

0 V = * = Pd(PPh3)4

0

^'T r^V^O

n-BuLi

I

r^A*/ II I ^N)^)

||

THF,-30°C ^ S - ^ \ ^

O

P(

J

^° lyl) 3,

/\R 3 examples, 69 - 98% Scheme 20 R

THF

reflux

nil

\J\*!Z

f^TV

WJk

/\

/

R R 3 examples, 79 - 97%

Although the yield is only moderate, the conjugate addition of phenylboronic acid to coumarin catalysed by a Rh complex derived from a triene scaffold gives 4-phenyldihydrocoumarin with 98% ee <04OL3873>. A Suzuki cross-coupling of the triflates from 4-hydroxycoumarins with heteroarylboronic acids leads to 4-heteroarylsubstituted coumarins <04SL2797> and a Ni-catalysed cross-coupling of 4mesyloxycoumarins with aryl and vinyl halides gives 4-substituted coumarins <04SL2364>. l-Hydroxy-l-methoxyallenyl-4,4-dialkylisochromans, available from dihydroisocoumarins, undergo a Pd(O)-catalysed ring expansion to benzoxepanones. In the absence of the Pd catalyst, the dihydroisocoumarins can be converted directly into a benzoxocanone (Scheme 20) <04SL481>. 6.4.2.7

Chromones

4-Oxobenzopyran-3-carbaldehyde (3-formylchromone) continues to prove a valuable synthetic intermediate. A one-pot synthesis of 4-oxobenzopyran-3-nitriles is based on a Vilsmeier-Haack synthesis of 4-oxobenzopyran-3-carbaldehyde <04TL847>. 3-Formylchromones react with cyanacetamides and other electron-deficient acetic acid amides to give 5-(o-hydroxyaroyl)-2-pyridones 49 <04SL2287>. The thermal rearrangement of nitrones 50 derived from 3-formylchromone is solvent dependent, affording either 2-amino-3formylchromones or 3-aminomethylenechroman-2,4-diones <04TL6169>. (£)-3-Styrylchromones are expeditiously formed by a microwave-assisted Knoevenagel reaction between the formylchromone and phenylacetic acids <04SL2717>.

311

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

EWG ^i.CHO j^T" + HN r TMSC, Ar V Y ^ ^ / Y ' (M)» ^ 8exampies

fYT ^ O ^

R*

°~w

' L X k AX

100 °C

£2 °

O

NHR

[

ll

I

2(PPh 3 ) 2 , R ^ , Et3N, DMF, 80 °C, N 2 , (ii) Cul, R — = Scheme 21 O

O

^PhMe

reflux

^ J L ^ e , c P

ROH _

[

reflux

9 examples, 40-85%

|T

|T

kJ^xAp1°-45%

R e a g e n t s : (i) pdcl

24 examples, 62 - 90%

^>^XJ

^rY

^^X^Ph

•

50

. - X x H O

[

|T |T

12 examples, 60-98%

Flavones, flavanones and chalcones are regioselectively hydroxylated on treatment with dimethyldioxirane offering a useful approach to polymethoxylated flavonoids <04T2647> and their epoxidation has been achieved with H2O2 in an ionic liquid <04T967>. Both flavone and flavanone are regioselectively acetoxylated at the 5-position by iodobenzene diacetate <04TL9065> and 5,7-dioxygenated flavones are iodinated at the 6-position by benzyltrimethylammonium dichloroiodate <04TL3635>. 3-Enynyl derivatives result when 3-iodoflavones and their thio analogues are subjected to sequential Heck and Sonogashira coupling reactions (Scheme 21) <04TL2305>. Following the synthesis of chroman-3-ones from salicylaldehydes by reaction with acrylonitrile and subsequent hydrolysis and a Curtius reaction, their behaviour towards the protected P-amino ketone 51 has been studied. Both 5- and 8-methoxychromanones afforded 5//-benzopyrano[3,4-6]pyridines whereas other chromanones gave spirocyclic aminochromans <04S121>.

10 ^Y^ii i R ~ O y ^ i

^Ao^ 5 R

°x° r ^ y 0 ! ^

\ ) 0 OCXM H.N^-^

R ° K

°Me

R = 7-OMe(53%) 51 4 R = 10-OMe (45%) examples, 32 - 45% Reagents: (i)4-TsOH, cat. MgSO4, anhyd. CH2CI2, reflux, then BF3.OEt2, reflux

6.4.2.8

oMe

XJC n Xj

« 55

Xanthones and Xanthenes

9-Arylxanthenes are formed when electron-rich aromatic aldehydes react with an excess of arynes. Initial nucleophilic attack by the carbonyl oxygen atom on the aryne generates a benzoxete which isomerises to an o-quinone methide. A [4+2]cycloaddition with the aryne completes the sequence <04OL4049>. Ar

18 examples, 16-70%

378

J.D. Hepworth and B.M. Heron

The xanthene-based dialkynol 52 undergoes a cycloaromatisation on treatment with SOCI2 to give a benzo[6]fluorene 53. Acidic thermolysis yields the p-methylenequinone derivative 54 through an intramolecular radical acylation <04TL4711>.

65o o / < n X ^s-H^-y o M ^ i ™ ^ H v > A 71 y Me

\=/

I

°-~VJ ^T 53

VV

Ph

O

^ £ 1 CO2Me

RT

||

>

^

\ ( ^^^-Ph

reflux

MeO-T^-^^Ph

A ^1 L

MeO-ty^y^O

52 OH

J^X/^? _. R2 ob

54

^-V^v.

O

I

RUlf*

Ph

R2^ll

^A^^A^

OH 0

R1 T O ' 4 examples, 20 - 42% 4 examples, 40 - 43% Reagents: (i) NaH, anhyd. THF, Ar, RT then 80 °C; (ii) LiAIH4, THF then aq. HCI

The bixanthenyl 55 which possesses the ring system of the secalonic acids has been obtained from the 7-bromoxanthene via the arylboronic ester and a subsequent Suzuki coupling <04JOC6830>. The anionic polycondensation of acetonaphthones 56 with homophthalates gives dibenzo[6,/]xanthones and offers an approach to the naturally occurring hypoxyxylerone system <04SL2693>.

6.4.3

HETEROCYCLES CONTAINING ONE SULFUR ATOM

6.4.3.1

Thiopyrans and analogues

2,6-Disilylated 4//-thiopyrans are formed by the thionation of l,5-bis(acylsilanes) presumably via the thioacylsilane (Scheme 22) <04TL87>. The heptynoate sulfoxides 57 obtained in three steps from 3,3-dimethylbut-l-yne are cyclised to tetrahydrothiopyrans on treatment with diethylzinc under Pd-catalysis; the overall process is an intramolecular sulfinylzincation. The vinylzinc intermediate, which is formed with high syn-selectivity, can be transmetalated and trapped with electrophiles to give trisubstituted vinylic sulfoxides. Oxathianes can be formed in an analogous manner though in somewhat lower yields <04H(62)263>. 0=

\ (

TMS CoCI2.6H2O [ j ^ j | LgX^EWG — \ , , — L g > y E W G + SMS — K s S i ^ S i R , o O X E W / , B 1'

O=/

2 examples "75%

63

SiR3 Scheme 22

57 2 examples, 31 - 90% Reagents: (i) 2 mol% Pd2(dba)3.CHCI3, Et2Zn, THF, _78 o c _ R J , h e n H^o+. ^ 2 mQ|0/o p d 2 ( d b a ) 3 C H c i 3 , Et2Zn, THF, -78 °C - RT, CuCN, 2 LiCI, RBr

379

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

The acyl-protected 2,4-diaminothiabutadiene 58 R1 = Ac or Boc, cycloadds regioselectively to acrylic dienophiles to give 2-aminothiopyrans following elimination of the 4-dimethylamino substituent and deprotection <04S1633>. The heterodiene 59 undergoes a facile [4+2] cycloaddition with various dienophiles to give dihydrothiopyrans predominantly as the cis adduct. At higher temperatures and in the presence of a Lewis acid, the trans adduct is preferentially formed and indeed the cis product is converted to the thermodynamically stable adduct under these conditions. Enantiopure dihydrothiopyrans result from the use of a chiral dienophile <04T1827>. R1HN

T S + ^ R 2 hydr°quinone R i H N Y S Y R 2 AICI3 H2N S R^ ^ lR3PhMe,60°C H^ R 3CH 2 CI 2 ,RT I^R3 NMe2

10 examples, 43-90% Ph S

58

Ph

Ph

S

T + iR ^ T NMe2

^30^

^N

CH2CI2

+

Y " ^ 'COR NMe2

59

JL^J

^ N

"Q

°

^ AJ

|

JC^°

-^n

fj

^-^^COR NMe2

MgBr2,0 °C

f^V^ J

[I ^ ^

4

6Q

The adduct 60 from the DA reaction between pentacene and thiophosgene is soluble and a thin film can be deposited on a suitable surface. Thermolysis induces a retro-DA and regenerates pentacene <04TL7287>. Arynes cycloadd dihydroindole-2-thiones to give benzthiopyrano[2,3-Z>]indoles<04H(63)2785>. The proline-catalysed aldol reaction of tetrahydro-4//-thiopyran-4-one with aldehydes, which is accelerated by water <04SL1891>, 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 <04TL8347>. 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 <04S2900> and a one-pot conjugate addition - aldol reaction sequence provides benzo[Z>]thioxanthene-6,l 1-diones from naphthoquinone and 2-acylthiophenols (Scheme 24) <04BCJ2095>. 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% °

J.D. Hepworth and B.M. Heron

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 <04OBC1531>. 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) <04JMC1833>. 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 <04SL971>. 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) <04TL1343>. 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 <04T8899>. Linear arrays of fused pyrandioxin-cyclohexane rings as found in natural products derived from the milkweed family have been described e.g. 63 <04EJO4911>. 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 <04TL7277>.

^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 <04BMCL1433>. 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 <04JMC1290>. 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 <04JOC3242>. 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 <04JOC984>.

H*

T' H

HA

y^*

T'H

H<

L^OH 65

ONH 2 66 II R

3-V/OH

TH

O v

T ^ F

3°"'

H

O

X'H

KOH/A|

P ^

0 H

°2S"CH R 2 68

67

(i) AIBN, ArSH, O2, hv A r S - ^ Q - 0

(ii)R'R2C=O,4-TsOH MeCN

H

2°3

CH CI

< ^

2 2.5 °C - RT

6^AT T

R Br 5 examples, 15 - 84% Ri

R3\_n^R2

10

examples

25-80%

Scheme 27

A variety of functionalised spiro 1,2,4-trioxanes has been synthesised from allylic alcohols in a one-pot radical-initiated reaction with a thiophenol and molecular oxygen. The resultant hydroperoxide is trapped by an alicyclic ketone (Scheme 27). The 6(phenylthiomethyl) group lends itself to further manipulation <04OL3035>. 6.4.5

HETEROCYCLES CONTAINING TWO OR MORE SULFUR ATOMS

6.4.5.1

Dithianes and Trithianes

Various 1,3-dienes are converted into 3,6-dihydro-l,2-dithiins on heating with either linear and cyclic diselenatetrasulfides 69 which act as S transfer reagents <04TL9181>. The disulfoxide 70, derived by the addition of S2C12 to 3,4-di-r-butylthiophene 1-oxide with subsequent oxidation, undergoes a retro DA reaction to generate S2O which is readily trapped by dienes to give dihydro 1,2-dithiin 1-oxides <04JA9085>.

382 R

^

J.D. Hepworth and B.M. Heron

R'SeSSSeR'69

refiux

A

R

>^S

f-Bu t

K

CH2CI2| s *0

R

^f

Y^SO

30 c

RXJ

tsujzr/>o ° » A ~ ~ R A > 70

R = Me (81%), R = Ph (86%)

Diacenaphtho[l,2-c:l',2'-e]-l,2-dithiin 71 is formed along with a diacenaphtho[l,2Z>:l',2'-e]-l,4-dithiin and diacenaphtho[l,2-&:l',2'-<5T]thiophene when acenaphthylene is heated with sulfur <04JOM65>. The value of 1,3-dithianes in the synthesis of natural products has been discussed <04ACR365>. Previously unknown thiopropenoylstannanes can be generated from stannylated allenes by thionation with hexamethyldisilathiane (HMDST). They behave as thiabutadiene, reacting with in situ generated thioaldehydes and thioacylsilanes and with added aldehydes to give stannylated 1,3-dithiins (Scheme 28) <04SL2159>.

D

R3Sn

C\

i^L^/VJ*^3 ^^-—\

T°T°\ "

y^^/

HMDST

[RSn S R1

THF,-78°C RCHO

^ L

S-S

R-J^^-Ts

+

^ HS

DBU SH CHCI3, RT Scheme 29

T J

° R

S

S^ 1

^

T

R

14 examples, 15 - 49%

Scheme 28

SO2Me

^VSnR3

^ R

59-97%

The reaction of l-phenyI-2-chloroethane-l,l-dithiol with Na2S affords thiophenacyl (2-mercapto-2-phenylvinyl) sulphide which on treatment with methanolic HC1 gives 2,6-diphenyl-l,4-dithiin offering a new approach to such compounds <04CHE1216>. 1,4-Dithian-2-ones are formed when 2,2-disulfonyloxiranes are treated with 1,2-dithiols (Scheme 29) <04BCJ1897>.

6.4.6

HETEROCYCLES CONTAINING BOTH OXYGEN AND SULFUR IN THE SAME RING

6.4.6.1

Oxathianes

Unsaturated sulfonates e.g. 72 undergo a RCM using a second generation Grubbs' catalyst 9 to give 5,6-dihydro-l,2-oxathiine 2,2-dioxides. The 5,6-dihydro derivative behaves as a dienophile towards cyclohexa-l,3-diene, giving the endo sultone with complete diastereoselectivity <04S1696>. O ^i/b-

^^^^^. 79 o

"•

Q.75mol%cat9 V CH2CI2 [I j reflux \ / 99%

\ J _ sealed tube 200 °C

.(^_SO2 ^ W 0 \ I 92%

A series of polyspiro-l,3-oxathianes has been synthesised from the condensation of a 1,3-mercaptoalcohol vvith a diketone (Scheme 30) and their stereochemistries have been

383

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

examined. When two oxathiane rings are separated by an odd number of carbocycles the compound exhibits cis and trans isomers, but separable enantiomers exist when an even number intervene <04T3173>.

XExD°<M>° i f r WXixpQCX: Scheme 30

8 examples, 31 - 83%

Chiral iy«-2,3-disubstituted 2,3-dihydro-l,4-benzoxathiins 73 are available from the reaction of enantio-enriched mercaptoethanols with quinone ketals. An initial Michael addition is followed by cyclisation and aromatisation <04TL5429>. A synthesis of annulated 1,4-oxathiin-2-ones involves an anionic rearrangement under directed metalation conditions as the key step. N,N-Diethy\ o-methylsulfanylaryl carbamates, readily available from phenols, are deprotonated at the SMe group which initiates rearrangement to a thioacetamide from which the oxathiinone can be obtained (Scheme 31) <04T5215>. A

i ^ ^ A f 2 + MeoJ OH

^^SMe

MeO

™SOTf,

T R

-78°C-RT

TFA

Y Y

^'

^V-v^A..,.

R^^^O^''Ar2 73 9 examples, 15-61%

kASCH2CONEt2 10 examples, 63 - 93% Scheme 31

U

Y <%,Tf k ?4

reflux

P h

k^JLgJ

11 examples, 81 - 92%

Thermal decomposition of l,4-dihydro-2,3-benzoxathiin 3-oxides generates o-xylylenes which can be trapped by methyl 2-acetamidoacrylate yielding tetralin-based a-amino acids <04S558>. A phosphazene base [EtN=P(NMe2)2(N=P(NMe)2)3)] is used to generate the ylide from chiral oxathiane 74 in a two-step asymmetric synthesis of aziridines from tosylimines <04JOC1409>. 6.4.7

REFERENCES

03MI1 04ACR365 04ACR397 04ACR961 04AG(E)l 15 04AG(E)866 04AG(E)1381 04AG(E)2665 04AG(E)3195 04AG(E)3459

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386 04OBC3573 04OL91 04OL751 04OL1501 04OL1581 04OL3035 04OL3191 04OL3637 04OL3873 04OL4045 04OL4049 04OL4159 04OL4235 04OL4311 04PHC1 04RCB1137 04S69 04S87 04S121 04S558 04S1102 04S1150 04S1409 04S1466 04S1601 04S1633 04S1696 04S1783 04S2767 04S2900 04SL45 04SL481 04SL577 04SL603 04SL971 04SLU01 04SL1755 04SL1772 04SL1851 04SL1891 04SL1897 04SL1909 04SL2013 04SL2159 04SL2194 04SL2197 04SL2281 04SL2287 04SL2364 04SL2425 04SL2449 04SL2541 04SL2618

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Six-membered ring systems: with O and/or S atoms 04SL2693 04SL2717 04SL2797 04T449 04T521 04T967 04T1435 04T1659 04T1827 04T2629 04T2647 04T3173 04T3359 04T4349 04T5069 04T5215 04T5273 04T5499 04T5931 04T6239 04T6335 04T7405 04T7431 04T8043 04T8375 04T8669 04T8899 04T10197 04TA1987 04TL29 04TL83 04TL87 04TL351 04TL411 04TL847 04TL939 04TL1005 04TL1343 04TL1683 04TL1689 04TL2293 04TL2305 04TL3373 04TL3493 04TL3611 04TL3635

387

E. Chevenier, C. Lucatelli, U. Pandya, W. Wang, Y. Gimbert, A.E. Greene, Synlett 2004, 2693. V.L.M. Silva, A.M.S. Silva, D.C.G.A. Pinto, J.A.S. Cavaleiro, T. Patonay, Synlett 2004, 2717. I.P. Beletskaya, O.G. Ganina, A.V. Tsvetkov, A.Y. Fedorov, J.-P. Finet, Synlett 2004, 2797. A.M. Bernard, C. Floris, A. Frongia, P.P. Piras, F. Secci, Tetrahedron 2004, 60, 449. E. Sundby, L. Perk, T. Anthonsen, A.J. Aarsen, T.V. Hansen, Tetrahedron 2004, 60, 521. R. Bernini, E. Mincione, A. Coratti, G. Fabrizi, G. Battistuzzi, Tetrahedron 2004, 60, 967 K.M. Dawood, Tetrahedron 2004, 60, 1435. L. Fournier, P. Kocienski, J.-M. Pons, Tetrahedron 2004, 60, 1659. A. Harrison-Marchand, S. Collet, A. Guingant, J.-P. Pradere, L. Toupet, Tetrahedron 2004, 60, 1827. C.B. de Koning, R.G.F. Giles, l.R. Green, N.M. Jahed, Tetrahedron 2004, 60, 2629. H.-W. Chu, H.-T. Wu, Y.-J. Lee, Tetrahedron 2004, 60, 2647. A. Terec, I. Grosu, E. Condamine, L. Breau, G. Pie, Y. Ramondenc, F.D. Rochon, V. PeulonAgasse, D. Opris, Tetrahedron 2004, 60, 3173. R. Grigg, M. Nurnabi, M.R.A. Sarkar, Tetrahedron 2004, 60, 3359. G. Bringmann, R.-M. Pfeifer, P. Schreiber, K. Hartner, M. Schraut, M. Breuning, Tetrahedron 2004, 60, 4349. A.D. Thomas, Josemin, C. V. Asokan, Tetrahedron 2004, 60, 5069. T.K. Pradhan, C. Mukherjee, S. Kamila, A. De, Tetrahedron 2004, 60, 5215. S. Ranganathan, K.M. Muraleedharan, N.K. Vaish, N. Jayaraman, Tetrahedron 2004, 60, 5273. S.A. Vizer, K.B. Yerzhanov, A.A.A.A. Quntar, V.M. Dembitsky, Tetrahedron 2004, 60, 5499. H. Sheibani, M.R. Islami, H. Khabazzadeh, K. Saidi, Tetrahedron 2004, 60, 5931. K.C. Majumdar, P.K. Basu, P.P. Mukhopadhyay, Tetrahedron 2004, 60, 6239. G. Bringmann, R.-M. Pfeifer, P. Schreiber, K. Hartner, N. Kocher, R. Brun, K. Peters, E.-M. Peters, M. Breuning, Tetrahedron 2004, 60, 6335. J.H. Koh, C. Mascarenhas, M.R. Gagne, Tetrahedron 2004, 60, 7405. T.N. Tekavec, A.M. Arif, J. Louie, Tetrahedron 2004, 60, 7431. D. Banti, E. Groaz, M. North, Tetrahedron 2004, 60, 8043. S. Kobayashi, Y. Takahashi, K. Komano, B. H. Alizadeh, Y. Kawada, T. Oishi, S. Tanaka, Y. Ogasawara, S. Sasaki, M. Hirama, Tetrahedron 2004, 60, 8375. P. Cironi, C. Cuevas, F. Albericio, M. Alvarez, Tetrahedron 2004, 60, 8669. J. Hellberg, E. Dahlstedt, M.E. Pelcman, Tetrahedron 2004, 60, 8899. S. Das, A. Pramanik, R. Frohlich, A. Patra, Tetrahedron 2004, 60, 10197. C. Wolf, Z. Fadul, P.A. Hawes, E.C. Volpe, Tetrahedron: Asymmetry 2004,15, 1987. H. Ishida, A. Nozawa, H. Hamano, H. Naoki, T. Fujita, H.F. Kaspar, K. Tsuji, Tetrahedron Lett. 2004, 46, 29. M. Gruttadauria, P.L. Meo, R. Noto, Tetrahedron Lett. 2004, 45, 83. J.-P. Bouillon, A. Capperucci, C. Portella, A. Degl'Innocenti, Tetrahedron Lett. 2004, 45, 87. Y. Ishikawa, S. Nishiyama, Tetrahedron Lett. 2004, 46, 351. D.A. Bianchi, F. Rua, T.S. Kaufman, Tetrahedron Lett. 2004, 46, 411. G.J. Reddy, D. Latha, C. Thirupathaiah, K.S. Rao, Tetrahedron Lett. 2004, 45, 847. A. Shimbashi, Y. Ishikawa, S. Nishiyama, Tetrahedron Lett. 2004, 45, 939. M. Li, J. Scott, G. A. O'Doherty, Tetrahedron Lett. 2004, 45, 1005. P. Preedasuriyachai, P. Charoonniyomporn, O. Karoonnirun, T. Thongpanchang, Y. Thebtaranonth, Tetrahedron Lett. 2004, 45, 1343. W.-S. Kim, J.-H. Lee, J. Kang, C.-G. Cho, Tetrahedron Lett. 2004, 45, 1683. A.G. Chittboyina, Ch.R. Reddy, E.B. Watkins, M.A. Avery, Tetrahedron Lett. 2004, 45, 1689. H. Hamamoto, K. Hata, H. Nambu, Y. Shiozaki, H. Tohma, Y. Kita, Tetrahedron Lett. 2004, 45, IIV?,. M. Pal, K. Parasuraman, V. Subramanian, R. Dakarapu, K.R. Yeleswarapu, Tetrahedron Lett. 2004, 45, 2305. V.-H. Nguyen, H. Nishino, Tetrahedron Lett. 2004, 46, 3373. J.S. Yadav, B.V.S. Reddy, D. Narsimhaswamy, P.N. Lakshmi, K. Narsimulu, G. Srinivasulu, A.C. Kunwar, Tetrahedron Lett. 2004, 45, 3493. G. Mehta, K. Islam, Tetrahedron Lett. 2004, 45, 3611. J. Quintin, G. Lewin, Tetrahedron Lett. 2004, 45, 3635.

388 04TL4711 04TL4795 04TL5243 04T5429 04TL5505 04TL5857 04TL6147 04TL6151 04TL6169 04TL6299 04TL6995 04TL7011 04TL7225 04TL7277 04TL7287 04TL7895 04TL8347 04TL8583 04TL9065 04TL9197 04TL9181 04TL9369 04TL9479

J.D. Hepworth and B.M. Heron D. Rodriguez, D. Quintas, A. Garcia, C. Saa, D. Dominguez, Tetrahedron Lett. 2004, 45, 4711. H. Fuwa, S. Fujikawa, K. Tachibana, H. Takakura, M. Sasaki, Tetrahedron Lett. 2004, 46, 4795. K. Fujiwara, D. Sato, M. Watanabe, H. Morishita, A. Murai, H. Kawai, T. Suzuki, Tetrahedron Lett. 2004, 46, 5243. P.G. Dormer, A.M. Kassim, J.L. Leazer, Jr., F. Lang, F. Xu, K.A. Savary, E.G. Corley, L. DiMichele, J.O. DaSilva, A.O. King, D.M. Tschaen, R.D. Larsen, Tetrahedron Lett. 2004, 46, 5429. S.K. Ghosh, R.P. Hsung, J. Wang, Tetrahedron Lett. 2004, 45, 5505. J.-T. Shin, S. Shin, C.-G. Cho, Tetrahedron Lett. 2004, 45, 5857. A.A. Birkbeck, Z. Brkic, R.G.F. Giles, Tetrahedron Lett. 2004, 45, 6147. C D. Gabbutt, B.M. Heron, D.A. Thomas, M.E. Light, M.B. Hursthouse, Tetrahedron Lett. 2004,45,6151. T. Ghosh, C. Bandyopadhyay, Tetrahedron Lett. 2004, 45, 6169. T. Komiyama, Y. Takaguchi, S. Tsuboi, Tetrahedron Lett. 2004, 45, 6299. C.G. Saluste, S. Crumpler, M. Furber, R.J. Whitby, Tetrahedron Lett. 2004, 45, 6995. K. Fujiwara, A. Goto, D. Sato, Y. Ohtaniuchi, H. Tanaka, A. Murai, H. Kawai, T. Suzuki, Tetrahedron Lett. 2004, 46, 7011. H.-E. Lee, S. Lee, B.G. Kim, J.S. Bahn, Tetrahedron Lett. 2004, 45, 7225. K. Ito, Y. Imahayashi, T. Kuroda, S. Eno, B. Saito, T. Katsuki, Tetrahedron Lett. 2004, 45, 7277. N. Vets, M. Smet, W. Dehaen, Tetrahedron Lett. 2004, 45, 7287. D. Mai, A. Patra, H. Roy, Tetrahedron Lett. 2004, 45, 7895. D.E. Ward, V. Jheengut, Tetrahedron Lett. 2004, 45, 8347. S. Barroso, G. Blay, I. Fernandez, J. R. Pedro, Tetrahedron Lett. 2004, 45, 8583. O. Prakash, H. Kaur, V. Sharma, V. Bhardqaj, R. Pundeer, Tetrahedron Lett. 2004, 45, 9065. R. Akue-Gedu, J.-P. Henichart, D. Couturier, B. Rigo, Tetrahedron Lett. 2004, 45, 9197. A.Z. Rys, Y. Hou, I.A. Abu-Yousef, D.N. Harpp, Tetrahedron Lett. 2004, 45, 9181. M.P. Nguyen, J.N. Arnold, K.E. Peterson, R.S. Mohan, Tetrahedron Lett. 2004, 45, 9369. Z.-W. You, Y.-Y. Wu, F.-L. Qing, Tetrahedron Lett. 2004, 45, 9479.

389

Chapter 7

Seven-membered ring systems John B. Bremner Institute for Biomolecular Science and Department of Chemistry, University ofWollongong, Wollongong, NSW2522, AUSTRALIA John [email protected]

7.1

INTRODUCTION

Seven-membered heterocycles, particularly fused systems, continued to attract attention through 2004. Systems with nitrogen, oxygen or sulfur as heteroatoms, or combinations of these, are the principal focus of this Chapter. A summary is also provided on derivatives of pharmacological interest, together with some comments on future directions. A thorough review <04CRV2617> on pentathiepines has been published, while a four-step synthesis approach to seven membered heterocycles involving a ring formation strategy has been reviewed by Byrne and Gilheany <04SL933>. A review on the use of $-(N,Ndialkylamino)propiophenones in the synthesis of nitrogenous heterocyclic compounds including 7-membered ring examples, has also been published <04MI387>. Methods for the preparation of oxepines <04MI627>, benzoxepines <04MI653>, thiepines and selenium analogues <04MI705>, and benzothiepines and selenium/tellurium analogues <04MI717> have been reviewed.

7.2

SEVEN-MEMBERED SYSTEMS CONTAINING ONE HETEROATOM

A number of new syntheses and reactions have been described, although activity in this particular area has not been as high as in previous years.

7.2.1

Azepines and derivatives

Continuing the trend of recent years in which ring-closing metathesis reactions have been actively pursued in the synthesis of heterocyclic systems, the preparation of the syn and anti azepinones 2 and 3 respectively was achieved from the hydrochloride salt of the precursor 1 using Grubbs' ruthenium catalyst. The syn isomer 2 showed particularly strong in vitro binding (subnanomolar) to the K-opioid receptor <04BMCL5693>.

390

J.B. Bremner

Reagents: (i), 1M HCI in Et2O (4 equiv), DCM, 25 °C, 30 min; solvent removal; Grubbs' catalyst (0.05 equiv), DCM, 40 °C, 16 h (2: 30%; 3: 13%).

Azepanones were also the focus of synthetic activity reported by David and Dhimane <04SL1029>. Such 6-substituted 3-aminoazepanones form the core of a number of cyclolysine-based bioactive natural products. A convenient and novel approach to these derivatives was based on electrooxidation of the compounds 4 to give the methoxy derivatives 5 in moderate yields. These latter derivatives in turn could then be converted via 6 to the enamides 7. Oxidation of the latter then afforded, ultimately, the 6-acetoxy azepinones 10, via 8 and 9. A useful conformational study of novel polyhydroxylated azepanes has been reported, with *H NMR spectroscopy and molecular modelling (molecular mechanics, molecular dynamics and Monte Carlo methods) informing the conformational analysis <04EJOC4119>.

391

Seven-membered ring systems 7.2.2

Fused azepines and derivatives

A neat free radical cyclization process has been applied to the synthesis of new cyclopentanone-annulated azepines 13 from chiral vinylogous amides. The free radical was generated from the phenylselenide group in 12 (made in turn by N-acylation of 11) using BusSnH and l,l'-azobis(cyclohexanecarbonitrile) (ACN) as the initiator <04SL1917>. O ^ ^

O J H

SePh

N

81%

O

^ ^ \ J SePh j Ph

67o/o

H

^^H~J H I D.

O^OMe O^ e 11 12 F3C 13 F3C U I V l e Reagents: (i), n-BuLi, THF, -78 °C, 2 h; (ii), (S)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetyl chloride, THF, -78 °C to rt, overnight; (iii), Bu3SnH, ACN, toluene (0.01 M), reflux, 10 h.

A review of approaches to the design and synthesis of azabicycloalkane amino acids as constrained dipeptide mimetics has been reported. These approaches include 7-membered lactam ring formation by free radical cyclization from a substituted proline precursor <04SL1449>. The synthesis of benzazepine derivatives continues to command considerable attention, particularly because of their pharmacological activity. Base-induced intramolecular cyclization of the ester derived from the acids 14 gave the 1-benzazepines 15 in moderate to excellent yields. The yields were affected by the nature of the substituent group R1 on nitrogen, with the highest yield being obtained with an TV-benzyl derivative (15, R1 = CH2Ph, R2 = Br, R3 = Et) <04TL9335>. It is also worth noting the usefulness of this approach for the synthesis of analogous 8-membered ring derivatives (although being much less successful for the 9- and 10-membered systems). R1 N^/s^COaH

a

R1 N

or1)EtBr,K2CO3, DMF

CH0

"

1)Mel, K2CO3, DMF 2) 28%NaOMe in MeOH, (MeO)2CO

^

,JLJL

2)20%NaOEtinEtOH,(EtO)2CO

*

^ ^

C

/ O

2

R

3

Reaction of the aminophenylbutanol 16 with a new rhodium-based catalytic system (Cp* = pentamethylcyclopentadienyl) gave the tetrahydro-1-benzazepinone 17 in 86% yield. This represents one of the few methods for direct catalytic cyclization to this system <04OL2785>. r j ^ ^ r / v ~ - / ^ - ' O H [Cp*RhCI2]2(10.5%Rh)

[i^V^^X

^^/N 16

^^^N—4 17 H O

H

2

86%

Samarium diiodide-induced ketyl couplings are of significant synthetic interest, and Reissig et al. have reported an elegant application of the reaction in the case of the precursor 18. Reaction of 18 with 2 equivalents of samarium diodide and HMPA gave the 2benzazepine 19 from an 8-endo-dig cyclization reaction of the ketyl radical from the

392

J.B. Bremner

aldehyde. One disadvantage to this approach is the use of the carcinogen HMPA, and further studies to replace it would be worthwhile <04SL422>.

More classical approaches to the 2-benzazepine system, in particular the 2-benzazepinone 23, have been reported by Le Diguaher et al. The first was based on (5)-phenylalanine carboxamide 20 via the protected acetoxy compound 21 and acid-catalysed cyclization to 22; A^-alkylation and carbamate deprotection then afforded 23. The second, more general route, was based on N-Eoc aminomalonate 25 and 2,2'-dibromo-o-xylene, and then steps via 26 and 27. Yields were fair to moderate. The benzazepinone 23 was converted into the Nsubstituted derivatives 24, which were potent and specific farnesyl transferase inhibitors; such compounds are of interest as potential anti-tumour agents <04BMCL767>.

Reagents: (i), (a) ClCO2Me, CH2C12 pyridine, 0 °C, rt, 24 h; (b) (CHO)n, (Ac)2O, AcOH, it, 24 h (21, 90%); (ii), TfOH, CH2C12, rt, 24 h (22, 77%); (iii), (a) NaH, RBr, Bu4NI, rt, 24 h; (b) HBr, AcOH, (S, 23) or (iv), BiPh3, pyridine, Cu(OAc)2, DMF, CH2C12, rt, 24 h; (iv), EtONa, EtOH, rt, 12 h, (26, 88%); (v), RNH2, THF, NEt3, reflux; (vi), (a) KOH; (b) EDC; (c) Lil, pyridine, reflux; (d) HC1, ether; (vii), (a) NaBH(OAc)3, CH2C12, 0 °C, rt, 12 h; (b) HC1, ether, or formic acid, EtOH.

As part of a programme to prepare stereochemically defined 2,5-disubstituted-3//-3benzazepines, the enamine 28 was converted to the nitrile 29 (15:1 mixture of diastereomers;

Seven-membered ring systems

393

trans, (3-CN : l-cis, a-CN). This mixture could then be epimerized to afford the cis nitrile 30 in32%yield<04SL1394>.

The (5)-2-substituted 3H-3 -benzazepine 35 (a rigid analogue of (S)-phenylalanine) was accessed in a multistep sequence from the fused 3-benzazepine derivative 31 obtained in turn via an acyliminium ion-mediated 7-membered ring cyclisation. A key step in the formation of 35 was the lipase-catalysed acylation of the primary alcohol 33 using vinyl acetate as the acylating agent affording the acetate 34 in 46% yield and high ee <04H(63)17>.

Reagents: (i), Et3SiH (5 equiv.), BF3.2Ac0H (1.2 equiv.), CH2C12, rt, 94%; (ii), KOH (10 equiv.), MeOH, reflux; (iii), CbzCI (1.3 equiv.), NaHCO3, (1.3 equiv.), THF-H2O (1:1), rt, 92% (from 32); (iv), Novozym 435®, CH2=CHOAc, THF, 0 °C, 46%; (v) 0.05N NaOH, MeOH, 0 °C, 94%; (vi), NaClO2 (2 equiv.), 5% NaCIO (cat.), TEMPO (cat.), MeCN, pH 6.86 buffer, 35 °C, 92%; (vii), 5% Pd-C (cat.), H2 (1 atm), MeOH, rt, then, 4N HC1, AcOEt, 88%.

Interest has also continued in the fusion of other heterocyclic rings to the 7-membered aza systems or in the fusion of this system to more than one ring; potential pharmacological activity is a significant driving force for this interest. Illustrative examples of fusion of

394

J.B. Bremner

another heterocyclic ring include the 5//-pyrido[2,3-6]azepin-8-one 37 and the isoxazolo[4,5c]azepin-4-ones 41. In the former case, tin-free radical cyclisation of the xanthate 36 was the key step using dilauroyl peroxide (DLP) as the radical initiator in chlorobenzene <04OL3671>. In the latter case, the 7-membered ring was completed by intramolecular Michael type addition of the 7V-benzylamide derivative formed in situ from the methyl ester 40 on the double bond <04S2550>. The Bayliss-Hillman reaction was used to prepare 39 from the starting isoxazole aldehyde 38, followed by hydroxyl group protection as the acetate 40. Yields of 41 were low to moderate (e.g. 57%, Ar = Ph, EWG = COOr-Bu).

V

0 E t

AcO-^

£ Cl

N

Et

AcO^

XA

^OAc

N

q_/°

Cl

DLP, DCE

N

Bu

_X cl

N-~A Bu

N

Bu

36 51% Ar

37 35%

Ar

'\^-CO2Me

(i)

A

CHO

Ar

/>—CO2Me

(ii)

\

_\-OH

38

39

>-CO2Me

_\-OAc

EWG

a: Ph b: 4-CIC 6 H 4 c: 2,4-CI 2 C 6 H 3

N-A

O

40

EWG (iii)J '

Ar

BnHN

\ EWG

A r

+

W ^ EW(

3

41

Reagents: (i), CH2=CHEWG, DABCO, anhyd THF, rt, 5 min; (ii), AcCl, pyridine, anhyd CH2Cl2, 0-5 °C, 5 min; (iii), PhCH2NH2, MeOH, rt, 2-5 h.

Incorporation of the nitrogen in both the 7-membered ring and another fused ring has also been described. Ring expansion of the cw-aziridine 42 by CO insertion to the azetidinone 43 then set up a ring-closing metathesis reaction using Grubbs'(H) catalyst to afford the fused azepine 44 in 50% yield <04H(63)2495>.

p h <

?H V ^ ^ - ^ .

L ^ «

Co

2(CO) 8 , DMF,

CO(500psi), 110 °C 42%

Ph,_ 0

OH l^

/-N-v/^^ 43

HO Grubbs' catalyst (II)

CH2CI2, reflux 50%

ph

°

\ ^

J ^ ^ ^ J 44

An efficient two-step synthesis of the octahydro-5//-dibenz[6/]azepin-10-ones 46 has been reported based on the ketone and ester reactivity in 2-carbethoxymethyl cyclohexanone 45. Reaction with anilines under reductive conditions afforded the amino ester intermediates

395

Seven-membered ring systems

which then underwent standard acid mediated cyclisation to a cis/trans fused mixture of the products 46 (e.g. R = H; cis/trans ratio 1.0 : 0.6) <04MI261>. H j

UU

H

P

*HjNJU Jisa^ CJJJLf!^ C J N J > 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. <04H(63)1113>. 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 <04SL2721>.

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.

(i). (ii) a,X = O

b , X = H2

Reagents: (i), BH 3 .SMe 2 , THF, reflux; (ii), 20% KOH, reflux.

The highly symmetric spiro cation 57 has been shown to afford only the fused dibenzazepine-dibenzazocine derivative 58 (and none of the regioisomeric amine 59) on treatment with the phosphazene base P4-f-Bu. This is the product of a [1,2]-Stevens rearrangement of the intermediate ylide, the geometry of which is important in determining reaction path selectivity. In the presence of enantiopure BINPHAT as a counterion, the rearrangement led to some enantioselectivity in the reaction <04SL1565>.

Seven-membered ring systems

7.1.3

397

Oxepines and fused derivatives

Relatively few reports appeared on oxepine systems in 2004. The preparation of benzene oxide/oxepine has been observed in the gas phase reaction of benzene with oxygen atoms. Further reaction of this product with these atoms then gave a mixture of products including a compound thought to be oxepin-4,5-epoxide or oxepin-2,3-epoxide <04MI391>. Of relevance to this work is the report of the first observation of a 4,5-benzoxepin-2,3-oxide by 'H NMR <04TL4789>. Other fused systems have been of interest. The synthesis of a novel bicyclic oxepinopyrimidine 62 has been described. Acetylation of the alcohol 60 afforded the acetate derivative 61 which was then cyclised to the oxepine derivative 62 plus 63 on treatment with concentrated HC1 <04H(63)2523>.

The novel dibenzo[6,/]furo[2,3-cf]oxepine derivatives 67 and 68 have been accessed by epoxidation of the 10,11-double bond in 64 followed by Grignard addition with ring opening to give 66. Reaction of 66 with IPy2BF4, in DCM at room temperature for 2 min. then gave 67 and 68 in a 1:1 mixture in 99% yield <04CPB262>. In the first example of an acidcatalysed reaction in the solid state, heating the crystalline 2:1 inclusion compound of 2, 2'bis(hydroxydiphenylmethyl)biphenyl and formic acid gave, on cyclodehydration, the dihydrodibenzo[c,e]oxepine in 89% yield <04H(62)749>.

398

7.1.4

J.B. Bremner

Thiepines and fused derivatives

As with oxepines, little activity was reported for thiepines. The benzothiepine 73, a CCR5 antagonist and potential oral HIV-1 therapeutic, was synthesised efficiently on a large scale starting from the disubstituted benzene 69. A Suzuki-Miyaura reaction with 70 then gave 71 in high yield. This was followed by reaction with ethyl 4-mercaptobutyrate in the presence of base to realise the benzothiepine 72. Oxidation to the sulfone moiety, ester hydrolysis and acid-amine coupling then gave the final product 73 <04T10851>.

Seven-membered ring systems

7.3

399

SEVEN-MEMBERED SYSTEMS CONTAINING TWO HETERO ATOMS

7.3.1 Diazepines and fused derivatives The 5-imino-l,4-diazepane 76 was prepared from the known diazepinone 74, by initial Nprotecting group interconversion to give 75 followed by a three-step amide to amidine conversion. The compound 76 was prepared in connection with studies on nitric oxide synthase inhibitors but it proved to be inactive as an inhibitor of this enzyme <04BMCL5907>.

Reagents: (i), Pd(OH) 2 , H2, EtOH, rt; (ii), BocjO, CH 2 C1 2 , it; (iii), Me 3 OBF 4 , CH 2 C1 2 ; (iv), NH 4 C1, EtOH, reflux; (ix), HC1, EtOAc, rt.

A large amount of activity on 1,4-benzodiazepine derivatives was reported in 2004. Tetrahydro-1,4-benzazepin-2-one derivatives are of interest as |3-turn peptidomimetics and their solid-phase synthesis was reported by Kim et al. <04JCO207>. The diasteroselective synthesis of two enantiopure tetrahydro-1,4-benzodiazepin-5-ones was also achieved based on intramolecular azide cycloaddition and subsequent stereoselective reduction of the 1,4benzodiazepinone products <04TA687>. A different approach to tetrahydro-1,4benzodiazepin-5-ones 80 involves the 1,2-thiazine 1-oxides 77 as key intermediates. These intermediates were then converted to the nitroaryl amides 78 (R1, R2, R3 = H or Me) which could be cyclised to 80 after hydrogenation of the nitro group via the intermediates 79 <04T3349>.

Reagents: (i), SOC12, pyridine, THF, rt, 4 h; (ii), R'CH=CH-CR 2 =CHR 3 , THF, rt, overnight; (iii), PhMgBr, THF, -40 °C, 3 h; (iv), sat. NH 4 Cl(aq.); (v), MeOH, P(OMe) 3 , 60 °C, 10-15 h; (vi), Dess-Martin periodinane, CH 2 CI 2 , rt, 1 h; (vii), H 2 , Pd/C, MeOH, rt, 16-20 h.

400

J.B. Bremner

1,4-Benzodiazepine-based inhibitors 82 (Z = SO2 or CH 2 ; R = aryl, CF 3 , Bn) of mitrochondrial F1F0 ATP hydrolase were accessed by cyclisation of the diamino intermediates 81 and subsequent reduction and selective A^-substitutions <04BMCL1031>.

Reagents: (i), Ph(CH2)2C(=O)CO2Et, toluene, reflux, Dean-Stark trap; (ii), 1,2-DCE, TFA, Et3SiH; (iii), NaOH/MeOH; (iv), LAH, THF; (v), RS(=O)2C1, NEt3, CH2C12; (vi), NaH, DMF, RCH2Br; (vii), imidazolylcarboxaldehyde, Na(OAc)3BH, DCE, HOAc.

The reduction of arylazides with sodium iodide in acidic media has been used to access the 1,4-benzodiazepine-2,5-diones 85 (R = H, alkyl, Ph, Bn) from 84, the latter being prepared in turn from the azido acid chloride 83. Further applications of this azide reduction methodology in heterocyclic synthesis can be anticipated <04TL8187>.

A new, broadly based synthesis of l,4-benzodiazepine-3,5-diones has been described by Bergman et al. <04JOC6371>. It utilises the Af-substituted anthranilic acid 86, which was Nnitrosated to give 87 and then cyclized to the dione 89 via 88. Removal of the ./V-nitroso group then afforded 90; this represents a novel use of the A'-nitroso group in 7-membered ring synthesis. The compound 91 was also used to prepare an N-ethoxycarbonyl derivative of 90.

401

Seven-membered ring systems

a

COOH

87

N ^ C O O E t 90% ^ * ^ N ^ C O O E t 86 H NO

(iii) | 91%

a

COOH

88

^^COOH

(iv)>

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% <04JA14475>. 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) <04SL2533>.

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 <04BMCL1547>.

402

J.B. Bremner

Me0

-Y^^N°2

(i)

MeO-^CO 2 H

MeO^^X

OTBS

^OTBS ;'

(iv) ^ O y ^ Y

M e O ^ Y ^ "

MeO^A^^

o 93

uw V

Troc^OX L

N H

(vi) ^ 0

o

r,\\\— X = NO,

. ,,

X = TBS

X = NHTroc J 0(

Me

' l

N

Tro<

OH

Me

; OH

°TT y\ - ^ ° l V y\ ^~ Me °TT N;: V;

MeO^^Y-N^J^ O

MeO^^V-N^^ O 95 p ^ i i ) 9 6 X = OTf J g X = CH=CHCONMe2 Troc = 2,2,2-Trichloroethoxycarbonyl " ^ ^I CH^CHCONHI

MeO^^^-N^^^ O 9 7z = C 0 N M e

98Z = CO2Me 99 Z = CONH2

Reagents: (i), (COC1)2> DMF, TEA, CH2C12, 55%; (ii), Raney nickel, hydrazine, MeOH, 98%; (iii), Troc-Cl, pyridine, DCM, 86%; (iv), (COC1)2, DMSO, TEA, DCM, -60 °C, 99%; (v), AcOH, H2O, THF, 93%; (vi), (COCI)2, DMSO, TEA, DCM, -60 °C, 55%; (vii), Tf2O, pyridine, DCM, 30%; (viii), CH2=CHCONMe2, DABCO, (CH3CN)2PdCl2, MeOH, 45-55 °C, 59%; (ix), CH2=CHCOOMe, (PPh3)2PdCl2> TEA, DMF, 75-78 °C, 10%; (x), CH2=CHCONH2, DABCO, (CH3CN)2PdCl2, MeOH, 45 °C, 48%; (xi), 10% Cd-Pb, THF, NH4OAC, 97; 34%, 98; 90%, 99; 36%.

In closely related chemistry to that used in the preparation of 97-99, C2-substituted analogues lOla-e were accessed by Stille coupling of the appropiate tributyltin derivative with the SEM (2-(trimethylsilyl)ethoxymethyl)-protected trifate analogue 100. The SEM group was removed after reduction of the carbonyl group with NaBHj to give a carbinolamine intermediate, followed by treatment with silica gel in ethanol/water to give the cytotoxic cyclic imine products <04BMCL5041>. SEMQ M e C ^ ^ . N ^

JL-sA. 100

SEMQ RSnBu3/Pd[PPh3]4

H

M ' I

THF/reflux

o

101a:R = ^ ^

M

e0 v ^^.N--f H

^-^\^v N I \ 101a-e O

101b:R=^n] 101cb:R= —^E—Ph

101d:R=_^j]

101e:R=

—=—H

Kamal and co-workers have reported a new approach for the solid-phase synthesis of the pyrrolo[2,l-c][l,4]benzodiazepines 102 using a thiol Wang resin. The interesting feature of this approach was the reductive cleavage and cyclization achieved in the last step on reaction with DIBAL-H; yields of the products 102 ranged from 57% (R = 7-OMe, 8-OBn) to 65% (R = H) <04TL7667>.

403

Seven-membered ring systems

DMF,

Reagents: (i), NEt3> CH2C12, 0 °C, 6 h; (ii), TFA, CH2C12, rt, 1 h; (iii), 2-azidobenzoic acid, TBTU, DIPEA, rt, 6 h; (iv), TPP, anhydrous toluene, rt, 3 h; (v), DIBAL-H, CH2C12, -78 °C, 12 h.

Reduction of the aryl azides 103 using Zn-ammonium formate as the reducing agent, afforded the pyrrolobenzazepinediones 104a-c in high yields. Prior reduction of the ester in 103 to the aldehyde in 105, followed by reduction of the azide then gave the reduced analogues 106 <04TL6517>. R1

^

N

P°0CH3

R1

R2KJ^^

DIBAL-H, CH2CI2[

II 103 O Zn/HCOONH4 CH3OH, rt 85-90% H

RZ^^V^N

104 O

M .CHO

^JUytJ

-75 °C, 45 min 105

1 O Zn/HCOONH4 CH3OH, rt 75-80%

O

~}

a: R1 = H,

R2 = H

b:Ri = OMe, R^ = OBn

R2'^r\-N~^

f

^

c: R1 = OMe, R2 = OMe

Karaal has extended the azide reduction/DIBAL-H methodology to the synthesis of C2-azido analogues of the pyrrolo-benzodiazepine derivatives 107 and 108 <04TL3499>.

404

J.B. Bremner

Reagents: (i), SOCl2, NEt3, DMF, C6H6; (ii), MsCl, NEt3, CH2Cl2; (iii), NaN3, DMF, 50 °C; (iv), DIBAL-H, CH2CI2, -78 °C; (iv), HMDST, MeOH, rt, 4 h.

Other novel isoquinolino-fused 1,4-benzodiazepine derivatives have been reported in connection with studies on their DNA recognition potential. The approach to these derivatives was based on the l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 109, and functional group interconversions to set up the groups for the eventual cyclisation of 110 to the fused 7-membered system 111 <04BMCL4371>.

: R = Bru , .... R = H J(vm)

Reagents: (i), 1) BnOCOCl, NaOH (aq), 36 h, 94%; 2) SOC12, MeOH, reflux, 6 h, 96%; (ii), LiBH4, THF/MeOH, 6 h, 70%; (iii), 1) IBX, DMSO, 6 h, 76%; 2) EtSH, BF3.Et2O, CH2C12, 18 h, 66%; (iv), TMSI, CH3CN, 4 h, 83%; (v), 4-benzyloxy-5-methoxy-2-nitrobenzoyI chloride, NEt3, THF, 4 h, 60%; (vi), SnCl2.2H2O/MeOH, reflux, 2.5 h, 76%; (vii), HgCl2, CaCO3, CH3CN/H2O, 2.5 h, 79%; (viii), 10%Pd-C, 1,4cyclohexadiene, EtOH, 6 h, 70%.

Seven-membered ring systems

405

Smaller rings have also been fused to the 1,4-benzazepinone derivatives, as illustrated by (3-lactam annelation from the Staudinger reaction of the imine group in 112 with the acid chlorides R2CH2COC1 in the presence of base <04EJO535>.

The reaction of o-phenylenediamines with ketones is a well established procedure for the synthesis of 1,5-benzodiazepines. Recent attention has focussed on the use of high yielding conditions for the reaction involving solid acid catalysts (cerium(III) chloride/sodium iodide supported on silica gel <04MI921> or the heteropoly acid salt, Ag3PWi204o <04S901>). These reactions occurred at room temperature in neat diamine, and the acid catalyst was then removed by simple filtration; yields were generally high and the acid catalysts could be reused. A chalcone can also be used in this reaction in the presence of piperidine to give a 2,4diaryl-2,3-dihydro-l//-l,5-benzodiazepine, but in low yield <04ZN(B)73>. A highly regio- and diastereoselective 1,3-dipolar cycloaddition of nitrile oxides to the imine groups in 2,4-dimethyl-3//-l,5-benzodiazepines to afford bis[ 1,2,4oxadiazolo[l,5]benzodiazepine] adducts has been reported by Baouid and co-workers; stereochemical features were confirmed by single crystal X-ray crystallography on one of the adducts <04SC3565>. Ring expansion of homophthalic anhydride 114 on reaction with N-i-Vi-N'methylhydrazine in acetic acid resulted in the 2,3-benzodiazepinedione derivative 115 in moderate yield. The combination of the less hindered nitrogen (NCH3) and the more reactive carbonyl group in 114 may explain the regioselectivity observed. Functionalisation of C5 by the azido group then led ultimately via the amine 116 and the peptide 117 to the 2,3benzodiazepine-l,4-diones 118. These final compounds were designed to act as peptidomimetics at the carboxy terminus of hydroxyamides; one such compound 118 (R = 3,5-F2C6H3), for example, had an IC50 of 5 nM in a cell-based y-secretase inhibition assay <04BMCL3535>.

406

J.B. Bremner

Reagents: (i), (Me)HNNHCH(Me) 2 , HOAc, pyridine, reflux, 12 h, 60%; (ii), KN(SiMe 3 ) 2 , -78 °C, trisyl azide, then HOAc; (iii), 10% Pd-C, EtOAc, H 2 (1 atm), 40 min; (iv), Boc alanine, EtOC(O)Cl, NEt 3 , 0 °C, 3 h; (v), CF 3 CO 2 H-CH 2 Cl2, rt, 2 h; (vi), P-EDC, CH 2 C1 2 , 18 h.

7.1.2

Dioxepines, dithiepines and fused derivatives

Conformational equlibria (gauche/trans) of 2,2'-bi-l,3-dioxepanyl and 2,2'-bi-l,3dithiepanyl in solution have been investigated through dipole moment assessment. Both compounds favour the gauche form at 25 °C in solution, in contrast to the situation in the solid state where the trans conformation is favoured as determined by X-ray crystallographic analysis. A crystal packing effect may be responsible for this latter situation, since CH—O or CH—S hydrogen bonds are predicted to stabilize the gauche over the trans conformations <04JPC(A)6874>. Substituent effects on reaction path selectivities have been reported in the cyclisation of the acetals 121 with BF3.etherate. Thus 121a gave only the 1,4-benzoxepine 122a while 121b afforded both 122b and the 10-membered ring derivative 123b. A common 10membered ring progenitor of these systems was proposed in one sequence and a 12membered ring precursor in a second sequence. The precursors 121a-b were obtained from the salicyl alcohols 119a-b via the acetals 120a-b by sequential reaction with MEMC1 and BrCH2CH(OCH3)2/NaH <04Tl 1453>.

Reagents: (i), K2CO3, anhydrous acetone, MEMC1; (ii), BrCH2CH(OMe)2, NaH, anhydrous DMF; (iii), BF3.OEt in anhydrous Et2O.

Seven-membered ring systems

407

The mild, water-soluble Lewis acid, indium(III) chloride is finding increasing use in organic synthesis, including heterocyclic syntheses. An indium(III) chloride catalysed synthesis of a range of new dibenzo[of,/][l,3]dioxepines 125 has been described based on the reaction of 2,2'-dihydroxybiphenyl 124 with ketones or P-keto esters capable of enolisation; yields of the products 125 were low to moderate <04TL6909>.

Phenols or thiophenols have also been used in a classical nucleophilic displacement approach to the 1,5-benzodioxepines 126 and the corresponding 1,5-benzodithiepines 127. Crystal structures for 126a and 127a were reported and conformational comparisons made with those from energy calculations <04JST79>.

7.1.3

Miscellaneous derivatives with two heteroatoms

Classical ring expansion methodology has been used to prepare the 1,4-oxazepinone 132 (X = O) and 1,4-thiazepinone 132 (X = S) derivatives from the corresponding oximes 129 prepared in turn from 128. The seven-membered ring compounds were then converted into the imines 132 in a three-step sequence via 131 <04BMCL5907>.

408

J.B. Bremner

fXvi

V O 128 (X=O S)

'

(i),(ii)

r "i

(in)

f ~\

*V

HN^

NOTs 129

\>

(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 <04JMC3089>.

R

R2

yvR3

CV ^INT

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 <04JA8744>. 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^^OBn "

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 <04CCC1818>.

n U~J

(l)

K?

°<^f

92% '

B°j ~^T pkl

°TS

0Ts

X^^,0

139

(iV)

,

ffij

H

2N^-v^0 i

140 (v)

R = H, X = Cl

1 (ii) 96%

72%

i

R = Ac, X = Cl -*=H ..... . . . .

i

R = A C , x = N 3 rw

O

r^oH

Reagents: (i), Cl(CH 2 ) 3 OH, BF 3 .Et 2 O, CH 2 Cl 2 , 40 °C; (ii), Ac 2 O, pyridine, rt; (iii), NaN 3 , DMF, 90 °C; (iv), H2, Pd/C, EtOH, rt, then MeONa, MeOH, rt; (v), DBU, BuOH, 120 °C.

A concise high yield synthesis of the l,4-benzazepin-3-one 145 from 143 via 144 has been outlined by Merour et al. The synthesis can be performed in a one-pot format without isolation of 144 <04H(63)1093>.

0H (T^ KJ\

°

r,-^01 u

1

H N

143

Y^1

B3N, CH2CI2' 93/o

fTr 0H

VsAs |

°YNY^1 144

K2CO3, acetone reflux, 2.5 h

^ , 0 ^ [ || U Q

qUanl

^ " ^ V _ 145

\=\

OMe

Intramolecular carbon-oxygen bond formation by acid-catalysed ketal interchange has also been utilised to access the 4,1-benzoxazepine 148 from 147, the latter being prepared in turn from its silyl protected analogue 146. The sulfonamides were then converted in high yield to the 4,1-benzoxazepines 149 and 150 .

410

J.B. Bremner OMe

OMe

MeO^

^-^^^,02

OCT.

MeO^

- ^

CCOH

146a (70%) ^ \ b (80%) NO

^

-^

147a (83%) b (100%)

2

SO2

H N

1

^^/ N "^\

Qf

^^HQ2

('")

r^V

\

yowe —- QJ^ o h

148a (100%) b(100%)

(iv)

OMe

? N~^

^

—-

<^Y A ^.. UJ^o>~-OMe

149(98% from 148a and 90% from 148b)

150d (69%) e (79%) f (89%) a 2-NO2; b 4-NO2; d R = CO(CH2)2CH3; e = R = COCF3; f R = COPh Reagents: (i), TBAF (1 equiv), THF, rt, 1 h; (ii),p-TsOH (0.03 equiv), anhydrous toluene, 110 °C, 2 h under argon for 148a and 148b; (iii), PhSH (1.1 equiv), K2CO3 (3 equiv), DMF, rt, 1 h; (iv), CH3(CH2)2COC1 (2 equiv), TEA (3 equiv), anhydrous CH2C12, 0-5 °C, 3 h under argon for 150f.

Ring-closing metathesis methodology has been applied to the synthesis of the 1,5benzothiazepine 1,1-dioxide 152 from 151 in moderate yield using Grubbs' catalyst 153 <04TL9171>.

o o

o o

V'

%'

a

' -^-^*•f^

151 Ts

5% catalyst 7

i \ Mes-N

ff^V' A

toluene, 50 "C, 24 h; ^ + 5% 7, 80 "C, 24 h

152

N-Mes

Y

V

" ^ h Ts

153

A new method for the preparation of dibenzo[6,/][l,4]thiazepines has been described. The method is based on S-amination of the 9//-thioxanthen-9-ols 154, which gave the ring expanded products 156 in low to moderate yields (e.g. 58%, R = Et), together with the salts 155 and thioxanthene-9-one 157. The intermediacy of imino thioxanthylium cations (derived from 155) followed by intra- or intermolecular migration of the imine nitrogen to C9 (to afford a nitrenium ion intermediate) are suggested for the pathway leading to 156 <04HAC246>. R OH

R OH

R

^ A c ^ k ^ CH2CI2, 0°C I ^ A c A ^ + C L J j 154

155

NH

2 "

0Mes

156

O

+

KjA^cXj^ 157

Using solvent-free conditions (SFC), a one-pot synthesis of frww-octahydro-benzo[6]l,4oxathiepin-2-one 161 from 158 and 159 via 160 has been reported. A good overall yield was

Seven-membered ring systems

411

obtained; benzo[e]l,4-oxathiepin-5-ones have been prepared similarly by thiolysis of epoxides <04JOC8780>. +

C\° ^ ^

C lH r-/ °

SFC, 50 °C (~y°H _SfC^ (^iP~\ CO2H ^/V^ 150°ckAqV 8hi65o/o

HS

158

159

160

20 h

° 161 6 1 % overall yield from 158

Novel B, Si 7-membered heterocycles 165 have been prepared from the bis(silyl)ethynes 162 on reaction with triallylborane. The initial products were 163 and 164 (from 162c) from 1,1 -allylboration. The alkenes 163 then underwent intramolecular hydrosilylation under mild conditions and without a catalyst to give the 7-membered ring compounds. The alkene 164 could also be converted to 165 via 163 <04MI43>.

A

+ BAII 3

:62 a b c d

7.4

7.4.1

"2BWSiR2

>

I _ A,,-Br w

2

R1 R2 Me Me3Si i-Pr Me3Si Ph Me3Si Ph Ph2HSi

+ AU B

r —*•

SYSTEMS

\=/

R1

All

SiMe

)=< J All SiHPh2 164

SEVEN-MEMBERED HETEROATOMS

AM

All = ally I

CONTAINING

THREE

OR

MORE

Systems with N, S and/or O

Further applications of the use of the versatile starting material, diaminomaleonitrile 166, in the synthesis of heterocyclic derivatives have been reported. For example, reaction of 166 with chlorocarbonylisocyanate 167 in the presence of triethylamine gave the isocyanate 168 which, on heating in the presence of sodium hydroxide, cyclised to the l,3,5-triazepine-2,5dione 169. This heterocycle then served as a precursor for the synthesis of a range of other ring fused triazepinediones <04MI71>.

H2N

NH2+

£

>K NC CN

CI^N=C=O

166

167

N

Y

10%NaOH

• C~^ JL™ DCM fl H2N' CN

A

94%

89% 168

7

HNr l rf-\\

Y

l H

169

^

CN

412

J.B. Bremner

A series of new l//-l,2,4-triazepin-7-ones 172 could be accessed via the reaction of the nitrilimines 170 with (3-alanine to afford 171, and then CDI-mediated dehydration to the seven-membered ring system <04M435>. R

R

/ ~ \

/

y—P N-NH

9\

V-f J V, H3C Cl

NEt3

HP H C

H

H3C

HN^ 171

3

R

< \ N - N H

^

CDI/THF

p

57-74%

170

^COOH NH 61

2

"76%

"

R

ov

X

%^/CHz

(

0 H

a R=H b R=CH3 c R=CI

^

o + _V-^ ^—=N-N

172 CDI=1,1'-carbonyldiimidazole

Imidazo-fused analogues 174 of the 1,2,4-triazepine system have been synthesised from pre-formed imidazoles 173. Reaction of 173 with Af,./V'-dimethylhydrazine.2HCl and the appropriate orthoformate then resulted in the triazepine derivatives 174; the formation of the imidates 175 is proposed to occur initially, followed by the ring closed intermediates 176. Reaction of 176 with the alcohol would then give 174 <04JMC1044>.

H

?i l

H N

R ^ ][ } ^ N

HC(OR'3)3/R'OH (R1 = Me or Et) rtto reflux

173

I r

o

CH3NHNHCH3.2HCI "

H3C ? R 1 R "NA ^ H 3 C-N' I! x) ^

174

175

62%

b; R' = CH2CH3 30% R 0H

'

HA x>

(R = .CH2C6H4-p-OlVle)

^

a;R' = CH3

R!

H^N Y

N

CH3NHNHCH3 L

/0HR N-
'

H ,C

176

©

? N=^N -I

A novel conversion of 2-aryl-l,2,3,4-tetrahydroquinazolin-l-ols 178 to the 2,1,4benzoxadiazepine 179 has been described. Reaction of 178 (obtained in turn from oxidation of the quinazolines 177) with arylisocyanates in toluene at room temperature gave 178 in yields ranging from 60% (R = 4-CH3OC6H4; Ar = Ph) to 85% (R = 2-furyl; Ar = Ph). The mechanism proposed involves initial attack by Nl on the isocyanate to give an activated Noxide and then ring enlargement after heterolytic cleavage of the adjacent N1-C2 bond. It is possible, however, that this rearrangement could proceed via a radical process analogous to the Meisenheimer rearrangement of jV-oxides <04TL8973>.

413

Seven-membered ring systems

r/:S;*^NH

H2O2-WO42-

^ ^ • N ^ R

MeOH, rt '

V- A r ^*Y^"NH ^ ^ N

H

2eqArNC0 R

toluene,

^^W^-N

rt

^ A

177

, o

N

OH

H

i

178

HN-^-Q

179

Ar Cyclocondensation of the acids 180 mediated by acetic anhydride provided convenient access to the new l,3,4-benzothiadiazepin-5-ones 181 in good yield <04H(63)l 153>.

a

co H

2

6

N-NH-Ar

•

^S^\ c

| 8k

20-30 min

180

Ar

7^V^ N - 4

Ac2O/reflux,

27/

^,5

N3

fN~£

-181 Ar= Ph, p-CIC6H4, p-CH 3 C 6 H 4

An intramolecular SNAr reaction in the synthesis of the dibenzothiadiazepine dioxides has been reported by Lebegue and co-workers. Reaction of 186 (formed in turn by standard reactions from 182 and 183 via 184 and 185) with Cu in DMF at reflux in the presence of K2CO3, followed by amide hydrolysis, gave 187 in 45-72% yields. The amines 187 were then converted to the p-methoxybenzyl derivatives 188 as potential cytotoxic compounds; compounds 188a and 188b displayed only weak antiproliferative activity against the L1210 leukemia cell line <04H(63)2457>.

a

so 2 ci

NO2

182

H2N.^. B r ^ " ^

1

183

H SO2—N^^.

a

(ii)

^ ^ S O

2

y CH 3 — N ^ * .

I jLNo2 — [ T

184

(iii)

^ ^ S O

2

,CH 3 N , ^

—

1 ^NxH

I J-NO2 — I JT 185

H3C^O

186

°

(iv)

Oj

PH,

*

^~^ a: 8-substituted b: 9-substituted

O O CH (v)

(^^ V^S W A N A ^ N ^ V ^

H 188

"

UL0CH

°CH3

X

/

s'"N'

^

~Y\

U^NA^NH2 H

187

Reagents: (i), DMF, pyridine, 75 °C, 68-91%; (ii), DMF, NaH, CH3I, rt, 86-88%; (iii), 1) Fe, AcOH, reflux; 2) Ac2O, 60 °C, 76-89%; (iv), 1) DMF, Cu, K2CO3, reflux; 2) 12N HCI, EtOH, reflux, 45-72%; (v), 1) THF, AcOH, 4-anisaldehyde, 55 °C; 2) THF, NaBH3CN, 50 °C, 64-70%.

The incorporation of main group elements into seven-membered ring systems is an area of continuing interest. One new representative in this field is the aluminium-sulfur allenyl

414

J.B. Bremner

heterocycle 189, formed from reaction of an aluminacyclopropene derivative with carbon disulfide. Compound 189 formed yellow crystals and the structure was elucidated from spectroscopic and X-ray crystallographic analysis <04JA10194>.

7.5

SEVEN-MEMBERED SYSTEMS OF PHARMACOLOGICAL SIGNIFICANCE

A number seven-membered ring derivatives have been made or studied for their potential or actual pharmacological properties. Examples include azepane derivatives as PKB (protein kinase B) inhibitors <04JMC1375>, 5,6,7,8-tetrahydro-4//-thieno[3,2-6]azepine derivatives as novel arginine vasopressin antagonists <04JMC101>, NG38, an azepanyl substituted purine which is a potent inhibitor of estrogen sulfotransferase <04MIo924>, dibenz[6,/]azepin-5-yl methylpteridines as potent and selective microbial dihydrofolate reductase inhibitors <04JMC2475>, benzodiazepine receptor binding properties of imidazo[2,l-6]thiazepines <04EJM205>, l,4-benzodiazepin-2-ones as endothelin receptor antagonists <04JMC2776>, 1-naphthoxepine oxime ethers as potential hypotensive agents <04BMCL3177>, and 2-iV,Af-dimethylaminoethyl-2,3,3a,12b-tetrahydrodibenzo[6,/]furo[2,3JJoxepine derivatives as potential anxiolytic agents <04CPB262>. Interesting metabolic studies on the 1,4-benzodiazepine anxiolytic drug, oxazepam 190, have also been reported; gender and genotype determinants were found for (5)-oxazepam glucuronidation by human liver cells, while glucuronidation of (^?)-oxazepam was independent of these determinants <04MI656>.

7.6

FUTURE DIRECTIONS

As with other synthetic operations, the application of green chemistry techniques and design principles to the synthesis and chemistry of 7-membered ring heterocyeles is likely to increase in the future. Some neat applications of solvent-free, heterogeneous conditions have already been realised in this area, and the potential for wider application is significant. The application of microwave-induced reactions in ring synthesis also has great scope with new approaches to seven-membered rings. Seven-membered ring systems continue to occupy an important position in new medicinal agent design, and their importance is likely to continue especially with respect to the introduction of a range of different heteroatoms.

Seven-membered ring systems 7.7

415

REFERENCES

04BMCL767 04BMCL1031 04BMCL1547 04BMCL3177 04BMCL3535

04BMCL4371 04BMCL5041 04BMCL5693

04BMCL5907

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416 04JMC2475 04JMC2776

04JMC3089 04JOC6371 04JOC8780 04JPC(A)6874 04JST79 04M435 04MI43 04MI71 04MI261 04MI387 04MI391 04M1627 04MI653 04MI656 04MI705 04MI717 04MI921 04MIo924 04OL2785 04OL3671 04S901 04S2550 04SC3565 04SL422 04SL933 04SL1029 04SL1394 04SL1449 04SL1565 04SL1917 04SL2331 04SL2533 04SL2721 04T3349 04T10851 04T11453 04T11547 04TA687 04TL3499 04TL4789 04TL6517 04TL6909

J.B. Bremner A. Rosowsky, H. Fu, D.C.M. Chan, S.F. Queener, J. Med. Chem. 2004, 47, 2475. M.H. Bolli, J. Marfurt, C. Grisostomi, C. Boss, C. Binkert, P. Hess, A. Treiber, E. Thorin, K. Morrison, S. Buchmann, D. Bur, H. Ramuz, M. Clozel, W. Fischli, T. Weller, J. Med. Chem. 2004, 47, 2776. K. Audouze, E.O. Nielsen, D. Peters, J. Med. Chem. 2004, 47, 3089. P. Wiklund, M. Rogers-Evans, J. Bergman,/ Org. Chem. 2004, 69, 6371. F. Fringuelli, F. Pizzo, S. Tortoioli, L. Vaccaro,./. Org. Chem. 2004, 69, 8780. Y. Lam, M.W. Wong, G.S.M. Kiruba, H.H. Huang, E. Liang, J. Phys. Chem. A 2004, 108, 6874. J. Jamrozik, G. Zak, J. Grochowski, M. Markiewicz, P. Serda, J. Mol. Struct. 2004, 687, 79. B. Abu Thaher, J.A. Zahra, M.M. El-Abadelah, H.-H. Otto, Monatsh. Chem. 2004, 135, 435. B. Wrackmeyer, O.L. Tok, Y.N. Bubnov, Appl. Organomet. Chem. 2004, 18, 43. H.H. Abdel-Razik, ARK1VOC2004, 71. A. Palma, JJ. Barajas, V.V. Kouznetsov, E. Stashenko, A. Bahsas, J. Amaro-Luis, Lett. Org. Chem. 2004, 7,261. R. Abonia, B. Insuasty, J. Quiroga, M. Nogueras, H. Meier, Mini-Reviews in Organic Chemistry 2004, 7,387. T. Berndt, O. Boege, Z. Phys. Chem. 2004, 218,391. S. von Angerer, Science of Synthesis 2004, 17, 627. S. von Angerer, Science of Synthesis 2004,17, 653. M.H. Court, Q. Hao, S. Krishnaswamy, T. Bekaii-Saab, A. Al-Rohaimi, L.L. Von Moltke, D.J. Greenblatt, J. Pharmacol. Exp. Therapeut. 2004, 310, 656. A.L. Schwan, Science of Synthesis 2004,17, 705. A.L. Schwan, Science of Synthesis 2004,17, 717. G. Sabitha, G.S.K.K. Reddy, K.B. Reddy, N.M. Reddy, J.S. Yadav, Adv. Synth. Catal. 2004, 346,921. Z. Travnicek, M. Zatloukal, Ada Cryst. 2004, £60, o924. K. Fujita, Y. Takahashi, M. Owaki, K. Yamamoto, R. Yamaguchi, Org. Lett. 2004, 6, 2785. E. Bacque, M.E. Qacemi, S.Z. Zard, Org. Lett. 2004, 6, 3671. J.S. Yadav, B.V.S. Reddy, S. Praveenkumar, K. Nagaiah, N. Lingaiah, P.S. Saiprasad, Synthesis 2004, 901. S. Batra, A.K.. Roy, Synthesis 2004,2550. K. Nabih, A. Baouid, A. Hasnaoui, A. Kenz, Synth. Commun. 2004, 34, 3565. M. Berndt, S. Gross, A. Hoelemann, H.-U. Reissig, Synlett 2004, 422. L.A. Byrne, D.G. Gilheany, Synlett 2004, 933. M. David, H. Dhimane, Synlett 2004, 1029. J.E. Cobb, S.S. Nanthakumar, R. Rutkowske, D.E. Uehling, Synlett 2004, 1394. L. Belvisi, L. Colombo, L. Manzoni, D. Potenza, C. Scolastico, Synlett 2004, 1449. L. Vial, M.-H. Goncalves, P.-Y. Morgantini, J. Weber, G. Bernardinelli, J. Lacour, Synlett 2004,1565. M. Cordes, D. Franke, Synlett 2004, 1917. A. Garcia, E. Gomez, D. Dominguez, Syn/ett 2004, 2331. A. Kamal, K.L. Reddy, V. Devaiah, N. Shankaraiah, Synlett 2004, 2533. A. Palma, J.J. Barajas, V.V. Kouznetsov, E. Stashenko, A. Bahsas, J. Amaro-Luis, Synlett 2004,2721. K. Hemming, C. Loukou, Tetrahedron 2004, 60, 3349. T. Ikemoto, T. Ito, A. Nishiguchi, K. Tomimatsu, Tetrahedron 2004, 60, 10851. E. Saniger, M. Diaz-Gavilan, B. Delgado, D. Choquesillo, J.M. Gonzalez-Perez, S. Aiello, M.A. Gallo, A. Espinosa, J.M. Campos, Tetrahedron 2004, 60, 11453. M. Diaz-Gavilan, F. Rodriguez-Serrano, J.A. Gomez-Vidal, J.A. Marchal, A. Aranega, M.A. Gallo, A. Espinosa, J.M. Campos, Tetrahedron 2004, 60, 11547. E. Beccalli, G. Broggini, G. Paladino, T. Pilati, G. Pontremoli, Tetrahedron Asymmetry 2004, 15, 687. A. Kamal, K.L. Reddy, G.S.K. Reddy, B.S.N. Reddy, Tetrahedron Lett. 2004, 45, 3499. D. Nauduri, A. Greenberg, Tetrahedron Lett. 2004, 45,4789. A. Kamal, K.S. Reddy, B.R. Prasad, A.H. Babu, A.V. Ramana, Tetrahedron Lett. 2004, 45, 6517. G. Tocco, M. Begala, G. Delogu, C. Picciau, G. Podda, Tetrahedron Lett. 2004, 45, 6909.

Seven-membered ring systems 04TL7667 04TL8187 04TL8973 04TL9171 04TL9335 04ZN(B)73

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418

Chapter 8

Eight-membered and larger ring systems George R. Newkome The University of Akron, Akron, Ohio USA [email protected]

8.1

INTRODUCTION

In the twenty-first century, there will continue to be a noticeable trend from studies of classical "crown ethers" towards directed polyazamacromolecules, for metal atom complexation and the introduction of multiple heteroatoms for directed self-assembly, including the use of metal atom centers, as a source of the heteroatom. Numerous reviews and perspectives have appeared throughout 2004 that are of interest to the heteromacrocyclic scientist and those delving into supramolecular chemistry at the molecular level, as well as those studying supermolecules (nanoconstructs): supramolecular chemistry and nanofabrication <04OBC3409>; chiral tetraaza-ligands for use in asymmetric syntheses <03ASC1173>; syntheses of expanded porphyrins <03ACIE5134>; the application of cavitands for molecular recognition <04EJO451>; supramolecular catalysis of two-component reactions <04ACR113>; bridged calix[6]arenes <03JIPM165>; synthesis and characterization of polymacrocycles and their protonated ions <03CCR65>; polycatenation, polythreading, and polyknotting in coordination networks <03CCR247>; oxidations catalyzed by metallocorroles <04ASC165>; supramolecular aspects of crown-substituted tetrapyrroles <04RCR5>; catalysis by perfluorinated polymercuramacromolecules, as examples of anticrown ethers <03RCB2539>; residual topology associated with intertwined macromolecules <04CEJ2804>; crown ethers, as sensors for ions and molecular scaffolds for materials and biological models <04CRV2723>; soft supramolecular materials <04JIPM3>; ion selective polymer-supported crown ethers <04RFP3>; metal chemistry of TV-confused porphyrins ; one-pot construction of Borromean rings <04ACIE1068>; structural factors in the nonlinear optical properties of phthalocyanines and related materials <04CRV3723>; supramolecular metal complexes, based on crown-substituted tetrapyrroles <04RCR5>; phthalocyanines, as molecular conductors <04CRV5503>; tetrathiafulvalene, cyclophanes, and related cages <04CRV5115>; tetrathiafulvalenes, oligoacenes, and their buckminsterfullerene derivatives <04CRV4891>; macrocyclic formazans <04JHC135>; shape-persistent macrocycles <04CEJ1320>; mercuracarborands ; modification of macrocycles by azaheterocycles <03H593>; molecular tectonics <03CCR157>; chiral thioether ligands in coordination chemistry and asymmetric catalysis <03CCR159>; catalysis with immobilized (metallo)porphyrins <04CEJ1320; 03RCR965>; molecular

Eight-membered and larger ring systems

419

elevator(s) <04SCI1845>; synthesis of heterocycles via microwave irradiation <04H903; O4MI1>; supramolecular aspects of tetrathiafulvalene leading to molecular devices <03SM309>; construction and complexation of thio-, seleno-, and telluro-ether ligands <02HAC550>; aromatic side chains of amino acids, as neutral donor groups for alkali metal cations <03CC2847>; and macrocycles created under thermodynamic control <04JIPM81>. Each year there are interesting presentations that capture a unique niche and this year's perspective goes to Julius Rebek in which he describes a plethora of his adventures <04JOC2651> ranging from molecular devices, recognition, and encapsulation <04OBC3051>; it is always fun to review, briefly, the fullness of a researcher's modern history. As always, because of space limitations, only meso- and macrocycles possessing heteroatoms and/or subheterocyclic rings have been reviewed; in general, lactones, lactams, and cyclic imides have been excluded. In view of the delayed availability of some articles appearing in previous years, several have been incorporated, where appropriate. I apologize in advance that it is impossible to do justice, to this topic and the numerous researchers that have elegantly contributed to the field, in the allotted pages. 8.2

CARBON-OXYGEN RINGS

Crown ethers possessing appended substituents continue to be a major thrust in this area in order to probe new amphiphilic and utilitarian purposes. Simple benzocrown ethers possessing different subunits, such as: alkenes O3RCB2656; 04T2043>; allyl, which was subsequently appended to a polysilane backbone <04EPJ57>; urea, as a precursor to dynamic self-assembly via //-bonding <04JIPM133; 03JA9647>; salicylaldimine Schiff bases <04S1011>; and benzothiazole <04JIPM125> representing the simple conversions; whereas, di(monosubstituted benzocrown)s have also been prepared in analogous ways and studied, generally as either supramolecular complexes <04TL5961; 04NJC870; 03JIPM53> or macromolecular constructs O4MCP801; 04PM7389>. Aryl-expanded crowns have been used as the molecular shuttle between multiple recognition sites or stations <04ACIE2121>. 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 <04MM7514>. 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 <04JOC4403>. 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 <03T9939>. Mono- <04ACIE4954; 04JOC2902; 04TAL123; 04JOC206>, di- O4J0C6938; 04TL3387>, and multiple <04JOC2877> 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 <03JIPM149>.

An improved route, which circumvents the oligomer formation, of 2,11,20,29-tetraoxa[3.3.3.3]paracyclophane 3 has recently appeared <04JOC3654>. 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 <04OL3261; 04OL3257>. 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 <04TL7435>. Intramolecular McMurry coupling of dialdehydes derived from xylenyl dibromide and 4hydroxybenzaldehyde generated cw-stilbenophanes as well as cyclophane diols <04T2351>. 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 <04TL2927>. New Cjv cavitands 7 with protective side chains were prepared and their host-guest properties evaluated <04TL9119>.

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 <04CEJ155>.

Eight-membered and larger ring systems

421

It has been thirty years since the work of Richman and Atkins <74JA2268> 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 <03JOC10169> or 6,6"te(bromomethyl)[2,2':6\2"]-terpyridine <04IC5134>. 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 <04CC2206>. 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) <04JA12395>. 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) <04TL6165>.

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 <03DT1186>; [2 + 2] condensations with 2,6pyridinedicarboxaldehyde with 3,3-diamino-iV-methyldipropylamine or 6w(3-aminopropyl)amine <03DT3172> as well as TV^l-naphmylmemylazaethyO-TVjN-dKaminoethyOamine <04IC6114>; 4-alkoxy-2,6-diformylpyridine with 4,4'-di(aminomethyl)biphenylmethane <04TL1643>; (S,S)-6,6'-fc(4-ethyoxyphenyl)-2,2'-dihydroxy-33'-diformyl[l,r]-binaphthalenyl with l,2-diphenylethene-l,2-diamine <04JOC6284>; l,10-phenanthroline-2,9-dicarboxaldehyde with 4,7,10-/r;s(/>tolylsulfonyl)-4,7,10-triazatridecane-l,13-diamine <04EJI4061>; l//-pyrazol-3,5-dicarboxaldehyde TV-(l-alkyl)-AyV-di(aminoethyl)amine <04JA823>; and [3 + 3] condensations: 2,6-diformylpyridine with fra«5-cyclohexane-l,2diamine<04EJO1117>. 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 <04CC178; 04JOC6079>. Carbaporphyrinoid systems with semiquinone, cycloheptatriene or indene subunits have been prepared and treated with Ag(I)OAc to generate the stable Ag(III) derivatives <04OL549>, also see: <04IC5258>. 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 <04T2427>. Porphyrins can not only be TV-confused <04OL1393> but now inverted as well as dimeric <04ACIE5077; 04JIPM33> and there are doubly TV-fused pentaporphyrins <04ACIE876; 04ACIE2951>. 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 <04JOC6404>. 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 <04T1895>.

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 <04EPJ403>. Spontaneous ring-opening polymerization of macrocyclic [-1,4-SC6H4-CO-C6H4-

Eight-membered and larger ring systems

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 <04MRC808>. 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 <04JOC2945>. 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 <04OM81>.

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 <04JOC2945>. 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 <04ACIE1959>. 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 <04CC138> 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 <04S369>. 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 <03CC2847> by the use of an incorporated iV-substituted aza-component, e.g., mono-A'-substitution: phenyl <04TL213>, 2,2-diphenyl-2//benzo[/]chromenyl <03RCB2661>, 1-pyrene <04CC224>, or simple removable protecting group <04JOC6949>; di-A^-substituted crowns: -benzyl <04ICA4144>, -pyrenylacetamide

Eight-membered and larger ring systems

425

<04TL7557>, -methylcarbonylethoxide <04RCB396>, linear amine terminated PEGs <04CHE343>, -4-pyridinyl <04JOC2910>, -(5-tert-butyl-2-hydroxybenzyl) <03POL3249>; the attachment azacrown ethers to calixarene <04CEJ4436; 04JOC4879>, biphenyl <04T4683>, cyclen <04TL6055>, bridging calixarenes O4T5041; 03TAL709>, acridone <04TA1487>, glucose or mannose <04SL643>, c«-l,3,5,7-tetraoxadecalin <03CEJ6071>, diphenylglycolurilbased receptors <04T291>, or l,l'-binaphthocrowns <04T5041>. 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 <04TL9553>. A novel ring-transformation of benzocrown ethers, as a synthon, to generate functionalized azacrown ethers has appeared <04RJO1200>. 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 <04MM3996>.

The nitrogen component is commonly introduced into the crown ether framework in order to create a specific binding site; specific moieties are: piperazine <04JOC5290>, pyridine O4JIPM97; 04JIPM151; 04TA2803; 04CC152>, phenanthroline O4JIPM81; 04IC1895; 04ACIE2392; 04CC474; 03HCA4195>, bipyridine O4ACIE4482; 04TL4719; 04CC152>, terpyridine <04CC384; 04CC474>, porphyrin <04OL671>, and acridone <03T9371>. The synthesis of core-modified mono-meso-free monooxacorroles has been accomplished in three different [3 + 1] acid-catalyzed condensations and coupling methodologies <04JOC5135>; the related oxasmaragdyrin- and oxacorrole-ferrocene conjugates have also been reported <04CEJ1423>. 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 <04OBC3442; 04TL5461>. 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 <04ACIE2392>. 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 <04OL2596>. 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 <04EJO1236>. 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 <04CEJ2804>.

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 <04JPS(A)186>. 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 <03HAC273>. 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

Eight-membered and larger ring systems

All

were presented <04JOC3928>. 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 <04PI1845>. 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 <04EJI3779>. 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 <04CEJ6497>.

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 <04TL129>; 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 <04T1541>. 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 <04OL747>. 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 <04DT2771>. 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 <04JOC6796>. 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 <04CC374>.

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, <04EJI2086> 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 <04JOC1813>. 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 <04ICA4129>. 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

Eight-membered and larger ring systems

429

EtOH under high dilution conditions; the 1 -selena-4,7-dioxacyclononaane was isolated in only trace amounts <03DT2852>.

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 <03DT2852>. 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 <04JOM1452>. 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 <04CC322>. 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 <04OM4513>. 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 <04TL299>. A simple synthesis of related N3S, N2S2, N2O2, N2SO, and N2OS porphyrins from readily available precursors has recently appeared <04EJO2223>.

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 <04JOC6886>. 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 <04EJI4371>. 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 <04OL861>. 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

<04JA16187>. 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 <04CC428>.

Eight-membered and larger ring systems

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* <04DT2780>. 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 <04ACIE5016>; 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 <04JOC964>. 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 <04IC6579>. 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 <04JOC2910>. 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] <04JA13896>; also see <04CEJ2199> 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 <04CEJ2689>. 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 <04OL1079>. The reaction of a ligand

Eight-membered and larger ring systems

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 <04IC1895>.

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 <03DT603>. 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-
439 Bicyclo[10.10.10]dotriacontanes, 95 Bicyclo[m.3.0]alkan-3-on-2-yl-l-oxonium ylide, 149 Bicyclobutylidenes, 246 2,2'-Biindole, 123 2,3'-Biindoles, 129 l,l'-Binaphthocrowns, 425 Biotin, 89, 207 2,2'-Bipyridines, 261, 263, 266 2,2'-Bipyrroles, 113,422 2,3-Bis( 1,2,4-triazin-3-yl)-4,4'-bipyridine, 340 3,4-Bis(methylene)tetrahydrofurans, from bis(propargyl) ethers, 157 2,2'-Biselenophene, 103 Bisindolylarylethanes, 129 Bisindolylarylmethanes, 128 Bisindolylmethanes, 129 Bisindolylpyrazolylmethanes, 129 Bispyrido[3,2-e]pyrrolo[l ,2-a]pyrazines, 327 Bispyrrolo[l,2-a]quinoxalines, 327 Bispyrrolo[l,2-a]thieno[3,2-e]pyrazines, 327 Bistratamides, 201, 210 4,5'-Bithiazol-4'-ol, 199 2-(2',2'-Bithienyl)-l,3-benzothiazoles, 97 2,2'-Bithiophenes, 90, 100 Bixanthenyl, 378 Borromean rings, 418 Botryllazine B, 323 Brefeldin, 5 Bromocondurital, 21 6-Bromopenem, 70 Bryostatin, 19 Buckminsterfullerene, 418 Bullvalene, 89 Butenolide, 8, 9 y-Butenolides, 145 (+)-Calanolide A, 367 Calix[2]arene[2]triazines, 425 Calix[4]arene-thiacrown-4,426 Calix[4]phyrin, 119 Calix[4]pyrrole[2]carbazole, 119 Calix[6]arenes, 418 Calix[6]azacryptand, 429 Calixarenes, 420, 424 Calixpyrroles, 119 Callystatin A, 27 Camptothecin, 275 Carbasugars, 21, 22, 26 Carbazol-4-ones, 124 Carbazolequinones, 133 Carbazomycin B, 135 Carbazoquinocin C, 135 Carbazostatins, 134 B-Carbolines, 130, 131 Carpamic acid, 286

440 Catenaries, 423, 425, 432 Caulersin, 131 Cefuroxime, 70 Cephalothin, 70 Chemiluminescence, 74 2-Chloro-3-nitrothiophenes, 93 2-Chloro-4,6-bis[(heptadecafluorononyl)oxy]-1,3,5triazine, peptide coupling reagent, 341 6-Chlorohyellazole, 126 Chroman-4-ols, 3-allenyl, from salicylaldehydes and l,4-dibromobut-2-yne, 370 Chromano[4',3':4,5]pyrano[3,2-c]coumarins, 367 Chromans, 367-370 (-)-Chromazonarol, 368 Chromenes, 367-370 Chromium(III) porphyrin, 74 Chromones, 376-377 Chryso[6]thiophene, 96 Cinnolino[5,4,3-crfe]cinnoline, 308 Cispentacin, 69 Clavicipitic acid, 135 (+)-Clusifoliol, 368 Colchicines, 26 Conduritals, 21 Conodusarine, 134 Coumarins, 375-376 Coumarins, Pechmann synthesis, use of sulfamic acid, 366 Coumestrol, 163 Crown ethers, 419 Cryptands, 423, 425 Cyathin, 27 Cycloalka[6]pyrano[2,3-/i]coumarins, 376 Cyclohepta[6]pyrimido[5,4-rf)furan-8,10(9ff)-diones, 354 Cyclohepta[A]pyrimido[5,4-rf]pyrrole-8(6//), 10(9//)diones, 354 Cyclohepta[c][l,2,5]oxadiazoles, 257 Cyclooxygenase-1 inhibitors, 240 Cyclopenta[2,l-6:3,4-6]dithiophen-4-one, 92 Cyclopenta[6,6']dipyran, 364 Cyclopenta[6]benzofuran, 163 Cyclopenta[6]indolones, 124, 129 Cyclopenta[6]thiophenes, 251 Cyclophanes, 426 Cyclopropanes,12 Cyclotetrasilane, 78 Cyclothiazomycin, 210 Cyclotriphosphazene, dendrimers, 344 Cyclotriphosphazenes, 343-344 Cystothiazole A, 204, 210 Cystothiazole B, 203, 204, 210 Dehydrovoachalotine, 135 Dendrobine, 23 Deoxo-Fluor, 201

Index 3-Deoxy-8-oxatropanes, 214 1 -Deoxy-D-galactohomonoj irimycin, 287 1-Deoxy-D-gulonojirimycin, 297 Deoxypancratistatin, 21 4,6-Di-(2-pyridyl)-l,3,5-triazine, 341 Diacenaphthof 1,2-6:1 ',2'-rf]thiophene, 382 Diacenaphtho[l,2-6:l',2'-e]-l,4-dithiin, 382 Diacenaphtho[l,2-c: 1 ',2'-e]-l,2-dithiin, 382 Diaminocarbene, 77 l,10-Diaza[18]crown ether, 425 l,2-Diaza-l,3-butadienes, 203 1,4-Diazabicyclo[4,3,0]nonanes, 70 1,4-Diazabicyclo[4,4,0]decanes, 69 1,4-Diazepane, 5-imino, 399 2,4-Diazepentadienes, 179 Diazepines, 399-406 1,4-Diazepines, 408 1,5-Diazocines, 408 Diazonamide A, 247, 248 5//-Dibenz[6,c]azepines, 395 5//-Dibenz[6/)azepin-10-ones, 394 Dibenzazepine-dibenzazocine, 396 Dibenzo[fe,rf]tellurophene, 84 Dibenzo[A,/][l,4]thiazepines, 410 Dibenzo[6,/]furo[2,3-rf|oxepines, 397 Dibenzo[6,/]xanthones, 378 Dibenzo[6rf]pyrans, 367 Dibenzo[c,e]oxepine, dihydro, 397 Dibenzo[d,/][l,3]dioxepines, 407 Dibenzoftirans, via benzymes, 159 Dibenzoselenophene-Se-oxide, 103 Dibenzothiophene S-oxides, 95 3,4-Dibromothiophene, 91 3,4-Dicyanothiophene, 91 Dicyclopenta[6.rf|thieno[l,2,3-crf:5,6,7cW]diphenalene, 87 Difluorodioxoles, 228 1,2-Digermacyclobutadienes, 78 Digermadisilene, 78 Dihydro[l]benzopyrans, 367-370 Dihydro[2]benzopyrans, 370-372 l,4-Dihydro-2,3-benzoxathiin 3-oxides, 383 4,5-Dihydroazocines, 338 2,3-Dihydrobenzo[6]thiophenes, 89 3,4-Dihydrobenzo[g]isoquinoline-l(2//)-one, 279 2,3-Dihydrobenzoxazepines, 72 2,3-Dihydrofurans, from 2,2-dimethyl-5-methoxycarbonyloxy-3-pentyn-l-ols, 157 2,5-Dihydrofurans, from 3,6-dihydro-l,2-dioxines, 158 2,5-Dihydrofurans, from bis(allyl) ethers, 158 Dihydrofurans, properties, 145-149 Dihydrofurans, synthesis, 155-158 Dihydroindolizino[8,7-i>]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-<3]pyrimidines, 317, 321 4-Pyrazolo[l,5-A]pyridazin-3-ylpyrimidin-2-amines, 309 Pyrazolo[l,5-6]pyridazines, 308, 350 Pyrazolo[l,5-c][l,3,5]triazines, 349 Pyrazolo[l,5-rfl[l,2,4]triazines, 348 Pyrazolo[3,4-6]pyrazines, 177 l//-Pyrazolo[3,4-6]pyridines, 177, 348 Pyrazolo[3,4-c]pyridazines, 308, 354 2tf-Pyrazolo[3,4-rf]pyridazin-7(6//)-one, 305 l//-Pyrazolo[3,4-(/|pyrimidin-4(5//)-ones, 314, 348

446 Pyrazolo[3,4-rf]pyrimidin-4-ones, 315, 320 Pyrazolo[3,4-rf]pyrimidines, 322, 350 l//-Pyrazolo[4,3-c]pyridine, 177, 262, 263 Pyrazolo[4,3-c]pyrrolizines, 178 5//-Pyrazolo[4,3-c]quinolines, 178 l//-Pyrazolo[4,3-rf]pyrimidin-7-ones, 312, 347 1 //-Pyrazolo[4,3-e][ 1,2,4]triazines, 345 Pyrazolo[4,3-e][l,2,4]triazolo[l,5-e]pyrimidines, 316,354 Pyrazolo[5,l-c][l,2,4]triazines, 345 Pyrazolyl-2-pyrazolines, 176 Pyreno[2,l-A]pyrrole, 121 Pyrethrins, 228 Pyridazines, 305 Pyridazino[l,4]oxazin-3-ones, 306 Pyridazino[3',4':3,4]pyrazolo[5,1 -c] 1,2,4-triazines, 309 Pyridazino[3,4-6][1,5]benzoxazepin-5(6//)ones, 309 Pyridazino[4,3-6]indoles, 309 Pyridazino[4,5-6][l,4]oxazines, 307 5//-Pyridazino[4,5-6]indoles, 306 Pyridazino[4,5-/|[l,3,5]triazepine, 306 3(2//)-Pyridazinones, 249 3(2//)-Pyridazinones, 307, 308 [1,4]Pyridazinooxazine[3,4a]tetrahydroisoquinolines, 307 Pyridazo[2,3-6]phenazine-6,l 1-dione, 356 Pyridine /V-oxides, 271 Au(III)-Pyridine-2-carboxylate, 144 Pyridinium salts, 261, 271 Pyridinophane, 269 2-(2-Pyridinyl)pyrroles, 113 Pyrido[l ',2': 1,2]imidazo[5,4-rf]-1,2,3-triazinones, 185 Pyrido[l ,2-a]pyrimidin-2-ones, 316 2//-Pyrido[l,2-a]pyrimidines, 270, 321 Pyrido[l,2-a]pyrimidinium salts, 315 Pyrido[l,2-a]quinolin-3-ones, 316 5//-Pyrido[2,3-6]azepin-8-one, 394 Pyrido[2,3-rf]pyrimidin-2(l//)-ones, 315 Pyrido[2,3-rf]pyrimidin-7(8//)-ones, 314 Pyrido[2,3-rf]pyrimidine-2,4(l//,3//]-dione, 312 Pyrido[2,3-rf]pyrimidine-2,4-diones, 351 Pyrido[2,3-rf]pyrimidines, 313, 315, 352 Pyrido[2,3-rf]pyrimidinones, 322 Pyrido[2,3-/6,5-/]di[l,2,4]triazolo[4,3-a]pyrimidin5(l//)-ones, 315 Pyrido[3',2':4,5]thieno[3,2-rf]pyrimidines, 316 Pyrido[3,4-rf]pyridazin-3-ones, 353 Pyrido[3,4-rf]pyrimidin-4(3//)-one, 313 Pyrido[4,3-rf]pyrimidin-4(3//)-ones, 314, 351 2-Pyridones, 267 Pyridopyrazines, 352 Pyridylalanines, 265 Pyrimidines, 309

Index 4(3//)-Pyrimidinones, 309 Pyrimido[l,2-6][l,2,4,5]tetrazinones, 350 1 //,3//-Pyrimido[2,1 -/]purine-2,4-diones, 356 Pyrimido[4,5-c]pyridazin-5,7-diones, 351 Pyrimido[4,5-c]pyridazine-5,7( 1 H,6H)-dione, 307 Pyrimido[4,5-c]pyridazines, 352 l//,8//-Pyrimido[4,5-rf]pyrimidin-2,7-diones, 316 Pyrimido[4,5-rf]pyrimidine-2,5-diones, 322 Pyrimido[4,5-rf]pyrimidines, 313, 352 2//-Pyrimido[4,5-e][l,2,4]triazines, 351 Pyrimido[5,4-rf)pyrimidines, 322 Pyrrole-3-boronic acid, 116 1//-Pyrroles, 4,5-dioxo-4,5-dihydro, 354 Pyrrolo[l,2-a]pyrazines, 326 Pyrrolo[l,2-a]quinoxalines, 327 Pyrrolo[l,2-c]oxazoles, 115 Pyrrolo[2,l-c][l,4]benzodiazepines, 401, 402 Pyrrolo[2,l-/|[l,2,4]triazine, 349 4//-Pyrrolo[2,3,4rfe]pyrimido[5',4':5,6][l,3]diazepino[l,7-a]indole, 313 Pyrrolo[2,3-a]carbazoles, 120 Pyrrolo[2,3-6]pyrazines, 113, 325 Pyrrolo[2,3-6]pyrroles, 114 Pyrrolo[2,3-6]quinoxaline, 113 Pyrrolo[2,3-af)pyrimidine-6-carboxylate, 313 Pyrrolo[2,3-rf]pyrimidines, 110, 320, 350 Pyrrolo[3,2-c]pyridines, 77 Pyrrolo[3,2-c]quinoline, 273 Pyrrolo[3',4':3,4]pyrido[l,2-a]benzimidazoles, 185 Pyrrolo[3,4-c]isoxazoles, 240 6//-Pyrrolo[3,4-rf|pyridazines, 308 Pyrrolo[4',5':5,6]pyrido[3,4-6]indole, 121 Pyrrolo[4,5-ft]indole, 325 Pyrrolobenzazepinediones, 403 Pyrrolobenzoxazine, 122 Pyrroloquinoline alkaloids, 117 4-(l//-l-Pyrrolyl)pyridine, 116 Pyrylium salts, 27, 372-373 Quaterthiophene, 98 o-Quinodimethane, 270 Quinolines, 273 Quinolino[2,l-Z>]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-
Index 4//-Thiopyrans, from thionation of 1,5bis(acylsilanes), 378 Thiostrepton, 210 2-Thiouracils, 320 9//-Thioxanthen-9-ols, 410 9//-Thioxanthenol, 43 Titanacyclopent-3-yne, 78 Titanium tetraisopropoxide, 110 Tonghaosu, 11 Tri(thiazole), 197 l//-l,2,4-Triazepin-7-ones, 412 l,3,5-Triazepine-2,5-dione, 411 1,2,4-Triazine 4-oxides, 337 1,3,5-Triazine, 2,4,6-trichloro, 339 1,3,5-Triazine, 2,4,6-trichloro, coupling reactions, 340 l,2,4-Triazine-3,5-diones, 337 l,2,4-Triazine-3,5-diones, 338 l,2,4-Triazine-3-carboxylic acid derivatives, 337 l,2,4-Triazine-3-thion-5-ones, 345 1,3,5-Triazines, 2,4,6-tris(aryIchalcogeno), 339 1,2,4-Triazines, 263 Triazines, 337-342 Triazines, applications, 340-342 1,2,4-Triazines, boron-containing, 337 1,2,4-Triazines, cycloaddition/retro-cycloaddition reactions, 338 1,3,5-Triazines, from dicyandiamide and nitriles, 339 l,2,4-Triazino[5,6-A]indole-3-thiols, 353 1,2,4-Triazino[5,6-A]indoles, 354 l,2,4-Triazole-5-thiones, 190 1,2,4-Triazoles, 190 1,2,4-Triazoliumsalt, 191 1,2,4-Triazolo[l ,2-a]pyridazines, 307 [1,2,4]Triazolo[l ,3]thiazinones, 346 1,2,4-Triazolo[l,5-a][ 1,3,5]triazines, 348 l,2,4-Triazolo[l,5-a][l,3,5]triazines, 349 l,2,4-Triazolo[l,5-a]pyrimidin-7-one, 311 l,2,4-Triazolo[l,5-a]pyrimidines, 319, 322 1,2,4-Triazolo[ 1,5-e]pyrimidines, 321 l,2,4-Triazolo[l,5-c]pyrimidines, 349 l,2,4-Triazolo[l,5-rf|[l,2,4]triazines, 345 1,2,4Triazolo[2",3"/6',l']pyrimido[4',5'/2,3]pyrido[l,2a]benzimidazoles, 354 l,2,4-Triazolo[3,4-a][l,3,5]triazines, 339 l,2,4-Triazolo[3,4-c][l,2,4]triazines, 345 5//-1,2,3-Triazolo[4,3-a][2]benzazepines, 186 Triazolo[4,3-a]pyrimidines, 312, 314, 346 l,2,4-Triazolo[4,3-a]quinoxalin-l-one, 355 l,2,4-Triazolo[4,5-a]pyrimidin-4-ones, 314 [l,2,3]Triazolo[5,l-rf][l,2,5]trazepin-9-ium-olates, 354 1,2,3-Triazolopyridylboronic acids, 188 2,4,6-Trichloro[l,3,5]triazine, 175

Index Trifluoromethylbenzo[6]naphtho[rf]furans, 54 Trioxanes, 381 1,2,4-Trioxolanes , spiro, 234 Trisindolylarylmethanes, 128 Trisoxazolines, 245 3,1 l,19-Trithia[3.3.3]pyridinophane, 428 Trithia[3]peristylane, 89 Trithianes, 381-382 1,2,5-Trithiepanes, 217 Tropoloisoquinolines, 26 2-Tropyliobenzo[A]thiophenes, 92 TTFs, 231-232 Tubulysins, 197,210 Tylonolide, 5 2-Ureido-4(l//)-pyrimidinone, 319 Vallesamidine, 135 Variolins, 109 Vebturicidins, 24 Verdazyl radicals and diradicals, 342, 343 Vincamajinine, 135

449 Vinyldioxolanes, 228 2-VinyItetrahydrofuran, cis, and tram, 148 2-Vinylthiophenes, 94 Violet-quinone, 161 (-)-Virantmycin, 74 Viridin, 143 Vitamin D analogs, 4, 187 Widdrol, 27 Xanthenes, 377-378 Xantheno[l,9-«/|azepinone, 396 Xanthones, 377-378 Xyloketal D, 370 Yatakemycin, 134 Zaragozic acid, 6 2-zetinones, 64-72 Zinc(II) porphyrin, 432 Zoanthamine, 26 Zyzzyanone A, 117

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