Advances in Heterocyclic Chemistry, Volume 87

The Literature of Heterocyclic Chemistry, Part VIII, 1999–2001 L.I. BELEN’KII and V.N. GRAMENITSKAYA N. D. Zelinsky Inst...

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The Literature of Heterocyclic Chemistry, Part VIII, 1999–2001 L.I. BELEN’KII and V.N. GRAMENITSKAYA N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. General Sources and Topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. General Books and Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. General Topics by Reaction Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Specialized Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Natural and Synthetic Biologically Active Heterocycles . . . . . . . . . . . . . . . . . . . . . III. Three-Membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. One Heteroatom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Two Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Three Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Four-Membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. General Topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. One Heteroatom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Two Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Five-Membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. General Topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. One Heteroatom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Two Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Three Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Four Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Six-Membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. One Heteroatom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Two Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Three Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Four Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Rings with More Than Six Members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Seven-Membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Medium Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Large Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. Heterocycles Containing Unusual Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Phosphorus Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Boron Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Silicon, Germanium, Tin, and Lead Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . E. Selenium and Tellurium Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. Other Unusual Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1 ADVANCES IN HETEROCYCLIC CHEMISTRY VOLUME 87 ISSN: 0065-2725 DOI: 10.1016/S0065-2725(04)87001-6

ß 2004 Elsevier Inc. All rights reserved

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[Sec. II.A

I. Introduction This survey is a sequel to seven already published in Advances in Heterocyclic Chemistry (66AHC(7)225, 79AHC(25)303, 88AHC(44)269, 92AHC(55)31, 98AHC(71)291, 99AHC(73)295, 01AHC(79)199). It includes monographs and reviews published during the period 1999–2001 as well as some published earlier but omitted in Part VII. Like Parts III–VII, this survey is based mainly on short bibliographic papers published by the authors in Khimiya Geterotsiklicheskikh Soedinenii since 2002 (02KGS404, 02KGS992, 03KGS447, 03KGS776). Sources not only in English but also in Russian, Japanese, Chinese, Czech, and other languages are surveyed and classiﬁed. This feature of the survey should cause no problem because some of the sources are available in English translations and practically all others have informative English abstracts as well as quite understandable and useful schemes and lists of references. As before, carbohydrates are not covered. Such compounds are mentioned only in general cases (e.g., anomeric eﬀect) as well as when carbohydrates serve as starting compounds for the synthesis of other heterocycles or they are present as fragments of a complex system including another heterocyclic moiety such as nucleosides.

II. General Sources and Topics A. GENERAL BOOKS AND REVIEWS 1. Textbooks and Handbooks Handbook of Heterocyclic Chemistry: 00MI1. Applied homogeneous catalysis with organometallic compounds: 96MI7. Aqueous-phase organometallic catalysis: 98MI2. Basic principles of drug design: 00MI15. Biologically active substances of plant origin (a dictionary in 3 volumes): 01MI79. Chemistry for pharmacologists and biochemists/pharmacology for chemists and biochemists: 01MI71. Fundamentals of medicinal chemistry: 01MI67. Fundamentals of organic chemistry of drugs: 01MI68. Mass spectrometry of heterocycles: 01MI66. Organic reaction mechanisms: 99MI19. Palladium-catalyzed organic reactions: 97MI1. 2. Annual Reports a. Comprehensive Reports.

00PHC1, 01MI145, 01PHC1, 02PHC1.

b. Specialized Reports Devoted to Basic Series of Heterocycles. Three-membered heterocycles: 00PHC57, 01PHC52, 02PHC52. Four-membered heterocycles: 00PHC77, 01PHC71, 02PHC75.

Sec. II.A]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

3

Pyrrole and its benzo derivatives: 00PHC114, 01PHC111, 02PHC114. Furan and its benzo derivatives: 00PHC134, 01PHC130, 02PHC139. Thiophenes, selenophenes, and tellurophenes: 00PHC92, 01PHC87, 02PHC90. Five-membered heterocycles with more than one N atom: 00PHC161, 01PHC167, 02PHC180. Five-membered heterocycles with N and S (Se) atoms: 00PHC185, 01PHC188, 02PHC200. Five-membered heterocycles with O and S (Se, Te) atoms: 00PHC204, 01PHC205, 02PHC222. Five-membered heterocycles with O and N atoms: 00PHC219, 01PHC217, 02PHC235. Pyridine and its benzo derivatives: 00PHC237, 01PHC238, 02PHC257. Diazines and their benzo derivatives: 00PHC263, 01PHC261, 02PHC279. Triazines, tetrazynes, and fused polyaza-systems: 00PHC294, 01PHC296, 02PHC310. Six-membered heterocycles with O and/or S atoms: 00PHC317, 01PHC317, 02PHC332. Seven-membered heterocycles: 00PHC339, 01PHC340. Heterocycles with eight-membered and large rings: 00PHC352, 01PHC378, 02PHC356. c. Reports Devoted to Individual Problems. Alcohols, ethers, and phenols including cyclic ethers, heterocyclic alcohols and ethers: 00JCS(P1)2529. Applications of stochiometric transition metal complexes in synthesis and transformations of heterocycles: 00JCS(P1)109. Catalytic applications of transition metals in organic synthesis (particularly, in syntheses and transformations of heterocycles): 00JCS(P1)3335. Catalytic asymmetric syntheses of heterocycles: 00JCS(P1)275. Carbon–carbon bond-forming solid-phase reactions: 99CRV1549, 01CRV137. Cyclizations of imines into aziridines and -lactams: 00JCS(P1)125. Functionalized polymers as reagents for transformations of heterocycles: 00S1035. Heterocycles as ligands in catalysts for asymmetric synthesis: 00JCS(P1)275. Heterocycles as ligands in catalytic syntheses of alcohols, ethers, and phenols: 00JCS(P1)2529. Heterocyclic imines, enamines, and oximes: 00JCS(P1)125. New methods for the synthesis of heterocycles annelated by three-, four-, ﬁve-, six-, and seven-membered saturated and partially unsaturated carbocycles: 00JCS(P1)477. 3-1,3,4-Oxadiazolines as versatile sources of reactive intermediates: 00JCS(P1)2161. Preparative biotransformations of heterocycles: 00JCS(P1)611. Protecting groups in the synthesis and transformations of heterocycles: 00JCS(P1)2495. Rapid analog syntheses of heteroaromatic compounds: 00JCS(P1)2845.

4

[Sec. II.B

L.I. BELEN’KII AND V.N. GRAMENITSKAYA

Recent developments in indole ring synthesis: 00JCS(P1)1045. Saturated oxygen 3–9-membered heterocycles: 00JCS(P1)1291. Synthesis of cyclic peptides: 01JCS(P1)471. Synthesis of heterocycles by radical cyclization: 00JCS(P1)1. Synthesis of thiols, selenols, sulﬁdes, selenides, sulfoxides, selenoxides, sulfones, and selenones (as well as S- and Se-substituted heterocycles, S- and Seheterocycles): 00JCS(P1)835, 01JCS(P1)335. Thin-layer chromatography (with special paragraphs devoted to dyes, pigments, pesticides, drugs, alkaloids, purines, pyrimidines, nucleic acids, toxins, and vitamins): 00AC(12)9R. 3. Nomenclature Comprehension and application of its basic principles: 01M1. Does CIP nomenclature adequately handle molecules with multiple stereoelements? A case study of vancomycin and cognates: 01AG(E)701. Glossary of terms used in combinatorial chemistry: 99PAC2349. NMR nomenclature. Nuclear spin properties and conventions for chemical shifts (IUPAC recommendations 2001): 01PAC1795. 4. History of Heterocyclic Chemistry, Biographies Jacobus Henricus van’t Hoﬀ hundred years impact on stereochemistry: 01AG(E)3783. History of the discovery of stable nitroxide radicals: 00MI19. Publication list of Prof. H. B. Kagan: 01T2960. Scientiﬁc biography of Prof. Ya. L. Gol’dfarb: 01KGS3. 5. Bibliography of Monographs and Reviews The literature of heterocyclic chemistry, 1997–1999: 01AHC(79)199. a. Specialized Surveys. 01KGS997, 03KGS447, 03KGS776.

01KGS409,

02KGS404,

02KGS992,

B. GENERAL TOPICS BY REACTION TYPE Activation of unreactive chemical bonds by metal complexes (a general survey): 99MI26. Activation of the N–N triple bond in molecular nitrogen and its chemical transformation into organonitrogen compounds: 99MI27. Annular tautomerism of six-membered heterocycles: 01AHC(81)253.

Sec. II.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

5

Applying biological principles to the assembly and selection of synthetic superstructures: 01CSR287. Cyclic aromatic systems with hypervalent centers, in particular, heterapentalenes: 01CRV1247. Photophysical and photochemical processes in supramolecular systems: 01MI128. Quantitative measure of aromaticity for mono-, bi-, tricyclic penta- and hexaatomic heteroaromatic ring systems and their interrelationships: 01CRV1421. Recent advances in computing heteroatom-rich ﬁve- and six-membered ring systems: 01AHC(81)1. Self-assembly via multiple hydrogen bonding interactions in synthetic macromolecular systems: 01CSR83. Structural aspects of aromaticity: 01CRV1385. Supramolecular chemistry (general monograph): 99MI5. Supramolecules with properties of molecular recognition: 01CSR158. Synthetic cyclopeptides, cyclodextrins, crown-containing compounds as models of cation-conducting channels: 01CSR274. Three-dimensional aromaticity in polyhedral boranes and related molecules: 01CRV1119.

1. Structure and Stereochemistry a. Theoretical Aspects. Spectroscopy, structure, and photochemical behavior of carbenes in matrices (heterocyclic carbenes and heterocycles as carbene precursors): 01MI61. b. Molecular Dimensions. Contribution of X-ray crystallographic analyses of heterocyclic compounds toward organic chemistry: 99YGK1092. Powder X-ray diﬀraction for structure determination of heterocycles: 01AG(E)1626. Structure investigations of new coordination compounds: 01KK243. c. Stereochemical Aspects. A survey of supramolecular chemistry (1993–1994): 96MI2. Atropoisomerism, particularly, in cyclopeptides: 01CSR145. Control of reactivity in aggregates of amphiphilic molecules: 96MI3. Design of self-replicating systems: 96MI5. Metal template control of self-assembly in supramolecular chemistry: 96MI1. Nuclear Overhauser eﬀect in structural and conformation analysis of heterocycles and biopolymers: 00MI34. Stoichiometric asymmetric processes, e.g., synthesis and transformations of heterocycles: 01JCS(P1)95. Synthesis of hetero-bridged syn-facially fused norbornadienes (‘‘[n]polynorbornadienes’’) and their topological diversity: 00EJO3363.

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[Sec. II.B

Arene complexes of rare-earth metals, among them complexes with heterocyclic ligands: 00UK856. Enantioselective nucleophilic catalysis with ‘‘planar-chiral’’ heterocycles (sandwich compounds): 00ACR412. d. Betaines and Other Unusual Structures. Diazene-derived cyclic azomethine imines: 00JHC541. Heterobicyclopentadienyl complexes of group-3 metals: 01EJI891. Heterocyclic nitrones: 00S759. Heterocyclic phosphorus ylides: 00PHC22. C60 Hexakisadducts with an octahedral addition pattern (particularly, fullerenoheterocycles): 01EJO829. Metal–carbene complexes stabilized by ring heteroatoms: 01JOM(617–618)56. Nonbenzenoid cyclopropanes (including cyclopropaannelated heterocycles): 01EJO849. Stable heterocyclic carbenes: 00CRV39. Structure and dynamics of cationic organic p-complexes (three-membered p- and -complexes with N-, P-, and Hal-cations): 00ZOR479. Zwitterions with heterocyclic fragments among them those with metals as heteroatoms: 00EJI577. e. Miscellaneous Substituted Heterocycles. Chemistry of N-(1-haloalkyl)heteroarylium salts: 00AHC(77)183. Chemistry of vicinal polycarbonyl compounds among them derivatives of heterocycles: 00CRV1121. Cyclic diaryliodonium ions: 00CSR315. Heterocyclic guanidines and guanidine-substituted heterocycles: 01MI134. Monoorganyl derivatives of tellurium(IV) (heterocycles with Te-containing substituents): 00UK940. Progress in the synthetic methods of phosphonyl heterocyclic compounds: 00MI23. Recent trends in the chemistry of ﬂuorinated ﬁve- and six-membered heterocycles: 01JHC793. Six-, seven-, and eight-membered heteryladamantanes: 00ZOR329. Stability of the metal conﬁguration in chiral-at-metal half-sandwich compounds (with heterocycles as ligands at metal atom): 01EJI905. Synthesis of photochromic dihetarylethenes: 01KGS19.

2. Reactivity a. General Topics. Activation of racemic and nonracemic catalysts by their binding with chiral additives among them heterocycles: 00AG(E)3532. Anion recognition by derivatives of heterocycles: 01AG(E)486. Application of microwave activation in heterocyclic chemistry: 00KGS1308.

Sec. II.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

7

Applications of enzymes in organic solvents for transformations of heterocycles: 00AG(E)2226. Arene-catalyzed lithiation in transformations of heterocycles: 00EJO225. Arylation with organolead and organobismuth reagents: 01T5683. Asymmetric cyclopropanation reactions using chiral metal catalysts with heterocyclic ligands: 00MI53. Carbanionic reactivity of the anomeric center in carbohydrates: 01CRV81. Chemical reactions catalyzed by DNA polymerases: 00MI45. Cine- and tele-substitution reactions: 01T1639. Degenerate ring transformations in heterocyclic systems: 99AHC(74)1, 00JHC427. Electrochemical reactions and mechanisms: 00MI6. Electron transfer in covalently linked supramolecular systems based on organic compounds: 01MI39. Electron transfer in host–guest and cage-type supramolecular systems: 01MI43. Electron transfer in hydrogen-bonded donor–acceptor supramolecules: 01MI42. Electron-transfer reactions of heteroaromatic compounds: 01MI33. Enzyme-catalyzed reactions of heterocycles: 00MI5. Formaldehyde N,N-dialkylhydrazones as C1 building blocks in asymmetric synthesis: 00SL1228. Fragmentation and cleavage of heterocycles mediated by SmJ2: 01OPP567. Heterocycles as reagents and ligands in immobilized heterogeneous catalysts: 95MI1. Heterocycles in encapsulation and assembly: 00H(52)493. Heterocyclic carbene protonation: 01MI59. Metal carbenes in organic synthesis (general monograph): 99MI18. Nitro compounds in synthesis and transformations of heterocycles: 01MI32. Organoselenium compounds in stereoselective reactions of heterocycles: 00AG(E)3740. Origin of p-facial diastereoselection in carbonyl addition, application of the exterior frontier orbital extension model to 1,3-diheteran-5-ones (heteroatom ¼ O,S): 00H(52)1435. Photochemical dimerization in solution of heterocyclic substituted alkenes bearing an electron-withdrawing group: 01H(54)475. Prototropic tautomerism of heteroaromatics: 00AHC(76)1. Reactions in high-temperature aqueous media: 01CRV837. Reactions of alkyl carbonates with heterocycles and use of cyclic carbonates in synthesis: 00T8207. Reactions of ketone analogs RR0 M ¼ X (M ¼ Ge, Sn, Pb; X ¼ S, Se, Te) with heterocycles: 00ACR625. Reactions of some heterocycles with XeF2 as ﬂuorinating reagent and radical initiator: 01UK262. Recent advances in chemo-, regio- and stereoselective hydroformylation: 01S1. Role of metal–oxygen intermediates in biological and chemical alkane monooxygenations: 01IZV1712.

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[Sec. II.B

Selective reactions of amino groups in polyamino compounds (particularly those in heterocyclic polyamines) by metal-chelated or -mediated methods: 01T4801. Self-assembly of cyclic nanostructures mediated by transition metals: 00CRV853. -Silyl ketone controlled asymmetric syntheses with participation of heterocycles: 00SL1371. Solvent-free organic syntheses among them syntheses with participation of heterocycles: 00CRV1025. Structures, properties, and synthetic applications of heterocyclic sulfoximines: 00S1. Supercritical ﬂuids in synthetic organic chemistry (including reactions of heterocycles in supercritical CO2): 01JCS(P1)917. Tandem transformations with participation and formation of heterocycles initiated and determined by Michael reaction: 00UK1091. Tautomerism of ﬁve-membered heterocycles with one heteroatom: 00AHC(76)85. Tautomerism of ﬁve-membered heterocycles with two or more heteroatoms: 00AHC(76)157. Tautomerism involving other than ﬁve- and six-membered rings: 00AHC(77)1. Tautomerism of fused ﬁve–six, ﬁve–ﬁve, and six–six ring systems with heteroatoms in both rings: 00AHC(77)51. Transition-metal catalyzed multi-component carbocyclization and related reactions with participation of heterocycles: 99YGK912. Vinylogous aldol reaction of heterocyclic silyloxy dienes and its synthetic application: 00PAC1645. Water-accelerated organic transformations: 01CC299. b. Reactions with Electrophiles and Oxidants. Acetylenic coupling of alkynyl-substituted heterocycles including construction of macrocycles: 00AG(E)2632. Addition of metal derivatives of ﬁve-membered heterocycles to chiral nitrones: 00SL442. Application of Vilsmeier reagents in organic synthesis including acylation, chlorination, chloroformylation, aromatization, and dehydration reactions of heterocycles: 00MI51. Reactions of perﬂuoroalkyl halides with heterocyclic derivatives: 00UK538. Structure and reactivity of nitrozonium complexes of organic compounds including azines, crown ethers, and heterocyclic cations from NO þ and oleﬁns or arenes: 01UK241. Vinylogous Mannich reactions: 01T3221. c. Reactions with Nucleophiles and Reducing Agents. Nucleophilic triﬂuoromethylation reactions of organic compounds (in particular, heterocycles) with (triﬂuoromethyl)trimethylsilane: 00T7613. Reactivity of copper(I) complexes with heterocyclic ligands towards dioxygen: 00EJI2311.

Sec. II.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

9

Translocation of heteroatoms in rings and its role in Dimroth rearrangement of heterocycles: 00AHC(75)79. d. Reactions toward Free Radicals, Carbenes, etc. Cyclic nitroxide radicals: 01MI5. Cyclization of alkoxyl radicals: 01MI12. Enantioselective radical-mediated reactions of carbonyl derivatives of some heterocycles with organotin reagents: 01YGK560. Homolytic aromatic substitution in heterocyclic series: 01MI3. Hydrogen atom abstraction: 01MI8. Isonitriles as useful trap in radical reactions leading to heterocycles: 01MI2. Nitrogen-centered radicals: 01MI11. Radical cyclizations in alkaloid synthesis: 01MI9. Radical reactions of heterocycles on solid support: 01MI4. Rearrangements of epoxides: 01MI7. Sulfur-centered radicals: 01MI13. Synthesis of oxacyclic natural products: 01MI10. Unusual radical cyclizations: 01MI6. e. Reactions with Cyclic Transition State. Cycloadditions (including those with participation and formation of heterocycles) under microwave irradiation conditions: 00EJO3639. Diels–Alder reactions in water: 00PAC1365. Oleﬁn metathesis and related reactions in carbohydrate chemistry (formation and ring opening of heterocycle): 00CC519. Recent advances in Lewis acids catalyzed hetero-Diels–Alder reactions in aqueous media: 01EJO439. Stereoselective 1,3-dipolar cycloadditions to heterocyclic compounds; 00JHC551. f. Heterocycles as Intermediates in Organic Synthesis. Asymmetric synthesis by Diels–Alder reaction with participation of (S)-Nacryloylindoline: 01PAC283. Chiral P,N-bidentate ligands in coordination chemistry and organic catalysis with participation of rhodium and palladium (P,N-bidentate phosphorus containing 4,5-dihydrooxazoles as ligands): 00UK721. Enantioselective catalysts with heterocyclic ligands: 01AG(E)284. Functionalized polymers (among them polymers with grafted heterocyclic residues, which are used for automated combinatorial synthesis): 01AG(E)650. Heterocycles as chiral auxiliary substances and ligands in reactions of enolates: 00T917. Heterocycles as ligands in carbene complexes using as catalysts of oleﬁn metathesis: 00AG(E)3012. Heterocycles as reagents for introduction of protective groups: 00T2339.

10

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[Sec. II.B

N-Heterocycles, crown ethers and their analogs as additives promoting selectivity and activity of lipases in reactions of esteriﬁcation and esters hydrolysis: 00T2905. N-Heterocyclic carbenes in transition-metal-complex synthesis: 00JOM(600)12. Heterocyclic protective groups: 00T2339. N-Fluorinated heterocycles as ﬂuorinating agents: 00MI13. Formylation of carbohydrates using reactions of 2-lithiumthiazole or 2lithiumbenzothiazole with sugar lactones followed by deoxygenation of ketones obtained and CHO group formation from thiazole fragment: 00PAC1577. Glyoxylic acid derivatives in asymmetric synthesis (N-glyoxyl-(2R)-bornane10,2-sultam as a key compound): 00PAC1589. Heterocycles in derivatization reactions in capillary electrophoresis of amino acids: 00CLY347. Heterocycles in the synthesis of carbosubstituted conjugated dienes: 01UK830. Heterocyclic acyl and formyl anion equivalents: 01AHC(79)89. Late-metal catalysts (with heterocycles as ligands) for ethylene homo- and copolymerization: 00CRV1169. Modelling the hydrodenitrogenation of aromatic N-heterocycles in the homogeneous phase: 01EJI43. New trends in peptide coupling reagents (heterocycles as reagents): 01OPP203. Preparation of achiral and enantiopure geminally disubstituted -amino acids for -peptide synthesis (heterocycles in synthesis of -amino acids): 00EJO1. Preparation of mono-, 1,1-di-, trans-1,2-di- and trisubstituted ethylenes by benzotriazole methodology: 01SL458. Recent advances in catalytic enantioselective Michael additions (catalysts with heterocyclic ligands): 01S171. Synthetic application of chiral pool derived heterocycles: 00JHC509. Synthetic applications of electrochemical reduction of allyl ethers in the presence of nickel complexes with bipyridines and tetraazamacrocycles as ligands: 00CCC844.

3. Synthesis a. General Topics, Nonconventional Synthetic Methodologies. Advances in selenocyclofunctionalization reactions (synthesis of N-heterocycles, selenolactonization, and formation of macroheterocycles): 01T1411. Application of enzymes in organic solvents for syntheses of heterocycles: 00AG(E)2226. Application of microwave irradiation in the synthesis of heterocyclic compounds: 01MI136. Arene-catalyzed lithiation in the synthesis of heterocycles: 01SL1197. Asymmetric synthesis of heterocycles, in particular, asymmetric epoxidation and hetero-Diels–Alder reactions: 01MI148.

Sec. II.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

11

Baylis–Hillman reaction (condensations of aldehydes with ,-unsaturated carbonyl compounds or nitriles) with participation and formation of heterocycles: 01MI142. Benzotriﬂuoride and derivatives as solvents for organic synthesis and ﬂuorous synthesis: 99MI14. Carbene complexes of transition metals containing 1,3-butadienyl fragment in syntheses of heterocycles: 00EJO17. Catalyzed asymmetric arylation reactions (with participation or formation of heterocycle): 01AG(E)3284. Chiral nitrone reagents for cycloaddition reactions: 00JHC481. Click chemistry (diverse chemical function from a few good reactions): 01AG(E)2007. Design and management of organic syntheses through free-radical cascade processes: 01AG(E)2224. Development of general-purpose chiral synthons from carbohydrates: 00CRV4267. Electrophile-induced 5-endo cyclizations: 02PHC19. Electrophilic nature of carbenoids, nitrenoids, and oxenoids ([1 þ 2] cycloaddition reactions): 01CRV697. Enantioselective organocatalysis (heterocycles as ligands and auxiliary compounds): 01AG(E)3726, 01CRV757. Formation of heterocycles on insertion of carbenes into CH bonds of alkoxides: 01MI64. Hydrogen bonding in noncovalent synthesis of molecular strands, oligomers with heterocyclic fragments: 01T1139. Increase in intricacy as a tool for evaluating organic syntheses: 01T6855. Intramolecular free-radical conjugate additions: 01T7237. Kinetic resolutions by means of cycloaddition reactions: 01EJO2999. Metal catalysis in water: 99MI12. Modern solvent systems in industrial homogeneous catalysis: 99MI16. Multicomponent reactions with participation of isonitriles in syntheses of heterocycles: 00AG(E)3168. New methodology of electrophilic addition reaction as a method for ‘‘assembling’’ polyfunctional compounds from simple precursors (cyclic vinyl ethers, thiiranium, and thiophanium ions in electrophilic addition reactions): 01IZV1862, 01MI129. Noncovalent synthesis using hydrogen bonding: 01AG(E)2382. Novel heterocyclic construction via dipolar cycloadditions to 1,2-dicarbonyl compounds: 00JHC659. Oleﬁn metathesis in synthesis of heterocycles including macrocycles: 00AG(E)3012. Organic synthesis (basic principles): 98MI1, 01MI31. Organometallic chemistry directed towards organic synthesis (heterocyclization of functionalized allenes, carbopalladation of 1,1-dibromoalk-1-enes to give fused heterocycles): 01MI131.

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[Sec. II.B

Palladium in the synthesis of heterocycles: 00T5959. Perﬂuorinated solvents as novel reaction medium in organic chemistry: 99MI13. Polymer-supported catalysis in synthetic organic chemistry: 01T4737. Preparative biotransformations with participation and formation of heterocycles: 01JCS(P1)1475. Radical translocation reactions in synthesis of heterocycles: 01CSR94. Reactions in ionic liquids (mainly in N-alkylpyridinium and 1,3-dialkylimidazolium salts): 00PAC1391, 00PAC2275, 01CC2399. Reactions in supercritical carbon dioxide (scCO2): 99MI15. Recent progress in the chemistry of multicomponent reactions (syntheses of heterocycles): 01PAC187. Regeneration of carbonyl compounds from the corresponding oximes: 01S1903. Ring expansion reactions of phenylnitrene: 01MI63. Self-assembling of heterocycles: 00CRV3483. Silica gel in organic synthesis, particularly, in formation and transformation of heterocycles: 01UK1094. Silylation as new strategy of using of aliphatic nitro compounds in organic synthesis (cyclic silyl nitronates, heterocyclization): 01IZV1850. p-Shielding in organic synthesis, particularly, in Diels–Alder reactions: 01T7999. Since 1995 the new chemistry of multi-component reactions and their libraries including their heterocyclic chemistry: 00JHC647. Solid-phase reactions with C–C bond formation in syntheses of heterocycles: 99CRV1549. Solvent-free syntheses of heterocycles: 99MI17, 00CRV1025. Syntheses of cyclic iodonium salts and other heterocycles from alkenyliodonium salts: 00UK118. Syntheses of diverse and complex molecules, among them heterocycles, on the solid phase: 00ACR215. Synthesis of heterocycles from molecular nitrogen as a nitrogen source: 00JHC623. Syntheses of heterocycles induced by microwave irradiation: 01PAC147, 01PAC193. Synthesis and application of ﬂuorinated heterocycles: 01MI65. Synthetic methodologies derived from electron-deﬃcient alkynes (with participation and formation of heterocycles): 01MI130. Transition-metal catalyzed multi-component carbocyclization and related reactions of bifunctional molecules with the formation of heterocycles: 99YGK912. Three-component Ni-catalysed cyclizations, couplings, and cycloadditions (among them syntheses of heterocycles): 00ACR467. Various aspects of the reaction of a chiral catalyst or reagent with a racemic or enantiopure substrate: 01T2449. Water as solvent in organic synthesis: 99MI11.

Sec. II.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

13

b. Synthetic Strategies and Individual Methods. Applications of aliphatic unsaturated non-proteinogenic -H--amino acids (including heterocyclizations): 00JCS(P1)4197. Asymmetric hetero-DielsAlder and related reactions: 99MI24. Development of asymmetric synthesis of heterocycles: 99YZ787. Diacetylene-based industrially promising syntheses of heterocycles: 00UK642. Formation of heterocycles in nucleophilic addition to nitrones: 00S759. Junjappa-Ila heteroaromatic annelation: 01PHC1. Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry: 00CRV2091. Methods for the synthesis of conjugated !-aminoketones containing heterocyclic fragments: 00UK1111. Multi-step organic synthesis using solid-supported reagents and scavengers (including synthesis of heterocycles): 00JCS(P1)3815. New applications of polyfunctional organometallic compounds in synthesis of heterocycles: 00AG(E)4414. Nucleophilic addition/ring closure sequence for the stereocontrolled synthesis of heterocycles: 99MI2. Nucleophilic vinyl substitution in the synthesis of heterocycles: 01KGS41. Palladium-catalyzed heterocyclizations reactions of allenes: 00CRV3067. Polymeric scavenger reagents in organic synthesis (including synthesis of heterocycles): 01EJO1213. Preparation of optically active derivatives of heterocycles as a result of autocatalysis: 00CC887. Protecting groups: 00MI3. Radical addition of organohalides to multiple bonds in the synthesis of heterocyclic compounds: 01KGS570. Solid-phase asymmetric synthesis of heterocycles and heterocycles as auxiliary reagents: 01MI126. Soluble polymer supported synthesis and transformations of heterocycles: 00ACR546. Synthesis of heterocyclic and carbocyclic compounds via alkynyl, allyl, and propargyl organometallic cyclopentadienyl iron, molybdenium and tungsten complexes: 00CRV3127. Syntheses of heterocycles using metathesis reactions: 01MI104, 01MI127. Synthesis of heterocyclic compounds from metallated unsaturated compounds and isothiocyanates: 00KGS1443. Synthesis of monotriﬂuoromethyl-substituted saturated heterocycles: 00T3635. Synthesis of sterically hindered heteroaromatic ketones under conditions of phase transfer and metal complex catalysis: 01KGS8. Thermolysis of N-vinylimino ylides and syntheses of mesomeric betaines involving back-donated 1,6-cyclization: 00YZ630. Transannular Diels–Alder strategy applied to total synthesis (transformations of macroheterocyclic trienes): 01T4243.

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[Sec. II.B

c. Versatile Synthons and Specific Reagents. Alkyl 2-substituted 3-(dimethylamino)propenoates and related compounds as versatile reagents in heterocyclic chemistry: 00SL1077. Chiral acetylenic sulfoxides and related compounds in heterocyclic synthesis: 99MI3. Derivatives of -halocrotonic acids, convenient reagents in the synthesis of heterocycles: 00KGS435. -Diazo--dicarbonyl compounds in synthesis of heterocycles: 01MI140. Early transition metal carbenoid reagents in epimetallation and metallative dimerization of unsaturated substrates (synthesis of heterocycles with participation of carbenoid reagents): 01JOM(617–618)148. -Halosulfones in the synthesis and transformations of heterocycles: 01SL1. (Het)aroylpyruvic acids and their derivatives as promising ‘‘building blocks’’: 01UK1039. Organohypervalent iodine compounds in the synthesis of heterocycles: 01SL565. -Silyl ketone controlled asymmetric syntheses of heterocycles: 00SL1371. Stereoselective syntheses of heterocycles with lithiated methoxyallene: 00JHC597. Sulfamides in the synthesis of heterocyclic compounds: 00UK239. N-Sulfonyl imines—useful synthons in stereoselective organic synthesis: 99MI4. Syntheses of heterocycles by aza-Wittig reaction: 01MI139. Syntheses and transformations of heterocycles with participation of triﬂyc anhydride: 00T3077. Synthetic applications of the dearomatization agent pentaammineosmium(II): 01T8203. Transition metal reagents and catalysts: 00MI2. Using ring-opening reactions of oxabicyclic compounds as a strategy in organic synthesis: 99MI1. d. Ring Synthesis from Nonheterocyclic Compounds. Acetylenic and allenic sulfones in syntheses of heterocycles by 1,3-dipolar cycloaddition: 01T5263. Acylic stereocontrol between remote atom centers via intramolecular and intermolecular stereo-communication (formation of heterocycles): 01T2917. Addition of carbon-centered radicals to imines and related compounds (heterocyclizations): 01T5461. Aromatic nucleophilic denitrocyclization, particularly, in synthesis of heterocycles: 01CLY540. Asymmetric 1,3-dipolar cycloadditions for the construction of enantiomerically pure heterocycle: 01OPP103. Brook rearrangement in tandem bond formation strategies (formation of heterocycles as the result of C ! O or O ! C migrations of silyl groups): 01T2065.

Sec. II.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

15

Catalytic enantioselective rearrangements and cycloadditions involving ylides from diazo compounds: 01CSR50. Combinatorial methods for optimization of Diels–Alder aza-reaction, epoxidation and other transformations leading to heterocycles: 01S1431. Conformations of open-chain compounds favorable for heterocyclization and annelation: 00AG(E)2054. Diels–Alder reactions on solid supports: 01T7053. -Halovinylaldehydes as versatile reactive intermediates in the syntheses of polycyclic fused heterocycles: 00H(53)941. Metal mediated carbometallation of alkynes and alkenes containing adjacent heteroatoms (reactions are accompanied by heterocyclization): 01T5899. New routes to heterocycles from unsaturated carbanions, heterocumulenes and thiocarbonyl compounds: 01EJO4569. 4- and 5-Oxocarboxylic acids as versatile synthons for the preparation of heterocycles: 00H(53)1379. Perﬂuorinated acyl(aroyl)pyruvates as building blocks for the synthesis of heterocycles: 00H(52)1411. Radical aryl migration reactions leading to formation of heterocycles: 01T9649. Reactions of conjugated haloenolates with nucleophilic reagents (formation of heterocycles): 01T2643. Recent advances in the synthesis of heterocycles from oximes: 00H(53)2285. Ring closure reactions of suitably ortho-substituted maleanilic acids in synthesis of heterocycles: 00H(53)476. Sulfur ylides in the synthesis of hetero- and carbocyclic compounds: 01UK744. Synthesis of heterocycles based on ketones of adamantane series: 01ZOR489. Synthesis of heterocycles based on reactions of acetylacetaldehyde with aromatic and biogenic amines and indoles: 01H(55)1365. Synthesis of heterocycles by C–C bond-formation and its application: 01MI105. Ynamines and ynamides in synthesis of heterocycles: 01T7575. e. Syntheses by Transformation of Heterocycles. Formation of fused heterocycles from acetylenic or allenic sulfones and pyrroles or furans as dienes: 01T5263. Syntheses of carbohydrate related compounds by using aldolase-catalyzed reaction, in particular, transformations and syntheses of heterocycles: 00YZ42. 4. Properties and Applications (Except Drugs and Pesticides) a. Dyes and Intermediates. b. Substances with Luminescent and Related Properties. Advances and prospects of organic photochromics: 01MI133. Chiroptical molecular switches (photochromic compounds among them dihetarylethenes, fulgides, and spiropyrans permitting undestructive read-out of information using change of optical rotation: 00CRV1789.

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[Sec. II.B

Crown ethers and their analogs as luminescent sensors: 01PAC503. Diaryl- and dihetarylethenes for memories and switches: 00CRV1685. Electron-transfer dyads suitable for novel self-assembled light-harvesting antenna/electron-transfer devices (bacteriochlorin-fullerene dyad): 01PAC469. Fluorescent chemosensors containing polyamine receptors (mainly polyheterocyclic amines: 00EJI2143. Luminescent iridium(III) polyimine complexes with heterocycles as ligands: 00CSR385. Organic photochromism (IUPAC Technical Report summarizing data on terminology in the ﬁeld and classiﬁcation of photochromic compounds): 01PAC639. Photoactive molecular wires based on metal complexes with 2,20 -bipyridine, phenathroline, and 2,20 :60 ,2-terpyridine as ligands: 00CSR1. Three-dimensional optical data storage using photochromic materials (spirobenzopyrans, dihetarylethenes, azobenzene derivatives: 00CRV1777. Use of luminiscence probes for spectral characterization of polymer matrices: 01CLY102. c. Organic Conductors (Except Polymers). Electron transfer in molecular wires based on metal complexes: 01MI50. Heterocycles as conductive molecules: 97MI2. Oligothienylenevinylenes as a new class of multinanometer linear p-conjugated systems for micro- and nanoelectronics: 00ACR147. Protonic molecular wires containing metal complexes: 01MI52. d. Coordination Compounds. Aromatic interactions in complexes formed by heteroaromatic compounds: 01JCS(P2)651. Axially chiral bidentate heterocyclic ligands in asymmetric catalysis: 01T3809. Chiral catalysts with heterocyclic ligands and asymmetric synthesis of heterocycles with participation of metal carbene complexes: 01JOM(617–618)98. Cyclophosphazenes as scaﬀolds for the construction of multi-site coordination ligands: 01CSR193. Electron transfer in covalently linked supramolecular systems containing metal complexes: 01MI41. Electron-transfer processes in mononuclear polypyridine-type metal complexes: 01MI34. Enantioselective acyl transfer using chiral cyclic phosphines as ligands in catalysts: 01SL1499. Heterocycles as ligands in complexes of radioactive elements: 01UK974. Luminescent carbon-rich rhenium(I) complexes with 2,20 -bipyridine ligands: 01CC789. Oxygen scavenging metal chelates with heterocyclic ligands: 01CSR205. Progress in catalytic asymmetric hydrogenation (asymmetric hydrogenation of N- and O-heterocycles, heterocycles as chiral ligands in catalysts: 01MI132.

Sec. II.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

17

Strategies for the construction of supramolecular compounds through coordination chemistry (heterocycles as ligands): 01AG(E)2022. Tris-2,20 -bipyridinecomplex of ruthenium(II) as chlorophyll model in photosystem (II): 01CSR36. Union of planar complexes with N-heterocyclic ligands to three-dimensional complexes: 01CC509. e. Polymers. Foldamers, polymers existing in speciﬁc compact conformation, among them are olygopyridines and nucleotide mimics: 01CRV3893. New polymer synthesis by nitroxide mediated living radical polymerizations: 01CRV3661. Polyaniline and polypyrrole as representatives of conducting polymers: 01CLY484. Polymer monolayers and Langmuir-Blodgett ﬁlms of conducting oligo- and polythiophenes: 00UK963. Supramolecular polymers with N-heterocyclic monomeric units: 01CRV4071. Synthesis and molecular electronic properties of oligomers with alternating 2,5-thienylene and ethynylene subunits: 00ACR791. Synthesis of polymeric enzyme-like catalysts with N-heterocyclic fragments as active centers: 01SL1343. Synthesis of ultrapure, processable, and high-mobility organic transistor semiconductors (thiophene oligomers, anthradithiophenes, benzodithiophenes, phtalocyanins, polythiophenes): 01ACR359. f. Miscellaneous. Bis(ethylenedithio)tetraselenafulvalene (BETS) as a source of molecular magnetic superconductors: 00CSR325. Electron-transfer approaches to an optically controlled molecular switch: 01MI51. Electron transfer-based molecular logic gates: 01MI53. Electron transfer-based molecular antennas: 01MI54. Electron transfer in molecular memory devices: 01MI55. Electron transfer in nonlinear optics: 01MI56. Ionic liquids (mainly pyridinium and imidazolium salts) as new ‘‘solutions’’ for transition metal catalysis: 00AG(E)3772. Photochromic fulgides, fulgimides and related compounds for memories and switches: 00CRV1717. Photochromic spiropyrans and spirooxazines for memories and switches: 00CRV1741. Protein crystals cross-linked by compounds with pyridine and/or succinimide fragments as novel catalytic materials: 01AG(E)2204. Switching devices based on interlocked molecules, catenanes with heterocyclic fragments: 01ACR433. Syntheses and properties of functionalyzed dendrimers containing heterocyclic fragments: 00UK699.

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[Sec. II.C

C. SPECIALIZED HETEROCYCLES 1. Nitrogen Heterocycles (Except Alkaloids) a. General Sources and Topics. Advances in the chemistry of azatricyclo[4.3.1.1.3,8]undecane (4-azahomoadamantane): 01ZOR959. Cyclic N-acyliminium salts and related intermediates: 00T3817. Nitrogen-containing ligands for asymmetric homogeneous and heterogeneous catalysis: 00CRV2159. Nitrogen pyramidal amides (N-benzoyl-7-azabicyclo[2.2.1]heptanes): 01YZ65. Sulfonimidic acids and their derivatives (S,N-heterocyclic sulfonimides): 00ZOR167. Synthesis and chemistry of bridgehead azabicycloalkenes: 01AG(E)820. b. Structure and Stereochemistry. Cyclic azomethines and their hydrogenated derivatives: 00KGS579. Synthesis of neutral p-allylpalladium complexes having bisnitrogen ligands (mainly, those related to 2-(pyrazol-3-yl)pyridine, 2-(imidazol-2-yl)pyridine, and 2,2-bipyridine) and palladium-catalyzed cyclopropanation of ketene silyl acetals with allylic acetates: 00YGK736. c. Reactivity. Catalysis of isomerization of amides, derivatives of cyclic amines: 00ACR849. ortho-, meta-, and para-Cyclizations in structure modiﬁcations of p-deﬁcient azaaromatic compounds: 01MI99. Cyclic imines with glycine or alanine fragment as templates for asymmetric synthesis of -amino acids: 00EJO2689. Exploring the chemistry of 3-substituted 2-azanorbornyls in asymmetric catalysis: 00SL1092. Reactions of highly electrophilic ﬂuoro-containing compounds with cyclic enamines, isoquinoline, quinoline, pyridine and indole derivatives: 01MI77. Some aspects of the Lewis base and ligand behavior of N-heterocyclic carbenes: 01JOM(617–618)105. Strategies of the regioselective N-functionalization of tetraazacycloalkanes: 00SL561. d. Synthesis. Allylic boron and zinc derivatives in synthesis of nitrogen heterocycles: 00PAC1641. Amidoalkylating agents in the synthesis of N-heterocycles: 92MI1. Annelation of azomethines with -di- or ,0 -tricarbonyl compounds: 01MI75. Bis-triazenes as precursors of heterocycles: 01OPP59. Catalytic asymmetric hetero-Diels–Alder reactions of imines: 00AG(E)3558. Diels–Alder reactions of 1-azadienes: 00T5259. Heterocyclizations of trisubstituted formamidines containing aryl or hetaryl substituent at the imine N-atom: 00UK924.

Sec. II.C]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

19

Metallation-based functionalization of azines and azoles: 01EJO3975. 6-Methylenecyclohexa-2,4-diene-1-imines (aza-ortho-xylylenes), their syntheses, valence isomerization to benzazetines, and application to the synthesis of heterocycles: 01EJO3587. Organosilane-induced synthesis and functionalization of sulfur-containing N-heterocycles: 00EJO2171. Rhodium(II) mediated cyclizations of diazo alkynyl ketones: 01JOM(617–618)3. Phosphonium reagents for the synthesis of nitrogen heterocycles: 01MI89. Stereoselective C–C bond formation and cyclizations of biradicals (with formation of pyrrolidine or piperidine rings): 00PAC1623. Syntheses and applications of optically active N-bicyclic compounds: 00YZ1117. Synthesis and properties of nitrogen heterocycles containing a spiro cyclopropane fragment: 00UK507. Synthesis of N-heterocycles by Diels–Alder cycloaddition of ,-unsaturated N,N-dimethylhydrazones: 01H(54)1095. Synthesis of lactams using trasition metal catalysis of selective cyclocarbonylation reactions: 00SL161. Use of polyvalent-iodine compounds in the synthesis of nitrogen-containing heterocycles: 00MI30.

2. Oxygen Heterocycles a. Chemistry of Individual Classes of O-Heterocycles. Cyclic ethereal oxonium ylides: 00YGK934. Chemistry of bridgehead oxabicycloalkenes: 01AG(E)820. b. Reactivity. Organosilane-induced synthesis and functionalization of sulfur-containing O-heterocycles: 00EJO2171. c. Synthesis. Asymmetric synthesis of O-heterocycles: 00JCS(P1)1785. Catalytic asymmetric hetero-Diels–Alder reactions of carbonyl compounds: 00AG(E)3558. The eﬀect of ring strain on the ease of lactonization of bifunctional chain molecules: 00EJO3117. Heterocyclization on alkylation of phenols with terpenoids leading to partially hydrogenated polycyclic fused furans and pyrans: 00KPS198. Intramolecular [4 þ 3] cycloaddition reaction, in particular, with participation of furan derivatives: 01ACR595. Oxygen-containing heterocyclic compounds on the base of 1,5-diketones: 00KGS1155. Photoinduced [2 þ 2] cycloaddition of double C¼O bonds to triplet benzene derivatives: 01ACR1.

20

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[Sec. II.D

Synthesis of lactones by transition metal catalysis of selective cyclocarbonylation reactions: 00SL161. Syntheses of O-heterocycles by Co-mediated cyclizations, particularly, by Pauson-Khand reaction: 00JCS(P1)1657. Synthesis of oxygen heterocycles via alkynyltungsten compounds: 01PAC265. 3. Sulfur Heterocycles a. Chemistry of Individual Classes of S-Heterocycles. Sulfonimidic acids and their derivatives (S,N-heterocyclic sulfonimides): 00ZOR167. b. Structure and Stereochemistry. New aspects of hypervalent organosulfur compounds: 99MI9. Sulfur radical cations: 99MI8. c. Reactivity. Cyclic sulﬁtes and cyclic sulfates in organic synthesis: 00T7051. d. Synthesis. Asymmetric [4 þ 2] cycloadditions mediated by sulfoxides: 99MI6. Organosilane-induced synthesis and functionalization of S-heterocycles: 00EJO2171. Synthesis of vinyl sulfoxides, derivatives of S-heterocycles: 00ZOR11. Thiocarbonyl compounds as speciﬁc tools for organic synthesis: 99MI7.

D. NATURAL AND SYNTHETIC BIOLOGICALLY ACTIVE HETEROCYCLES 1. General Sources and Topics Bioactive natural products: 00MI33. Biodegradable polymeric materials based on starch: 00UK494. Chem-Bioinformatics and QSAR: 01CRV619. Forensic science: 99AC(12)235R. Metal ion eﬀects in isotopic hydrogen exchange in biologically important heterocycles: 00ACR672. Molecular recognition of photoinduced electron transfer ﬂuoroionophores: 00H(52)945. QSAR and QSPR in nitrogen heterocycles: 01MI90. Role of metal–oxygen intermediates in biological alkane monooxygenations: 01IZV1712. Stereocontrolled additions to dihydropyridines and tetrahydropyridines as an access to N-heterocycles related to natural products: 01AHC(78)269. Structure–property relationships in functional conjugated oligomers: 99PAC2053.

Sec. II.D]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

21

The chelate eﬀect in binding, catalysis, and chemotherapy: 00PAC333. Three-dimensional database searching of bioactive compounds and their application: 00YGK676. a. Biological Functions of Natural and Synthetic Bioactive Heterocycles. Free-radical mechanisms of biological action of nitrofurans: 00MI39. Hemoglobin as oxygen carrier: 01CRV2797. Models of hemoprotein active sites: 96MI4. Nitrogen heterocycles as ligands of serotonin receptors: 01MI85. Synthetic hydrogen-bonding receptors (heterocycles) for biologically essential monosaccharides: 00YGK1077. Thermodynamic aspects of molecular recognition in solutions of crown ethers, cryptands and cyclodextrins: 01MI80. b. General Approaches to Syntheses of Biologically Active Heterocycles. A novel synthesis of porphobilinogen, synthetic and biosynthetic studies: 00JHC487. Application of chiral (salen)Co in catalytic asymmetric reaction and natural product syntheses: 00MI26. Biological activity of 5- and 6-membered azaheterocycles and their synthesis based on 5-aryl-2,3-dihydrofuran-2,3-diones: 01KGS291. Boron Heterocycles as Platforms for Building New Bioactive Agents: 00PHC1. Carbohydrates in the synthesis of natural products: 01AG(E)1576. Concepts for the total synthesis of deoxy sugars: 01S507. Development of synthetic methods for 4-substituted indoles and their applications for the syntheses of natural products: 00YZ363. Eﬃcient synthesis of organometallics of pyridine quinolines and diazines: new synthetic methodologies for azaaromatic biomolecules: 00JHC615. Electrophile-induced cyclizations in syntheses of physiologically active azaheterocycles: 00JHC607. Heterocycles in synthesis of insect pheromones: 01MI69. Nickel-catalyzed cyclization of 1,3-dienes with a tethered carbonyl group and its application to synthesis of natural products: 01YGK576. Pauson–Khand reaction and related [2 þ 2 þ 1] cycloadditions in the syntheses of some natural heterocycles: 00T3263. Reactions of 1,3-dipolar cycloaddition of nitrile oxides in synthesis of natural compounds and their analogs: 01UK730. Rearrangements of sulfoxides and sulfones in total synthesis of natural compounds: 01UK1013. Silyloxy-Cope rearrangement of syn-aldol products (formation of tetrahydropyrans and piperidines used in syntheses of natural compounds): 01SL1079. Solid-phase synthesis of oligosacharides and glycoconjugates: 00UK869. Stereoselective total synthesis of axially chiral natural products via biaryl lactones: 01ACR615. Sulfones and sulfoxides including heterocyclic ones in total synthesis and transformations of biologically active natural compounds: 00UK403.

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[Sec. II.D

Survey of the most important achievements of the twenty century in the ﬁeld of total synthesis of natural compounds: 00AG(E)44. Synthesis of cyclopropane ring-containing natural products: 01T8589. Syntheses of biologically active azine and azole derivatives: 01MI91. Syntheses of natural saturated O-heterocycles with bicobalt hexacarbonyl complex of acetylene: 00YGK25. Synthesis of biologically active natural heterocycles using metal-mediated key reactions: 00YZ1035. Synthesis of 2-deoxyglycosides; 1988–1999: 00T8385. Tartaric acid and tartrates in the synthesis of bioactive molecules: 01S1281. The -alkyl Suzuki–Miyaura cross-coupling reaction in natural product synthesis: 01AG(E)4544. The eﬃcient total synthesis of bioactive microbial natural heterocycles: 00YGK828. Total syntheses of the 1990s: 00AG(E)1538.

2. Alkaloids a. General. Alkaloids as chirality transmitters in asymmetric catalysis: 00MI7. Biological activity of alkaloids (a microreview): 01MI103. Isolation, total synthesis, and biological activity of phenanthroindolizidine and phenanthroquinolizidine alkaloids: 01S2365. b. Structure. Structure and synthesis of antimalarial quinazoline alkaloid febrifugine: 01YGK569. c. Synthesis. Development of intramolecular oxidative phenolic coupling reactions using hypervalent iodine(III) reagents and their application to the synthesis of Amaryllidaceae alkaloids: 00YZ1061. Eﬃcient stereoselective syntheses of piperidine, pyrrolidine, and indolizidine alkaloids: 99YGK834, 01PAC573. Enantioselective total synthesis of marine alkaloids, manzamine A, and related compounds: 00JHC567. New approaches to total synthesis of manzamine A, ircinal A, and related alkaloids: 99YGK1004. New synthetic methods and strategies for the total syntheses of pumiliotoxin A class alkaloids: 99YGK981. Recent chemistry of benzocyclobutenes, in particular, their use in the synthesis of alkaloids and other heterocycles: 01T625. Recent progress in eﬃcient syntheses of Amaryllidaceae and morphine alkaloids: 00JHC535. Synthesis of strychnine: 00CRV3455.

Sec. II.D]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

23

Total synthesis of montanine-type Amaryllidaceae indole alkaloids: 00PAC1773. Vinyl isocyanates as useful building blocks for alkaloid synthesis: 00SL1. d. Individual Groups of Alkaloids. Alkaloids containing isoquinolinequinone unit: 00MI9. Biological activity and new trends in the chemistry of isoquinoline alkaloids: 01MI92. Biological aspects of aporphinoid alkaloids: 00MI8. Chemical studies on the analgesic indole alkaloids from the traditional medicine (Mitragyna speciosa) used for opium substitute: 00YZ959. Chemical transformations of tricyclic quinazoline alkaloids: 01MI101. Cinchona alkaloids and their derivatives as catalysts and ligands in asymmetric synthesis: 01S961. Diterpenic acid-based alkaloid-like compounds as new group of nootropic agents: 01MI97. Diterpenoid alkaloids of getizane type: 00KPS345. Electrochemical determination of alkaloids of the morphine series: 00CLY1075. Glycosidase-inhibiting glycomimetic alkaloids (piperidine analogs of sugars), their biological activity and therapeutic perspectives: 00YGK666. Palladium chemistry in pyridine alkaloid synthesis: 00PHC37. Progress in studies of novel marine bisindole alkaloids: 00MI50. Quinoline alkaloids of Orixa Japonica: 01H(54)1139. Recent progress on the lupine alkaloids in leguminous plants growing mainly in Japan: 00YZ923. Sanguinarine (naphto[1,2-c]isoquinoline derivative) and related alkaloids: 00CLY15. Simple indolizidine and quinolizidine alkaloids: 01MI58. Tebaine-based syntheses of -opioide agonists: 01MI102. The Almaline group of indole alkaloids: 01MI57. The pharmacology and therapeutic aspects of colchicines: 00MI11.

3. Antibiotics a. General. Bacterial RNA as targets of carbohydrate-based antibiotics in connection with resistance to the latter: 01AG(E)3508. Comparison of new natural immunosuppressors with cyclosporine A by the mechanism of action: 00MI36. Genetic and biochemical studies on the regulatory mechanism of the selfresistance and biosynthesis of antibiotics: 01YZ193. Use of various antibiotics for the treatment of patient with acute sinusits: 00MI38.

24

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[Sec. II.D

b. Antitumor Antibiotics. Synthesis and mode of action of azinomycins (antitumor antibiotics with 1azabicyclo[3,1,0]hex-2-ylidene structural fragment): 01T4467. Synthesis of benzonaphthopyranone C-glycoside ravidomycin: 00PAC1783. Synthetic studies on the A 83586 C and bryostatic antitumor macrolides and the monoamycin antibiotics: 00PAC1659. c. -Lactam Antibiotics. Cephalosporines, their signiﬁcance, and history of discovery: 01MI112. Cephoperazon (medoceph) in the modern treatment of heavy forms of bacterial infections: 01MI114. -Lactams, structure-activity relationship: 00MI24. Modern signiﬁcance of cephalosporine antibiotics by treatment of infections in hospital: 01MI113. Structural aspects of carbopenem antibiotics: 01H(54)497. d. Macrocyclic Antibiotics. Cyclic peptide antibiotics produced by bacteria of Bacillus genus: 01KPS103. Macrolide antibiotics with 1-(2-methylthiazol-4-yl)propen-2-yl substitutent, Epothilones A–D, and their thiazole-modiﬁed analogs as novel anticancer agents: 99PAC2019. Main properties and treatment of community acquired pneumonias of Azitromycin (Sumamed, 15-membered macrolide with N-atom in aglycone ring): 00MI43. Strategy and methodology for the total synthesis of polyether ionophore antibiotics: 00CRV2407. e. Miscellaneous Antibiotics. Antimicrobial activity, pharmacokinetics, and clinical signiﬁcance of Levoﬂoxacin (Tavanik), new quinolone of III generation: 01MI116, 01MI117. Arthrotoxicity and mechanism of action of quinolones and ﬂuoroquinolones: 00MI40. Conformational ﬂexibility of cyclosporins: 01CLY9. Fluoroquinolones in the treatment of pneumonia: 00MI42. (E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)4-methylhex-4-enoic (mycophenolic) acid as antibiotic and immunosuppressant: 00CRV3801. Lomeﬂoxacin (Maxaquin), a broad-spectrum antimicrobial agent, results of its 10-year use in Russian hospitals: 00MI37. Role of Peﬂoxacin (Abactal) in modern therapy of bacterial infections: 00MI41. Spiramicin (rovamicin) in the treatment of toxoplasmose of pregnant women: 01MI115. Synthetic studies toward pyranonaphthoquinone antibiotics: 00PAC1635, 00T1937.

Sec. II.D]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

25

4. Vitamins Biological activity of oxythiamine synthetic derivatives: 00KFZ(6)8. Methods for control and standardization of drugs containing liposoluble vitamins: 01KFZ(10)41. Synthesis and reactions of antimalarial bicyclic peroxides: 00JHC639.

5. Drugs a. General. Analysis of pharmaceuticals and related drugs: 99AC(12)217R. Application of bioreduction to the asymmetric syntheses of chiral drugs: 01MI118. Applications of green chemistry in the manufacture of oligonucleotide drugs: 01PAC175. Biotransformation of terpenoids from the crude drugs and animal origin by microorganisms: 01H(54)529. Brazilian phytochemical diversity: bioorganic compounds produced by secondary metabolism as a source of new scientiﬁc development, varied industrial applications, and to enhance human health and the quality of life: 99PAC1663. Chemical aspects of drugs eﬀect on functions of organism: 01IZV1293. Computer prognosis of biological activity of chemical compounds as starting point for the search and optimization of basic structure of new drugs: 01MI95. Continuing evolution of the drug discovery process in the pharmaceutical industry: 01PAC67. Design and development of novel polymeric prodrugs prepared by mechanochemical solid-state polymerization: 00YZ1337. Detection of drugs and poisons: 01AC2735. Development of measurement of new quinolones in body ﬂuids by HPLC using column switching and their application to drug interaction: 01YZ319. Expanded porphyrins as synthetic materials with potential medical utility: 99PAC2009. Finding drug candidates in virtual and lost/emerging chemistry: 00JHC669. Importance of biodiversity to the modern pharmaceutical industry: 99PAC1655. Novel reagents and reactions for drug design: 00PAC347. Novel routes to chiral drugs: 01MI93. Pharmaceutical and related drugs: 01AC2805. Property-based design: optimization of drug absorption and pharmacokinetics: 01JMC1314. Studies on the eﬃcient syntheses of N-heterocyclic drug metabolites: 00YZ1135. Targeting RNA with small-molecule drugs: 01ACR836. Thermodynamic modeling of crystal deposition (particularly, that of xanthine, uric acid, and urates) in humans: 01PAC785.

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[Sec. II.D

b. Definite Types of Activity. Anti-carcinogenic structure modiﬁcation by ﬂuorine-substitution in azapolycyclic aromatica: 00YZ1373. Antimicrobial preparations as immunomodulators of biological reactivity of organism: 01MI119. Anti-tumor activity of some polynitrile derivatives including derivatives of 2-pyrroline, pyrrole, 2,7-dioxabicyclo[3,2,1]octane, pyrido[30 ,40 :3,4]pyrrolo[1,2-a]1,3,5-triazine, pyrrolo[3,4-c]pyridine, and 1,2,3,4-tetrahydropyridine: 00KFZ(4)11. Assesment of anti-tremorogenic drugs using nicotine-induced tail-tremor model and elucidation of the mechanism: 01YZ259. Asymmetric synthesis of an endothelin receptor antagonist (pyridine derivative): 99YGK1016. C- and N-Substituted mono- and bicyclic piperidines as new synthetic analgesics and anesthetics: 01MI96. Chemistry, design, and structure-activity relationship of cocaine antagonists (N-heterocycles as antagonists): 00CRV925. Comparative QSAR analysis of 5-reductase inhibitors (azasteroids as inhibitors): 00CRV909. Current and novel approaches to the drug treatment of schizophrenia: 01JMC407. Design of piperidine derivatives as selective sigma ligands: 01PAC1499. Drugs used by Alzheimer’s disease: 01KFZ(4)3, 01MI120. From cancer prevention to cancer treatment using some N-heterocycles as drugs: 00YZ987. GABA-activated ligand gated ion channels: medicinal chemistry and molecular biology: 00JMC1427. Heterocycles as corticotropin releasing factor (CRF) receptor modulators: 00JMC1641. Heterocycles as ligands of peroxysomatic proliferationally activated receptors: 00JMC527. Heterocycles as pain-relieving agents: 99JMC1481. Heterocycles as platelet glycoprotein IIb–IIIa antagonists: 00JMC3453. Heterocycles as sodium channel blockers: 01JMC115. N-Heterocycles as potassium channel modulators: 01JMC1627. Heterocycles for treatment to cocaine abuse: 99JMC2721. Heterocyclic ligands for glutamate receptors: design and therapeutic prospects: 00JMC2609. Histamine receptors and histaminergic substances: 00KFZ(3)3. Isolation and identiﬁcation of trypanocidal coumarin derivatives from the Rutoles: 01PAC617. Lipophilic nitrogen heterocycles as prospective class of antituberculosis preparations: 01MI100. Main directions of search of new anti-tubercular agents including derivatives of heterocycles: 00KFZ(1)12. Main trends in design of drugs for chemotherapy of AIDS: 00MI44.

Sec. II.D]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

27

The NCI (National Cancer Institute, USA) experience in international collaboration in drug discovery and development: 99PAC1619. New dermatological agents for the treatment of psoriasis: 01JMC281. New developments in anti-HIV chemotherapy: 01PAC55. New developments in A1 and A2 adenosine receptor antagonists: 01PAC1411. Novel strategies for the discovery of plant-derived anticancer agents: 99PAC1611. Perspectives in animal healh: 01JMC641. Perspectives of epilepsy treatment by a herbal mixture prescription ‘‘saikokeishito-ka-shakuyaku’’ (SK): 01YZ295. Physiologically active compounds including heterocycles interacting with glutamate receptors: 00ZOR1273. Piperidine and pyrrolidine derivatives as arginine mimetics: 01T7073. Physiologically active compounds interacting with serotonin (5-hydroxytriptamine) receptors: 01UK382. Policyclic heterocycles as antagonists of opioid receptors: 01JMC2259. Syntheses of HIV protease inhibitors: 01S2203. Syntheses of non-nucleoside reverse transcriptase inhibitors (heterocycles as inhibitors): 00S479. Synthesis of acyclovir, gancyclovir, and their prodrugs (guanine derivatives with antiviral activity): 00S329. Synthesis of thymidine derivatives as potential drugs against HIV: 01ZOR807. The use of boron clusters in the rational design of boronated nucleosides for neutron capture therapy of cancer: 00JOM(614–615)37. c. Individual Substances and Groups of Compounds. Antitumor acridines with diaminoalkyl pharmacophoric group: 01PAC1421. Application of polymers and copolymers of acrylic acid and ethylene oxide derivatives in pharmacy: 01KFZ(1)33. Chemistry and total synthesis of natural antitumor terpenoid taxol: 01CC867, 01MI123. Chemistry of biologically important synthetic organoselenium compounds: 01CRV2125. 1-(Chloromethyl)silatran as regulator of functional activity1of connective tissue: 01KFZ(9)3. Dibenzoxepines as treatments for neurodegenerative diseases: 99PAC2039. Discovery and development of novel anticancer drug capecitabine (N4-amyloxycarbonyl-50 -deoxy-5-ﬂuorocytidine): 99YZ881. Donepezil hydrochloride, an acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease: 99PAC2031. 2-(4-Methyl-1-piperazinyl)-10-methyl-3,4-diazaphenoxazine dihydrochloride (Azafen) as antidepressant: 00KFZ(5)16. New drugs based on alkaloids and nitrogen-containing terpenoids: 01MI84. New medical materials on the basis of modiﬁed polysaccharides: 00KFZ(11)36. Pharmacological role of isatin, an endogenous MAO inhibitor: 00YZ352.

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[Sec. II.D

Porphyrins in chemical control of cell diﬀerentiation of human myeloleukemia: 00YZ104. Pyrazidol (Pyrlindole, 2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2-j,k]carbazole hydrochloride) as antidepressant: 00KFZ(9)12. Pyrazino[1,2,3-a,b]--carboline derivative, Inkazan (Metralindole), as antidepressant: 01KFZ(2)3. Quinolizidine alkaloids and ﬂavonoids in Sophora Flavescens Soland roots: 01MI121. Rational design and synthesis of homochiral azole antifungal agents: 01PAC1477. Recent studies on taxol related water-soluble prodrugs: 01MI122. Research and development of an antiplatelet agent cilostazol: 00YZ1247. Retinoic acid and its heterocyclic analogs as new promising chemopreventive and chemoterapeutic agents in oncology: 01PAC1437. Synthesis of {1-[(4-tert-butylaminocarbonyl)-2-methoxyphenylsulfonyl]-40 -(2morpholinoethoxy)-5-ethoxyspiro(quinoline-3,10 -cyclohexane)-2-one, the vasopressin receptor 2 antagonist SR-121463: 01PAC1401. Targeting of ellipticine drugs on tumor cells: 01CLY549.

6. Pesticides Strigol-type bis--lactones as germination stimulants: 99CC2017. Synthesis of O-heterocyclic pheromones: 00ACR102. Trends in research of crop protection (heterocycles as insecticides, herbicides and fungicides): 00AG(E)1725.

7. Miscelaneous a. Enzymes, Coenzymes, and Their Models. Angiotensin II antagonists: 00YZ1261, 01CRV2727. Calix[4]arenes as dinuclear metallo-phosphodiesterase models: 00CSR75. Zn-Chelates with tripodal ligands containing N-heterocyclic fragments as analogs of zinc enzymes: 00CC1971. Comparative QSAR study of tyrosine kinase inhibitors: 01CRV2573. Correlation of three-dimentional structure and mechanism for heme-containing oxygenases and peroxidases: 01MI37. Cytochrome oxidase, electron transfer in respiration: 01MI36. Discovery and application in cell biology of Lactacystin, a proteasome inhibitor: 00YZ935. Electrochemical and photochemical activation of redox enzymes: 01MI49. Electron transfer conjugated with ATP hydrolysis in nitrogenase: 01IZV1706. Heme peroxidases, their structure, function, mechanism, and involvement in activation of carcinogens: 00CCC297.

Sec. II.D]

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29

Se,N-Heterocycles as antioxidants with glutathione peroxidase activity: 00CSR347. Heterocycles as inhibitors of caspases and possible anti-inﬂammatory and antiapoptotic drugs: 00JMC3351. Heterocycles as cyclin-depedent kinase inhibitors, useful targets in cell cycle regulation: 00JMC1. Heterocycles as protease inhibitors: 00JMC305. Inhibitors of cyclin-dependent kinases: 01CLY295. Interaction of structure of protein globule and bioluminescence spectra of ﬁreﬂy luciferase: 01IZV1670. Investigations of the roles of the distal heme environment and the proximal heme iron ligand in peroxide activation by heme enzymes via molecular engineering of myoglobin: 01ACR818. Model studies for molecular recognition of carbonic anhydrase and carboxypeptidase: 01ACR171. New heterocyclic structures from unsaturated aldehyde derivatives. Inhibition of -fucosidases: 00JHC455. NMR studies of ligand binding with dihydrofolate reductase: 00AG(E)290. Plant cytochromes P450 and peroxidases and their role in degradation of environmental contaminants: 01CLY212. Preparation of novel speciﬁc aminopeptidase inhibitors with a cyclic imide skeleton: 00YZ909. L-Proline as an enzyme mimic and new asymmetric syntheses using small organic molecules as chiral catalysts: 01AG(E)529. Pyridoxal 50 -phosphate-dependent ,-elimination reactions of O-acetylserine sulfhydrylase: 01ACR49. Roles of human cytochrome P450 enzymes involved in drug metabolism and toxicological studies: 00YZ1347. Structural aspects of catalysis mechanism and inhibition of dihydrofolate reductase: 01IZV1652. Synthesis of inhibitors of HIV-RT and thrombin: 99PAC2025. Synthetic studies on N-heterocyclic antagonists of cholecystokinin receptor: 00YGK766. Telomeres and telomerase (enzyme having RNA subunit and conducting replication of the ends of linear chromosomes, in particular, those of human cells): 00AG(E)33. Use of inhibitors to study reactions catalyzed by enzymes requiring pyridoxal phosphate as coenzyme: 00PAC373.

b. Amino Acids and Peptides. Designer cyclopeptides for self-assembled tubular structures: 00PAC365. Designer hybrid cyclopeptides for membrane ion transport and tubular structures: 01ACR919. Disulﬁde-bonded cyclic peptides: 00SL172.

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[Sec. II.D

N-Heterocycles in the synthesis of mimetics of polypeptides of -hairpin group as reagents for drug and vaccine discovery: 00SL429. Palladium-catalyzed heterocyclizations of amino acid and peptide derivatives: 00SL1523. Peptide and protein recognition by designed molecules of heterocycles: 00CRV2479. Peptide-based heme-protein models: 01CRV3165. Peptide segment coupling by prior ligation with various heterocyclic derivatives and proximity-induced intramolecular acyl transfer: 00T3449. Reactions, synthesis and biological activities of amino acid derivatives: 01MI124. Recent advances in study on cyclic peptides from marine sponges: 01MI143. Substrate dehydrogenation by ﬂavoproteins: 01ACR299. Syntheses and applications of -turn mimetics of peptides and proteins: 01T7431. Synthesis of modiﬁed peptides containing -amino aldehydes on the C-end: 00MI17. Tryptophan rotamers that report the conformational dynamics of proteins: 01PAC415. c. Plant Metabolites. Antihypertensive chromenes and ﬂavones in the leaves of kumis kucing (Orthosiphon aristatus) in Java island: 00YZ474. Asymmetric total synthesis of terpenoids possesing novel structure of macrocyclic ethers with two bibenzyl fragments: 00YGK1167. Biological and pharmacological activity of lignans: 00CLY111. Chemical composition of genus Lamium L.S.L. species (Iridoids, terpene glycosides of 6-membered cyclic acetals): 00MI48. Chemistry and biology of plant-leaf movements, N-heterocycles as factors of the movement: 00AG(E)1400. Distribution, chemistry and activity of anti HIV–1 active Calophyllum coumarins: 00H(53)453. Flavonoids, alkaloids, and vitamins C and E as components of some species of Elaegnaceae family plants: 01KPS87. Flavonoids and methylxantines in cocoa beans and chocolate: 01CLY610. Indole derivatives in vegetables of the Cruciferae family: 00MI46. Plant O-heterocycles: 01KPS3. Research of furostanol saponins (steroid saponins with tetrahydrofurane ring E): 00MI25. Sesquiterpene lactones and acetogenin lactones from the Hepaticae: 01H(54)1057. Stereocontrolled syntheses of unsymmetrically substituted furofuran lignans: 00H(52)1399. Strategies for the synthesis of ellagitannins (macrocyclic diesters of hexahydroxydiphenyl-2,20 -dicarboxylic acid and sugars): 01S1585.

Sec. II.D]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

31

Structure, biological activities, and total syntheses of macrocyclic ethers with two bisbibenzyl fragments from liverworts: 00YGK654. Taxanes (tetracyclic terpenoids with oxetane fragment), anticancer drugs with unique mechanism of action: 00CLY226. d. Heterocycles Produced by Marine Organisms. Guanidine metabolites of Ptilocaulis spiculifer and related compounds (marine alkaloids with tricyclic guanidine fragment); isolation and synthesis: 00CSR57. Marine cyanobacteria—a proliﬁc source of natural products: 01T9347. Marine O-heterocycles, macrolides, and alkaloids: 01EJO633. Marine polar steroids with O- and N-heterocyclic fragments: 01UK763. Nitrogen-containing metabolites from marine bacteria: 00MI10. Recent advances in tetrodotoxin research: 00YZ825. Synthesis and biological activity of the marine metabolite cylindrospermopsin: 01CSR303. Total syntheses of pinnatoxin (a macrocycle with O- and N-heterocyclic fragments): 00YGK877. Total synthesis of antillatoxin, an ichthyotoxic cyclic lipopeptide from marine cyanobacterium Lyngbya majuscula: 00YGK634. Total synthesis of marine oxylipins: 01YGK599. Total synthesis of polycavernoside A, macrolide toxine from red algae Polycavernosa tsudai: 99YGK993. e. Cyclodextrins. Cyclodextrin-based molecular machines: 01ACR456. Cyclodextrin host–guest systems containing azaaromatic moieties: 00H(53)1595. The gas-phase chemistry of cyclodextrin inclusion complexes: 01ACR653. f. Other Topics. Absorption and ﬂurescence spectra of 8-aza-(D-homo)-gona-12,17(a)-diones: 01MI73. Antifungal metabolites (O-heterocycles) produced by micromycetes: 00CLY21. Cyclohexane epoxides—chemistry and biochemistry of ( þ )-cyclophellitol: 01EJO1607. Dendrobatidae frog poisons (hexacyclic systems with N- and N,O-heterocyclic fragments): 00CLY230. Homogeneous redox catalysis in CO2 ﬁxation: 01MI48. Medium and temperature eﬀects on the redox chemistry of cytochromes: 01EJI2989. Microbial production of colored azaphilone metabolites (6,7-dihydroisochromene-8-one or 6,7-dihydroisoquinoline-7-one derivatives: 00CLY105. Microtubule inhibitors: 01CLY700. Novel microbial metabolites, macrospelides (15-membered unsaturated trilactams) and madindolines (tetrahydrofuro[2,3-b]indole derivatives): 99PAC1673.

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[Sec. III.B

Organotransition metal modiﬁed sugars: 01JOM(615–618)119. Rationally designed bicyclic lactams control diﬀerent turn motifs and folding patterns in hexapeptide mimics: 00EJO695. Recent developments in the chemistry of odorants (O-heterocycles including macrocycles): 00AG(E)2980. Redox modulation by molecular recognition: 01MI47. Role of the geme active site and protein environment in structure, spectra, and function of the cytochrome P450S: 00CRV407. Spectroscopic and dynamic studies of the epidermal chromophores, transurocanic acid and eumelanin: 00ACR307. Syntheses and biological evaluation of ( þ )-lactacystin (2-pyrrolidone derivative, a secondary metabolite from Streptomyces) and analogs: 00EJO2513. Syntheses of CP-225917 and CP-263114 (polycyclic saturated O-heterocycles, fungal metabolites with properties of enzyme inhibitors): 00AG(E)1415. Structure of ‘‘endogenous ouabain’’(a steroidal -lactone): 99PAC1643. Synthesis of insect pheromones-heterocycles: 01MI69.

III. Three-Membered Rings A. ONE HETEROATOM 1. One Nitrogen Atom Asymmetric aziridination: 99MI20, 00MI35. 2H-Azirines as synthehic tools in organic chemistry: 01EJO2401. Recent synthetic applications of chiral aziridines: 00S1347. The use of polypyrazolylborate copper(I) complexes as catalysts in the conversion of oleﬁns into aziridines: 01JOM(617–618)110.

2. One Oxygen Atom a. Reactivity of Oxiranes. Application of InCl3 in rearrangements of epoxides: 00EJO2347. Asymmetric catalysis of epoxide ring-opening reactions: 00ACR421. Asymmetric ring opening of epoxides and related reactions: 99MI25. Chemical transformations of spirooxiranes: 01ZOR1431. Coupling of 2,3-disubstituted oxiranes with 2-substituted 2-metallo-1,3dithianes: 00YGK857. Epoxide hydrolases in asymmetric synthesis: 00MI20. Exchange reaction of oxiranes with -hydroxyalkyl sulﬁdes, selenides, and phosphines: 00IZV575. Oxygen-directed carbocyclizations of epoxides: 00T8779.

Sec. IV.A]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

33

Reactions of epoxides with ester, ketone and amide enolates: 00T1149. b. Synthesis of Oxiranes. Advances in the asymmetric epoxidation of double bond using salen manganese(III) complexes as catalysts: 01MI106. Asymmetric epoxidation of allylic alcohols: 99MI21. Asymmetric epoxidation of electron-deﬁcient oleﬁns: 00CC1215. Asymmetric epoxidation of alkenes other than allylic alcohols: 99MI22. Asymmetric epoxide formation of enones and aldehydes: 99MI23. Biosynthesis of chiral epoxides: 01MI138. Chiral ketone-catalyzed asymmetric epoxidation of oleﬁns: 00S1979. Formation of oxiranes in reactions of organic hydrotrioxides RCOOOH with alkenes and cycloalkenes: 01UK123. The use of polypyrazolylborate copper(I) complexes as catalysts in the conversion of oleﬁns into epoxides: 01JOM(617–618)110.

3. One Sulfur Atom Catalytic macrocyclizations of thiiranes by metal carbonyl complexes: 00ACR171.

B. TWO HETEROATOMS 1. Two Nitrogen Atoms Carbene generation from diazirines: 01MI60. 2. Two Sulfur Atoms Chemistry of dithiiranes: 00AHC(77)221.

C. THREE HETEROATOMS Formation of thiadioxiranes in reactions of singlet oxygen with sulﬁdes (persulfoxides as intermediates): 01ACR875.

IV. Four-Membered Rings A. GENERAL TOPICS Ynolate anions as equivalents of ketenyl anions and their transformations into -lactones and -lactams: 00YZ1233.

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[Sec. IV.C

B. ONE HETEROATOM 1. One Nitrogen Atom Development of catalytic approach to the enantioselective synthesis of -lactams: 01AG(E)4377. -Lactam-based synthesis of complex nucleoside antibiotics and macrocyclic peptides: 00PAC1763. -Lactams as versatile intermediates in - and -amino acid syntheses: 01SL1813. Non-classical polycyclic -lactams: 00T5743. 4-Oxoazetidine-2-carbaldehydes as useful building blocks in stereocontrolled synthesis: 01CSR226. Progress in the synthesis and application of -lactams: 01MI144. Recent progress in the synthesis and reactivity of azetidine-2,3-diones: 01OPP315. Progress in the stereoselective syntheses of -lactams mediated by oxazoline N-oxides: 00PAC1721. The S-thioester enolate/imine condensation as a shortest way to -lactams: 00EJO563.

2. One Oxygen Atom Paterno-Bu¨chi reaction of N-acyl enamines and aldehydes—the development of a new synthetic method and its application to total synthesis and molecular recognition studies; synthesis of oxetanes and their transformations: 00SL1699. Progress in the stereoselective syntheses of -lactones mediated by oxazoline N-oxides: 00PAC1721. The -elimination route to stereodeﬁned -alkylidenebutenolides: 01CC141.

3. One Sulfur Atom Catalytic macrocyclizations of thietanes by metal carbonyl complexes: 00ACR171.

C. TWO HETEROATOMS Chemistry of 1,2-dithietanes, and 1,2-dithietes: 00AHC(77)221. Formation of 1,2-dioxethanes in reactions of organic hydrotrioxides RCOOOH with alkenes and cycloalkenes: 01UK123. New mechanistic and synthetic aspects of singlet oxygen chemistry, formation, and transformations of 1,2-dioxethanes: 00T9151.

Sec. V.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

35

V. Five-Membered Rings A. GENERAL TOPICS Aromatic N-haloazoles: 00AHC(75)1. Catalytic enantioselective 1,3-dipolar cycloaddition reactions of nitrones: 00CC1449. Eﬃcient chiral control based on ﬁve-membered heterocyclic and related systems: 00YZ1323. Formation of cumulenes, triple-bonded, and related compounds by ﬂash vacuum thermolysis of ﬁve-membered heterocycles: 01EJO2209. Photochemical isomerization of pentaatomic heterocycles: 01AHC(79)41. Regio- and stereochemistry of 1,3-dipolar cycloaddition of nitrile oxides to alkenes: 01UK464. Ring-opening reactions of ﬁve-membered nitrogen-containing heterocycles: 01MI107. Ring transformations of ﬁve-membered heterocycles and their fused derivatives: 01EJO3405. Stereocontrolled asymmetric syntheses of 5-membered N-heterocycles: 00PAC1691. Stereoselection in 1,3-dipolar cycloaddition reactions of chiral allyl ethers: 01EJO1039. Syntheses and properties of azafulvalenes: 00AHC(77)115. Tricyclic azoloquinolines: 01AHC(78)189.

B. ONE HETEROATOM 1. General Synthesis, reactions, and biological activity of furan and thiophene oximes: 01KGS156. Synthetic utility of furan-, pyrrole- and thiophene-based 2-siloxydienes: 00CSR109.

2. One Nitrogen Atom Phosphorus-containing indole and pyrrole derivatives: 00KGS1587. a. Monocyclic Pyrroles. Analytical application of oligopyrrole macrocycles: 01CCC693. Mechanisms of pyrrole electropolymerization: 00CSR283. Organometallic compounds of pyrroles: 01AHC(79)115.

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[Sec. V.B

b. Hydropyrroles. Mechanisms and stereoselective syntheses of dihydropyrrolones from ironsubstituted ,-unsaturated imines and organolithium and Grignard reagents: 00EJO3961. Stereoselective and enantioselective synthesis of chiral pyrrolines via conjugate additions of allylsulfone carbanions: 00PAC1671. Syntheses and applications in heterocyclic chemistry of pyrrolidinetrione derivatives: 01S811. Synthesis and properties of dioxopyrrolines of isoquinoline and phenanthridine series: 01MI74. c. Porphyrins and Related Systems. Porphyrins and related compounds (general monograph): 00MI4. Acidic and complex forming properties of tetraazaporphyrines: 01KK483. Advances in modern synthetic porphyrin chemistry: 00T1025. Advances in the synthesis of petroporphyrins: 00MI31. Biomimetic electron-transfer chemistry of porphyrins and metalloporphyrins: 01MI35. Building molecular wires from the colors of life conjugated porphyrin: 99CC2323. Carbaporphyrinoids with benzene, azulene, cyclohexatriene, indene or pentalene fragment instead of one or two pyrrole rings: 00SL279. Electron transfer in covalently linked supramolecular systems containing porphyrin units: 01MI40. Extracoordination of molecules on metalloporphyrins as a factor of catalytic and enzymatic activity of porphyrins: 01MI81. Giant porphyrinoids, from ﬁgure eight to nanomolecular cavities: 00AG(E)1763. Macrocyclic eﬀect and biological activity of metalloporphyrins: 01MI83. Molecular design of porphyrin-based artiﬁcial molecular and ion recognition systems with allosteric guest responces: 01ACR865. Molecular size, length, and the extent of electronic p-conjugation in discrete giant porphyrin arrays: 01SL1663. Oligomeric porphyrin arrays: 99CC1771. Photobleaching of porphyrins and chlorins: 01T9513. Photosynthesis with participation of synthetic porphyrins: 01ACR40. Porphyrins in high-performance liquid chromatography: 00ZAK1014. Spectral properties of porphyrines, their precursors, and derivatives: 01UK656. Synthesis and spectral investigations of diporphyrins bonded on mesopositions: 00SL296. Synthesis and potential applications of porphhyrin derivatives: 00JHC527. Synthesis of porphyrins from dipyrrolylmethanes: 00UK337. Synthetic molecular systems on the basis of porphyrins as models for study of energy transfer by photosynthesis: 01UK1059. Synthetic routes to multiporphyrin arrays: 01CRV2751.

Sec. V.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

37

Thermodynamics of molecular complex formation in solutions of natural porphyrins: 01MI82. The role of the electronic structure of the porphyrin as viewed by EPR/ ENDOR method in the eﬃciency of biomimetic model compounds for photosynthesis: 01EJO4379. d. Indoles, Carbazoles, Related Systems, and Hydrogenated Derivatives. Chemistry of sulfur-containing indoles: 02PHC1. New approach to the annelated 5-hydroxy-substituted indoles based on Nenitzescu reaction: 01MI88. Nucleophilic aromatic substitution of hydrogen in syntheses of indole derivatives: 01H(54)445. Organometallic compounds of indoles and carbazoles: 01AHC(79)115. Recent developments in the synthetic methods of indole ring compounds: 01MI137. Synthesis and properties of carbazole-1,4-diones: 00H(52)977. e. Isoindoles (Including Phthalocyanins and Porphyrazines). A retro Diels–Alder reaction in the synthesis of fused-skeleton isoindolones and saturated hetero polycycles: 00JHC439. Acetylenic phthalocyanines and phthalocyanine analogues: 01EJO2797. Phtalocyanines as active materials for optical limiting: 01EJO3759. Photobleaching of phthalocyanins used in photodynamic therapy: 01T9513. Phthalocyanine thin ﬁlms: 99PAC2145. Phthalocyanines in high-performance liquid chromatography: 00ZAK1014. Selective synthetic approaches to phthalocyanines: 00EJO2821. Synthesis, structure, and properties of coordination compounds of iron phthalocyanine series and their analogs: 00UK355. Synthetic potential of phthalimide SET photochemistry: 01ACR523. Traditional and electrochemical methods for the synthesis of phthalocyanines and their metal complexes: 00KK323. f. Polycyclic Systems Including Two Heterocycles. Indolocarbazoles: 01AHC(80)1. Indolopyridines with nodal heteroatom: 01KGS1155. Pyrroloquinolines: 01KGS1587. Synthesis and biological activity of benzo[b]furoindole and benzo[b]thienoindole derivatives: 01MI98. Synthesis of fused 7-azanorbornanes: 01PHC25. Synthesis of 1,(7)-substituted pyrrolizidin-3-ones: 00T6359. Synthetic methods for the stereoisomers of swainsonine and its analogs (1,2,8trihydroxyindolizidines): 00T8579. 3. One Oxygen Atom a. Furans. Benzylfurans in the synthesis of benzannelated heterocycles: 01IZV1436.

38

L.I. BELEN’KII AND V.N. GRAMENITSKAYA

[Sec. V.B

2-Furylphosphines as ligands for transitional-metal-mediated organic synthesis: 01CRV997. Organometallic compounds of furans: 01AHC(78)1. Recent advances in metal-mediated synthesis of substituted furans: 00MI22. Synthesis of furans from sucrose: 01CLY202. b. Hydrofurans. Stereoselective construction of the tetrahydrofuran nucleus by alkoxyl radical cyclizations: 01EJO619. c. Annelated Furans. New approach to annelated 5-hydroxy-substituted benzofurans, based on Nenitzescu reaction: 01MI88. Organometallic compounds of benzannelated furans: 01AHC(78)1. Resveratrol (bioactive 2,3-dihydrobenzofuran derivative): 00CLY602. Synthesis and biological activity of benzo[b]furoindole derivatives: 01MI98. d. Five-Membered Lactones. A novel production of -butyrolactone catalyzed by homogeneous ruthenium complexes: 00YGK787. Catalyzed transformations of bisketenes into potentially biologically active compounds, in particular, into 5-alkoxyfuran-(3H)-ones: 00SL13. Eﬀect of ligands on divalent palladium-catalyzed carbon–carbon coupling reactions in highly enantioselective synthesis of optically active -butyrolactones: 01PAC247. 2(5H)-Furanones: 01AHC(81)107.

4. One Sulfur Atom Thermal reactions of sulfur, hydrogen sulﬁde and its derivatives with organic compounds (syntheses of thiophenes, benzothiophenes, thienothiophenes): 01ZOB1941. a. Thiophenes. Chemistry of thiophene 1,1-dioxides: 99MI10. Molecular structure of compounds containing 2,20 -bithienyl fragment: 00KGS725. Organometallic compounds of thiophenes: 01AHC(78)1. Thermal methods for the synthesis of thiophene and its derivatives: 00KGS3, 00UK90. b. Annelated Thiophenes. 1,3-Dihydrobenzo[c]thienylium (thiophtalylium) salts: 00KGS147. Organometallic compounds of benzannelated thiophenes: 01AHC(78)1. Recent trends in isomeric thienoquinoxalines [1980–2000]: 01JHC809. Synthesis and biological activity of benzo[b]thienoindole derivatives: 01MI98.

Sec. V.C]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

39

C. TWO HETEROATOMS 1. General Carbene complexes derived from lithiated azoles: 01JOM(617–618)170. Chemistry of trimethylsilylazoles: 01ZOR165. Reactions of oxazoles, thiazoles, imidazoles, and corresponding azolines with isocyanates or ketenes including acylation followed by [2 þ 2], [2 þ 2 þ 2], [3 þ 2], [3 þ 3], and [4 þ 2] annelation: 01T6651. Rigid-chain polybenzobisazoles and molecular composites based on them: 01UK88.

2. Two Nitrogen Atoms a. Pyrazoles. Organometallic complexes of pyrazoles: 01AHC(80)157. Organometallic complexes of pyrazolylborates and related ligands: 01AHC(81)167. Polypyrazolylborate copper(I) complexes as catalysts in the conversion of oleﬁns into aziridines and epoxides: 01JOM(617–618)110. Pyrazol-3-ones. Synthesis and applications: 01AHC(80)73. b. Imidazoles. Chemical properties and application of imidazoline-2-ones and their derivatives: 00MI29. Packing regularities in structures of chelates based on 3-imidazoline nitroxide radical: 01KK317. Preparation of imidazolidinone chelated carbene complexes: 01JOM(617– 618)182. Synthesis of chiral imidazolinylidene transition metal complexes and their application in asymmetric catalysis: 01JOM(617–618)70. c. Annelated Imidazoles. Benzimidazole-2-ylidenes with ferrocenyl substitutuents: 01JOM(617–618)28. Properties of 2,3-dihydroimidazo[1,2-a]pyridines: 00KGS1011.

3. One Nitrogen and One Oxygen Atom a. 1,2-Heterocycles. Carbene and radical pathways in pyrolysis of benzisoxazolones: 00JHC631. Preparation and synthetic utility of 3-isoxazolols: 01OPP515. Synthesis and biological activity of steroid isoxazoles: 00KGS291. b. 1,3-Heterocycles. Fused munchnones in recyclization tandems: 00JHC519.

40

L.I. BELEN’KII AND V.N. GRAMENITSKAYA

[Sec. V.D

Hemilability of hybrid ligands and the coordination chemistry of oxazolinebased systems: 01AG(E)680. Phosphinooxazolines as versatile, modular P,N-ligands for asymmetric catalysis: 00ACR336. 4. One Nitrogen and One Sulfur Atom Thiazolylketoses as a new class of versatile intermediates for glycoside synthesis: 99CC2133. 5. Two Sulfur Atoms New concept in tetrathiafulvalene chemistry: 01AG(E)1372. New redox materials based on functionalized di-1,3-dithiolyliden 9,10anthracenediylidenes: 99PAC2137. Reagents for preparation and cleavage of 1,3-dithiolanes: 00UK1032. Structure of organic metals on the basis of bis(ethylenedithio)tetrathiafulvalene with photochromic nitroprusside anion, (BEDT-TTF)4M[FeNO(CN)5]2, (M ¼ Na þ , K þ , NH4 þ , Tl þ , Rb þ , Cs þ ): 01KK283. Synthesis and chemistry of dithioles: 01S1747. Tetrathiafulvalenes as building blocks in supramolecular chemistry: 00CSR153.

D. THREE HETEROATOMS 1. Three Nitrogen Atoms a. Monocyclic systems. Selective biotransformation reactions on D-arabino- and D-threo-hydroxyalkyltriazoles: 01PAC167. Synthesis of chiral triazolinylidene transition metal complexes and their application in asymmetric catalysis: 01JOM(617–618)70. b. Annelated Triazoles. Carbene and radical pathways in pyrolysis of benzotriazoles: 00JHC631. Chemistry of 1,2,4-triazolo[4,3-c]pyrimidines: 00AHC(75)243. Chemistry of 1,2,4-triazolo[1,5-c]pyrimidines: 00AHC(77)345. Eﬃcient synthetic routes to polyfunctional compounds with benzotriazole participation: 00PAC1597. 2. Two Nitrogen Atoms and One Oxygen Atom Monocyclic furazans and furoxans: 01AHC(78)65. Trichloromethylarenes in synthesis of 1,3,4-oxadiazoles: 01MI87.

Sec. VI.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

41

E. FOUR HETEROATOMS Alkylation and related electrophilic reactions at endocyclic nitrogen atoms in the chemistry of tetrazoles: 00H(53)1421. Methods for the synthesis of mono- and polynuclear NH-tetrazoles: 00KGS867.

VI. Six-Membered Rings A. GENERAL 1-Azabutadienes as dienes in Diels–Alder reactions: 01T6099. Imines as dienophiles in Diels–Alder reactions: 01T6099.

B. ONE HETEROATOM 1. One Nitrogen Atom a. Pyridines. Achieving positional selectivity in pyridine synthesis: 00JHC451. Dendrimers based on electroactive metal complexes with pyridine fragments: 01CCC1. Dipolar and non-dipolar pyridine metal complexes for nonlinear optics: 00EJI229. Directed metallation of pyridines: 01T4059. Enzymatic syntheses of pyridine derivatives: 99YGK1064. Ring transformation of pyridines and benzo derivatives under the action of C-nucleophiles: 00H(53)1607. Ruthenium polypyridine complexes as models for the photosynthetic reaction center: 01ACR905. Selective preparation of pyridine derivatives from two diﬀerent alkynes and a nitrile: 01PAC271. Solventless three-phase syntheses of pyridine derivatives: 01CC2159. b. Pyridinium Compounds, Ylides, Pyridine N-Oxides. Catalytic reduction of pyridinium salts: 01KGS807. Redox-tunable pyridinium assemblies and their interactive spin-based functions: 99PAC2079. c. Applications of Pyridines. Oligopyridine liquid crystals as novel building blocks for supermolecular architectures based on metal coordination and hydrogen bonding: 00AG(E)2454.

42

L.I. BELEN’KII AND V.N. GRAMENITSKAYA

[Sec. VI.B

d. Bipyridines and Related Systems. Molecules comprising at least two 2,2-bipyridine units as ligands: 00CRV3553. Spin crossover phenomena in Fe(II) complexes with tridentate ligands related to 2,20 :60 ,2-terpyridine: 00CSR419. e. Hydropyridines. Stereoselective synthesis of piperidines: 00S1781. Synthesis of new 3-piperidinol-type chiral building blocks and their application to the alkaloids syntheses: 99YGK1075. f. Biologically Active Pyridines and Hydropyridines. Enantioselective automultiplication of chiral pyridylalkanols by asymmetric autocatalysis: 00ACR382. g. Pyridines Annelated with Carbocycles. Application of InCl3 in the synthesis of quinolines: 00EJO2347. Directed metallation of quinolines: 01T4059. Nucleophilic aromatic substitution of hydrogen in syntheses of quinoline derivatives: 01H(54)445. Photoactive mono- and polynuclear Cu(I)-phenanthrolines: 01CSR113. Synthesis of 3,4-dihydroisoquinolines: 01MI78. Synthesis of 1(2H)-isoquinolines: 01KGS723. h. Pyridines Annelated with Heterocycles. Chemistry of nitronaphthyridines: 00AHC(77)285. Directed metallation of carbolines: 01T4059. Indolopyridines with nodal heteroatom: 01KGS1155. Properties of 2,3-dihydroimidazo[1,2-a]pyridines: 00KGS1011. Pyridopyridines: 01UK345. Pyrroloquinolines: 01KGS1587. Structure, properties, and general methods for the synthesis of naphthyridines: 00UK218. Synthesis of annelated quinolizine derivatives from cyclic Schiﬀ bases by [2 þ 4] cyclocondensation: 01MI86. Synthetic methods for the stereoisomers of swainsonine and its analogs (1,2,8trihydroxyindolizidines): 00T8579. Tricyclic azoloquinolines: 01AHC(78)189.

2. One Oxygen Atom Catalytic reduction of pyrilium salts: 01KGS807. Conformational space and dynamic stereochemistry of dixantylene and its S- and N-analogs: 01EJO15. Reactions of ﬂuoro- and chlorocontaining chromones with aliphatic mono-, di-, and triamines: 01MI76. Solventless three-phase syntheses of 3-carboxycoumarins: 01CC2159.

Sec. VI.C]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

43

Synthesis of 2,2-dimethyl-4-chromanones: 00JHC1389. Synthesis of 2,2-dimethyl-2H-chromenes: 00H(53)1193. 3. One Sulfur Atom Catalytic reduction of thiopyrilium salts: 01KGS807.

C. TWO HETEROATOMS 1. Two Nitrogen Atoms a. 1,2-Heterocycles. Chemistry of 1H-1,2-diazaphenalene: 01MI94. Chemistry of pyridazines: 00AHC(75)157. Nucleophilic substitution of hydrogen atoms in pyridazine series: 01KGS1611. b. 1,3-Heterocycles: Monocyclic Pyrimidines and Hydropyrimidines (Except Pyrimidine Nucleoside Bases and Nucleosides). Enantioselective automultiplication of chiral pyrimidylalkanols by asymmetric autocatalysis: 00ACR382. Recent advances in the Biginelly dihydropyrimidine synthesis: 00ACR879. Recent advances in the synthesis of 3,4-dihydropyrimidinones: 01MI108. Synthetic applications of the pyrolysis of Meldrum acid derivatives: 01S2059. c. Annelated Pyrimidines (Except Purines, Pteridines, and Flavins). Chemistry of 1,2,4-triazolo[4,3-c]pyrimidines: 00AHC(75)243. Chemistry of 1,2,4-triazolo[1,5-c]pyrimidines: 00AHC(77)345. Synthesis of substituted quinazolin-4(3H)-ones and quinazolines via directed lithiation: 00H(53)1839. d. Pyrimidine Nucleoside Bases and Purines. Combinatorial syntheses of purine derivatives: 01AG(E)339. Enzymatic syntheses of purine derivatives: 99YGK1064. Simultaneous determination of theophylline and its metabolites by HPLC: 00YZ1051. Synthesis and biological activity of 2- and 6-C-substituted purine bases: 00CLY978. e. Nucleotides and Nucleosides. Advances in synthesis of sugar-modiﬁed nucleosides in past 10 years: 01YGK331. Bicyclic nucleosides and conformational restriction of oligonucleotides: 00JCS(P1)3539. Biocatalytic selective modiﬁcations of conventional nucleosides, carbocyclic nucleosides, and C-nucleosides: 00CRV4319. Chemistry and biochemistry of cyclic ADP-ribose and its analogs: 00YGK1144.

44

L.I. BELEN’KII AND V.N. GRAMENITSKAYA

[Sec. VI.C

Dialdehyde derivatives of nucleosides, nucleotides, and oligonucleotides: 00MI47. Metal ion-binding properties of the antiviral nucleotide analog, 9-[2(phosphonomethoxy)ethyl]adenine (PMEA): 99PAC1727. New nucleoside analogs, synthesis, and biological properties: 00PAC1705. Purine 8-O and 8-S-cyclonucleosides, synthesis, and properties: 00CLY355. Syntheses and properties of novel conformationally restrained nucleoside analogs: 99YGK969. Synthesis and biological activity of 2- and 6-C-substituted purine bases, nucleosides, and acyclic nucleotide analogs: 00CLY978. Synthesis and biological activity of thionucleosides: 00S1637. Studies on syntheses of a novel antiherpetic nucleoside A-5021 and related compounds: 00YGK683. Transformations of -xylofuranosylnucleosides: 00MI18. f. Nucleic Acids. Aﬃne sorbents containing nucleic acids and their fragments: 01UK581. Analysis of noncovalent complexes of DNA and RNA by mass spectrometry: 01CRV377. Antisense molecules as nucleic acid mimics: 01CC1419. Capillary electrophoresis for the analysis of nucleic acids: 00AC(12)111R. Chemical etiology of nucleic acid structure: 00PAC343. Construction of reagents for directed cleavage of ribonucleic acids: 01UK562. Development of functional nucleic acids and peptides by combinatorial chemistry and downsizing methods: 00YGK1133. Dynamics of photoinduced charge transfer and hole transport in synthetic DNA hairpins: 01ACR159. Eﬀect of chirality of ribose on nucleic acid structure and function: 99YZ689. Electron transfer and charge transport process in DNA: 01MI38. Fluorescence correlation spectroscopy in nucleic acid analysis: 01MI147. From equilibrium to kinetic footprinting of RNA structure: 01JCS(P2)1263. Long-distance charge transport through DNA: 01PAC449. Long-range transfer in DNA transient structural distortions control the distance dependence: 00ACR253. Mimicking the structure and function DNA, insights into DNA stability, and replication: 00AG(E)990. Molecular mechanisms of DNA recognition and function by bioactive compounds: 00YZ1409. Molecular mechanisms of mutations induced by DNA lesions: 00YZ1159. Nucleic acid conformation diversity: 01CSR70. Nucleic acid synthesis and molecular recognition: 99YZ625. Recognition of DNA sequences by pyrrole-imidazole polyamide: 00YGK975. Strategies for the design of drugs targeting RNA and DNA–protein complexes: 00AG(E)1890. Study on electron transfer of nucleic acid precursors and their modiﬁed structure: 01MI125.

Sec. VI.C]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

45

Synthesis of ﬂuorescently labeled oligonucleotides and nucleic acids: 00CSR97. Synthetic control of DNA triplex structure through chemical modiﬁcations: 96MI6. Use of nucleic acids for construction of nanostructures: 01AG(E)4128. g. 1,4-Heterocycles: Pyrazines and Hydropyrazines. Chemistry of pyrazino-bis-steroids: 00MI49. Complexes of pyrazine, 4,40 -bipyrazine, and similar N-heterocycles with two coordinated MLn groups: 00ACR755. (5S) and (5R)-Ethyl 3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine-2-carboxylates as key compounds in asymmetric synthesis of -substituted serines: 00YGK756. Pyrazine functional derivatives in the asymmetric synthesis of -substituted serines: 00YZ28. h. Annelated Pyrazines. Fluorescence correlation spectroscopy of ﬂavines and ﬂavoproteins: 01MI146. Recent trends in isomeric thienoquinoxalines [1980–2000]: 01JHC809. New pyrazinone derivatives as chiral reagents in asymmetric synthesis of -amino acids: 00JHC467.

2. One Nitrogen and One Oxygen Atom New oxazinone derivatives as chiral reagents for the asymmetric synthesis of amino acids: 00JHC467. Preparation of morpholine-2,5-diones: 01CLY22. Selective biotransformation reactions on ( )-benzoxazines: 01PAC167. Synthesis and reactions of 2-hetero (RO-, RS- or RR0 N)-4H-3,1-benzoxazin-4ones: 00JHC1369. Synthesis of heterocyclic compounds on the basis of isatoic anhydrides (2H3,1-benzoxazine-2,4-diones): 01KGS435.

3. Two Oxygen Atoms Optical spectra and photophysical properties of polychlorinated dibenzop-dioxins: 00UK1128. Synthesis and chemical properties of 6-aryl-2,2-dimethyl-1,3-dioxin-4-ones: 01KGS1011.

4. One Oxygen and One Sulfur Atom Stereostructure, peculiarities of physicochemical properties, and some transformations of 1,3-oxathianes: 00MI16.

46

[Sec. VII.B

L.I. BELEN’KII AND V.N. GRAMENITSKAYA

5. Two Sulfur Atoms Formation of thianthrenes in thermal reactions of sulfur, hydrogen sulﬁde, and its derivatives with organic compounds: 01ZOB1941. Generation of 2-substituted 2-metallo-1,3-dithiane derivatives and their coupling with 2,3-disubstituted oxiranes: 00YGK857.

D. THREE HETEROATOMS Synthesis of 01EJO3191.

melaminecyanuric/barbituric

acid

derived

nanostructures:

E. FOUR HETEROATOMS Annelated 1,2,4,5-tetrazines: 01JHC541. Synthesis of new substituted 1l4-1,2,4,6-thiatriazines: 00JHC583.

VII. Rings with More Than Six Members A. SEVEN-MEMBERED RINGS 1. One Heteroatom Introduction of nitrogen atom into six-membered ring and formation of sevenmembered N-heterocycles: 00T4317. 2. Two Heteroatoms Synthesis and chemical tranformations of 1,5-benzothiazepines: 00JHC199. Synthesis and chemical transformations of 1,4-, 4,1-, and 1,5-benzoxazepines: 01JHC1011.

B. MEDIUM RINGS Metal-mediated synthesis of medium-sized heterocycles: 00CRV2963. New synthetic methods for construction of medium-sized cyclic ethers and convergent coupling of polyether fragments: 01YGK193. Synthesis of medium-sized heterocycles by the ring-closing metathesis reaction: 00AG(E)2079.

Sec. VII.C]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

47

C. LARGE RINGS 1. General Problems Planar chirality—synthesis and transformations of 8- to 10-membered heterocycles bearing (E)-oleﬁn units: 01EJO1801. a. Structure, Stereochemistry, Reactivity, Design. Changing the reactivity of heterocyclic enediynes by metal-ion coordination: 00EJO381. b. Synthesis. Eﬃcient syntheses of rotaxanes and catenanes based on hydrogen bonding: 01YGK206. Formation of macrocyclic lactones and oxalactones by metal carbene transformations: 01SL1364. c. Applications. Macroheterocycles as synthetic receptors: 00JCS(P1)3155.

2. Crown Ethers and Related Compounds s-Block metal inverse crowns: 01CC1049. Cation dependent pericyclic reactions of crown-containing photochromic compounds: 01IZV1882. Crown-ethers in radiochemistry: 00UK840. Development of chiral crown ethers: 01MI109. Interactions of alkali metals cations (complexed with crown-ethers and kryptands) with aromatic p-systems: 00EJO2967. Molecular design of crown ethers-based artiﬁcial molecular and ion recognition systems with allosteric guest responses: 01ACR865. Recent highlights in hemicarcerand chemistry: 01ACR95. Studies on azacrown ether compounds and macrocyclic polyamines: 01MI110. Studies on crown ethers cyanine dyes: 00H(53)1821.

3. Miscellaneous Macroheterocycles Analytical application of oligopyrrole macrocycles: 01CCC693. Attractive intramolecular edge-to-face aromatic interactions in ﬂexible organic molecules, particularly, in, heteraphanes: 01ACR885. Calixarenes bearing azaaromatic moieties: 01H181. Catenanes and rotaxanes as chemically, electrochemically, and photochemically guided artiﬁcial molecular machines: 00AG(E)3348. Chiral cyclodextrins, crown ethers, and macrocyclic antibiotics in chiral separations using capillary electrophoresis: 00CRV3715.

48

L.I. BELEN’KII AND V.N. GRAMENITSKAYA

[Sec. VIII.B

Cyclodextrins and their derivatives as stationary phases for separation of enantiomers by capillary gas chromatography: 00CLY10. Development in the research of bridged calix[6]arenes: 00MI28. Electron transfer processes in pseudorotaxanes: 01MI43. Electron transfer processes in rotaxanes and catenanes: 01MI44. Electron transfer processes in metal-assisted catenanes, rotaxanes, and knots: 01MI45. Electron transfer processes in dendrimers: 01MI46. From rotaxanes to knots. Templating, hydrogen bond patterns, and cyclochirality: 00PAC2223. Heteroatom-briged calixarenes: 00EJI2303. Inner-phase stabilization of reactive intermediates (macroheterocycles as molecular containers, carceplexes): 01EJO423. Molecular mobility and topological chirality of rotaxanes: 01ACR465. Rotaxanes. From supramolecular self-organization to molecular devices: 00MI21. Self-assembling of rotaxanes, catenanes, and molecular knots: 00CRV3483. Self-assembling nanotubes from cyclic peptides and depsipeptides: 01AG(E)988. Supramolecular devices based on rotaxanes and polyrotaxanes: 01UK28. Supramolecular recognition in macrocyclic polyamines: 01MI135.

VIII. Heterocycles Containing Unusual Heteroatoms A. GENERAL Formation of P-, Si-, and Ge-heterocycles from corresponding heavy allenes E ¼ C ¼ E0 : 00CRV3639.

B. PHOSPHORUS HETEROCYCLES Applications of phosphorus heterocycles in homogeneous 01MI30. Aromaticity of phosphorus heterocycles: 01CRV1229. 1. Chemistry of Individual Classes of P-Heterocycles The birth of phosphorus–carbon heterocyclic chemistry: 01MI14. Phosphiranes and phosphirenes: 01MI15. Diphosphiranes and diphosphirenes: 01MI16. Diphosphetanes, dihydrodiphosphetes, and diphosphetes: 01MI19.

catalysis:

Sec. VIII.B]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

49

Modulating phospholane ligands in asymmetric catalysis: 00ACR363. Phosphetanes: 01MI17, 01MI18. Phospholanes and phospholenes: 01MI20. Phospholes: 01MI21, 01MI22. Heterophospholes: 01MI23. Phosphinanes, dihydro-, and tetrahydrophosphinanes: 01MI24. Phosphinines: 01MI25. Six-membered rings with two or more heteroatoms with at least one phosphorus atom: 01MI26. Phosphorus-containing macro- and spiro-heterocycles: 01MI27. Bicyclic and polycyclic systems with a ring junction phosphorus atom: 01MI28. Compounds with phosphorus at the spiro position: 01MI29. From phosphathiafulvenes to phosphabenzenes and stable six-membered phosphaallenes: 00PAC1769. Organometallic compounds of phospholes: 01AHC(79)115. Synthesis and reactions of oxaphospholanes using hydroxyalkylphosphonium salts: 00YGK548. Zirconium-phosphorus chemistry (metallocycles, P,Zr-heterocycles): 00AG(E)314.

2. Structure and Stereochemistry Vibrational spectra, force constants, and conformations of molecules of trivalent tricoordinated phosphorus compounds including P-heterocycles: 00UK817.

3. Reactivity Amides of trivalent phosphorus acids (including cyclic amides) as phosphorylating reagents for proton-donating nucleophiles: 00CRV3755. Functionalization of PIII phosphocavitandes: 01MI111. 7-Membered cyclic phosphoramidites as ligands in catalytic asymmetric conjugate addition: 00ACR346.

4. Synthesis Flash vacuum thermolysis in synthesis of new reactive heterocycles with P ¼ Si double bonds: 00EJO3253. Phosphorus ylides containing ﬂuorine atoms bonded to phosphorus (reactions leading to the formation of P-heterocycles): 01SL1065. Syntheses of cyclophosphanes from silylphosphanes: 00CRV3341.

50

L.I. BELEN’KII AND V.N. GRAMENITSKAYA

[Sec. VIII.D

C. BORON HETEROCYCLES 1. Chemistry of Individual Classes of B-Heterocycles Highly Lewis acidic bifunctional B-heterocycles: 00EJI2131. Nickel and iron bisdicarbollides: 00JOM(614–615)27. Organometallic compounds of boroles: 01AHC(79)115. Small cage C2B4-carborane: 00JOM(614–615)10. 2. Structure and Stereochemistry Boron-bridged group-4 ansa-metallocene complexes: 01EJI321. The structural chemistry of boron-rich derivatives of alkali metals, particularly, salts with cage carbaboride anions: 00EJI1679. 3. Reactivity Metal induced B-H activation of semi-sendwich Cp*Rh-, Cp*Ir- (p-cymol)R-, and (p-cymol)Os-complexes containing 1,2-dicarba-closo-dodecaborane(12)dichalcogenate ligand: 01IZV1444. 4. Synthesis Photochemical reactions with participation and formation of B-heterocycles: 00T7339. 5. Applications Forced exo-nido rhoda- and ruthenacarboranes as catalyst precursors: 00JOM(614–615)48.

D. SILICON, GERMANIUM, TIN, AND LEAD HETEROCYCLES 1. Chemistry of Individual Classes of Heterocycles Anionic chemistry of four- and ﬁve-membered silyl-substituted p-electronic systems, formation of polycyclic Si-heterocycles: 99YGK945. Chemistry of cyclic siloxanes: 00YGK926. Germatranes and their analogs: 01KGS1451. Oligoorganocyclocarbosiloxanes: 01MI72. Organometallic compounds of siloles: 01AHC(79)115.

Sec. VIII.E]

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

51

Silicon heterocycles as starting compounds, intermediates, and reaction products: 00MI32. Spin chemistry of short-living intermediates in reactions of germanorbornadienes and digermabicyclooctadienes: 01IZV1830. Stable cyclic silylenes: 00ACR704. Thermally stable cyclic bis(amino)silylenes: 01JOM(617–618)209. Unsaturated Si-heterocycles: 00PAC2333.

2. Structure and Stereochemistry Electronic structure of Si-, Ge-, and Sn-heterocycles: 00MI12. Homoatomic polyhedra as structural modules in Zintl ions [E9]3 and [E9]4 (E ¼ Si, Ge, Sn, Pb): 01AG(E)4101.

3. Reactivity Development of reactions of silacyclopropanes as new methods for stereoselective organic synthesis: 00ACR813. Reactions of 4-sila-2,5-cyclohexadienylidenes investigated by direct spectroscopic methods: 01MI62. Stereoselective introduction of C2-units and the ring enlargement reaction of (3-oxa-2-silacyclopentyl)methyl radicals into 4-oxa-3-silacyclohexyl radicals via a pentavalent silicon-bridging radical: 01YGK589.

4. Synthesis Dehydrocondensation of organylsilanes giving Si–Si bonds (formation of Siheterocycles): 00UK150. Flash vacuum thermolysis in synthesis of new reactive heterocycles with N ¼ Si, P ¼ Si, and S ¼ Si double bonds: 00EJO3253. Transition-metal-catalyzed additions of silicon-silicon and silicon-heteroatom bonds to unsaturated organic molecules (particularly, with formation of Siheterocycles): 00CRV3221.

E. SELENIUM AND TELLURIUM HETEROCYCLES 1. General Sources and Topics Syntheses of benzo[b]telluroles, benzo[b]selenophenes and dibenzotellurolo [3,4-b]tellurole: 01YGK355.

52

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[Sec. VIII.F

2. Chemistry of Individual Classes of Heterocycles Telluriumnitrogen-containing heterocycles: 01AHC(79)1. Thermal methods for the synthesis of selenophene and its derivatives: 00KGS3.

F. OTHER UNUSUAL HETEROCYCLES 1. Metallacycles Carbene complexes (Ti and Zr-cycles): 01JOM(617–618)81. Formation of Ti- and Zr-heterocycles in reactions of titano- and zirconocenes with diynes and polyynes: 00ACR119. Heck reaction as a sharpening stone of palladium catalysis: 00CRV3009. Highly polar metal–metal bonds in ‘‘early-late’’ heterodimetallic complexes (metallocycles): 00AG(E)2658. Inorganic antimony and bismuth 3-, 4- and 6-membered rings with organic substituents: 00CSR403. Intramolecular ortho-palladation of N-donor ligands with formation of N,Pdcycles: 00MI52. Metallabenzenes: 01CRV1205. Metal complex catalysis in the synthesis of organoaluminum compounds (formation of Al-heterocycles): 00UK134. Organometallic polymers formed by ring-opening polymerization of ferrocenophane: 01MI141. Organotitanium complexes (including Ti-heterocycles): 00CRV2835. Palladacycles as intermediates in Heck reaction: 01T7449. Palladacycles as simple, and eﬃcient catalyst precursors for homogeneous catalysis: 01EJI1917. Reactions of ruthenium and osmium cluster carbonyls with heteroatomsubstituted and functionalized alkynes (metallocycles): 00IZV1. Ring-opening polymerization of strained metallocyclophanes: 99CRV1515. Self-assembling of metallacycles: 00CRV3483. Structures and reaction mechanisms of organocuprate clusters including closed Cu-Li clusters: 00AG(E)3750. Synthesis and reactivities of cubane-like sulﬁdo clusters containing noble metals: 00ACR46. Synthesis, structure, and properties of exohedral metallofullerenes MnC60 (M ¼ transition metal): 00ZSK164. Titanacyclopropanes as versatile intermediates for carbon-carbon bond formation in reactions with unsaturated compounds: 00PAC1715. Zirconium-phosphorus chemistry (metallocycles, P,Zr-heterocycles): 00AG(E)314.

Refs.]

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2. Metal Chelates and Related Complexes Chelate complexes of cyclopentadienyl ligands bearing pendant O-donors: 00CRV1495. Diimine Ni- and Pd-chelates as highly active catalysts for oleﬁn polymerization: 00MI27. Ligand oxidation as method of intramolecular activation of metal chelates: 01IZV549. Liquid-crystal complexes with heterocyclic ligands and chelates: 00KK803, 00KK883. Metal chelates with N-containing ligands: 00AG(E)468. Ni, Co, Fe, and Pd Chelates as catalysts for oleﬁn polymerization: 01AG(E)534. Platinum group organometallic ‘‘pincer complexes’’ as sensors, switches, and catalysts: 01AG(E)3750. Supramolecular magnetic materials with heterocyclic and chelate structural fragments: 00ACR647. Synthesis of metal chelates: 00MI14. Thin copper ﬁlms from vapor phase of volatile Cu(I) and Cu(II) chelates by chemical vapor deposition (CVD): 00UK1149.

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58 00AHC(75)157 00AHC(75)243 00AHC(76)1 00AHC(76)85 00AHC(76)157 00AHC(77)1 00AHC(77)51 00AHC(77)115 00AHC(77)183 00AHC(77)221 00AHC(77)285 00AHC(77)345 00CC519 00CC887 00CC1215 00CC1449 00CC1971 00CCC297 00CCC844 00CLY10 00CLY15 00CLY21 00CLY105 00CLY111 00CLY226 00CLY230 00CLY347 00CLY355 00CLY978 00CLY1075 00CRV39 00CRV407 00CRV853 00CRV909 00CRV925 00CRV1025 00CRV1121 00CRV1169 00CRV1495 00CRV1685 00CRV1717 00CRV1741 00CRV1777

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00JCS(P1)4197 00JHC199 00JHC427 00JHC439 00JHC451 00JHC455 00JHC467 00JHC481 00JHC487 00JHC509 00JHC519 00JHC527

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Refs.] 00MI1 00MI2 00MI3 00MI4 00MI5 00MI6 00MI7 00MI8

00MI9 00MI10

00MI11 00MI12

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64 00MI30 00MI31 00MI32 00MI33 00MI34 00MI35 00MI36 00MI37 00MI38 00MI39 00MI40 00MI41 00MI42 00MI43 00MI44 00MI45 00MI46 00MI47 00MI48 00MI49 00MI50 00MI51 00MI52 00MI53 00PAC333 00PAC343 00PAC347 00PAC365 00PAC373 00PAC1365 00PAC1391 00PAC1577 00PAC1589 00PAC1597 00PAC1623 00PAC1635 00PAC1641 00PAC1645 00PAC1659

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Refs.] 00PAC1671 00PAC1691 00PAC1705 00PAC1715 00PAC1721 00PAC1763 00PAC1769 00PAC1773 00PAC1783 00PAC2223 00PAC2275 00PAC2333 00PHC1 00PHC22 00PHC37 00PHC57 00PHC77 00PHC92 00PHC114 00PHC134 00PHC161 00PHC185 00PHC204 00PHC219 00PHC237 00PHC263 00PHC294 00PHC317 00PHC339 00PHC352 00S1 00S329 00S479 00S759 00S1035 00S1347 00S1637 00S1781 00S1979 00SL1 00SL13 00SL161 00SL172 00SL279 00SL296 00SL442 00SL429

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

65

A. Hassner, C. Ghera, T. Yechezkei, V. Kleiman, T. Balasubramanian, and D. Ostercamp, Pure Appl. Chem., 72, 1671 (2000). Y. H. Kim, S. M. Kim, D. H. Park, and S. W. Youn, Pure Appl. Chem., 72, 1691 (2000). M. J. Wanner, P. Y. F. Deghati, B. Rodenko, and G. J. Koomen, Pure Appl. Chem., 72, 1705 (2000). O. G. Kulinkovich, Pure Appl. Chem., 72, 1715 (2000). O. Dirat, C. Kouklovsky, M. Manduit, and Y. Langlois, Pure Appl. Chem., 72, 1721 (2000). C. Palomo, J. M. Aizpurua, I. Ganboa, and M. Oiarbide, Pure. Appl. Chem., 72, 1763 (2000). M. A. Hofmann, U. Bergstoss, and M. Regitz, Pure. Appl. Chem., 72, 1769 (2000). G.-K. Sha, S.-J. Huang, C.-M. Huang, A.-W. Hong, and T.-H. Jeng, Pure Appl. Chem., 72, 1773 (2000). K. Suzuki and H. Sigel, Pure Appl. Chem., 72, 1783 (2000). C. Reuter, R. Schmieder, and F. Vogtle, Pure Appl. Chem., 72, 2223 (2000). K. R. Seddon, A. Stark, and M.-J. Torres, Pure Appl. Chem., 72, 2275 (2000). M. Kiza, Pure Appl. Chem., 72, 2333 (2000). M. P. Groziak, Progr. Heterocycl. Chem., 12, 1 (2000). R. A. Aitken and T. Massil, Progr. Heterocycl. Chem., 12, 22 (2000). J. J. Li, Progr. Heterocycl. Chem., 12, 37 (2000). A. Padwa and S. S. Murphree, Progr. Heterocycl. Chem., 12, 57 (2000). L. K. Mehta and J. Parrick, Progr. Heterocycl. Chem., 12, 77 (2000). E. T. Pelkey, Progr. Heterocycl. Chem., 12, 92 (2000). D. M. Ketcha, Progr. Heterocycl. Chem., 12, 114 (2000). S. Greve and W. Friedrichsen, Progr. Heterocycl. Chem., 12, 134 (2000). L. Yet, Progr. Heterocycl. Chem., 12, 161 (2000). P. A. Bradley and D. J. Wilkins, Progr. Heterocycl. Chem., 12, 185 (2000). R. A. Aitken, Progr. Heterocycl. Chem., 12, 204 (2000). Th. L. Gilchrist, Progr. Heterocycl. Chem., 12, 219 (2000). R. D. Larsen and J.-F. Marcoux, Progr. Heterocycl. Chem., 12, 237 (2000). B. R. Lahue and J. K. Snyder, Progr. Heterocycl. Chem., 12, 263 (2000). C. Ochoa and P. Goya, Progr. Heterocycl. Chem., 12, 294 (2000). J. D. Hepworth and B. M. Heron, Progr. Heterocycl. Chem., 12, 317 (2000). D. J. LeCount, Progr. Heterocycl. Chem., 12, 339 (2000). G. R. Newkome, Progr. Heterocycl. Chem., 12, 352 (2000). M. Reggelin and C. Zur, Synthesis, 1 (2000). H. Gao and A. P. Mitra, Synthesis, 329 (2000). O. S. Pedersen and E. B. Pedersen, Synthesis, 479 (2000). M. Lombardo and C. Trombini, Synthesis, 759 (2000). S. J. Shuttleworth, S. M. Allin, R. D. Wilson, and D. Nasturica, Synthesis, 1035 (2000). W. M. Coull and F. A. Davis, Synthesis, 1347 (2000). M. Yokoyama, Synthesis, 1637 (2000). S. Laschat and T. Dickner, Synthesis, 1781 (2000). M. Frohn and Y. Shi, Synthesis, 1979 (2000). J. H. Rigby, Synlett, 1 (2000). M. M. Dejmek and R. Selke, Synlett, 13 (2000). B. El Ali and H. Alper, Synlett, 161 (2000). M. Pons, F. Albericio, M. Royo, and E. Giralt, Synlett, 172 (2000). T. D. Lash, Synlett, 279 (2000). D. P. Arnold, Synlett, 296 (2000). T. Tejero, Synlett, 442 (2000). J. A. Robinson, Synlett, 429 (2000).

66 00SL561 00SL1077 00SL1092 00SL1228 00SL1371 00SL1523 00SL1699 00T917 00T1025 00T1149 00T1937 00T2339 00T2905 00T3077 00T3263 00T3449 00T3635 00T3817 00T4317 00T5259 00T5743 00T5959 00T6359 00T7051 00T7339 00T7613 00T8207 00T8385 00T8579 00T8779 00T9151 00UK90 00UK118 00UK134 00UK150 00UK218 00UK239 00UK337 00UK355 00UK403 00UK494 00UK507 00UK538 00UK642 00UK699 00UK721 00UK817 00UK840 00UK856

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Refs.] 00UK869 00UK924 00UK940 00UK963 00UK1032 00UK1091 00UK1111 00UK1128 00UK1149 00YGK25 00YGK548 00YGK634 00YGK654 00YGK666 00YGK676 00YGK683 00YGK736 00YGK756 00YGK766 00YGK787 00YGK828 00YGK857 00YGK877 00YGK926 00YGK934 00YGK975 00YGK1077 00YGK1133 00YGK1144 00YGK1167 00YZ28 00YZ42 00YZ104 00YZ352 00YZ363 00YZ474 00YZ591 00YZ630 00YZ825 00YZ909 00YZ923 00YZ935 00YZ959 00YZ987 00YZ1035 00YZ1051 00YZ1061 00YZ1117 00YZ1135

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

67

N. K. Kochetkov, Usp. Khim., 69, 869 (2000). G. V. Oshovskii and A. M. Pinchuk, Usp. Khim., 69, 924 (2000). A. A. Maksimenko, A. V. Zakharov, and I. D. Sadekov, Usp. Khim., 69, 940 (2000). V. V. Arslanov, Usp. Khim., 69, 963 (2000). A. K. Banerjee and M. S. Laya, Usp. Khim., 69, 1032 (2000). E. V. Gorobets, M. S. Miftachov, and F. A. Valeev, Usp. Khim., 69, 1091 (2000). Yu. V. Smirnova and Zh. A. Krasnaya, Usp. Khim., 69, 1111 (2000). E. A. Gastilovich, V. G. Klimenko, N. V. Korol’kova, and R. N. Nurmuchametov, Usp. Khim., 69, 1128 (2000). V. N. Vertoprakhov and S. A. Krupoder, Usp. Khim., 69, 1149 (2000). M. Isobe and K. Kira, Yuki Gosei Kagaku Kyokaishi, 58, 25 (2000). K. Okuma, Yuki Gosei Kagaku Kyokaishi, 58, 548 (2000). F. Yokokawa and T. Shioiri, Yuki Gosei Kagaku Kyokaishi, 58, 634 (2000). Y. Fukuyama, M. Kodama, and Y. Asakawa, Yuki Gosei Kagaku Kyokaishi, 58, 654 (2000). N. Asano, Yuki Gosei Kagaku Kyokaishi, 58, 666 (2000). K. Kurogi, Yuki Gosei Kagaku Kyokaishi, 58, 676 (2000). T. Tsuji, Yuki Gosei Kagaku Kyokaishi, 58, 683 (2000). A. Satake, Yuki Gosei Kagaku Kyokaishi, 58, 736 (2000). Sh. Sano and Y. Nagao, Yuki Gosei Kagaku Kyokaishi, 58, 756 (2000). Y. Satoh, Yuki Gosei Kagaku Kyokaishi, 58, 766 (2000). Y. Hara and K. Takahashi, Yuki Gosei Kagaku Kyokaishi, 58, 787 (2000). T. Sunazuka, Yuki Gosei Kagaku Kyokaishi, 58, 828 (2000). M. Ide and M. Nakata, Yuki Gosei Kagaku Kyokaishi, 58, 857 (2000). A. K. Nagasawa, Yuki Gosei Kagaku Kyokaishi, 58, 877 (2000). K. Hirabayashi and A. Mori, Yuki Gosei Kagaku Kyokaishi, 58, 926 (2000). A. Oku, T. Mori, and Y. Sawada, Yuki Gosei Kagaku Kyokaishi, 58, 934 (2000). H. Iida and H. Sugiyama, Yuki Gosei Kagaku Kyokaishi, 58, 975 (2000). M. Inouye, Yuki Gosei Kagaku Kyokaishi, 58, 1077 (2000). N. Sugimoto, Yuki Gosei Kagaku Kyokaishi, 58, 1133 (2000). S. Shuto, M. Fukucka, and A. Matsuda, Yuki Gosei Kagaku Kyokaishi, 58, 1144 (2000). M. Kodama, H. Hioki, and S. Yoshio, Yuki Gosei Kagaku Kyokaishi, 58, 1167 (2000). Sh. Sano, Yakugaku Zasshi, 120, 28 (2000). T. Kajimoto, Yakugaku Zasshi, 120, 42 (2000). Y. Koiso, O. Nakajima, and D. Matsumura, Yakugaku Zasshi, 120, 104 (2000). N. Hamaue, Yakugaku Zasshi, 120, 352 (2000). F. Yamada, Yakagaku Zasshi, 120, 363 (2000). K. Ohashi, T. Bohgaki, and H. Shibuya, Yakugaku Zasshi, 120, 474 (2000). T. Tomimori, Yakugaku Zasshi, 120, 591 (2000). Y. Matsuda, Yakugaku Zasshi, 120, 630 (2000). T. Matsui, Y. Ohtsuka, and K. Sakai, Yakugaku Zasshi, 120, 825 (2000). H. Takahashi, M. Komoda, H. Kakuta, and Y. Hashimoto, Yakugaku Zasshi, 120, 909 (2000). S. Ohmiya, K. Saito, and I. Murakashi, Yakugaku Zasshi, 120, 923 (2000). H. Tomoda and S. Omura, Yakugaku Zasshi, 120, 935 (2000). H. Takayama, N. Aimi, and Sh. Sakai, Yakugaku Zasshi, 120, 959 (2000). K. Shudo, Yakugaku Zasshi, 120, 987 (2000). Y. Aoyagi and A. Ohta, Yakugaku Zasshi, 120, 1035 (2000). H. Nakazawa, J. Kizu, and Y. Matsushima, Yakugaku Zasshi, 120, 1051 (2000). M. Arisawa, H. Tohma, and Y. Kita, Yakugaku Zasshi, 120, 1061 (2000). H. Nakano, Yakugaku Zasshi, 120, 1117 (2000). K. Otsubo, Yakugaku Zasshi, 120, 1135 (2000).

68 00YZ1159 00YZ1247 00YZ1233 00YZ1261 00YZ1323 00YZ1337 00YZ1347 00YZ1373 00YZ1409 00ZAK1014 00ZOR11 00ZOR167 00ZOR329 00ZOR479 00ZOR1273 00ZSK164 01AC2735 01AC2805 01ACR1 01ACR40 01ACR49 01ACR95 01ACR159 01ACR171 01ACR299 01ACR359 01ACR433 01ACR456 01ACR465 01ACR523 01ACR595 01ACR615 01ACR653 01ACR818 01ACR836 01ACR865 01ACR875 01ACR885 01ACR905 01ACR919 01AG(E)284 01AG(E)339 01AG(E)486 01AG(E)529 01AG(E)534

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01JOM(617–618)209 01KFZ(1)33

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Refs.] 01KFZ(2)3 01KFZ(4)3 01KFZ(9)3 01KFZ(10)41 01KGS3 01KGS8 01KGS19 01KGS41 01KGS156 01KGS291 01KGS409 01KGS435 01KGS570 01KGS723 01KGS807 01KGS997 01KGS1011 01KGS1155 01KGS1451 01KGS1587 01KGS1611 01KK243

01KK283 01KK317 01KK483 01KPS3 01KPS87 01KPS103 01M1

01MI2 01MI3 01MI4 01MI5 01MI6 01MI7 01MI8 01MI9

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Refs.] 01MI119 01MI120 01MI121 01MI122 01MI123 01MI124 01MI125 01MI126 01MI127 01MI128 01MI129 01MI130 01MI131 01MI132 01MI133 01MI134 01MI135 01MI136 01MI137 01MI138 01MI139 01MI140 01MI141 01MI142 01MI143 01MI144 01MI145 01MI146

01MI147 01MI148 01OPP59 01OPP103 01OPP203 01OPP315 01OPP567 01OPP515 01PAC55 01PAC67 01PAC147 01PAC167 01PAC175

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

79

A. V. Nikitin, T. V. Smolkina, and A. I. Iordanova, Antibiot. Khimioter., 46(2), 33 (2001). S. O. Bochurin, Voprosy Med. Khim., 47, 155 (2001). I. V. Sakaeva, E. I. Sakanyan, E. E. Lesnevskaya, and K. F. Blinova, Rastit. Resursy, 37(1), 111 (2001). J.-L. Li, X. Feng, B. Lui, and Y. J. Yuan, Youji Huaxue, 21, 428 (2001). L. Xu and F. P. Wang, Youji Huaxue, 21, 493 (2001). D.-W. Ma, Youji Huaxue, 21, 842 (2001). Y-Ch. Wang, Y-F. Sun, B. Dai, Sh-P. Wu, and Zh-Q. Jiang, Youji Huaxue, 21, 890 (2001). M. Lei, Y.-G. Wang, and Y. Z. Chen, Youji Huaxue, 21, 436 (2001). B.-X. Zhao, Youji Huaxue, 21, 445 (2001). Ch.-H. Tung, L.-Z. Wu, and L.-P. Zhang, Youji Huaxue, 21, 784 (2001). W. A. Smit, M. I. Lazareva, and R. Caple, Ros. Khim. Zh., 45(4), 3 (2001). X.-Y. Lu, Youji Huaxue, 21, 769 (2001). Sh.-M. Ma, Youji Huaxue, 21, 833 (2001). Z. Qiao and M. Wang, Youji Huaxue, 21, 325 (2001). C.-M. Wang, G.-L. Pan, L.-H. Zhao, X.-J. Ming, and M.-G. Fan, Youji Huaxue, 21, 954 (2001). H.-X. Gao, R.-H. Lu, and H. Q. Wang, Youji Huaxue, 21, 485 (2001). Q.-X. Xiang, J.-S. You, Y. Liu, X.-Q. Yu, and R.-G. Xie, Youji Huaxue, 21, 557 (2001). Y.-W. Sha, Y. Wang, and J. Ge, Youji Huaxue, 21, 102 (2001). L. Shi, X.-P. Wang, and T.-X. Cai, Youji Huaxue, 21, 200 (2001). Z.-Y. Li, H. Jin, and J. Shi, Youji Huaxue, 21, 247 (2001). M.-W. Ding and Z.-J. Liu, Youji Huaxue, 21, 1 (2001). L.-B. Chen, Q.-H. Zang, and J.-X. Xu, Youji Huaxue, 21, 89–96 (2001). W.-L. Jia, L.-F. Tang, J.-F. Chai, and J.-T. Wang, Youji Huaxue, 21, 126 (2000). A.-M. Zhang, W. Wang, and G.-Q. Lin, Youji Huaxue, 21, 134 (2001). Y.-H. Wang, S.-J. Yan, J.-Y. Su, L.-M. Zeng, and H. Li, Youji Huaxue, 21, 16 (2001). M.-T. Liang and D.-X. Wang, Youji Huaxue, 21, 97 (2001). Ph. M. Weintraub, K. Turnbull, D. M. Ketcha, E. Fossum and M. McMills. ‘‘Annual Reports in Organic Synthesis—2000’’, Academic Press, London (2001). A. J. W. G. Visser, P. A. W. van den Berg, M. A. Hink, and V. N. Petushkov, in ‘‘Fluorescence Correlation Spectroscopy. Theory and Applications’’, p. 9, Springer, Berlin etc. (2001). Z. Fo¨ldes-Papp and M. Kinjo, in ‘‘Fluorescence Correlation Spectroscopy. Theory and Applications’’, p. 25, Springer, Berlin etc. (2001). G.-Q. Lin, Y.-M. Li, and S. C. Chan, ‘‘Principles and Applications of Asymmetric Synthesis’’, Wiley-Interscience, New York (2001). K. Yaugau, Org. Prep. Proced. Int., 33, 59 (2001). S. Karlsson and H.-E. Hogberg, Org. Prep. Proced. Int., 33, 103 (2001). F. Albericio, R. Chinchilla, D. J. Dodsworth, and C. Najera, Org. Prep. Proced. Int., 33, 203 (2001). B. Alcaide and P. Almendros, Org. Prep. Proced. Int., 33, 315 (2001). D. B. G. Williams, K. Blann, and J. Caddy, Org. Prep. Proced. Int., 33, 567 (2001). U. S. Sorensen and P. Krogsgaard-Larsen, Org. Prep. Proced. Int., 33, 515 (2001). E. De Clercq, Pure Appl. Chem., 73, 55 (2001). E. Ratti and D. Trist, Pure Appl. Chem., 73, 67 (2001). M. Kidwai, Pure Appl. Chem., 73, 147 (2001). A. A. Raunak, A. K. Prasad, N. A. Shakil, Himanshu, and V. S. Parmat, Pure Appl. Chem., 73, 167 (2001). Y. S. Sanghvi, V. T. Ravikumar, A. N. Scozzan, and D. L. Cole, Pure Appl. Chem., 73, 175 (2001).

80 01PAC187 01PAC193 01PAC247 01PAC265 01PAC271 01PAC283 01PAC415 01PAC449 01PAC469 01PAC503 01PAC573 01PAC617 01PAC639 01PAC785 01PAC1401 01PAC1411

01PAC1421 01PAC1437

01PAC1477 01PAC1499 01PAC1795 01PHC1 01PHC25 01PHC52 01PHC71 01PHC87 01PHC111 01PHC130 01PHC167 01PHC188 01PHC205 01PHC217 01PHC238 01PHC261 01PHC296 01PHC317 01PHC340 01PHC378 01S1

L.I. BELEN’KII AND V.N. GRAMENITSKAYA

[Refs.

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Refs.] 01S171 01S507 01S811 01S961 01S1281 01S1431 01S1585 01S1747 01S1903 01S2059 01S2203 01S2365 01SL1 01SL458 01SL565 01SL1065 01SL1079 01SL1197 01SL1343 01SL1364 01SL1499 01SL1663 01SL1813 01T625 01T1139 01T1411 01T1639 01T2065 01T2449 01T2643 01T2917 01T2960 01T3221 01T3809 01T4059 01T4243 01T4467 01T4737 01T4801 01T5263 01T5461 01T5683 01T5899 01T6099 01T6651 01T6855 01T7053 01T7073 01T7237 01T7431 01T7449 01T7575

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

81

N. Krause and A. Hoﬀmann-Roder, Synthesis, 171 (2001). A. Kirschning, M. Jesberger, and K.-U. Schoning, Synthesis, 507 (2001). B. Zaleska and S. Lis, Synthesis, 811 (2001). K. Kacprzak and J. Gawronski, Synthesis, 961 (2001). A. K. Ghosh, E. S. Koltun, and G. Bilcer, Synthesis, 1281 (2001). S. Dahmen and S. Brase, Synthesis, 1431 (2001). K. Khanball and T. van Ree, Synthesis, 1585 (2001). G. H. Elgemeia and S. H. Sayed, Synthesis, 1747 (2001). A. Corsaro, U. Chiacehio, and V. Pistara, Synthesis, 1903 (2001). A. El-Aal, M. Gaber, and H. McNab, Synthesis, 2059 (2001). A. K. Ghosh, G. Bilcer, and G. Schiltz, Synthesis, 2203 (2001). Z. Li, Z. Jin, and R. Huang, Synthesis, 2365 (2001). L. A. Paquette, Synlett, 1 (2001). A. R. Katritzky and D. Toader, Synlett, 458 (2001). H. Todo and M. Katohgi, Synlett, 565 (2001). O. I. Kolodiazhnyi and R. Schmutzler, Synlett, 1065 (2001). Ch. Schneider, Synlett, 1079 (2001). M. Yus, Synlett, 1197 (2001). J. Suh, Synlett, 1343 (2001). M. P. Poyle and W. Hu, Synlett, 1364 (2001). E. Vedejs, J. A. Vackay, and E. Rozners, Synlett, 1499 (2001). N. Aratani, A. Tsuda, and A. Osuda, Synlett, 1663 (2001). C. Palomo, J. M. Aizpurua, I. Ganboa, and M. Oiarbide, Synlett, 1813 (2001). G. Mehta and S. Kotha, Tetrahedron, 57, 625 (2001). E. A. Archer, H. Hong, and M. J. Krische, Tetrahedron, 57, 1139 (2001). N. Petragnani, H. A. Stefani, and C. J. Valduga, Tetrahedron, 57, 1411 (2001). J. Suwinsky and K. Swierczak, Tetrahedron, 57, 1639 (2001). W. H. Moser, Tetrahedron, 57, 2065 (2001). H. B. Kagan, Tetrahedron, 57, 2449 (2001). D. Caine, Tetrahedron, 57, 2643 (2001). K. Mikami, M. Shimizu, H.-Ch. Zhang, and B. E. Maryanoﬀ, Tetrahedron, 57, 2917 (2001). H. B. Kagan, Tetrahedron, 57, 2960 (2001). S. K. Bur and S. F. Martin, Tetrahedron, 57, 3221 (2001). M. McCarthy and P. J. Guirg, Tetrahedron, 57, 3809 (2001). F. Mongin and G. Queguiner, Tetrahedron, 57, 4059 (2001). E. Marsault, A. Tiro, P. Nowak, and P. Deslongchamps, Tetrahedron, 57, 4243 (2001). T. J. Hodgkinson and M. Shipman, Tetrahedron, 57, 4467 (2001). B. Clapham, T. S. Reger, and K. D. Janda, Tetrahedron, 57, 4737 (2001). S. H. Lee and Ch. S. Cheong, Tetrahedron, 57, 4801 (2001). Th. G. Back, Tetrahedron, 57, 5263 (2001). G. K. Friestad, Tetrahedron, 57, 5461 (2001). G. I. Elliot and J. P. Konopelski, Tetrahedron, 57, 5683 (2001). A. G. Fallis and P. Forgione, Tetrahedron, 57, 5899 (2001). P. Buonora, J.-C. Olsen, and T. Oh, Tetrahedron, 57, 6099 (2001). M. C. Elliot, E. Kruiswijk, and M. S. Hong, Tetrahedron, 57, 6651 (2001). P. L. Fuchs, Tetrahedron, 57, 6855 (2001). J. Yli-Kauhaluoma, Tetrahedron, 57, 7053 (2001). L. Peterlin-Masic and D. Kikely, Tetrahedron, 57, 7073 (2001). W. Zang, Tetrahedron, 57, 7237 (2001). A. J. Souers and J. A. Elmann, Tetrahedron, 57, 7431 (2001). N. J. Whitcombe, K. K. Hii, and S. E. Gibson, Tetrahedron, 57, 7449 (2001). C. A. Ziﬁcsak, J. A. Mulder, R. P. Hsung, C. Rameshkumar, and L. L. Wei, Tetrahedron, 57, 7575 (2001).

82 01T7999 01T8203 01T8589 01T9347 01T9513 01T9649 01UK28 01UK88 01UK123 01UK241 01UK262 01UK345 01UK382 01UK464 01UK562 01UK581 01UK656 01UK730 01UK744 01UK763 01UK830 01UK974 01UK1013 01UK1039 01UK1059 01UK1094 01YGK193 01YGK206 01YGK331 01YGK355 01YGK560 01YGK569 01YGK576 01YGK589 01YGK599 01YZ65 01YZ193 01YZ259 01YZ295 01YZ319 01ZOB1941 01ZOR165 01ZOR489 01ZOR807

L.I. BELEN’KII AND V.N. GRAMENITSKAYA

[Refs.

G. B. Jones, Tetrahedron, 57, 7999 (2001). P. L. Smith, M. D. Chordia, and W. D. Harman, Tetrahedron, 57, 8203 (2001). W. A. Donaldson, Tetrahedron, 57, 8589 (2001). A. M. Burja, B. Banagis, E. Abou-Mansour, J. G. Burgess, and Ph. C. Wright, Tetrahedron, 57, 9347 (2001). R. Bonnett and G. Martinez, Tetrahedron, 57, 9513 (2001). A. Studer and M. Bossart, Tetrahedron, 57, 9649 (2001). I. P. Panova and I. N. Topchieva, Usp. Khim., 70, 28 (2001). L. G. Komarova and A. L. Rusanov, Usp. Khim., 70, 88 (2001). V. V. Shereshovets, S. L. Khursan, V. D. Komissarov, and G. A. Tolstikov, Usp. Khim., 70, 123 (2001). G. I. Borodkin and V. G. Shubin, Usp. Khim., 70, 241 (2001). V. K. Brel’, N. Sh. Pirkuliev, and N. S. Zeﬁrov, Usp. Khim., 70, 262 (2001). V. P. Litvinov, S. V. Roman, and V. D. Dyachenko, Usp. Khim., 70, 345 (2001). O. N. Zeﬁrova and N. S. Zeﬁrov, Usp. Khim., 70, 382 (2001). R. P. Litvinovskaya and V. A. Khripach, Usp. Khim., 70, 464 (2001). V. N. Silnikov and V. V. Vlasov, Usp. Khim., 70, 562 (2001). I. G. Shishkina, A. S. Levina, and V. F. Zarytova, Usp. Khim., 70, 581 (2001). N. Zh. Mamardashvili and O. A. Golubchikov, Usp. Khim., 70, 656 (2001). A. I. Kotyatkina, V. N. Zhabinskii, and V. A. Khripach, Usp. Khim., 70, 730 (2001). S. N. Lakeev, I. O. Maidanova, F. Z. Galin, and G. A. Tolstikov, Usp. Khim., 70, 744 (2001). V. A. Stonik, Usp. Khim., 70, 763 (2001). A. A. Vasil’ev and E. P. Serebryakov, Usp. Khim., 70, 830 (2001). B. I. Kharisov and M. A. Mendes-Rochas, Usp. Khim., 70, 974 (2001). E. N. Prilezhaeva, Usp. Khim., 70, 1013 (2001). S. G. Perevalov, Ya. V. Burgart, V. I. Saloutin, and O. N. Chupakhin, Usp. Khim., 70, 1039 (2001). N. V. Konovalova, R. P. Evstigneeva, and V. N. Luzgina, Usp. Khim., 70, 1059 (2001). A. K. Bonerghi, M. S. Laia-Mimo, and V. J. Vera-Vegas, Usp. Khim., 70, 1094 (2001). M. Sasaki and M. Inoue, Yuki Gosei Kagaku Kyokaishi, 59, 193 (2001). K. Kihara and T. Takata, Yuki Gosei Kagaku Kyokaishi, 59, 206 (2001). C. Ichikawa and K. Kato, Yuki Gosei Kagaku Kyokaishi, 59, 331 (2001). H. Sashida, Yuki Gosei Kagaku Kyokaishi, 59, 355 (2001). M. Murakata and O. Hoshino, Yuki Gosei Kagaku Kyokaishi, 59, 560 (2001). Y. Takeuchi and T. Harayama, Yuki Gosei Kagaku Kyokaishi, 59, 569 (2001). Y. Sato, M. Takimoto, and M. Mori, Yuki Gosei Kagaku Kyokaishi, 59, 576 (2001). S. Shuto, I. Sugimoto, and A. Matsuda, Yuki Gosei Kagaku Kyokaishi, 59, 589 (2001). H. Miyaoka and Y. Yamada, Yuki Gosei Kagaku Kyokaishi, 59, 599 (2001). T. Ohwada, Yakugaku Zasshi, 121, 65 (2001). H. Ogawara, Yakugaku Zasshi, 121, 193 (2001). K. Suemaru, H. Azoki, and Y. Gonuta, Yakugaku Zasshi, 121, 259 (2001). A. Sugeya, Yakugaku Zasshi, 121, 295 (2001). M. Kudo, T. Ohkubo, and K. Sugawara, Yakugaku Zasshi, 121, 319 (2001). M. G. Voronkov and E. N. Deryagina, Zh. Obshch. Khim., 71, 1941 (2001). V. A. Lopyrev, L. I. Larina, and M. G. Voronkov, Zh. Org. Khim., 37, 165 (2001). I. K. Moiseev, N. V. Makarova, and M. N. Zemtsova, Zh. Org. Khim., 37, 489 (2001). A. A. Malin and V. A. Ostrovskii, Zh. Org. Khim., 37, 807 (2001).

Refs.] 01ZOR959 01ZOR1431 02KGS404 02KGS992 02PHC1 02PHC19 02PHC52 02PHC75 02PHC90 02PHC114 02PHC139 02PHC180 02PHC200 02PHC222 02PHC235 02PHC257 02PHC279 02PHC310 02PHC332 02PHC356 03KGS447 03KGS776

THE LITERATURE OF HETEROCYCLIC CHEMISTRY

83

N. V. Averina, G. S. Borisova, and N. S. Zeﬁrov, Zh. Org. Khim., 37, 959 (2001). L. I. Kas’yan, A. O. Kas’yan, and I. N. Tarabara, Zh. Org. Khim., 37, 1431 (2001). N. D. Kruchkovskaya and L. I. Belen’kii, Khim. Geterotsikl. Soedin., 404 (2002). N. D. Kruchkovskaya and L. I. Belen’kii, Khim. Geterotsikl. Soedin., 992 (2002). J. Bergman and T. Janosik, Progr. Heterocycl. Chem., 14, 1 (2002). D. W. Knight, Progr. Heterocycl. Chem., 14, 19 (2002). A. Padwa and S. S. Murphree, Progr. Heterocycl. Chem., 14, 52 (2002). L. K. Mehta and J. Parrick, Progr. Heterocycl. Chem., 14, 75 (2002). E. T. Pelkey, Progr. Heterocycl. Chem., 14, 90 (2002). D. M. Ketcha, Progr. Heterocycl. Chem., 14, 114 (2002). X.-L. Hou, Zh. Yang, and H. N. C. Wong, Progr. Heterocycl. Chem., 14, 139 (2002). L. Yet, Progr. Heterocycl. Chem., 14, 180 (2002). D. J. Wilkins and P. A. Bradley, Progr. Heterocycl. Chem., 14, 200 (2002). R. A. Aitken and S. J. Costello, Progr. Heterocycl. Chem., 14, 222 (2002). S. Cicchi, F. M. Cordero, and D. Giomi, Progr. Heterocycl. Chem., 14, 235 (2002). D. S. Coﬀey, S. P. Kolis, and S. A. May, Progr. Heterocycl. Chem., 14, 257 (2002). G. H. C. Woo, J. K. Snyder, and Z-K. Wan, Progr. Heterocycl. Chem., 14, 279 (2002). C. Ochoa and P. Goya, Progr. Heterocycl. Chem., 14, 310 (2002). J. D. Hepworth and B. M. Heron, Progr. Heterocycl. Chem., 14, 332 (2002). G. R. Newkome, Progr. Heterocycl. Chem., 14, 356 (2002). N. D. Kruchkovskaya, V. N. Gramenitskaya, and L. I. Belen’kii, Khim. Geterotsikl. Soedin., 447 (2003). L. I. Belen’kii, Khim. Geterotsikl. Soedin., 776 (2003).

Annulated Heterocyclo-Purines I. Fused Five-Membered Heterocyclo-Purinediones, -Purinones, and -Purineimines ALFONZ RYBA´R Institute of Chemistry, Slovak Academy of Science, Bratislava 84538, Slovak Republic

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Purines Fused with Five-Membered Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Pyrrolo-Purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Oxazolo-Purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Thiazolo-Purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Imidazo-Purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Pyrazolo-Purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. Triazolo-Purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. Tetrazolo-Purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85 86 86 91 95 106 126 127 131 134

I. Introduction Various purines have successfully been employed in medicine for some decades. The eﬀort to obtain compounds with a greater selective eﬃcacy without the unwanted side-eﬀects then those of the parent purines, stimulated the study of annulated compounds. One route fulﬁlling this aim was the annulation of an heterocycle to the purine ring system. The purine skeleton oﬀers various possibilities for fusion of a further ring; the most studies tricyclic compounds were those with an annulation to bonds a, b, c, f, and i. 6

i N

N

a

f

d

b

N c

1

N e H

5

N

N7 4

2

N 3

8

N9 H

This review presents purines annulated with fused ﬁve-membered rings, as pyrrolo-, oxazolo-, thiazolo-, imidazo-, pyrazolo-, triazolo-, and tetrazolo-purines. Aiming to eliminate some misinterpretations (numbering of the skeleton in some papers did not match those in Chemical abstracts) atoms of the ﬁrst scheme in each chapter will be numbered. Each group of compounds includes the synthesis, reactions of the heterocyclic system in question, biological eﬀects, and, if accessible, also references about the detailed spectral data, X-ray analysis and so on. Papers were abstracted up to December 2002, inclusive vol. 137 of Chemical Abstracts. Purines annulated with six and more-membered rings will be treated in a subsequent review. 85 ADVANCES IN HETEROCYCLIC CHEMISTRY VOLUME 87 ISSN: 0065-2725 DOI: 10.1016/S0065-2725(04)87002-8

ß 2004 Elsevier Inc. All rights reserved

ALFONZ RYBA´R

86

[Sec. II.A

II. Purines Fused with Five-Membered Heterocycles A. PYRROLO-PURINES 1. Pyrrolo[1,2-a]purines A representative of this type of compounds, 6,7-dihydro-5H-pyrrolo[1,2-a]purine9-amine (3), was accessible by heating 5-amino-imidazole-4-carbonitrile (1) with 5-ethoxy-3,4-dihydro-2H-pyrrole (2) (88JCS(P1)593). Compound 3 shows a phytohormone eﬀect greater than that of benzyladenine (89JAP(K)1) (Scheme 1). An analogous structure, 1,4,4a,5,6,7-hexahydro-1,4,4a-trimethyl-9H-pyrrolo-[1,2a]purin-9-one (5), can be prepared by cyclization of a caﬀeidine homologue, 1methyl-4-methylamino-imidazole-5-[N-(4-oxopentyl)carboxamide] (4) in ethanolic hydrogen chloride (Scheme 2). The vasodilatation activity of compound 5 was reported in (86CPB36). 2. Pyrrolo[1,2-b]purines 1-H-Pyrrolo[2,1-b]purin-4(5H)-one (9) was synthesized from ethyl 4-aminoimidazole-5-carboxylate (6) and 2,5-(diethoxy)tetrahydrofuran in heated acetic acid to give ethyl 4-(pyrrol-1-yl)imidazole-5-carboxylate (7), which aﬀorded on treatment with hydrazine the required hydrazide. Subsequent reaction with isoamyl nitrite in acetic acid gave azide 8 followed by elimination of nitrogen to produce compounds 9. Yields are low in all steps (9–26%) (82H(17)405) (Scheme 3). 3. Pyrrolo[1,2-e]purines A representative of this group, 3,6,7,8-tetrahydro-4-oxo-4H-pyrrolo[1,2-e]-purine8-carboxylic acid and various derivatives were obtained from ethyl 5-ethoxy-3,4dihydro-2H-pyrrole-2-carboxylate (10) and amino-cyanoacetamide (11) in ethanolic NH2 NC

8

N

N

a

H2N 1

N H

7

N1

N

OC2H5

+ 2

3

N

N

4

3

a: BuOH, reflux / 48 hr

Scheme 1 O CH3-CO(CH2)3-NH-C N a: HCl - EtOH.

O

CH3 a

HN N CH3 4

N H3C

Scheme 2

CH3 N

N N CH3 5

Sec. II.A]

87

ANNULATED HETEROCYCLO-PURINES

H N

EtO2C

O

OEt a

H N

EtO2C

b,c

N3

1

H N

HN

8

4

N

N

N

H2N 6

N

N

+ O N

N

6

OEt

9

N5 H

O

8 7 a: AcOH,reflux / 1 hr; b: H2NNH2.H2O, EtOH, reflux / 1 hr; c: AlkONO, AcOH.

Scheme 3

O

a EtO2C

OEt

N

EtO2C

N

N

10 O HN

NH2 b

CONH2

N EtO2C

12

NH2

X 4

5

6

N

c, d, e N

N 1

N

CN

13

8

CO2Et

N

a: H2N-CH(CN)-CONH2 (11), EtOH - HCl, 50o / 10 min; N 20o / 12 hr; N CO2R b : HC(OEt)3, Ac2O, reflux, 14, X = Cl, R = Et 3 hr; 15, X = SH, R = OH c: POCl3, reflux, 3 hr; d: (H2N)2CS, EtOH, reflux; e: 2N HCl, reflux, 1 hr.

N

Scheme 4

hydrogen chloride giving pyrrolo-imidazole 12; its cyclization in a mixture of ethyl orthoformate and acetic anhydride aﬀorded ethyl 1,6,7,8-tetrahydro-4-oxo-4Hpyrrolo[1,2-e]purine-8-carboxylate (13). A stepwise treatment with phosphorus oxychloride and thiourea produced ethyl 4-chloro-7,8-dihydro-6H-pyrrolo[1,2-e]purine-8-carboxylate (14) and its thiouronium salt, respectively. Acid hydrolysis of this salt gave 1,6,7,8-tetrahydro-4-thioxo-4H-pyrrolo[1,2-e]-purine-8-carboxylic acid (15) (73KFZ(11)14) (Scheme 4). 4. Pyrrolo[2,1-f]purines Displacement of bromine by benzhydrylpiperazine in 8-(3-bromopropyl)-1,3dimethyl- or 1-isobutyl-3-methyl-3,7-dihydro-1H-purine-2,6-diones gave rise to the required product and small amounts of 1,3-dimethyl- or 1-isobutyl-3-methyl-1,6,7,8tetrahydro-2H-pyrrolo[1,2-e]-purine-2,4(3H)-dione and its [2,1-f ] position isomer. The structures of both substances were corroborated by 1H-NMR spectra (87EJM243). Of preparative importance are the following methods: the ﬁrst, and most simple is based upon intramolecular alkylation of 8-(3-chloropropyl)purine intermediate 18b in dilute alkali. The key intermediate 18b was obtained by a four-step synthesis starting from 6-chloro-1,3-dimethyluracil and 4-(hydroxybutyl-amino)-5nitrosouracil 16b, its cyclodehydration to 8-(3-hydroxypropyl)-purinedione 18a and reaction with thionyl chloride (85JHC105) (Scheme 5).

ALFONZ RYBA´R

88 O H3C

O a, b

N

H3C

Cl

N

O

c, d

X NH

N CH3

(CH2)4-Cl

NH2

N N C3H7

R

O

16a, X = H 16b, X = NO

O

O

O

N

O

CH3

H7C3

[Sec. II.A

H N

N N

(CH2)3-X

N

R 18a, R = CH3, X = OH (for 18b, X = Cl) 19a, R = C3H7, X = OH (for 19b, X = Cl) e, i

g, h O

NH2

H7C3

N

O NH-CO-(CH2)3-Cl R N

6

1

f O

5

N

4

NH2

N C3H7

N

O

R

17a k

N

8

20a, R = CH3 20b, R = C3H7

a : H2N-(CH2)4-OH, TEA-H2O, j reflux /1 hr; O b : NaNO2-H2O,0o, AcOH, 1 hr; H7C3 N N c : BuOH, reflux / 2 hr; O d : SOCl2, reflux / 1 hr; NH N o e : (for 20a) NaOH-H2O, 50 / 18 hr; O 2 f : AcOH, AcONa, 0o, Cl-CO-(CH2)3-Cl, 17b C3H7 r.t./ 2 hr; g : Ph2O, reflux / 1 hr; h : SOCl2, reflux / 2 hr; i : (for 20b) NaOMe-MeOH, reflux / 2 hr; j : NaOMe- MeOH, reflux / 2 hr; k : POCl3, 0o, reflux / 2 hr. Scheme 5

An alternate method started from 5,6-diamino-1,3-dipropyluracil which reacted with 4-chlorobutyryl chloride to give 6-amino-5-(4-chlorobutyryl)amino-1,3dipropyl-1H,3H-pyrimidine-2,4-dione (17a) and subsequently underwent cyclization in diphenyl ether under reﬂux. The water produced in this step hydrolyzed the product into 8-(3-hydroxypropyl)-1,3-dipropyl-7H-purine-2,4(1H,3H)-dione (19a). Heating the latter in thionyl chloride led to the appropriate 8-(3-chloropropyl) derivative 19b which underwent intramolecular alkylation with NaOCH3 to aﬀord the ﬁnal tricyclic 20b. Another route started from 6-amino-5-(4-chlorobutyl)amino derivative 17a by an intramolecular alkylation to 6-amino-5-(2-oxopyrolidin-1-yl)1,3-dipropyl-1H,3H-pyrimidine-2,4-dione (17b) and its subsequent cyclization by phosphorus oxychloride under reﬂux to 20b (94JHC81) (Scheme 5). The second method was based on a cycloaddition reaction of oleﬁnic and acetylenic dipolarophiles to xanthinium-(N7) ylides. Xanthinium-(N7) ylides 22 were generated from 7-substituted 1,3,9-trimethylxanthinium tosylates 21 by deprotonation with triethylamine in dry acetonitrile followed by reaction with dipolarophiles 23 and 25 (dimethyl fumarate, fumaronitrile, methyl acrylate, acrylonitrile and the like). Reaction with dimethyl fumarate aﬀorded the endo-(24a) and exo-(24b) adducts in a 3:2 ratio. The stereochemistry of these compounds was established by 1H-NMR and X-ray analysis (84H2199). With derivatives of acrylic acid 25, only endo adducts (26)

Sec. II.A]

O H N

a

H3C

N

CH2-CO-Ar b H3C N

N N

O

N

22

O

26

H N

N

O

N

e

O N

H3C

N

N _ + TsO N CH3

N

H N

H3C

CO H

N N X H CH3 CH H X 3 24a

H

N

N

+ O

N

CO X

N

H H CH3 CH X H 3

CO Ar

23-24, X = CN, CO2Me, CO-Ph

H

25-26, X = CN, CO2Me

N H H CH3 CH H X 3

c

Ar

O

Ar

O

d

CH2-CO-Ar

CH3 21, Ar = Ph, 4-Br-C6H4, duryl

_

C H-CO-Ar N + N CH3

O

O

CH3

H3C

89

ANNULATED HETEROCYCLO-PURINES

24b

a: DMF, NaH, Br-CH2-CO-Ar, r.t. / 5 hr; b:TsOMe, 140-160o / 2 hr; c: Et3N, CH3CN, r.t, N2-atm.; d: trans X-CH=CH-X (23); e: H2C=CH-X (25).

Scheme 6

were furnished (87JCS(P1)1211) (Scheme 6). An analogous cycloaddition with dimethyl acetylene dicarboxylate or methyl propiolate led to unsaturated derivatives of 24 and 26 with a C(7)–C(8) double bond (86CPB1328). The previous two methods started from a purinedione derivative and the pyrrole moiety was built up. The following methods start from the pyrrole rings, the purine moiety being fused. Thus, starting from cyclic cyanamidine 27 1-(ethoxycarbonylmethyl)-2-cyanoimino-pyrrolidine (28) was obtained by alkylation with ethyl chloroacetate. Compound 28 aﬀorded 2-amino-3-ethoxycarbonyl-5,6-dihydro-7Hpyrrolo[1,2-a]imidazole (29) by a cyclocondensation of the Claisen type. Further reaction with N,N-dimethylformamide diethyl acetal gave rise to 3-(ethoxycarbonyl)2-(N,N-dimethylaminomethylenamino)-5,6-dihydro-7H-pyrrolo[1,2-a]imidazole (30) and then ammonolysis at elevated temperature gave amidine 31 which cyclized immediately to 7,8-dihydro-3H-pyrrolo[2,1-f ]purin-4(6H)-one (32) (Scheme 7). The enol form of compound 32 can be transformed into 4-chloro derivative 33 by phosphorus oxychloride. Thiourea with the latter produced a 6-mercapto derivative through the respective isothiouronium salt and mild hydrolysis. The last three compounds revealed antitumor and antiviral activities against Herpes simplex type 1 and inﬂuenza virus, respectively (92KFZ(9–10)63) (Scheme 7). 4-Chloro derivative 33 reacted with other nucleophiles to form 4-methoxy-, 4-benzylamino-, and 4morpholino derivatives. Alkylation of the Na þ or K þ salt of 4-mercapto derivative 34 led to 4-benzylthio-, 4-(methoxycarbonyl)methyl-thio, and 4-(1-methyl-4nitroimidazol-5-yl)thio derivatives. Similarly alkyl-amines with 30 formed 3-alkyl7,8-dihydropyrrolo[2,1-f ]purin-4(6H)-ones (95KFZ(2)27).

ALFONZ RYBA´R

90 N-CN N R 27, R = H i

N

N vi

v NH

32

O

i : K2CO3, DMF, ClCH2CO2Et, 80o / 1 hr; ii :NaOEt, EtOH, reflux / 1 hr; iii : Me2N-CH(OEt)2,

N

33, X = Cl

N

N

N CO2Et 29, X = NH2 30, X = N=CH-NMe2 31, X = N=CH-NH2

28, R = CH2CO2Et N

N

X

N

ii, iii, iv 28

[Sec. II.A

toluene, reflux, 4 hr; iv : NH3-EtOH, 120o / 8 hr;

X

v : POCl3, reflux / 2 hr; vi : SC(NH2)2, EtOH; HCl. 34, X = SH

Scheme 7 N-CN 27

N

N

ii

i

N

iii

N

CN

36

35

N

N

N

CH2-CN

NH2

NH2

37

i : Na, toluene, reflux ; ClCH2CN,<5o / 1 hr; 20 o / 2 hr; ii : NaOEt, EtOH, 70o / 5min; iii : HCONH2, reflux, 50min.

Scheme 8

Alkylation of sodium cyclic cyanamidine 27 with chloroacetonitrile produced 1-cyanomethyl-2-(cyanimino)pyrrolidine 35. Thorpe-Ziegler reaction of the latter led to 2-amino-3-cyano-5,6-dihydro-7H-pyrrolo[1,2-a]imidazole (36) and cyclization with formamide on heating closed the third ring to 4-amino-7,8-dihydro-6H-pyrrolo [2,1-f ]purine (37) (91KGS754) (Scheme 8). 5. Pyrrolo[1,2-c]purines This unusual annulation was reported with saxitoxin, 2,6-diamino-4-{[(aminocarbonyl)oxy]methyl}-3a,4,8,9-tetrahydro-1H,10H-pyrrolo[1,2-c]-purine-10,10-diol (38a) isolated from tissue of a bullfrog and its derivatives, neosaxitoxin, 2,6diamino-4-{[(aminocarbonyl)oxy]methyl}-3a,4,5,6,8,9-hexahydro-1H,10H-pyrrolo[1,2-c]purine-10,10-diol (38b) (91MI1)), gonyautoxin, 2,6-diamino-4-{[(aminocarbonyl)oxy]methyl}-3a,4,5,6,8,9-hexahydro-1H,10H-pyrrolo[1,2-c]purine-9,10, 10-triol (38c) (Scheme 9). Application of these compounds as local anaesthetics was published by Kohane (98MIP1). H2N-CO2 H 5

N

H2N

4

N 8

38a

H2N-CO2

H2N-CO2 3

N

NH2 NH 1 OH OH

10

H HN H2N

H

H N

N

NH2 NH OH OH

HN H2N

H

N

9

38b

Scheme 9

38c

N

NH2 NH OH OH OH

Sec. II.B]

91

ANNULATED HETEROCYCLO-PURINES

B. OXAZOLO-PURINES 1. Oxazolo[2,1-f]purine-2,4-diones This heterocyclic skeleton is accessible by four methods: The ﬁrst involves an intramolecular cyclization of the enolform of 8-bromo- or 8-chloro-7-(acylalkyl)purinedione derivatives 39, which were prepared from the potassium salt of 8bromopurinediones and -bromodialkyl- or -bromoalkyl aryl ketones 41 under reﬂux in dimethylformamide giving derivatives of oxazolo[2,3-f ]-purine-2,4-dione 40 (86KGS1133) (Scheme 10). The second method is based on treatment of potassium salts of 8-halogeno-purine derivatives with derivatives of oxirane (e.g., epihalogenohydrin, glycidol, propylene oxide, butylene oxide, alkyl- or aryl-glycidyl ether) (42) in the presence of catalytic amounts of pyridine in propanol or aqueous ethanol to produce 8-halogeno-7(2-hydroxyalkyl) derivatives 43; intramolecular nucleophilic displacement (without isolation) in dilute hydroxide at room temperature or on heating (64JOC3126, 00EJO3489) furnished 7-substituted methyl-hexahydro-oxazolo[2,3-f ]purinediones 44 (62MI1, 69M1797, 87KFZ566). Enantiomers formed at chiral carbon-7 can be distinguished by 1H- and 13C-NMR in the presence of dirhodium tetrakis[(R)-methoxy--(triﬂuoromethyl)--phenyl-acetate] as a chiral auxiliary (00EJO3489) (Scheme 11). R3 O

R1

+

K N

N O

N

N

O R1 3

N

4

N R2

Br

N

O

N1

H, Alk;

R2 =

Alk;

i:

N

R2

39

R1,R3 =

5

R3

N

6 7

O

R2 39, 40,

C=C(OH)- R4

N

Br

N

O

R1

i

Br-CH(R3)-CO-R4(41),

O

R4

40

DMF, reflux, 0.5-1 hr.

R4 = Alk, Aryl Scheme 10

O H3C

N

O

N CH3

i:

+

H (or K ) N i N

X

H3C O

iii

CH2-R CH-OH CH2 ii N

O N N CH3

N 43

O

X

O H3C O

N

N N CH3

N

O 44

CH2 R

42-44, X = Cl, Br, R = Cl, Br, OH, H, Alk, AlkO, ArylO CH2-R (42), (cat.) pyridine, PrOH or H2O-EtOH; O + ii :NaOH-H2O, (or H2O-EtOH); iii : CH2-R , Bu4P Br , 90o / 12 hr, diglyme.

Scheme 11

ALFONZ RYBA´R

92 CH=CH2 CH2 N N

O i

H3C

N

N

CH3

45

CH2-Br CH2 N

N

O

OH

Br

[Sec. II.B O ii

H3C

N

O

OH

N N CH3

46

N

O 44

CH2 Br

i : Br2; ii : NaOH - H2O.

Scheme 12

Another method involved a reaction of 8-chlorotheophylline with an excess of phenyl or aryl glycidyl ethers, or epichlorohydrin in the presence of tetrabutylphosphonium bromide as a phase-transfer catalyst in diglyme at 90 C to produce 43 (92TL6307). Also, oxiranes and their precursors such as compounds of 3halogenopropane-1,2-diol type can be employed with 8-halogenoxanthine (65MI1). The third method closed the third oxazole ring having a bromomethyl group at C(7) (44) by a short heating of 7-(2,3-dibromopropyl)-8-hydroxyxanthines 46 (accessible by addition of bromine to 7-allyl-8-hydroxyxanthines 45 in alkali) (62MI1) (Scheme 12). Formation of the third oxazole ring can also be realized by a reaction of epichlorohydrin with 8-nitro- or 8-(methanesulfonyl)-4-(2-hydroxypropyl)-xanthine derivatives (75JPR745). The fourth method was based upon the reduction of 8-bromo-7-(acylmethyl)purine-2,6-dione 47 with sodium borohydride in alkali at ambient temperature through 8-bromo-7-[aryl-2-hydroxyethyl] derivative to 6,7-dihydro-7-aryl-oxazolo[2,3-f ]purinediones 48 (90UKZ215) (Scheme 13). Bromation of 1,3-dimethyl-7-phenyl-oxazolo[2,3-f ]-purine-2,4-dione 49 (bromine in acetic acid), took place at position 6 (compound 50). Nitration with potassium nitrate in sulfuric acid did not take place at C6 but instead gave 7-(4-nitrophenyl)oxazolo[2,3-f ]purinedione derivate 51 due of the protonation of the oxazolo-purine ring system by acid. Alkylation at position 1 with ethyl iodoacetate in dimethylformamide in the presence of potassium carbonate gave 52 (90KGS1396) (Scheme 14). Hydrolytic cleavage of the dihydro-oxazolo ring of 44 with conc. HX gave 8hydroxypurine-2,6-dione derivatives 53 and 54 (64JOC3126). The oxazole ring of 44 (R ¼ Cl) (1 mol) was similarly opened on ammonolysis with primary and secondary amines (2 mol); the substituted amino group entered position 7 of the xanthine derivative 55. Provided the substituent in position 7 of 6,7-dihydro-oxazolo[2,3f ]purinediones is a halogenomethyl group and a large excess of amine was used O

O

N N CH3

O

CH2-CO-Aryl

HN N

47

i Br

HN O

N N CH3

N 48

Scheme 13

O

Aryl

i : NaBH4, KOH-H2O, EtOH, r.t. / 3 days.

Sec. II.B]

93

ANNULATED HETEROCYCLO-PURINES O

R' O

ii

Br

N

i

N N

N

O

N N

Ph

49 O

Ph

N

50

R" 49, R' = Me, Et, R" = H, Me 52, R' = Me, Et, R" = Me, CH2CO2Et

N

iii

O 51 NO2

i : Br2, AcOH, reflux; ii : KNO3, H2SO4, 20o; iii : I-CH2-CO2Et, DMF, K2CO3, reflux or CH3-I, DMF, K2CO3, 35o.

Scheme 14 CH2-CH(OH)-CH2-OH N

CH2-CH(X)-CH2-R N i or ii N

OH

53, X = Cl, R = H, Cl, Br 54, X = Br, R = H, Cl, Br

O H3C O

N N N

N

X

iii

N O

CH2-R

55 iv

CH3 44, R = H, Cl, Br, OH R1 55, 56, X = HN-Alk, H2N-CH2-Ph, NAlk1Alk2, N R2 i : conc.HCl, brief boiling; ii : conc.HBr, brief boiling;

CH2-CH(OH)-CH2-X N N

X

56

iii : HNR'R'' (2 equiv.) ; iv : HNR'R''(10 equiv.)

Scheme 15

(1:10), two nucleophilic substitutions took place to form 8-substituted amino-7-(3substituted amino-2-hydroxypropyl)-purinedione 56 (75MI1, 82MI1, 85MI1, 70AP378, 70AP596) (Scheme 15). It is worth noting that the dihydro-oxazole ring cleavage of 44 with ammonia, alkylamines, aralkylamines, and cycloalkylamines proceeded much easier (reﬂux in ethanol, propanol) than the nucleophilic displacement of bromine in 8-bromo-7-(2hydroxyalkyl) 43 (autoclave, 160–170 C, ethanol) (87KFZ566). Opening of the oxazole ring of 7-hydroxymethyl, 7-aryloxymethyl or 7-alkoxymethyl derivatives 44 with hydrazine hydrate on reﬂux in methoxyethanol produced the corresponding 7-(2,3-dihydroxy- or 2-hydroxy-3-methoxy- or 2-hydroxy-3aryloxy-propyl)-8-hydrazinopurinediones (81KFZ59). Similar cleveage was encountered with the oxazole ring of unsaturated derivatives 57 with 2-4 molar excess of primary amines at 170–180 C giving 8-alkylamino-7acylalkyl-xanthines 58; these then underwent cyclization to the respective imidazopurinediones 59 (88KGS534). Thiazolo[2,3-f ]purinediones 60 were found to be similarly formed with sodium sulﬁde in dimethylformamide (Scheme 16). Depending on the catalyst, the dihydro-oxazole ring of 7-chloromethyl6,7-dihydro-oxazolo[2,3-f ]purinedione 44 (R ¼ Cl) was cleaved in two ways: 8-phthalimido-7-(2-hydroxy-3-chloropropyl)-purinedione 61 and 8-methoxy-7-(3phthalimido-2-hydroxypropyl)-purinedione 62 were created with KCN or NaN3 and with NaOCH3, respectively (78TL2049) (Scheme 17).

ALFONZ RYBA´R

94 O

O

R N O

CH3

N N

N

CH3

i

CH(CH3)-CO-Ph N

N

O

N

N

CH3

57 ii

N

O

R

Ph

O

O R

[Sec. II.B

N

S

N

CH3

R

58

ii

O

CH3

N

NH

R

Ph

N

O

N

N

i : H2N-R (excess), EtOH, 170-180o / 4-6hr; ii : Na2S.9H2O, DMF.

Ph

N R

CH3

60

CH3

N

59 Scheme 16

O H3C

CH(OH)-CH2Cl

N

N

O

44 (R=Cl)

O

i O

N

H HO C

N

N

CH3

O

ii H3C

N

CH2

N

O

N

O

61

O

i : Potassium phthalimide, cat. KCN, or NaN3;

N

N

CH3

62

OMe

ii : Potassium phthalimide, cat. NaOMe; Scheme 17

NH2

NH2 N

i

N N

N H

Br

NH2

N

ii

N N 63

N

Br

H2C HO

C C OTr H H2

O

N

N N

CH2-OTr

N 64

i : (S)-tritylglycidol, DMF, CsCO3, 20o / 12 hr; ii : THF, NaH, r.t. / 5 min.

Scheme 18

2. Oxazolo[3,2-e]purine-4-amines Heating 8-bromoadenine with tritylglycidol in formamide in the presence of a base produced (S)-8-bromo-9-[2-hydroxy-3-(trityloxy)propyl]adenine (63) which quickly cyclized to (S)-7-[(trityloxy)methyl]-7,8-dihydro-oxazolo[3,2-e]purin-4-amine 64 by NaH in an aprotic medium (00CCC1126) (Scheme 18). 3. Oxazolo[3,2-a]purin-9-ones This heterocycle was observed on cyclization of 6-amino-5-(cyclopentanecarboxamido)-3-propargyluracil (65) with NaOCH3 in methanol or with dilute

Sec. II.C]

95

ANNULATED HETEROCYCLO-PURINES

HC

HC

O NH2

C H2 N O

N H

i

H2 C O

NH2

HC

O

H2 C

NH-CO-R ii

N N H 65

O 1

H7 N

N 3

O

NH2

N H

R

N 9

66

65-68, R = cyclopentyl

i : ClCO-R; ii :NaOMe, MeOH or NaOH -H2O iii : PPSE

O

O

iii

O CH3-CO-CH2

N

7

N H3C

5

N H 67

O

H N1

9

N

N3

R

68

Scheme 19

alkali leading to 8-cyclopentyl-1-propargyl-3,7-dihydro-1H-purine-2,6-dione (66). Concurrent hydratation of the triple bond of the propargyl group took place to give 1-(2-oxopropyl) derivative 67 and a consecutive intramolecular cyclization aﬀorded 2-cyclopentyl-6-methyloxazolo[3,2-a]purin-9(1H)-one (68). Useful preparations employ the trimethylsilyl ester of polyphosphoric acid (PPSE) to cyclize 1-(2oxopropyl)purinedione derivative 67, or 3-propargyl-uracil derivative 65, to their tricyclic derivatives 68 only. These compounds are eﬃcient antagonists not only of A1 adenosine receptors (33 times more eﬀective than the reference 8-cyclopentyl-1propyl-purinedione), but also A2 adenosine receptors (55 times more eﬀective) (94JOC1928) (Scheme 19).

C. THIAZOLO-PURINES 1. Thiazolo[3,2-a]purine-2,4-diones The ﬁrst synthetic method leading to these heterocycles started from 6-amino-2thiouracil which cyclized with 1,2-dibromoalkanes to 7-amino-2-R-2,3-dihydro-5Hthiazolo[3,2-a]pyrimidine-5-ones 69. The latter was nitrosed at C-6 and reduced with sodium dithionite to 6,7-diamino-2,3-dihydro-2-R-5H-thiazolo-[3,2-a]pyrimidine-5one 70. The third imidazole ring was closed by fusion of the diamine 70 with urea or thiourea to 2-hydroxy- or 2-mercapto-6-R-6,7-dihydro-thiazolo[3,2-a]purin-9(1H)ones 71. An alternate route starting from 6-amino-2-thiouracil through 5,6-diamino2-thiouracil (2 steps) cyclized with dibromoethane to diamine 70. The annulation site of the thiazolo to pyrimidine rings of the intermediate 69 was corroborated by X-ray analysis. Compounds 71 were tested for antiviral eﬀect (Herpes simplex type 1, Vasicular stomatitis virus, Coxsackie virus), but no signiﬁcant eﬃcacy was found (89JHC1701, 91FES899) (Scheme 20). The second method employed methyl 4-amino-imidazol-5-carboxylate (72) which gave 1-R-2-R0 -4-isothiocyanato-imidazole-5-carboxylate (73) with thiophosgene and methyl 1-R-2-R0 -4-[1-(3-hydroxyethyl)thioureido]imidazole-5-carboxylate 74 with

ALFONZ RYBA´R

96

O

O

N

X

i, ii

NH H2N

[Sec. II.C

i : BrCH2CH(Br)-R, PrOH, 2N NaOH, r.t. / 1-2 hr; 60o / 7 hr or Na2CO3, DMF, 40o / 18 hr; ii : NaNO2, AcOH - H2O,

iii

N

H2N

SH

O

N

1

R

S

N

HX

N

9 3N

H

69, X = H; 70, X = NH2

7

N

S

4

5

71, X = S, O

69-71, R = H, Ph

iv

O H2N

25-40o

/ 6 hr; H2O,

100o,

R

Na2S2O4;

NH

H2N

iii : X=C(NH2)2, 205-210o; iv : Br-CH2-CH2-Br, dil. NaOH or Na2CO3, DMF.

SH

N

Scheme 20

ethanolamine. Cyclization proceeded with alkali to yield 7-R-8-R0 -1-(2-hydroxyethyl)-1H,3H-2-thioxopurin-6-one (75). The third ring of the intermediate 75 was closed by heating with acid giving 1-R-2-R0 -6,7-dihydro-thiazolo[3,2-a]purin-9(1H)one (76). A variation of this method was based on the same starting material 72, which reacted with 2-alken-1-yl-isothiocyanate to produce methyl 1-R-2-R0 -4-[1-(3alkenyl)thioureido]imidazole-5-carboxylate 77. Two similar cyclizations as shown with the previous method (through the intermediate 78) originated 1-R-2-R0 -6,7dihydro-6-methyl- (with allyl isothiocyanate) and 1-R-2-R0 -7-R00 -6,7-dihydro-6methylthiazolo[3,2-a]purin-9(1H)-one (79) (with 2-R00 -alken-1-yl isothiocyanate) (89PHA533) (Scheme 21).

R R'

N

O

R

CO2Me i, ii

N

CO2Me

N

R

N

N

iii

R'

R' X N 73, X = NCS 74, X = NHCSNH-(CH2)2-OH 77, X = NHCSNH-CH2-C(R'')=CH2

NH2

72 v

vi R R' 72-76, R, R' = Alk; 77-79, R = Ph, R' = H, R'' = H, Alk

75

78

N H

S iv

R N CH2-C(R'')=CH2

N

N H

O

O

N

N

(CH2)2-OH

N

R'

S

N N

N

S

76 vii O R

i : CSCl2 , H2 O, CH2 Cl2 , CaCO3 , ii :H 2 N-(CH 2 ) 2 -OH ; iii : 3N NaOH,60-100o / 30 min; v : CH2 =C(R'')-CH2-NCS; iv : conc.HCl, heat; vii ; conc.HCl, heat. vi : 3N NaOH, 60-100o / 30 min; Scheme 21

R'

N

N N

N 79

S

CH3 R''

Sec. II.C]

97

ANNULATED HETEROCYCLO-PURINES

O H2N

O

O

N

N

N Cl

N

X

S

Rf

i

80, X = NH2 81, X = NHCSNH-(CH2)2-Cl

N H

N

S

N

N 83

82 Rf O

Rf

ii Rf = ribofuranosyl

N

HN

i : S=C=N-(CH2)2-Cl, pyridine, 50o / 7 hr; ii : Br-(CH2)2-Br, H2O.

N

N

N

HS 84

N Rf

Scheme 22

Annulation of the bond ‘‘a’’ of the purine skeleton was evidenced by desulfuration of compound 76 with Raney-nickel: 1-ethyl derivative of hypoxanthine and 1-(2-R00 propyl) and 1-(2-R-ethyl) derivatives from compounds 79 and 71, respectively being the products. Further variant of this method utilized 5-amino-1-( -D-ribofuranosyl)-imidazole4-carboxamide 80, which reacted with 2-chloroethyl isothiocyanate to aﬀord 5-[3-(2chloroethyl)-1-thioureido]-1-( -D-ribofuranosyl)-imidazole-4-carboxamide (81), i.e., the reagent attacked the 5-amino group of the imidazole and not the nitrogen of the carboxamide owing to its low basicity. A long heating (3 days) in pyridine gave the required 3-( -D-ribofuranosyl)-6,7-dihydrothiazolo[3,2-a]-purin-9(1H)-one (83) through the intermediate 82 (91JOC4213) (Scheme 22). The crystallochemical structure of compound 83 was reported in Ref. 94AX(C)734. The third access was based on the reaction of 1,2-dibromoethane with 2-mercaptopurin-9-one or 2-mercaptoadenine and their derivatives. Preparation of compound 83 from potassium or sodium 2-mercaptoinosine (84) with an excess of 1,2dibromoethane in water exempliﬁed the ﬁrst reaction according to Scheme 22. The annulation site of thiazole to purine moieties was proven by desulfuration with Raney-nickel (after previous cleavage of the saccharide grouping) by the appearance of 1-ethylhypoxanthine (74CPB342). An example for the second reaction was the cyclization of 2-mercaptoadenine with an excess of dibromoethane giving a mixture of 3,6,7,9-tetrahydro-9-iminothiazolo[3,2-a]purine (85) and isomeric 4-amino-7,8dihydro-thiazolo[2,3-b]purine (86). Both isomers were separated by their much diﬀerent insolubility in chloroform (80JHC583) (Scheme 23). NH2 N

N

N N H

N

NH2

NH i SH

N

N N H

N 85

i : Br-CH2CH2-Br, DMF, K2CO3, 40o / 18 hr; Scheme 23

N

+ S

N 86

N

S

ALFONZ RYBA´R

98 OH

HS

Aryl

i

N N

OH

Alk

N

[Sec. II.C Aryl

N

O

ii

O=C S

N

N

87

Alk

N S

N N

88

N

89

i : Aryl-CO-CH2-(Cl/Br), H2O, iso-PrOH, KOH; ii :conc.H2SO4 Scheme 24

The fourth method employed alkylation of 2-mercaptohypoxanthine derivatives (87) with aroylmethyl halides to 2-(aroylmethylthio)-7-alkyl-hypoxathines (88) and their cyclization to 7-aryl-1-alkyl-thiazolo-[3,2-a]purin-9(1H)-ones (89) with conc. sulfuric acid (89UKZ1076) (Scheme 24). Compound 71 (R ¼ H; X ¼ O) was shown to have an immunomodulation eﬀect (88MIP1).

2. Thiazolo[2,3-b]purin-9-ones In addition to cyclization of 2-mercaptoadenines with dibromoethane to a mixture of [2,3-b] and [3,2-a] isomers (86, 85) shown in Scheme 23, the method starting from 2-aminothiazole also produced this heterocycle. This compound—a cyclic isothiourea—was condensed with ethyl nitrosocyanoacetate to 5-amino-6-nitrosothiazolo[3,2-a]pyrimidin-7-one (90). Reduction of the nitroso group with sodium dithionite to 6-amino derivative 91 followed by acylation with acyl chloride yielded 5-amino-6-acylaminothiazolo[3,2-a]pyrimidin-7-one (92). Heating 92 with polyphosphoric acid produced 2-aryl- or 2-heteroaryl-thiazolo[2,3-b]purin-4(3H)-ones 93. Known are two of its reactions: Phosphorus oxychloride ﬁrst chlorinated the molecule to a 4-chloro derivative and methanolic ammonia gave 4-amino-2-aryl- or 2-heteroaryl-thiazolo[2,3-b]purines 94. Alkylation of the sodium salt of 93 with methyl tosylate aﬀorded 3-methyl-2-aryl- or 2-heteroaryl-thiazolo[2,3-b]purin4(3H)-ones 95 (95JHC1725) (Scheme 25). O

O NH2 S

N

X

N

i, ii S

N

5

iii

NH2

6

N

S

NH2

H N3

4

N9

N

N

N

iv

R

R S

1

N

N

7

93

90, X = NO 91, X = NH2 92, X = NH-CO-R

94

v

CH3 N

92-95, R = H, Aryl, Heteroaryl i : NC-C(=NOH)-CO2Et, EtONa, EtOH, 5-10o ; reflux / 3 hr;

R N

ii : Na2S2O4 / 30%NH4OH, 70-80o; Cl-CO-R, pyridine, 0-5o; r.t. / overnight; iii : PPA, 100-110o / 6 hr; iv : POCl3; NH3 / MeOH; v : NaH, DMF, TsOMe

Scheme 25

95

Sec. II.C]

99

ANNULATED HETEROCYCLO-PURINES

3. Thiazolo[2,3-f]purin-4-ones and -2,4-diones Purines fused to thiazole ring at bond ‘‘f ’’ were the most studied subgroup of thiazolopurines; six methods were described to achieve this heterocycle: the ﬁrst issuing from 8-mercaptopurine derivative 96 and -halogenocarbaldehyde acetals gave purin-8-ylthiocarbaldehyde acetals 97 which underwent an easy hydrolysis to carbaldehydes 98 appearing together with their tautomeric-cyclic form 99. The same tautomeric mixture was also prepared from mercapto derivative 96 with halogenocarbaldehydes or their acetals. The existence of a cyclic tautomeric form was proven by their IR spectra of the solid reaction product lacking the band belonging to an aldehyde group but revealing that of a hydroxyl group at 3170 cm1. On the other hand, a solution of this reaction product in alcohols or dimethyl sulfoxide showed an equilibrium between both forms, the aldehyde being corroborated by formation of its dinitrophenyl-hydrazone.The mixture of tautomers 98 and 99 furnished the substituted 7-alkyl- or 7-aryl-thiazolo[2,3-f ]purine2,4(1H,3H)-diones 100 with dehydrating reagents. The annulation site of the thiazole ring was demonstrated by desulfuration of compounds 100 with Raneynickel giving a 7-substituted purinedione. The 9-substituted purinedione was not formed consistent with the ﬁnding that no [3,2-e]-isomers were isolated (72KGS996) (Scheme 26). Reaction of 8-mercaptopurine derivative 96 with -halogenoalkyl aryl- or -halogenoalkyl heteroaryl ketones or -halogenodialkyl ketones in alcohols or in the presence of dimethylformamide (methods A,B,C), or in an excess of -halogenodialkyl ketones (method D) gave 9-(acylalkylthio)purinediones 101 equilibrated with their cyclic tautomeric form 102 just as with tautomeric forms 98 and 99. The tautomers 101, and 102 were transformed by various dehydrating reagents into 6-alkyl- or 6-aryl- or 6,7-dialkyl- or 7-alkyl-6aryl-thiazolo[2,3-f ]purine-2,4(1H,3H)-diones 103, or, when using cycloalkanons into

O

O R'

H N

N

O

N R" 96

N H

R'

H N

i

S

N

S iv

CH(OEt)2 CH-R

97

N

O

N N

N

R"

ii

R

S

100 iii

O

H N N

CH=O S

CH-R

R'

6

N

OH

1

O

98

5

4a 3N

N R"

N

S

9

8

R

i : R-CH(Br)-CH(OEt)2, 99 EtOH, EtONa , reflux / + 96-100, R',R" = H,H; H,CH 12 hr; ii : H2O, cat.H ; 3; CH3,CH3 97-100, R = H, Alk, Aryl iii : POCl3 or conc.HCl, heat, or H2SO4, r.t.; iv : R-CH(Cl)-CHO or R-CH(Br)-CH(OEt)2, H2O (or H2O-MeOH) 45-100o / 30-45 min. Scheme 26

ALFONZ RYBA´R

100

[Sec. II.C O R'

O N N

O

N

R' O

OH N

N

N

R"

101

R

S i

N

CH-R

R'''

103

O

C=O S

N

R"

N R"

R'''

H N

N

O

A, B

R'

N

C

96 + R-CH(Cl / Br)-CO-R'''

R''' S

R

102

96, 101-103, R',R" = H,H; H,CH 3; CH3,CH3 Method A : [EtOH, EtONa, 60-65o / 1-13 hr]; for R = H, CH3; R''' = Alk, Aryl, Heteroaryl ; Method B : [EtOH or DMF, 5-6 hr / r.t.]; for R = H; R''' = C(CH3)3, Aryl ; Method C : [EtOH, reflux / 4-7 hr]; for R = H, CH3; R''' = Alk; R+R''' = (CH2)n, n = 3,4; [for Method A and B] i : - H2O, cat.H+. Scheme 27

6,7-trimethylene- or 6,7-tetramethylene-thiazolo[2,3-f ]-purine-2,4(1H,3H)-diones 103 (R þ R000 ¼ [CH2]3,4) (74KGS693, 87KGS1534). An exceptional case was the appearance of 6-chloromethyl derivative 103 (R ¼ H, R0 ¼ R00 ¼ H, Alk, R000 ¼ CH2Cl) from 1,3-dichloro-acetone (94KFZ(8)21) (Scheme 27). Method D is illustrated in Scheme 28: The sodium salt of 8-mercapto-xanthine reacted with chloroacetone and the resulting tautomeric intermediates were dehydrated with ethanolic hydrogen chloride to a tricyclic 6-methyl-thiazolo[2,3f ]-purine-2,4(1H,3H)-dione 104. The 8-mercaptohypoxanthine derivatives reacted similarly as the xanthines 96 with halogenated carbonyl compounds to aﬀord 6-alkylthiazolo[2,3-f ]purine-4(3H)one e.g., 105 (73CPB256) (Scheme 28). The structures of compounds 103 showing the ‘‘f ’’-bond fusion were proven by desulfuration with Raney- nickel yielding the 7-substituted purin-one or -dione. The second useful preparation of thiazolo[2,3-f ] purinediones started from 8bromopurine-2,6-diones 106, their conversion into sodium salts and reaction with -halogenated ketones to 7-[(X-benzoyl)methyl]- or 7-(acylmethyl)-8-bromopurinediones 107. The following reaction with sodium hydrogen sulﬁde and elimination of water gave 7-[(X-benzoyl)methyl]- or 7-(acylmethyl)-8-mercaptopurines 108 and

O

O H N

HN X

N

N

X = H, OH

CH3

HN SH

X

N N

N

S

104, X = OH 105, X = H

Method D : 1. NaOH-H2O, 2. Cl-CH2-CO-CH3, reflux / 30 min., 3. HCl-EtOH Scheme 28

Sec. II.C] O R'

101

ANNULATED HETEROCYCLO-PURINES

N

O

N

O

O H N

R'

i Br

N

CH2-CO-R ii N

N

O

N

N

R'

N

O

Br

CH2-CO-R N

N

SH

N

R'' iii : 107 100 108 107-108, 100, R', R'' = H, Alk; R = Alk, Aryl i :EtONa, EtOH, R-CO-CH2(Cl/Br), reflux / 5 hr; ii : NaHS, EtOH, reflux /25 hr; iii : - H2O, cat.H +. R''

R''

106

Scheme 29

CH2CH2-Cl 106 Na salt

N

i N 109

ii Br

O

O R'

N

AlkO2C-CH2

N

N

iii O

N

N

S

O

N R''

R'' 110

111

109-111, R', R'' = H, Alk

i : Br-CH2CH2-Cl, DMF;

ii : Na2S, DMF, reflux / 2 hr; iii ; (Cl/Br)-CH2-CO2Alk, DMF, K2CO3, reflux / 2 hr. Scheme 30

the required 7-alkyl- or 7-aryl- purine-2,4(1H,3H)-diones 100 (75KGS1121) (Scheme 29). The third method utilized 8-bromo-7-(2-chloroethyl)purine-2,4-dione 109 obtained by alkylation of the sodium salt of 8-bromopurinedione with 1-bromo2-chloroethane, followed by cyclization with sodium sulﬁde producing 1,3-dialkyl-6,7-dihydrothiazolo-[2,3-f ]purine-2,4(1H,3H)-diones 110 (96KFZ(3)49) (Scheme 30). Provided R0 ¼ H, compound 110 can by alkylated with halogenoacetates to compounds 111 revealing a diuretic eﬀect. Reaction of 8-mercaptohypoxanthine with 1,2-dibromoethane in liquid ammonia can be taken as a modiﬁcation of this method. The reaction product was the equimolar mixture of 6,7-dihydrothiazolo[2,3-f ]-purine-4(1H)-one and 7,8-dihydrothiazolo[3,2-e]purine-4(1H)-one (00ZOK160). The fourth method consisted in conversion of 1,3-dialkyl-7-aryloxazolo[2,3-f ]purine-2,4(1H,3H)-diones 57 with sodium sulﬁde to 1,3-dialkyl-7-aryl-thiazolo[2,3f ]purine-2,4(1H,3H)-diones 60 (cf. Scheme 16) (90KGS1396). The ﬁfth method was based on reaction of 8-halogeno-7-(thiiranylmethyl)purinediones 112 with primary or secondary amines to generate 7-[N,N-(R00 ,R000 ) aminomethyl]-6,7-dihydrothiazolo[2,3-f ]purine-2,4(1H,3H)-diones 113 (91KGS840, 94KFZ(9)33). This reaction was presumed to proceed through thiolate anion 114 which displaced bromide ion from position 8. Compounds 113 were tested for diuretic and hypoglycaemic eﬀects without any signiﬁcant result (Scheme 31).

ALFONZ RYBA´R

102 O R O

O

H2C

N

S

N N

[Sec. II.C

N

i

R N O

Br

N N

N

R'

R' 112

S

113

H2C

R'' C N H2 R'''

N N

112-114, R = H, CH3, R' = CH3, 113-114, R'' = H, Alk, PhCH2; R''' = Alk, cyclo-Alk, PhCH2, Aryl ; R''-N-R''' = piperidine, 4-Ph-piperazine

H2 R'' C N R''' S Br

114

i : H-NR''R''', EtOH or iso-BuOH, reflux / 2-5 hr. Scheme 31

O R O

N

NK N

N

i

N

Hlg

N

CH3 115-116, R = H, CH3

115

i : Cl-CH2

O

H2C

S

S Hlg

R N O

N N

N

S

CH3 , DMF, 95-100o / 1-2 hr.

CH2

O N

N Br

N 116

N

R O

CH3

Scheme 32

Also, heating potassium 8-halogenopurinediones with chloromethylthiirane is a reaction of this type. Instead of the expected 8-halogeno-7-(thiiranomethyl)purinediones 115 compounds 116 were obtained. This reaction course can be explained provided the intermediate 7-thiiranomethyl derivatives 115 ﬁrst reacted with the potassium salt of the starting xanthines to give a new intermediate with a thiolate side chain, which in turn closed the third thiazole ring. This reaction proceeded also when using an equimolar amount of potassium 8-halogenopurine (88KGS1284) (Scheme 32). The sixth method utilized the reaction of 8-mercaptopurine-2,4-diones with 2halogenoalkanoic acid to 8-[(1-carboxy-1-alkyl)thio]purine-2,4-diones 117 and their subsequent dehydratation to thiazolo[2,3-f ]purine-2,4,6-(1H,3H,6H)-triones 118. When halogenoacetic acid was applied a tricyclic compound with a methylene group in position 7 (118a) was obtained; the latter can undergo condensation with substituted 4-X-benzaldehydes or 5-X-furals to 7-[(4-X-phenyl)methylene]- or 7-[(5-X-furyl)methylene]-thiazolo[2,3-f ]purine-2,4,6(1H,3H,6H)-triones 119. The activated methylene group in compound 118a could also undergo coupling with substituted benzenediazonium ﬂuoro-borates to yield 7-[(X-phenyl)hydrazone]thiazolo[2,3-f ]purine-2,4,6,7(1H,3H)-tetrones 120 (82UKZ514, 88UKZ195) (Scheme 33). Electrophilic substitutions of thiazolo[2,3-f ]purinediones were demonstrated by the reaction of 1,3-dimethyl-6-phenylthiazolo[2,3-f ]purine-2,4(1H,3H)-dione (121) with bromine or N-bromosuccinimide producing the 7-bromo derivative 123.

Sec. II.C]

O

O R

O

103

ANNULATED HETEROCYCLO-PURINES

H N

N N CH3

N H

H N

i

CO2H

117

N

ii

CH-R'

S

N

S

R

N

O

N

O

N N

118 iv

R = H, CH3 117a-118a, R' = H; 117b-118b, R' = CH3;

R'

S

CH3

iii

O

N

N

CH-R''

S

O

N

119, R'' = Aryl; 120, R''' = Aryl, Heteroaryl

S

N-NH-R'''

120

119 i : R'-CH(Cl / Br)-COOH, AcOH, reflux / 30 min, or MeOH, reflux / 2 hr ; ii : Ac2O, reflux, 20 min; iii : (for 117a, 118a) AcONa, Ac2O, R''-CHO, reflux / 3 hr ; _

iv : (for 118a) AcOH, AcONa, Ac2O, R''-N2+ BF4 in MeOH, 20o / 18-20 hr . Scheme 33

O

O H3C

N

H3C

R

N

i O

N

N

S

R'

O

H3C O

CH3

N

S

124 O

H3C Ph

N N

N

ii

iii

N

C6H4-NO2(p)

N

CH3

CH3 121, R = Ph, R' = H 122, R = H, R' = Ph O

N

N

O S

Br

N

N N

N

S

C6H4-NO2(p)

CH3 125

123

i : (for 121) KNO3, H2SO4, r.t. / 3 hr ; ii ; (for 122) KNO3, H2SO4, r.t. / 3 hr ; iii : (for 121) Br2, CHCl3 / CCl4, 0o-r.t. / 2 hr or NBS, CCl4, reflux / 3 hr . Scheme 34

Attempts to brominate the free position 6 of compound 122 failed; so also did the attempt to nitrate 121 or 122 because the nitro group entered the most accessible position of the phenyl ring to give either 6-(4-nitrophenyl)- (124), or 7-(4nitrophenyl) derivative 125. Attempts to acylate, formylate, hydroxymethylate, chloromethylate of aminomethylate 6- or 7-substituted thiazolo[2,3-f ]purinediones 121 and 122 also resulted in failure. The bromo group of 7-bromo derivative 123 did not react with either ammonia or amines (81KGS1267) (Scheme 34). The alkylation at N(3) with halogenoacetate is illustrated in Scheme 30. Displacement of the enolic hydroxyls by chloride and further nucleophilic displacement with ammonia, amines or thiourea followed by hydrolysis of the

ALFONZ RYBA´R

104 X

OH i, ii, iii

N HO

N

N

N N

X'

N

S

127, X, X' = Cl 128, X = NH2, X' = Cl 129, X, X' = morpholino

126

SH

OH

CH3

N

[Sec. II.C

i then iv

CH3

N

N

N

N

130

131

N

S

i : POCl3, reflux, 3 hr ; ii : CH3Cl, EtOH, NH3(g), r.t. / 5 day; iii : morpholine, reflux / 1 hr ; iv : 1. (NH2)2C=S, EtOH, heat ; 2. NaOH-H2O.

Scheme 35

isothiuronium salt, constituted an access to further derivatives as illustrated in Scheme 35 (73CPB256). Reaction of the activated methylene group in the thiazole moiety with an aromatic aldehyde and coupling with diazonium salts is presented in Scheme 33. The IR spectra of [2,3-f ]-derivatives were reported in Ref. 87KGS1534; the massspectrometric fragmentations of these heterocycles were given in Ref. 81KGS1267 and 87KGS1534. 4. 4-Amino-thiazolo[3,2-e]purines The synthesis of this heterocycle was based on cyclization of 8-[(acylalkyl)thio]adenine derivatives 133 by heating with hydrogen chloride or with polyphosphoric acid producing 4-amino-2-X-7-R-8-R0 -thiazolo-[3,2-e]purine derivatives 134 in a modiﬁcation of the method of cyclization of 8-[(acylalkyl)-thio]purinedione derivatives 101 and 102 (cf. Scheme 27) aﬀording, however, compounds with a thiazole moiety fused to bond ‘‘f ’’ of the purine ring. A diversity of the 6aminopurine derivatives was manifested by the formation of compounds with a thiazolo moiety fused to bond ‘‘e’’ of the purine ring system. Some similarity with this approach is observed when alkylating xanthines and hypoxanthines to 7-alkyl-6hydroxypurines and adenines to 9-alkyl-6-aminopurines. Preparation of the crucial intermediates 133 started from 2-substituted 4,5,6-triaminopyrimidines and carbon NH2 N X

N

NH2

NH2 NH2 NH2

N

N

i, ii X

N

S-Y

iii

NH

3

X

N

N

S6 N

N

9

1

132, Y = H 133, Y = CH(R)-CO-R'

5

134

8

R

R'

132-134, X = H, SCH3, Cl; R =H, Alk, tert.Alk, Aryl; R' = H, Me i : CS2 in pyridine, 60-70o / 30 min or SC(NH2)2, fusion; ii : 0.4 N NaOH ; Br / Cl-CH(R)-CO-R', EtOH, r.t. / 3 hr ; iii :EtOH, HCl(g), 1 hr ; reflux / 2 hr or PPA, 140-150o / 3 hr . Scheme 36

Sec. II.C]

105

ANNULATED HETEROCYCLO-PURINES

disulﬁde or thiourea giving 8-mercaptoadenine derivatives 132; their alkylation with -halogenated ketones originated 133 which cyclized to 134 (Scheme 36). The fusion site was demonstrated by desulfuration of compounds 134 (X ¼ H and SCH3; R ¼ H; R0 ¼ Me) by Raney-nickel to 9-isopropyladenine and 134 (X ¼ Cl; R ¼ H; R0 ¼ Me) to 2-chloro-9-isopropyladenine, respectively (73CPB342). 5. Thiazolo[2,3-i]purines Three methods were reported to obtain the title compounds. The ﬁrst was based on a reaction sequence starting from 5,6-diamino-4-thiouracil-sodium salt, alkylation with 1,2-dibromoethane to 7,8-diamino-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine (135) and fusion with urea or thiourea under formation of a third ring to the respective 7,8-dihydrothiazolo[2,3-i]purine-2,5(1H,3H)-dione (136) and 2,3,7,8-tetrahydro-2-thioxothiazolo[2,3-i]purin-5(1H)-one (137) (92FES1315) (Scheme 37). The second method started from derivatives of 6-mercaptopurines and -halogenoalkyl or -aryl or -heteroaryl ketones with conversion to the respective 6[(acylalkyl)thio]- or 6-[(aroylmethyl)thio]- or 6-[(heteroaroylmethyl)thio]-purines 138 and tautomeric 7-hydroxy-7,8-dihydrothiazolo[2,3-i]-purines 139. The ﬁnal step of this synthesis was cyclodehydratation. The theoretically possible formation of thiazino[2,3,4-g,h]purine 141 was not observed. The cited fusion of the thiazole ring of compound 140 (R, R0 ¼ H) was corroborated by desulfuration with Raney-nickel to 1-ethylpurine (142) (96KGS 265) (Scheme 38). Also, preparation of tautomeric 138 and 139, having both substituents R,R0 ¼ H was described from 6-mercaptopurine and halogenoacetaldehyde dialkyl acetals to form 6-[(2,2-dialkoxyethyl)thio]purines (77PHA558). The acid hydrolysis of the acetal groups gave 2-[(9H-purin-6-yl)thio]acetaldehyde. An alternate method giving this aldehyde started from 6-mercaptopurine and glycidol to 6-[(2,3dihydroxypropyl)thio]purine and subsequent cleavage by periodic acid. 2-[(9HPurin-6-yl)thio]acetaldehyde was also present in the mixture as a cyclic tautomeric form as demonstrated by its reaction with semicarbazide or dinitrophenylhydrazine backed by IR and 1H-NMR (93 KGS1548) of the products. The third method is exempliﬁed by reaction of 6-chloropurine with epichlorohydrin in the presence of alkalies giving a 1:1 mixture of 7-hydroxymethyl-7,8-dihydrothiazolo[2,3-i]purine (143) and 8-hydroxy-8,9-dihydro-7H-thiazino[2,3-i]purine

NH2

HN O

N

S9

S

SH

NH2

i

NH2

N O

N

NH2

ii

7 6

O

H N1

N N 4

N3 H

135 136, X = O i : 2N NaOH-PrOH, Br-CH2CH2-Br, r.t. / 12 hr ; 50-55o / 4 hr ; 137, X = S ii : X=C(NH2)2, 220-230o . Scheme 37

X

ALFONZ RYBA´R

106

R

S CH(R)-CO-R'

SH N

N N

i

N

S

R'

N N 138

N H

N H

N

N

N 140 ii

R

R

R'

S

R' HO

X

N

N N

[Sec. II.D

iii

S H5C2 N N

N

N N

N

N

N

N

142

139

141

N

138-141, R = H, Alk; R' = Alk, Ar, Hetaryl

i : R-CH(Cl/Br)-CO-R', NaOH-H2O ;

H2SO4, 35-40o / 4 hr ;

ii : POCl3, reflux, 2-18 hr or PPA, 100o / 12 hr ; or iii : Ni-Raney . Scheme 38

N

N N i:

HO

S

SH HO-CH2

i

N H

N

N N

+

N

143

O

S N

N N

N

144

CH2Cl, MeOH, 1 equiv. 2N NaOH, r.t. / 24 hr . Scheme 39

(144). The unwanted product 144 could be separated by HPLC (72KGS996) (Scheme 39).

D. IMIDAZO-PURINES 1. Imidazo[1,2-a]purin-9-ones To date two methods were reported to achieve this ring system: in the ﬁrst 2aminopurin-6-one (guanine) derivatives 145 were treated with -halogenated carbonyl compounds to form a further ring fused to the ‘‘a’’ bond of the purine ring (compounds 146) (Scheme 40). Introduction of substituents R6, R7 in the basic skeleton depended on the -halogenated carbonyl compounds used. Substituents R2 and R3 had to be present initially in the starting guanine 145. The 7- or 9-substituted guanines were employed advantageously when alkylation of nitrogen atom in the tricyclic derivative had no regioselective course. Thus, 7-benzyl-3-methylguanine (145b) aﬀorded 1-benzyl-4,9-dihydro-4,6-dimethyl-1H-imidazo[1,2-a]purin-9-one (146b) (78JOC1644) and 9-(tri-O-acetyl- -D-ribofuranosyl)-3-methylguanine (145c)

Sec. II.D]

107

ANNULATED HETEROCYCLO-PURINES O

HN 1

N

6

R

7

R

2

N3

HN

R

R3

1

R2

N

N

N3 4

N CH3

H2N

R3

R5 146a R3 = H, Alk, Rf R5 = H, Alk, Acyl

N

O 7

H3C

N

R3

145c, R3 = (Ac)3Rf

9

N CH3

N

H3C

N

N

N

CH2-Ph N 1

N

N

i

145b

i

O

O

N CH3

9

N

N

145a X = Cl, Br R2, R6, R7 = H, Alk

H2N

N

6

R5

NH

N

7

R7-CH(X)-CO-R6

N9

CH2-Ph N

O

O

7

N 146b

R3

146c, R3 = (Ac)3Rf

N CH3

i :DMF, NaH, 2 hr / r.t.; BrCH2-CO-CH3, 18 hr / r.t.

Rf = ribofuranosyl

Scheme 40

O O N

HN

H3C

N H2N

N

N

N

i N

N

R 146a, R = H

CH2-O-C2H4-OH 145a

i : NaH, DMF, BrCH 2COCH3, NH4OH;

N CH2-O-C2H4-OH ii

147a, R = CH3

ii : CH3I, K2CO3, DMF Scheme 41

gave 3-(tri-O-acetyl- -D-ribofuranosyl)-5,9-dihydro-4,6-dimethyl-3H-imidazo-[1,2a]purin-9-one (146c) (87CPB4372). The substituent R5 can be present either in the starting guanine or introduced into the new heterocycle by alkylation. This method was applied when preparing new potential analogues of contemporaneous virostatica—derivatives of guanine, namely 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)-methyl]-6H-purin-6-one ¼ ‘‘acyclovir’’, 2-amino-1,9-dihydro-9-[(1,3-dihydroxy-2-propoxy)methyl]-6H-purin-6-one ¼ ‘‘gancyclovir’’ and simpler model compounds. Thus, the 1-sodium salt of acyclovir 145a reacted stepwise with bromoacetone and ammonia to give 5,9-dihydro-3-[(2-hydroxyethoxy)methyl]-6methyl-3H-imidazo[1,2-a]-purin-9-one (146a). Subsequent methylation with methyl iodide gave the corresponding 5-methyl derivative 147a. This substance is eﬀective against Herpes simplex type 1 and 2 (88JMC1351) (Scheme 41). 3-Methylguanine aﬀorded the 4,6-dimethyl derivative with bromoacetone and with -bromopropionaldehyde the isomeric 4,7-dimethylimidazo[1,2-a]purin-9-one. The position of methyl groups in both substances was veriﬁed by 1H-NMR (71TL2725). Also waterfree potassium carbonate can substitute sodium hydride. The diﬀerence in yields of the tricyclic product with both alkaline reagents was seen when reacting 7-benzyl-3methylguanine with bromoacetone and sodium hydride (yield 41%) or potassium carbonate (81%) (89CPB284, 90CPB2656). Water-free dimethyl sulfoxide was the

ALFONZ RYBA´R

108

[Sec. II.D

alternate medium for this cyclocondensation reaction. Thus, from 9-alkyl-3methylguanines and an excess of both bromoacetone and potassium carbonate originated 3-alkyl-3,4-dihydro-4,6-dimethyl-9H-imidazo[1,2-a]-purin-9-ones (alkyl ¼ methyl, ethyl, benzyl) (82T1767). Yields vary depending on the above alkaline reagents. The eﬀect of substituents in position 6 on the antiviral activity was studied with C3–4 ketones and also bromomethyl tert-butyl ketone and 4-Xphenylacyl bromides. Generally, an aryl substitution in position 6 enhanced the antiviral activity. The most eﬀective tricyclic analogues of gancyclovir and acyclovir were found to be 6-phenyl- or 6-(4-methoxyphenyl)- or 7-methyl-6-phenyl-3,9dihydro-3-[(1,3-dihydroxy-2-propoxy)-methyl]-5H-imidazo[1,2-a]purin-9-ones and 3-[(2-hydroxyethoxyethoxy)methyl]-analogues (94JMC3187, 01JMC4284). As found later, introduction of 4-(acyloxy)phenyl-, 4-(acylamino)-phenyl- and 4-(phenoxycarbonyloxy)phenyl groupings in position 6 of the tricyclic analogues of acyclovir and gancyclovir even raised their eﬃcacy. The 6-[4-(phenoxy-carbonyloxy)phenyl] tricyclic analogues were pharmacologically tested as potential antiherpetic substances (02JMC 5052). Chloroacetaldehyde reacted with sodium salts of acyclovir and gancyclovir to produce compounds 149a and 149b, respectively. Chloroacetaldehyde can be substituted by 2-bromo-1,1-diethoxyethane to give the intermediate 148 from which the ﬁnal product was achieved by acid hydrolysis and cyclocondensation (91JMC2380) (Scheme 42). A special case involved the use of glyoxal to form the third ring. For example, N2acetylguanine and trimeric glyoxal gave 5-acetyl-5,6,7,9-tetrahydro-9-oxo-3Himidazo[1,2-a]purine-6,7-diol at room temperature (87ACS(B)564) and guanine with aqueous glyoxal produced 5,6,7,9-tetrahydro-9-oxo-3H-imidazo-[1,2-a]-purine6,7-diol at elevated temperature (00JOC7697). The second method aimed to prepare 6,7-dihydroimidazo[1,2-a]purin-9-ones 154 from a derivative of 2,3-dihydroimidazo[1,2-a]pyrimidine-5-one, the purine moiety being built up as follows: the ﬁrst step involved reaction of 2-(methylthio)imidazolinium iodide with a convenient primary amine giving 2-(substituted amino)imidazoline 150 and then with ethyl oximinocyanoacetate and alkali produced 7-amino-2,3-dihydro-6-nitroso-R4,R6,R7-imidazo[1,2-a]pyrimidin-5(8H)one 151. Subsequent hydrogenation furnished the diamine 152, acylation and cyclization with boiling carboxylic anhydride originated the ﬁnal 6,7-dihydroR2,R4,R6,R7-imidazo[1,2-a]purin-9(4H)-one 154. The last two steps can be O N

HN H2N

N

i N

O N

N H2N

R 145a, b

O

(H5C2O)2CHCH2

N 148a, b

ii N R

N

N N H

N 149a, b

145, 148, 149: a = CH2-O-C2H4OH; b = CH2-O-CH(CH2OH)2 i : Br-CH2CH(OC2H5)2; K2CO, DMF; ii : 40% AcOH / reflux or 1.2 N HCl / r.t.

Scheme 42

N R

Sec. II.D]

109

ANNULATED HETEROCYCLO-PURINES

O

O N

R7

N 150

R6

HN R4

X

i, ii

153, 154 : R2 = H, Alk; 151-154 : R4 = X-C6H4CH2; R6 = H, Me, Me2; R7 = H, Me

5

R7

N 1

H2N

7

N

R

N

R4 151, X = NO 152, X = NH2 R N R

R

2

N H

N

154

H2N N

153

4

7

6

N R4

R

vi

R2 -CONH

N

R

N

O

N

R

6

iii or iv

O

2

N

v

N

R7

N N

N

R

6

R4

154a, R = H 154b, R = Me

vii

i :NC-C(NOH)-CO2Et, NaOEt, EtOH, reflux ; ii : H2, Pd/C, EtOH ; iii : R2 -CO2H, H2, Pd / C ; iv : HCO2H, Na2S2O4; v : (R2CO)2O, reflux ; vi : NaOH, H2O, reflux ; vii : NaOH, EtOH - H2O, CH3I, r.t. Scheme 43

substituted by reacting the nitroso group by either sodium dithionite in the presence of formic acid or hydrogenation in the presence of carboxylic acids containing more then one carbon atom to the 7-amino-6-acylamino derivative 153. Heating with alkali closed the third imidazole ring to the ﬁnal compounds 154. Some of them exhibited enhanced antiallergic and broncho-dilatation activities, the side eﬀects being reduced when compared with those of theophylline. Compound with the highest activity is 4-(chlorobenzyl)-6,7-dihydro-3H-imidazo[1,2-a]purin-9(4H)-one (80JMC1188) (Scheme 43). The third method was elaborated for preparation of 2-substituted tricyclic imidazo[1,2-a]purines 158. Since the 8-substituted guanines are little frequent, this synthesis started from more available 3-methyl-2-methylthio-7H-purin-6(3H)-one (155), which on heating with aminoalcohols produced the corresponding 2-(2hydroxyethylamino)-3-methyl-7H-purin-6(3H)-ones (156) and further heating in dehydrating media gave 4,6,7,9-tetrahydro-4-methyl-1H-imidazo[1,2-a]purin-9-ones (157). Subsequent oxidation with manganese dioxide led to 2,6- or 2,7-disubstituted4,9-dihydro-4-methyl-1H-imidazo[1,2-a]purines 158 in good yields (95JCS(CC)2041) (Scheme 44). The fourth route involved formation of the central ring of 6,7-dihydroimidazo[1,2-a]purine derivatives by reaction of 4-amino-1H-imidazol-5-carbonitrile (160) with 2-methylmercapto-imidazoline (159) to aﬀord the 4-imino derivative 161 under various conditions (01JHC743) (Scheme 45). Of interest are imidazo[1,2-a] purine substances from the so called wye-family, isolated from phenylalanine-transfer-ribonucleic acid (tRNAPhe) of various sorts of yeast: 4,9-dihydro-4,6-dimethyl-1H-imidazo[1,2-a]purine-9-one (‘‘wye’’, 162a); 4,9(‘‘wyodihydro-4,6-dimethyl-3- -D-ribofuranosyl-3H-imidazo[1,2-a]purine-9-one sine’’; ﬂuorescent Y-nucleoside from Candida albicans tRNAPhe, 162b); methyl

ALFONZ RYBA´R

110

O

O H N

N MeS

[Sec. II.D

N

OH

i

H N

N

ii

O

R'''

N

R' R''

CH3

N H

N

N

R'

R''

N

CH3

157

156 155 156 -158 : R' = Me, X-Ph; X = H, Hlg, HO, MeO, O2N; R'', R''' = H, Alk

R'

O

R'''

H N

N

R''

140o / 10-24 hr, or POCl3, reflux / 4-8 hr ; iii : MnO2, DMF,

N N CH3 iii

i : H2N-CH(R'')-CH(R''')-OH, 110o / 3-10 hr ; ii : PPA, 140o

H N

N

R'''

N

/ 10-24 hr .

158

N N CH3

R'

Scheme 44

NH N

CN

HN

HN

+ CH3S

N H 159

NH2

N

N N

N

160

N H

161

Scheme 45

4,9-dihydro--[(methoxycarbonyl)amino]-4,6-dimethyl-9-oxo-1H-imidazo[1,2-a]purine-7-butanoate (‘‘wybutine’’; Y-base, ﬂuorescent minor base from yeast, 163a); methyl 4,9-dihydro--[(methoxycarbonyl)amino]-4,6-dimethyl-3- -D-ribofuranosyl9-oxo-3H-imidazo[1,2-a]purine-7-butanoate (‘‘wybutosine’’; ﬂuorescent nucleoside from Saccharomyces cerevisiae tRNAPhe, 163b). Owing to their interesting antiviral eﬀects, these substances and their derivatives are subjected to intensive studies (Scheme 46). For their synthesis see paragraph on the synthesis of wybutine, wybutosine, and -hydroxywybutine, p. 115. O

O

N H3C

N 162a H

H3CO2C

N

N N N H CH3

H3C

H3C

H3CO2C

O

H2C

N N 163b

N N CH3 Rf 162b N

H

NH-CO2CH3 CH2

N

NH-CO2CH3 CH2

O

H2C H3C

N N CH3 Rf

N 163a

Scheme 46

H N

N

N

N N CH3

Sec. II.D]

O

O N H3C

111

ANNULATED HETEROCYCLO-PURINES

N

N

N

i H3C

N N H R 164a-c

O N

N

N

N

N

CH3

H3C

N

N

R

N

CH3 R

165a-c

166a,c,d ii

164 - 166 : a, R = HO-CH2CH2OCH2; b, R = tert.BuMe2Si-OCH2CH2OCH2 c, R = beta-D-ribofuranosyl d, R = AcO-CH2CH2-O-CH2

i : CH3 -I, DMF, K2 CO3 ; ii : CH2 N 2 , Zn I 2 , DCM-Et 2 O-DCM, r.t. / 45 min.

N

164a,c,d

Scheme 47

a. Reactions of the imidazo[1,2-a]purin-9-one ring system. Methylation of imidazo[1,2-a]purin-9-one derivatives possessing the unsubstituted N3 and N4 with methyl iodide took place at both these nitrogens. The methyl group entered regioselectively position 5 of imidazo[1,2-a] purin-9-ones substituted in position 3, e.g., with (2-hydroxyethoxy)methyl, (2-tert-butyldimethylsilyloxyethoxy)methyl or -D-ribofuranosyl groups (164a–c) under the same conditions producing compounds 165a–c (83MI1). On the other hand, the diazomethane reacted with the N4 of 3substituted-3,4-dihydro-6-methyl-9H-imidazo[1,2-a]purin-9-ones 164a–c to aﬀord the 4,6-dimethyl derivatives 166a,c,d. None of the tricyclic analogues of acyclovir with a N-4 methyl group reached the antiherpetic eﬃcacy of the parent compounds (91JCS(P1)589) (Scheme 47). The 4-[(substituted)benzyl]-6,7-dihydro-2-substituted-imidazo[1,2-a]purin-9(4H)ones 154a were methylated at position N1 with formation of compound 154b (80JMC1188) (Scheme 43). Benzylation and tritylation of this tricyclic system was studied in more detail (Scheme 48). Thus, benzylation of the 3-[(2-hydroxyethoxy)methyl]-6-methyl derivative 167 gave exclusively the N-5-benzyl derivative 168, but if the methyl group in position 6 O R''''

O N R'' 167

N H

N N

7

N1

N 3

i or ii

R''

N

5

N

N

N

4

R'''

OC2H4-OR'

168

OC2H4-OR'

O 167 -169, R' = H, tertBuMe2Si ; R'' = Alk, tertAlk, Aryl ; 168 -169, R''', R'''' = H, PhCH2, Ph3C;

R'''' R''

i : PhCH2-Br, DMF, K2CO3, r.t. ii : Ph3C-Cl, DMF, K2CO3 or Et3N, Ph3C-Cl, DCM Scheme 48

N N

N N

R''' 169

N OC2H4-OR'

ALFONZ RYBA´R

112

[Sec. II.D O

O N R'

R'''

N

N

N N

N

R'

N

Rf

H

N

N

i

N Rf

R"

171, R' = PhCH2, tertBu ; R'' = PhCH2, H ; R''' = H, PhCH2 i : PhCH2-Br, DMF, K2CO3

170, R' = PhCH2, tertBu ;

Scheme 49

was replaced by a substituted phenyl group at compound 167, a mixture of N-5benzyl- of 168, N-4-benzyl- of 169 and N-5,C-7-dibenzyl derivatives of 168 was obtained. The respective components were separated chromatographically. If position 6 was occupied by a bulky tert.-butyl group in 167 then the main product was N-4-benzyl derivative of 169. Benzylation of 6-(X-phenyl)- or 6-tert.-butyl-3- D-ribofuranosyl-5H-imidazo[1,2-a]purin-9-ones 170 took place in positions 5 and 7 of 171. The mixture of isomers was separated chromatographically (Scheme 49). Tritylation of 3-[tert.-butyldimethylsilyloxyethoxy)methyl]-3,9-dihydro-6-methyland 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-6-methyl-5H-imidazo-[1,2-a]purin-9ones (167) did not take place at N-5, but at C-7 to form 7-trityl derivatives and a small amount of 7-(4-benzhydryl)-phenyl derivatives of 168. Starting compounds having in position 6 of 167 only hydrogen aﬀorded a mixture of 5-trityl and 5,7ditrityl derivatives 168 and a small amount of 4-trityl derivatives 169. The presence of benzhydrylphenyl derivatives 168 indicated a probable radical reaction course (98T2941, 00HCA373) (Scheme 48). 5-Acetyl-6,7-bis-(acetoxy)-5,6,7,9-tetrahydro-3H-imidazo[1,2-a]purin-9-one (172a) obtained by acetylation of the condensation product of guanine with glyoxal underwent alkylation with acetoxybutyl bromide in the presence of a base to give a mixture of 1- and 3-acetoxybutyl derivatives 172b,c. With 1,4-dimethylpiperazine, 20% of the 1-alkyl isomer 172b and 10% of the 3-alkyl isomer 172c were obtained after chromatographic separation; with sodium hydride at a very low temperature, the 3-sodium salt aﬀorded regioselectively the 1-acetoxybutyl derivative 172b (86JHC625) (Scheme 50). b. Electrophilic displacements. Generally, all reactions of this type took place at position 7 of the heterocycle. Reactions of 1-benzyl-4,9-dihydro-4,6-dimethyl-1Himidazo[1,2-a]purin-9-one (173) were studied in more detail (99CPB1464). The O

O H N

HN H2N

N

N

AcO

H N

N

i

O ii

AcO

N

N

R

AcO

N Ac

N

N

172a

i : 1. O=CH-CH=O; 2. Ac2O; ii : DMF, -60o, NaH; Br(CH2)4OAc, r.t. / 2 hr.

Scheme 50

AcO

N

N

N

Ac 172b, R = 1-(CH2)4OAc 172c, R = 3-(CH2)4OAc

Sec. II.D]

113

ANNULATED HETEROCYCLO-PURINES

chloro derivative 174c can be prepared with N-chloro-succinimide in acetic acid. The another route the same substrate was chlorinated with N-chlorosuccinimide after previous treatment with n-butyllithium at 78 gave the 2-chloro derivative (29% yield). Monobromination of the starting compound 173 did not proceed regioselectively. Only bromination of the 2-chloro derivative aﬀorded the 7-bromo2-chloro-1-benzyl-4,9-dihydro-4,6-dimethyl-1H-imidazo[1,2-a]purin-9-one (75%). Iodination with elemental iodine (89CPB284) in the presence of sodium hydrogen carbonate produced the anticipated 7-iodo derivative 174a. Nitration with a nitric acidacetic anhydride gave the 7-nitro derivative 174b. Application of the VilsmeierHaack reaction formed the 7-formyl derivative 174d, important for further syntheses. Its reduction with sodium borohydride aﬀorded the 7-hydroxymethyl derivative 174e. Treatment of compound 173 with phosgene resulted in 4,9-dihydro4,6-dimethyl-9-oxo-1H-imidazo[1,2-a]purine-7-carbonyl chloride (174f). This intermediate was hydrolyzed to the corresponding acid 174g, ammonolyzed to the amide 174h and methanolyzed to the ester 174i. Acylation of the starting 173 with oxalyl chloride gave (4,9-dihydro-4,6-dimethyl-9-oxo-1H-imidazo[1,2-a]purin-7-yl-2oxoethanoic chloride and subsequent esteriﬁcation formed the corresponding methyl ester 174j (99CPB1464) (Scheme 51). 3-Substituted-4,9-dihydro-4,6-dimethyl-1H-imidazo[1,2-a]purin-9-ones, wyosine triacetate 175 (88T1273), gave with phosphorus oxychloride exclusively 20 ,30 ,50 -triO-acetyl-7-formylwyosine 176, with bromodimethyl-phosphonium bromide the 7bromo derivative of 176 and with iodine the iodo derivative of 176. Over one-day, the action of anhydrous aluminium chloride resulted in a migration of the saccharide moiety from position 3 to position 1 to gave the 4,9-dihydro-4,6-dimethyl-1-(20 ,30 ,50 tri-O-acetyl- -D-ribofuranosyl)-1H-imidazo[1,2-a]purin-9-one (177). The position of the ribofuranosyl substituent was given by 15N-NMR (Scheme 52). c. Rearrangements. 1-Benzyl-4,9-dihydro-4,6-dimethyl-7-substituted-1H-imidazo[1,2-a]-purin-9-ones (178), where alkyl, 2-alkenyl, hydroxymethyl, methoxymethyl or O

O X H3C

7

N N 174

N CH3

H3C

N

9

N

N

5

CH3

a : (for 174a) I2, DCM-H2O, NaHCO3;

173

CH2-Ph N 1

N3

b : (for 174b) HNO3-

174a, X = I 174b, X = NO 2 174c, X = Cl 174d, X = CH:O 174e, X = CH2-OH 174f, X = CO-Cl 174g, X = CO2H

Ac2O, 0o / 9 hr; c : (for 174c) NCS, AcOH, r.t. / 80 min;

174h, X = CO-NH2 174i, X = CO2Me

dark / 3 hr; d : (for 174d) POCl3, DMF, 0o / r.t.;

174j, X = C0-CO2Me

e : (for 174e from 174d)NaBH4, MeOH, r.t. / 30 min; f : (for 174f) COCl2, toluene, THF, pyridine, 0o; r.t. /30 hr ;

g : (for 174f) H2O;

h : (for 174h from 174f) NH3, DCM; i : (for 174i) MeOH, r.t. / 2 d; j : (for 174j) 1. (COCl)2, Et3N, THF, 0o;r.t. / 5 hr; 2. MeOH, r.t. / 15 min. Scheme 51

ALFONZ RYBA´R

114

[Sec. II.D

O

O R

H3C

1

9

OAc

CH3 O

H2C

ii

OAc

OAc

O OAc

AcO C H2

OAc

CH3 O AcO

N3

N

N

N

N

N

H3C

N

7

N

N

N

i

O 7

N

175

CH2

OAc

i : Electrophylic substitution

N

CH3

177

176, R = I, Br, CH:O

OAc

1

N

N

H3C

N

9

ii : DCM,AlCl3, 0o; r.t. / 24 hr

Scheme 52

O R H3C

7

N N 178

O

CH2-Ph N

H3C

1

N CH3

O

N i

_

N

Nu

N

R H3C

CH2-Ph N

N N

7

N

CH2-Ph N 1

N R

N

N CH3 180

CH3 179

178 - 180: a, R = CH2CH2CH(CH3)2; b, R = (E)-CH=CH-CH(CH3)2; c, R = CH2-OH; d, R = CH2-OCH3, e, R = CHO, f, R = CO2Me, g, R = Cl, h, R = Br, i, R = I i : NaOMe-MeOH, r.t. - reflux / 6-8 hr .

Scheme 53

formyl were the substituents, isomerized in the presence of a nucleophilic (Nu–) reagent to an equilibrium mixture with 6-substituted derivatives (position isomers) 180a–e. The nucleophilic reagent can be sodium methoxide. The rearrangement involved a cleavage of the N8–C9 bond with a transient binding of the nucleophile to C9 and recyclization of the N5–C9 bond (Scheme 53). After neutralization of the nucleophilic reagent the position isomers of both series were separated chromatographically. Yields of compounds 180 varied within 16–89%, those of compounds 182 within 37–98% (99CPB1464) (Scheme 54). An analogous rearrangement was observed with the preparation of 1-benzyl-4,9dihydro-4,6-dimethyl-7-(3-methyl-1-butenyl)-1H-imidazo[1,2-a]purin-9-one (185a) by a three-step synthesis from 1-benzyl-4,9-dihydro-4,6-dimethyl-7-(hydroxymethyl)-1H-imidazo[1,2-a]purin-9-one (183), which reacted with phosphorus tribromide to the corresponding 7-bromomethyl derivative 184a and with triphenylphosphine to the triphenylphosphonium bromide 184b. The latter reacted

Sec. II.D] O R

115

ANNULATED HETEROCYCLO-PURINES

7

N

CH2-Ph N

O i

1

ii

N

6

R

CH3

181

1

N

N N

N

CH2-Ph N

N

N

182

CH3

181, 182 : a, R = Me, b, R = COO-, c,R = CH2OH, d, R = CONH2, e, R = CO2Me, f, R = CO-CO2Me, g, R = CHO, h, R = I, i, R = NO2 i : 0,5 M MeONa-MeOH, r.t. / 1 hr ; ii : 10% H3PO4.

Scheme 54

with isobutyraldehyde in sense of the Wittig reaction to a mixture of oleﬁns in which the main product was the rearranged 1-benzyl-4,9-dihydro-4,7-dimethyl-6-(3-methyl1-butenyl)-1H-imidazo[1,2-a]purin-9-one (185b) in 74% yield and not the anticipated 7-(3-methyl-1-butenyl) derivative 185a. Carrying out the Wittig reaction in the presence of n-butyllithium at a very low temperature aﬀorded a mixture of (E)- and (Z)-isomers of the anticipated 7-(3-methyl-1-butenyl) derivative 185a in a 7:2 ratio. Compound 185a can be prepared alternatively by the Wittig reaction from 1-benzyl4,9-dihydro-4,6-dimethyl-9-oxo-1H-imidazo[1,2-a]purine-7-carbaldehyde (178e) and (2-methylpropyl)-triphenyl-phosphonium iodide with butyllithium as a base at a very low temperature as an equimolar mixture of geometric isomers 185a in a 50% yield. When this reaction was performed in the presence of two equivalents of dimsyl anion (NaCH2–SO–CH3) at room temperature, (E)-185b was isolated in 74% yield. Application of only one equivalent of the dimsyl anion resulted in formation of (E)185a in 26% yield. The mechanism of this rearrangement is given at the beginning of this paragraph (89CPB1221) (Scheme 55). The synthesis of wybutine, wybutosine, and -hydroxywybutine employed 4,9dihydro-4,6-dimethyl-9-oxo-3-[2,3,5-tris-O-(tert-butyldimethylsilyl)- -D-ribofuranosyl]-3H-imidazo[1,2-a]purine-7-carbaldehyde (186), which enabled the introduction of the (-aminobuten-3-yl)-carboxylic grouping into position 7 of the heterocyclic ring by a Wittig reaction with phosphorane derived from the inner salt of

H O=C H3C

i then ii

N N

N

O

H2C H3C

178e

Ph

X

O

CH2

N N

N N

R R'

O

CH2

N

iii

N

Ph

iv

N

N N

N

CH3

CH3

CH3

i : NaBH4, MeOH; ii : 1. PBr3,

183, X = OH 184a, X = Br 184b, X = Ph3P

185a, R = CH=CH-CHMe2, R' = CH3 185b, R = CH3, R' = CH=CH-CHMe2

178e

2.

Ph3P ; iii : Me2CH-CHO, MeOH, K2CO3, heat ; _

iv : Ph3P+CH2CH2Me2I , THF, n-BuLi, -78o, N2; < 0o / 1 hr .

Scheme 55

ALFONZ RYBA´R

116 H O=C

O

H

N

N H3C

N

CO2H H

O

MeO2C-NH

N N

[Sec. II.D

i R

CH3

H3C

N 188

H MeO2C-NH

N

R

CH3

186, 188, R = (tertBuMe2Si)3Rf

CH2

O

C H2 H3C

ii N

186 CO2Me

N

N

H

N

N N

163b

N CH3

+

i : Ph3P CH2

N R

CO2 (187), n-BuLi, H NHCO2Me

THF- HMPA, -70o --> 0o; ii : 1. TMS-CH2N2, C6H6-MeOH; 2. Pd / C, r.t.; 3. Bu4NF, H2Opyridine, r.t.

Scheme 56

(R)-2-[(methoxycarbonyl)amino]-3-triphenylphosphonio propanoate (187) to give the intermediate 188. Its methylation with trimethyl-silyldiazomethane, consecutive hydrogenation of the dimethyl ester and deprotection aﬀorded the tricyclic derivative with a saturated side chain similar to wybutosine 163b identical with the product isolated from natural material (02CPB530) (Scheme 56). An alternate strategy for introducing the (-aminobuten-3-yl)-carboxylic group in position 7 of the heterocycle is oﬀered by the Heck reaction of 7-iodo-1-benzyl-4,9dihydro-4,6-dimethyl-1H-imidazo[1,2-a]purine-9-one (178i) with (S)-N-(methoxycarbonyl)- or (S)-N-(benzyloxycarbonyl)-vinylglycine, catalyzed by palladium acetate (88TL4129, 98CPB1094). Wybutine 163a was obtained by a stepwise methylation of the carboxyl in the side chain with trimethylsilyldiazomethane, hydrogenative debenzylation and reduction of the double bond in the side chain. Wybutosine 163b was prepared by a similar reaction sequence from 7-iodo1-benzyl-4,9-dihydro-4,6-dimethyl-3- -D-ribofuranosyl-1H-imidazo[1,2-a]-purine-9one (Scheme 57). The tricyclic intermediate with (-aminobuten-3-yl)-carboxylic group 189 was utilized for the synthesis of -hydroxywybutine. The ﬁrst step was the cishydroxylation of the side-chain double bond by osmium tetroxide and N-methylmorpholine-N-oxide to a mixture of vicinal glycol isomers 191a (yield after isolation 69%) and 191b (yield 24%). Their relative conﬁguration was established by X-ray analysis. Triphosgene in pyridine or phosgene in dichlormethane converted the vicinal glycols into the cyclic carbamates 192a and 192b. Oxalyl chloride when used in place of phosgene gave the cyclic oxalates decarboxylating easily to the ﬁvemembered cyclic carbonates. The ﬁnal step of this synthesis was the hydrogenation of both the isolated cyclic carbonates under elimination of carbon dioxide to amino- -hydroxy-carboxylate 193a,b and hydrogenolysis of the benzyl group from position 1 to a mixture of diastereomers of -hydroxywybutine 194a (yield 48%) and 194b (yield 20%). The transformation of vicinal glycols 191a,b into cyclic carbonates

Sec. II.D]

117

ANNULATED HETEROCYCLO-PURINES

H Ph

O I

H2C

N

NH-CO2Me H

HO2C

N i

H3C

N

N

H3C

CH3

178i

H

CH2

ii

H N

N N

N

N

N

CH3

Pd(OAc)2,DMF, Bu4N + Cl - , NaHCO3, 45o / 24 hr ; ii : 1. Me3SiCHN2, MeOH, benzene; 2. Pd / C, H2, 50o

N

CH3

163a

N

CO2H H , i : CH2=CH NH-CO2Me

O

H2C H3C

N 189

NH-CO2Me

MeO2C

H2C

N

H

N

Ph

O

Scheme 57

192a,b and hydrogenolysis through elimination of carbon dioxide cleaving the C( )OCO bond to -monohydroxy derivatives 193a,b may be understood as a regioselective dehydroxylation of the original vicinal glycols (86TL4043, 97TL1979, 98CPB1220). The hydrogenolysis by-product was the tricyclic derivative with a saturated side chain without any hydroxyl group 163a (Scheme 58). An analogous

H H O=C

NH-CO2Me H

OMe

H3C

H O=C

Ph

O

CH2 N

N

H

N

N 189

H3C

NH-CO2Me OH ii H

H H OMe

O H

192a

191a

H

NH-CO2Me H ii OH

O=C OMe H HO 191b

R

H

NH-CO2Me H O C=O OMe O

O=C

H 192b

N N

NH-CO2Me O C=O

O=C

+

CH3

N N

i

N

NH-CO2Me OH O H

OMe H2C

O=C OMe HO H

iii

N

H

CH3 193a, R = CH2-Ph 194a, R = H

O=C

NH-CO2Me H OH

OMe H2C

iii 192a

i : N-methyl-morpholine N-oxide, OsO4 ii : COCl2 in DCM, pyridine; iii : Pd / C, H2

Scheme 58

193b, R = CH2-Ph 194b, R = H

ALFONZ RYBA´R

118 H

NH-CO2Me

O=C

192a

O

C=O OMe H2C

i

[Sec. II.D

H3C

CH2-Ph

N

N N

N

ii

N

i : 200-210o / 1-2 min; ii :NaBH4, MeOH

CH3

195

193a + 193b

Scheme 59

reaction sequence was applied to prepare -hydroxy-3-( -D-ribofuranosyl)wybutines as follows: methyl 4,9-dihydro-4,6-dimethyl-9-oxo-3-[2,3,5-tris-O-(tert.-butyldimethylsilyl)- -D-ribofuranosyl]-3H-imidazo[1,2-a]purin-7-yl-(-methoxycarbonylamino)-butenoate (188) was cis-hydroxylated with OsO4 and N-methylmorpholineN-oxide to the corresponding mixture of vicinal glycols, then transformed into cyclic carbonates (triphosgene-pyridine), which were subsequently hydrogenolyzed (elimination of carbon dioxide), and the protecting trialkylsilyl groups removed from the ribofuranosyl part of the molecule (Bu4NF, H2O-pyridine) (97TL1979). Short thermal decomposition of cyclic carbonates 192 formed a tricyclic -amino- oxocarboxylate 195 under elimination of carbon dioxide and then reduction by sodium borohydride aﬀording the mixture 193a,b an alternate method to regioselective dehydroxylation. Compounds 193a,b can be separated by HPLC using a chiral packing (yields 23 and 51%, respectively) (98CPB1220) (Scheme 59). d. Modification of the 9-carbonyl group. 4-[(4-Chlorophenyl)methyl]-4,6,7,9-tetrahydro-1H-imidazo[1,2-a]purin-9-one can be converted into the corresponding 9thione 196 by phosphorus pentasulﬁde, then, the resulting sodium salt of the thione can be methylated with methyl iodide to the 9-methylthio derivative 197 and ﬁnally treated with ammonia to give 4-[(4-chlorophenyl)-methyl]-4,6,7,9-tetrahydro-1Himidazo[1,2-a]purin-9-imine 198 (80JMC1188) (Scheme 60). e. Cleavage of the newly formed imidazole ring. The reaction of 3-[(hydroxyethoxy)methyl]-5,6-dimethylimidazo[1,2-a]purin-9(5H)-one (147a) with N-bromosuccinimide and subsequent hydrolysis led to the third N-ring cleavage aﬀording the

O H N

N N

i

N

H N

N N R

N

R

ii

N

N N R

N 197

196

iii

iii : NH3 - EtOH,

150o

Scheme 60

H N

N N

N

R 198

196-198, R = Aryl-CH2

i : P2S5, pyridine, reflux / 5 hr ; ii : NaOH - H2O, CH3I ;

NH

S-CH3

S

N

Sec. II.D]

O

O N

N H3C

N

i, ii N

N

CH3

N N

N

Ac 172b

iii

N

N

CH3

OC2H4-OH 199

O

(CH2)4OAc

N N

N

HN HN

OC2H4-OH O

AcO AcO

119

ANNULATED HETEROCYCLO-PURINES

(CH2)4-OH N

HN N

H2N

200

N

i : NBS, H2O ; ii : NH4OH ; iii : KOH-EtOH, r.t. / overnight; neutralization.

Scheme 61

N2-methylguanine derivative 199 (88JMC1351). Similarly 5-acetyl-6,7-bis-(acetoxy)1-(4-acetoxybutyl)-5,6,7,9-tetrahydro-1H-imidazo[1,2-a]purin-9-one (172b) produced 7-(4-hydroxybutyl)guanine (200) in 90% yield after hydrolysis (86JHC625) (Scheme 61). 2. Imidazo[2,1-b]purines Formation of the third ring proceded by reaction of 2-chloropurine derivative 203 with a trans-aminocyclopentanol giving the intermediate 204.The third ring was closed by activation with thionyl chloride to give 205. Catalytic debenzylation led to 206. The starting 203 was obtained by acylation of 6-amino-5-(benzylamino)-3alkylpyrimidine 201 to the 5-acylderivative 202. The carboxylic acid was responsible for the substituent at position 2 of the ﬁnal compound. An alternate method for less accessible carboxylic acids made use of the iodination of 205 (R ¼ H) to the 2-iododerivative 205 (R ¼ I) by a mixture of lithium diisopropyl amide and 1-chloro-2iodoethane followed by a palladium-catalyzed coupling with alkylacetylene and cuprous iodide as a co-catalyst to give 205 (R ¼ alkyn-1-yl). The triple bond on the side-chain was hydrogenated and simultaneously debenzylated over Pd(OH)2 to 206 (R ¼ saturated alkyl). The most eﬀective selective inhibitor of cyclic GMPphosphodiesterase of the 2-alkyl-derivatives was 206 (R ¼ [CH2]3CH[CH3]2) (99BMC7) (Scheme 62). O6-Ethyl or O6-benzylguanosine reacted with bromoacetaldehyde at pH 4.5 producing imidazo[2,1-b]purines 207 in contrast with guanosine which gave imidazo[a]purines with halogenoaldehydes. Catalytic debenzylation of 207b aﬀorded 209 with retained the ribofuranosyl residue (87JOC2374) (Scheme 63). 3. Imidazo[2,1-i]purines These can be synthesized by ﬁve methods. The ﬁrst one was based on a reaction of chloroacetaldehyde with substituted isoguanine 210 providing the tricyclic derivatives 211 (97JMC3248). Replacing the isoguanine by an adenine derivative

ALFONZ RYBA´R

120

Alk O

O

Ph

O

O

N

N

Alk X

N H

[Sec. II.D

a

NH2

201, X = H 202, X = CO-R

Ph

N

N

Alk 5

b, c, d 6

N

X

4

N

N N9

R

N

R'''

3

N

R

N 1

R' 203, X = Cl 204, X = NH-CH(R')-CH(R'')OH

a : excess POCl3; b : H2N-CH(R')-CH(R'')OH, DCM, iPrNEt2, NMP; c : SOCl2, DCM; d : Pd(OH)2, MeOH, HCO2NH4, heat

7

R'' 205, R'''= CH2-Ph 206, R'''= H , R', R''=Alk or R'-R''

Scheme 62

O

O-R Rf = ribofuranosyl a : 6M HCl, 90o / 6 hr ; b : H2 -1 atm, Pd/C, H2O-EtOH, r.t / 20 hr.

N N

N N

N

a or b

N X

207a, R = C2H5 } X= 207b, R = CH2Ph H, Rf

N

N N

N X

208, X = H 209, X = Rf

Scheme 63

213 aﬀorded 214a (72B3499). The second method involved cyclization of 5-amino-4(imidazol-2-yl)-1-R-imidazole 215 with carbon disulﬁde giving the 5-mercaptotricyclic 214a (87JMC2013). The third ring can also be obtained by cyclization of 215 with diethoxymethyl acetate under formation of 214a (70JCS(C)2206) (Scheme 64). Two other methods led to 7,8-dihydroderivates 217. Thus, the third one starting from a 6-chloro-20 -deoxyriboside derivatized with tert.-butyl-dimethylsilyl-chloride and ethanolamine gave 216. Following iodination with methyl-(triphenoxy)phosphonium iodide gave the expected N6-(2-iodoethyl)-derivative, which, then cyclized to the tricyclic 217. Similarly, the 7,8-dihydroderivatives 219 and 220 were prepared from the isoguanine 218 by heating in phosphorus oxychloride (98JOC4385) (Scheme 65). The fourth method was based on thermal cyclization of 1-(2aminoethyl)purinedione 223 obtained from 222 to the tricyclic 224. Derivative 223 was the by-product of an alkaline cyclization of the imidazo[1,2-a]pyrimidine derivative 222 (Scheme 66). The ﬁfth method was based on acylation of the substituted adenine by chloroacetic anhydride to N6-chloroacetic derivate 225 and cyclization to the 8-oxo derivative 226. The another route oﬀered the cyclization of 1-carboxymethyladenine derivative 227 by N,N0 -dicyclohexylcarbodiimide (69JOC3492) (Scheme 67). Compound 227 was obtained by alkylation of a substituted adenine with iodoacetic acid. Alkylation of the NH group of compound 211a or of its 7,8-dihydro-derivative 219 with alkyl bromide gave the 3-alkyl- 212 or 3-alkyl-7,8dihydro-derivatives 221, respectively (97JMC3248) (see Scheme 64). The 8-oxocompound 226 underwent a hydrolytic cleavage to 227 (69JOC3492).

Sec. II.D]

121

ANNULATED HETEROCYCLO-PURINES

N

NH2 N

N N

O

N

a

N 211a

O

N

N

Alk

O

N

211a, R' = H 211b, R' = Alk

N

N

a

6

N N4

213

Alk'

d : Alk'Br, k2CO3, DMF

b

R = Alk, ribofuranosyl

N H

c

O

N

H2N

N R

216

Alk

b :1M NaOH, 37o / 3 hr ; c : CS2, Li2CO3, DMSO, r.t./ 7days

N

N

N

N

a : H2O -ClH2CHO;

N3 R

214a

N

N

212

N1

N R

N

N

N9

8

NH2

HS

N

d

Alk

210, R' = H, Alk

N

N

R'

R'

N R

215

HO

[OP(:O)(OH)]2-OH OH

Scheme 64

N

NH(CH2)2-OH

O

R=

X = TBDMS

OX

N

N N 214b

a

N

OX

N

N R

217

N

N

Alk 218, R = H, Alk

N R 219

N N

c O

N

NH(CH2)-OH R N N b O

N

R N O

N N

N

Alk 219, R = H 220, R = Alk

221

N N

N

Alk

Alk'

a : (PhO)3MeP + I - ; DMF/Et3N r.t. / 45min; b : POCl3, reflux / 1hr ; c : Alk'-Br, K2CO3, DMF

Scheme 65

Derivatives of imidazo[2,1-i]purines showed interesting pharmacological properties; thus, compounds 212 are eﬀective antagonists of A2A and A3 adenosine receptors (02JMC3440); 2-cyclopentenyl-4-cyclopropylmethyl-8-pyridin-4-yl) derivative of 212 is a insulin-secretion enhancer (01MIP1); 4-phenyl derivatives of 212 exhibit a strong and selective vasodilatation eﬀect (01CPB188); 4-chlorophenyl derivatives of 224 reveal a bronchodilatation eﬀect (80JMC1188); 3,4-di-n-propylderivatives of 212 are

ALFONZ RYBA´R

122

N

O

O H2N-(CH2)2

NH-CHO N

a N

N

[Sec. II.D

N

O

NH2

H N N

O

N

N

C6H4-Cl(p)

C6H4-Cl(p) 222 a : aq. NaOH; b :

N

C6H4-Cl(p) 224

223 240o

H N

N

b

/ 5 min, (HOC2H4)2O Scheme 66

O N

NH-COCH2-Cl N

N N

225

b

N CH3

N

N N

NH

HO2C

N CH3

226

c e

H2C

N

N N

227

N CH3

a : (ClCH2CO)2O; d b: 1M NaOH, 100o / 30 min; 9-Me-adenine c : DCC, DMF - DMSO, 80 o /24 hr ; 9-Me-adenine d : ICH2-CO2H, H2O, 70o /1hr, r.t. / 48 hr ; e : 0.1M NaOH, 25o / 6 hr. a

Scheme 67

inhibitors of the cyclic AMP-phosphodiesterase (97JMC3248); 3-(5-O-phosphono- D-ribofuranosyl derivatives of 214a exhibit an inhibitory eﬀect against priones formation (02USP1) and the 3-(2-deoxy-5-O-phosphono- -D-erythro-pentafuranosyl derivative of 214b discloses a competitive inhibition of HIV-1 reverse transcriptase (02MI1). The crystallographical structure of compound 226 was studied by an X-ray analysis (70JA6604). 4. Imidazo[2,1-f]purines The ﬁrst of four methods leading to this heterocycle was the cyclization of 8(subst. amino)-7-acylmethyl-purinedione 228 to 1H- and 3H-imidazo[2,1-f ]purine2,4-dione 229. The starting compound 228 was obtained by an alkylation of potassium 8-(subst. amino)purinedione with either -acyl-methyl halogenide, or halogenoaldehyde (71KGS682, 71KGS686, 85FZK(2)54, 87KGS1105). Also, alkylation of potassium 8-halogeno- or 8-methylmercapto-purinedione with the above mentioned acylmethyl halogenide to 8-halogeno- or 8-methylmercapto-7acylmethyl-purinedione 230 followed by a reaction with a primary amine under closure of the imidazole ring to 229 was reported (71KFZ(2)22, 83KFZ160, 85FZK(2)54, 87KFZ566, 87KGS1105 (Scheme 68). A modiﬁcation of the ﬁrst method was represented by a pyridine-catalyzed alkylation of 8-bromopurinedione to 8-bromo-7-(2,3-dihydroxypropyl) compound

Sec. II.D]

123

ANNULATED HETEROCYCLO-PURINES

R3 HC CO N

R1

4

3

5

N

a O

NH-R

N

R3 HC CO N

O

R4

1

N

N

R2

9

R3

6

N

b

8

N

R4

7

R4

X N 230, X = Br, SCH3

R

228 229 228 - 230, R = Alk, Aryl ; R1, R2,R3 = H, Alk ; R4 = H, Alk, cycloAlk, Aryl a : HCO2H, reflux / 2 hr ; 170-175o

b : H2N-R4, DMF, reflux / 2-5 hr, or H2N-R4, MeOH (EtOH), Scheme 68

CH2-CHO N b

CH2-CH(OH)-CH2OH N a N

Br

O Me

Br

N

N

O

N N

N

N

Me R 232 231 233, R = Alk, cycloAlk, PhCH 2 a : HIO4 - H2O, r.t. / 10 hr ; b : H2N-R, EtOH, 140o / 8 hr. Scheme 69

231; the dihydroxypropyl grouping was then cleaved by periodic acid to 8-bromo-7acetaldehyde derivative 232 and condensed with a primary amine to 233 (87KFZ566) (Scheme 69). The second method served for preparation of 6,7-dihydro derivatives. The third imidazole ring was formed from 8-halogeno-7-(halogenoalkyl)-purinedione 234 and arylamine giving 235 (70KFZ(12)14, 62MI2, 80KPS623) or by cyclization of 8(subst. amino)-7-(2-halogenoalkyl) derivative 236 to 235 (97PHA279, 98JHC135) (Scheme 70). The starting 234 and 236 were obtained from 8-halogeno- or 8-(subst. amino)purinediones by alkylation. O R1 O

CH2CH(R)-Cl

N

N N

a O

X

N

R2

O R1

N

N N

N

N

234

R

N

R'

R2

N

b

CH2CH(Br)-R NH-R'

236

235 (CH2)2-N

N

CO CO

N

(CH2)2-NH2

b

235, R = R' = H

c N 237

Cl

N

Cl

238

a : H2N-Ar, heat; b : reflux, 4 hr ; c : H2N-NH2.H2O, EtOH, heat

Scheme 70

234 - 238 : X = Br, Cl R1 = H, Alk; R2 = Alk; R' = Aryl; R = H, Alk, CO2Et

ALFONZ RYBA´R

124

[Sec. II.D

O Me

N

O

N Me 239

H CH Cl 2 N a CH2 N N CH2 CH2Cl

O

N

+

f

N

240

Me

N CH2 CH2Cl

ClCH2 N

N

O

CH2 N

e

N

N Me

241

a : 1 equiv. aq.NaOH, 40-50o / 10 min

Scheme 71

The third synthesis involves cyclization of 8-chloro-7-(2-aminoethyl)purine-dione 238 to 235 (R,R0 ¼ H). The intermediate 238 was prepared by hydrazinolysis of the 7(2-phthalimidoethyl) derivative 237 (79S581). A special case of the third ring annulation constitutes a treatment of 8-bis(2-chloroethyl)amino-purinedione 239 with alkali producing a 50:26% mixture of [2,1-f ] 240 and [1,2-e] 241, respectively (85JHC105) (Scheme 71). Application of the fourth method made it possible to obtain tricyclic derivatives with a 7-oxo group at the newly formed ring. Thus, potassium 8- aminopurinedione was alkylated with a chloroacetate to 242 and then hydrolyzed to 8-amino-7carboxymethyl compound 243. The ring of 243 was closed by diphenylphosphoryl azide to 244. The methylene group in position 6 of 244 was reacted with aromatic aldehydes to give the corresponding arylmethylene compounds 245 (86KFZ1319) (Scheme 72). Position 6 of imidazo[2,1-f ]purinediones is the site of an electrophilic attack. The respective nitration, bromination, Mannich reaction, Vilsmeier formylation, acetylation and hydroxymethylation of 246 yielded compounds 247a, 247b, 247c, 247d, 247e and 247f. The last one can be obtained by reduction of 247d (79KGS1404, 83KFZ160, 85FZK(2)54, 84KFZ307) (Scheme 73). Alkylation of the 1,6,7,8tetrasubstituted 248 took place at N(3) of the heterocycle, alkylhalogenides, benzylchloride, halogeno-acetates and phenacyl-bromide being the alkylation agents. The 1,2-epoxy-alkanes and acrylonitrile reacted similarly (83KFZ160, 88UKZ1312) (Scheme 74). Treatment of the enol form of 248 with phosphorus oxychloride resulted in substitution of the hydroxyl group by chlorine yielding 250 (X ¼ Cl). Application of a stronger chlorination agent such as POCl3 with PCl5 aﬀorded 2,4dichloro compound 251 (X ¼ Cl), the methyl group at N(3) being eliminated as CH2-CO2Et (or Me) N a N 242

NH2

CH2-CO2H N b

O Alk

NH2

N 243

a : conc.HCl, 90o / 1 hr ; b : (PhO)2P(O)N3, DMF, TEA, r.t. / 12 hr. Scheme 72

O

N

N

R

O N H Alk' 244, R = H2 245, R = CH-Aryl N

N

Sec. II.D] O Alk

125

ANNULATED HETEROCYCLO-PURINES

N

N

O

246, 247 R = Alk, Aryl

X

N

a-f

N

Alk'

N

N

N

R

247b, X = Br

R

N

247c, X = CH2-NR1R2,

Alk''

Alk''

246

247a, X = NO2

247

CH2-N

a : (for 247a) HNO3, AcOH, 20o / 5 hr ; b : (for 247b) Br2, CHCl3, r.t. / 2 hr ; c : (for 247c) HNAlkAlk' or piperidine / morpholine / piperazine, CH2O, reflux /4 hr ; d : (for 247d) POCl3 - DMF,80o / 4 hr ; e : (for 247e) Ac2O, cat. H2SO4 or HClO4, 100o / 2 hr ; f : (for 247f) excess CH2O, AcOH, reflux / 5 hr.

R1 R2

247d, X = CH:O 247e, X = COCH3 247f, X = CH2-OH

Scheme 73

O N

O

N N

N

CH3

X

O

CH3

R

N

N N

Ph

X

X

N CH 250 3

Alk

248, R = H 249, R = Alk, CH2CO2Me, CH2-CO-Ph, CH2-CH(OH)-Alk, (CH2)2CN

N 251

250 - 251, X = Cl, NHAlk, NAlkAlk', N

R1 R2

Scheme 74

methyl chloride. The chlorine atoms of both compounds can be displaced by primary or secondary aminogroups. Chlorine at C(2) can be substituted at milder conditions, whilest substitution of both chlorine groups required higher temperatures (84KGS407) (Scheme 74). The enol form of 252 reacted with phosphorus pentasulﬁde to give 4-mercapto compound 253, subsequent methylation gave the 4-methylthio derivative 254 and the reaction with ethanolamine the 4-(2hydroxyethylamino) compound 255. Compound 253 underwent cleavage of the pyrimidine ring on treatment with Raney-nickel to form 5,6-dihydroimidazo[1,2-a]imidazole 256 (83KPS32) (Scheme 75). A mass spectral fragmentation of 1,8-dialkyl-7-phenyl derivatives of 229 appeared in Ref. 87KGS1105. OH

X N O

N N CH3

N

Ph N CH3

253, X = SH ; 254, X = SCH3 255, X = NH-CH2CH2-OH

H3C

N

a,b,c O

H3C N H

N CH3 252

253

N N

d 256

Ph N CH3

a : P2S5 ; b : CH3I, aq.NaOH; c : H2NCH2CH2OH; d : Raney - Ni Scheme 75

ALFONZ RYBA´R

126

[Sec. II.E

The N(8)-(phenylpiperazinopropyl) derivatives 235 showed a signiﬁcant antiserotonin, long-lasting hypothermic eﬀects and anticonvulsant properties (99EJM1085), the 6-piperidinomethyl-, morpholinomethyl- and N-methylpiperazinomethyl-derivatives 247c diuretic and neuroleptic eﬀects on the heart (85FZK(2)54). The N(8)-allyl- and hydroxyethyl derivatives of 235 displayed a positive inotropic eﬀect on heart tissue (70KFZ(12)14). 5. Imidazo[1,2-e]purines Tricyclic compounds 241 originated as a by-product on reaction of alkali with 8-[2-bis(chloroethyl)amino]purine 239 in 26% yield (85JHC105) (Scheme 71). 6. Imidazo[1,2,3-c,d]purines Compounds with a peri-fused imidazole ring to the purine ring 257 were only little studied. Their synthesis involved an intramolecular alkylation of 8-alkyl- or 8-aryl-9(2-mesyloxyethyl)-1-methyl-purinediones 260b. The necessary intermediates 260b were achieved by hydrogenation of the 6-[2-(hydroxyethyl)-amino]-3-methyl-5nitroso-pyrimidinedione 258 to 5-amino-6-[2-(hydroxyethyl)amino] compound 259; further reactions with the respective ortho-carboxylates and mesyl chloride gave 8alkyl- or 8-aryl-9-(2-hydroxyethyl)-purinediones 260 or 261 (98CCC407) (Scheme 76).

E. PYRAZOLO-PURINES The synthesis of pyrazolo[5,1-b]purin-2-ones 261 started from ethyl 7-aminopyrazolo[1,5-a]pyrimidine-6-carboxylates 262, following hydrazinolysis and reaction with HNO2 gave the corresponding azide and the modiﬁed Curtius reaction closed the third pyrazole ring of 261. The ﬁnal tricyclic 261 can be hydrolyzed to 6,7diamino-pyrazolo[1,5-a]purines (68CPB2195) (Scheme 77). Ethyl 3- -D-ribofuranosylpyrazolo[3,2-i]purine-9-carboxylate 268a, was prepared from the 6-chloro-9-ribofuranosylpurine derivative 264 protected by tetrahydropyran and isopropylidene groups through 6-cyanoacetyl derivative 265, which gave an -aminomethylene derivative 267 by partial hydrogenation. The third pyrazole ring of 268b was closed with hydrazine or its salts. Deprotection of the saccharide O H3C O

O X

N N H

258, X = NO 259, X = NH2

N

a, b

c

H3C

R

NH

N

(CH2)2OH

(CH2)2OX 260a, X = H 260b, X = Ms

Scheme 76

8

O

N

N1

6 5

N

N3

257, 260 ,261: R = Alk, Aryl

R

a : R-C(OEt)3, cat. 4 D-1 257 TSA,100o /2-4 hr ; b : MsCl, DCM, TEA, r.t. / 1 hr ; c : K2CO3, DMF, 120o / 0.5-1 hr.

Sec. II.F]

127

ANNULATED HETEROCYCLO-PURINES

7

X-CO

O

NH2

H N1

8

N

6

N1

N 4

3

261 - 263, R', R'' = H, Alk

HN

a, b

N

3

R'

4

R''

N

N8

5

a : H2NNH2, EtOH, reflux / 8 hr ; b : NaNO2, HCl, EtOH, 0o / 2 hr ; then reflux / 2 hr.

R'

6

R''

261

262, X = OEt 263, X = NHNH2

Scheme 77

R'

H

6 5

N

N7

a, b N 3

N9

R 264, R' = Cl 265, R' = CH(CN)-CO2Et

7

c

N

268a, 272a, R = R f ;

X

8

NH2

EtO-CO

N 6

N 5

N

N N

N1

264 - 268b, 269b 272b, R = R f with protecting groups

3

R 268a,b , X = CO2Et e d 269b , X = CONH2 270b , X = Br f 271b, X = NO2 272a,b , X = NH2 4

267

a : NC-CH2-CO2Et, NaH, DMF; b : 4 atm H2, Pd/C, C6H6 - DMF; c : 3 equiv.H2NNH2sulfate, C6H5N / EtOH, 100o /3 hr; d : Br2, AcOEt - buffer, r.t / 3 hr; e : Cu(NO3)2, Ac2O, r.t.; f ; Pd/C, then H +.

Scheme 78

moiety by triﬂuoroacetic acid aﬀorded the 3- -D-ribofuranosyl derivative 268a. Compound 268b with ammonia gave the corresponding amide 269b and subsequent bromination the 9-bromo-derivative 270b; its nitrodebromination reaction [Cu(NO3)2 3H2O, Ac2O] aﬀorded 9-nitro compound 271b and hydrogenation together with elimination of protecting groups produced 272a. The tricyclic compounds 270b–72b showed antileukemic activity (91TL7415, 92CPB2585) (Scheme 78).

F. TRIAZOLO-PURINES The most studied compounds of this group were purines with a triazole ring annulated to bond ‘‘i ’’. 1. [1,2,4]Triazolo[3,4-i and 5,1-i]purines The synthesis of [3,4-i]-annulated compounds started from 6-hydrazinopurine derivatives 273. The ﬁrst method involved reaction with aliphatic or aromatic ortho esters closing the third triazole ring and giving 274 (R0 ¼ Alk, Aryl). Use of carbon disulﬁde instead of the ortho esters produced the 3-mercapto-tricyclic 274 (R0 ¼ SH).

ALFONZ RYBA´R

128

[Sec. II.F

The 6-hydrazinopurine derivative was also starting material for the second method. Treatment with an aromatic aldehyde gave the corresponding 6aldehydohydrazone 275 and its reaction with azodicarboxylate (DEAD) the tricyclic 274. An alternate process was the ‘‘one-pot’’ access from the hydrazine derivative 273 without isolation of the in situ formed aldehydohydrazone 275. Another route to form the triazolo ring involved heating 275 with lead tetraacetate. Iodine of the 5-iodotricyclic 274 was capable of nucleophilic displacement by methoxy-, hydroxyl-, amino-, and mercapto groups. The rearrangement of [3,4-i]derivatives by reﬂuxing in formamide to [5,1-i]-analogues is seen in Scheme 81. The 3-aryl-5-iodo-7-(triacetyl-O-ribofuranosyl) compounds 274 represent a new class of xanthinoxidase inhibitors (65JOC3601, 67JOC2241, 99S655) (Scheme 79). The third approach was based on cyclodehydratation of 6-aroylhydrazido-purine derivative 278 under catalysis by p-toluenesulfonic acid giving rise to tricyclic 279. The necessary intermediate 278 was accessible easily by transformation of the 6methylthio derivative 277 by, e.g., isonicotinoyl hydrazide. Compounds 279 are stable in acid in contrast to parent triazolopurines 274 (X ¼ H). Notable is their bronchodilatation eﬀect, up to 100 greater than that of theophylline (92TL3151) (Scheme 80). The ﬁrst access to triazolo[5,1-i]purines is the rearrangement of their [3,4-i]analogues 274. The second method involving the alkaline cyclization of 4-amino-5acylamino-triazolo[2,3-c]pyrimidine (285) produced the third imidazole ring of 286. 2

H2NNH 1

R'

6

N

X

N7 R 3

N

a

N N1 4

N9 R

N

X

N9

6

N

273

c N N

X

N7

N 275

273 - 276, R = 7Alk, 9Alk, 9(Ac)3-R f ; X = H, I ; R' = Alk, Aryl, SH

R N

H2N

N

b

274 d

N H

Aryl-CH=N-NH

a : AcOC(R')(OEt)2, r.t. / 18-27 hr or R'C(OEt)3, AcOH, 55-80o / 4-7 hr or CS2, C5H4N; b : DEAD, MeCN, reflux / 1-5 hr or Pb(OAc)4, dioxane, reflux / 1-5 hr ; c : HCO2H, 180-185o ; d : AcO-CH(OEt)2, r.t. / 18-27 hr.

N

276

Scheme 79

N N

X N O

N N

N

R

N

a

N

C3H7-n 277, X = SMe 278, X = NHNH-CO-Aryl

O

N N

Scheme 80

277 - 279, R = H, Alk

N

C3H7-n 279

R

a : toluene - Cl2CHCHCl2, cat.TSA, reflux

Sec. II.F]

129

ANNULATED HETEROCYCLO-PURINES

Aryl

X NO2

N

N

NH2

280, X = Cl 281, X = NHNH-CO-Aryl

b,c,d

H2N

Aryl

N

N

NO2

N H

a N

Aryl

N

X

N

282

N9

N N1

N6

a N

NH2

7

NH2

N

4

283, X = NO2; 284, X = NH2 285, X = NH-CO-R'

N3 H

286 e

274

a : PPA, 120-130o / 3 hr; b : HC(OEt)3, CF3CO2H, reflux / 5 hr; c : 3 atm H2, Pd/C, AcOH, 12 hr; d : N2, C5H4N, R'-COCl, r.t. / 2 hr; e : H2NCHO, 180-185o.

R'

Scheme 81

The synthesis started from 4-amino-6-aroyl-hydrazido-5-nitropyrimidine 281 which, on heating in PPA, formed the triazole segment, but at the same time cleavage of the pyrimidine moiety took place producing the 2-(triazol-3-yl)-1,1-diaminoethylene 282. Employment of triethyl formate restored the pyrimidine portion giving the 4amino-5-nitro-derivative 283. The subsequent reduction of the nitro group and acylation of the 5-amino group resulted in 285 (65JOC3601, 88JOC382, 94JHC1171). A similar method starting from 4-amino-imidazol-5-carbonitrile is published in (02JMC3703). Triazolo[5,1-i]purines 286 are antagonists of adenosine-A2 receptors, the highest eﬃcacy was showen by a 3-(ﬂuorobenzyl)-5-amino-8-(2-furyl)derivative (93EJM569) (Scheme 81).

2. [1,2,4]Triazolo[4,3-a and 1,5-a]purines Their preparations copied those of their [i]-analogues. The ﬁrst method started from 2-hydrazinopurines 287 and suitable ortho esters yielding [1,2,4]triazolo-[4,3a]purin-9-ones 288 (R2 ¼ Alk, Aryl). Substitution of ortho esters by carbon disulﬁde led to 7-mercapto-derivative 288 (R2 ¼ SH). The 7-aryl-derivatives were better accessible by the second method—the oxidative cyclization of 2-arylidenehydrazino)derivatives 289, such as heating with diethyl azodicarboxylate, or oxidation with aerial oxygen (85CPB3113) (Scheme 82). O

O

6

N H

N CH3

287 R2-C(OEt)3

O

9

H N1

N

a

N

H2N

8

R2 N

N4 CH3

N 5

N

b R1

3

Aryl

H C N

N N H

289

288

a: or CS2, C5H4N; b : DEAD, 180-200o / 10-30 min or air, AcOH, reflux / 6 hr.

N CH3

287 - 289,

Scheme 82

R1 =

Alk, Aryl; R2 = Alk, Aryl, SH

ALFONZ RYBA´R

130 O

O

R'' N1

8

a

H2N N H2N

7

N

N

R

N

5

N

N H

290

[Sec. II.F

N3

4

O

R'

291

R, R1 = Alk R'' = Alk, Rf a : N2, (RCO)2O, TEA, DCM, r.t. / 60 hr.

Scheme 83

X R

R OH

O -OCH2

O O

N

OH

O

N CH3

O P O O O

P -OCH2 O

N

N

R= N

N

X = O, S 32

292 Scheme 84

Isomeric [1,5-a]-analogues of 291 can also be obtained by treatment of 1,2diamino-7,8-disubstituted purine-6,8-diones 290 with carboxylic anhydrides. Compounds of this type are potential B-cell-selective activators and the 6-methyl1-(2-piperidinoethyl)-3- -D-ribofuranosyl-derivate of 291 was shown to be an example (94JMC3561) (Scheme 83). Polyribonucleotides with a triazolo[2,3-a]purine as a heterocyclic component 292 were also interesting from a pharmacological point of view. Several amphipatic (hydrophobic base, hydrophilic backbone) polyribonucleotides showed moderate to potent antiviral activity against HIV and a greater one against human cytomegalovirus than the already known gancyclovir (98JMC4958) (Scheme 84). 3. [1,2,4] and [1,2,3] Triazolo[3,4-b and 5,1-b]purines Reaction of 2-hydrazinopurine 293 with diethoxymethylacetate or preferentially with N,N-dimethylformamide dineopentyl acetal produced [1,2,4]-triazolo[3,4b]purine 294. This compound is a strong UV-ﬂuorescence agent (82H(17)405) (Scheme 85). The 5-azido-4-cyanoimidazole (295) and malononitrile reacted to give [1,2,3]triazolo[5,1-b]purine-3-carbonitrile 296 (95JHC457) (Scheme 86). Heating 8-hydrazino-7-methylpurine-2,4-dione in formamide gave [1,2,4]triazolo[4,3-e]-purindione 297. Occupation of position 7 of the starting material N H2NNH

N N

293

N H

N

a N N

N N

N H 294

Scheme 85

a : [(CH3)2N-CH(OCH2-C(CH3)3]2, toluene, reflux / 6 hr.

Sec. II.G]

131

ANNULATED HETEROCYCLO-PURINES NH2 N3

HN

a, b NC

CN

N

N

N N N

295

a : CH2(CN)2, K2CO3, DMSO, 5-10o / 8 hr; b : HCl

N H

N 296

Scheme 86

CH3 N

O H3C N O

O N

e

N

CH3

NH

HN

O

H N

N Ph

O

S

(298)

N

N

R

O

NH2

N H

6

4

HN

N

O 8

a

9

N H

3

N

N

1

301

299, R = H 300, R = C(S)-NHNH-CO-Ph

297

N H

Ph

a :reflux in cresol / 7 hr.

Scheme 87

prevented other than the ‘‘e’’ annulation (59ZOB3742). Action of [1,3,4]-oxazole-2thione 298 on 4,5-diaminouracil 299 furnished [1,3,4]-triazolo[3,4-f ]purine-5,7-dione 301. Formation of the second and third ﬁve-membered rings proceeded through 5-thiosemicarbazidouracil 300 (93PHA109) (Scheme 87).

G. TETRAZOLO-PURINES The tetrazolo-purines exist in solution as a tautomeric equilibrium mixture of the cyclic form and the corresponding azidopurines (open form). The equilibrium position depended both on the solvent and the structure. The tetrazolotautomer is stabilized by the electrondonating groups and the azido-tautomer by the electronwithdrawing ones. The 2-azidopurine 303a, 2-azidoadenine 303b and 2-azidohypoxanthine 303c exhibited other additional tautomers—tetrazolo-[1,5-a]purine 302a, -[1,5-a]adenine 302b and -[1,5-a]hypoxanthine 302c and their tetrazolo[5,1-b]purine analogs 304a, 304b, and 304c, respectively. The tautomeric ratio was estimated from intensities of their 1H-NMR spectra using the respective 6H–8H and 5H–7H signals in DMS or in triﬂuoroacetic acid. The azide tautomer was conﬁrmed by its IR spectrum (Scheme 88).

N

N N

N

N N

302a,b,c

5

6

8

N

R

R

R

N H

6

N3

N

N N

8

N H

303a,b,c

302 - 304 , a : R = H; b : R = NH2; c : R = OH Scheme 88

N

N

N

N

N

N H

304a,b,c

7

ALFONZ RYBA´R

132

[Sec. II.G

The azide to [1,5-a]-tautomeric ratio for 303a : 302a ¼ 0.44; for 303b : 302b ¼ 2.7; for 303c : 302c ¼ 0.1. The azide to [1,5-b]-tautomeric ratio for 303a : 304a ¼ 3.5; for 303b : 304b ¼ 1.1; for 303c : 304c ¼ 0.5 (66JOC2210). The most studied compounds are derivatives with a tetrazole ring annulated to the ‘‘i’’ of the purine ring system.

1. Tetrazolo[5,1-i]purines The general preparation method was based on reaction of 6-chloropurine 305 with sodium azide or 6-hydrazinopurine 307 with nitrous acid or 1-alkyl-4-formamido-5tetrazol-5-yl)imidazole 308 with dimethoxymethylacetate. The ﬁrst one aﬀorded the required tetrazolopurine 306 in low yield. The second one involving 307 was more advantageous (ca. 70% yield). The third one employing the tetrazolylderivative was only little used. The ﬁnal 306 was primarily formulated as an ‘‘open’’ azide, but IR studies and X-ray diﬀraction analysis indicated the cyclic-tetrazole structure (66JOC2210, 70JHC75, 97JMC3248, 68AX(B)359). The N-(purin-6-yl)pyridinium chloride 309 was more reactive on substitution with a weak azide nucleophile (yield 87%) then the 6-chloro-analogue (yield 25%) at the same reaction conditions (96JCS(P1)15) (Scheme 89 and 90). The equilibrium was also studied between the 6-azido- and the tetrazolo[5,1-i]tautomers in relation to solvent applied. The 1H-NMR spectrum in CDCl3 showed a 2:3 ratio of the azido to tetrazolo species. The IR spectrum of a chloroform solution exhibited a very weak band at 2359 cm1 for an N3-group, while no absorption was found in a nujol mull (97T1595). Compounds 310 obtained from 6-chloro-3,7-di-n-propyl-purinone 311 and sodium azide (Scheme 90) are more eﬀective inhibitors of cyclic AMP-speciﬁc phosphodiesterase (PDE-IV) then theophylline and in addition do not display unwanted positive chronotropic action on heart—a common side eﬀect of alkylxanthines (97JMC3248). 2

Cl 6

a or b

N7

N

N N 4

R X

N

N9 H

305 305 - 307 : R = H, 7- or 9-Alk, R f, 9-([CH3]2C=)R f ; X = H, NH2

N

N

N

N9

N

d R

X

N

N7

6

306 c

H2 C Ph N

N

N H OCH-NH

N 308

H H2N N N N 307

Scheme 89

a : NaN3, EtOH, reflux / 1 hr; or 100o, sealed tube / 1.5 hr; b : NaN3, DMF, 100o / 3 hr or in DMSO; c : NaNO2 in 1M HCl or in AcOH-H2O; d : (EtO)2CHOAc, 100o / 3 hr.

Sec. II.G] Cl

+

N

-

N

N

N

N O

133

ANNULATED HETEROCYCLO-PURINES

N

a

N C3H7-n

N N H

Cl

O

N

O

N N C3H7-n

N C3H7-n 311

310

Rf

N

a : NaN3, EtOH, 100o, sealed tube / 1.5 hr.

309

Scheme 90

2. Tetrazolo[1,5-a]purines The simplest title compounds were synthetized from 2-hydrazino-3-methyl-8-Rpurines 312 and nitrous acid under formation of cyclic 4-methyl-tetrazolo[1,5-a]purin-9-one (313, R ¼ H, alkyl, aryl) and not 2-azido-3-purine. The cyclic structure was corroborated by IR and 1H-NMR spectra. The IR spectrum did not show the band of an azido group. With respect to the presence of the N(3)-methyl in the starting compound, the annulation had to take place at bond ‘‘a’’ of the purine skeleton (85CPB3113) (Scheme 91). 3. Tetrazolo[5,1-b]purines A similar method was applied when preparing exclusively the [5,1-b]-isomer from 2-hydrazino-1-methylpurinone. A useful access involved the treatment of nitrous acid and 4-amino-2-hydrazinopyrimidine-5-carbohydrazide (315) giving 5-amino-6azidocarbonyltetrazolo[1,5-a]pyrimidine 316. Subsequent heating and cyclization converted it to the corresponding isocyanate 317 and tetrazolo[5,1-a]purin-7-one 318, respectively (86H1899) (Scheme 92). 4. Tetrazolo[1,5-e]purines These compounds were prepared from derivatives of 8-hydrazinocaﬀeine (319) and nitrous acid producing 5,7,9-trimethyltetrazolo[1,5-e]purine-6,8-dione (320). Presence of the methyl group at C(7) of the original skeleton directed annulation to position ‘‘e’’ exclusively. Compound 320 exploded at about 180 C on rapid heating (59ZOB3742) (Scheme 93).

N HN H2N 312

N N CH3

O

O8

O

N H

a R

1N

N

N N

N 4

3

N CH3

N H5

313 312 - 314 : R = H, Alk, Aryl Scheme 91

7

R

H3C

4

5

N6

N

3N

N

N

N

2

1

N8 H 314

a : NaNO2, 5% HCl, r.t.

R

ALFONZ RYBA´R

134

[Refs. O

NH2 N HN H2N

N

CO a, b NH NH2

315

6 8

1

N

N

N4

N

N3

X

b

NH2

H3C 3

4

5

N6

N

N

N

N

N

2

1

316, X = CO-N3; 317, X = NCO

N H8 318

R

a : HNO2; b : heat

Scheme 92

O H3C N O

CH3 N NHNH2 N

N CH3

O a

H3C N O

N CH3

CH3 N N 320

N

N N a : in 10% H2SO4, NaNO2 - H2O, -5o

319 Scheme 93

REFERENCES 59ZOB3742 62MI1 62MI2 64JOC3126 65JOC3601 65MI1 66JOC2210 67JOC2241 68AX(B)359 68CPB2195 69JOC3492 69M1797 70AP378 70AP596 70JA6604 70JCS(C)2206 70JHC75 70KFZ(12)14 71KFZ(2)22 71KGS682

R. G. Glushov, E. S. Golovchinskaya, and O. Yu. Magidson, Zh. Obshch. Khim., 29, 3749 (1959) [CA 54, 19698 (1960)]. M. Eckstein, Dissertationes Pharm. (Poland), 14, 425 (1962) [CA 60, 8030 (1964)]. M. Eckstein, Dissertationes Pharm. (Poland), 14, 435 (1962) [CA 60, 8030 (1964)]. M. Eckstein, M. Gorczyca, and A. Zejc, J. Org. Chem., 29, 3126 (1964). C. Temple, Jr., C. L. Kussner, and J. A. Montgomery, J. Org. Chem., 30, 3601 (1965). F. De Martiis, C. Botre and F. Toﬀoli, Ann. Ist. Super. Sanita, 1, 708 (1965) [CA 65, 12204 (1966)]. C. Temple, Jr., C. L. Kussner, and J. A. Montgomery, J. Org. Chem., 31, 2210 (1967). C. Temple, Jr., C. L. Kussner, and J. A. Montgomery, J. Org. Chem., 32, 2241 (1967). J. Pickworth Glucker, D. van der Helm, W. E. Love, J. A. Minkin, and A. L. Patterson, Acta Crystallogr., Sect. B, 24, 359 (1968) [CA 68, 82146 (1968)]. A. Takamizawa, Y. Hamashima, S. Hayashi, and Sh Sakai, Chem. Pharm. Bull., 16, 2195 (1968). G. B. Chheda and R. H. Hall, J. Org. Chem., 34, 3492 (1969). K. H. Kleine and R. Haller, Monatsh. Chem., 100, 1797 (1969). K. H. Kleine and R. Haller, Arch. Pharm., 303, 378 (1970). R. Haller and K. H. Kleine, Arch. Pharm., 303, 596 (1970). J. Ohrt, R. Parthasarathy, and G. B. Chheda, J. Am. Chem. Soc., 92, 6604 (1970). G. Shaw and B. M. Smallwood, J. Chem Soc. (C), 2206 (1970). A. Giner-Sorolla, J. Heterocycl. Chem., 7, 75 (1970). P. M. Kochergin, I. V. Komissarov, A. A. Tkachenko, and V. V. Vlasov, Khim. -Farm. Zh., 4 (12), 14 (1970) [CA 74, 141700 (1971)]. P. M. Kochergin, Khim.-Farm. Zh., 5 (2), 22 (1971) [CA 74, 125638 (1971)]. A. A. Tkachenko, P. M. Kochergin, and F. A. Zubkov, Khim. Geterotsikl. Soedin., 7, 682 (1971) [CA 76, 126932 (1972)].

135

Refs.]

ANNULATED HETEROCYCLO-PURINES

71KGS686

A. A. Tkachenko, P. M. Kochergin, and G. F. Panchenko Khim. Geterotsikl. Soedin., 7, 686 (1971) [CA 76, 126931 (1972)]. H. Kasai, M. Goto, S. Takemura, T. Goto, and S. Matsuura, Tetrahedron Lett., 2725 (1971). J. A. Secrist, III, J. R. Barrio, N. L. Leonard, and G. Weber, Biochemistry, 11, 3499 (1972). M. I. Yurchenko, B. V. Kurmaz, and P. M. Kochergin, Khim. Geterotsikl. Soedin., 996 (1972) [CA 78, 43424 (1973)]. H. Uno, A. Arie, and K. Hino, Chem. Pharm. Bull., 21, 256 (1973). R. Marumoto, Y. Yoshioka, M. Honjo, and K. Hino, Chem. Pharm. Bull., 22, 342 (1974). R. G. Grushkov, V. G. Granik, V. A. Volskova, V. A. Tshernov, and A. A. Minakova, Khim.- Farm. Zh., 7 (11), 14 (1973) [CA 80, 47950 (1974)]. M. I. Yurchenko, Kochergin, P.M. and A.N. Krasovskii, Khim. Geterotsikl. Soedin., 693 (1974) [CA 81, 63581 (1974)]. K. Harsanyi, R. Szebeni, and D. Korbonits, J.Prakt. Chem., 317, 745 (1975). A. N. Krasovskii, M. I. Yurchenko, P. M. Kochergin, and I. I. Soroka, Khim. Geterotsikl. Soedin., 1121 (1975) [CA 84, 4907 (1976)]. M. Gorczyca, Pol. J. Pharmacol. Pharm., 27, 305 (1975) [CA 83, 178999 (1975)]. P. Nuhn, E. Schilling, G. Wagner, J. Hemmerling, K. Malberg, R. Shimke, H. Stu¨lpner, and H. Ambrosius, Pharmazie, 32, 558 (1977). Ch. R. Frihart, A. M. Feinberg, and K. Nakanishi, J. Org. Chem., 43, 1644 (1978). R. Szebeni and D. Korbonits, Tetrahedron Lett., 2049 (1978). Yu. V. Strokin, B. A. Priimenko, A. K. Sheinkman, and N. A. Kklyuev, Khim. Geterotsikl. Soedin., 1404 (1979) [CA 92, 94351 (1980)]. M. Eckstein and A. Drabczynska, Synthesis, 581 1979. J. A. Montgomery and H. J. Thomas, J. Heterocycl. Chem., 17, 583 (1980). D. L. Temple, Jr., J. P. Yevich, J. D. Catt, D. Owens, C. Hanning, R. R. Covington, R. J. Seidehamel, and K. W. Dungan, J. Med. Chem., 23, 1188 (1980). B. A. Priimenko, N. I. Romanenko, S. N. Garmash, N. I. Gnatov, and A. K. Sheinkman, Khim. Prir. Soedin., 623 (1980) [CA 94, 208813 (1981)]. A. A. Kremzer, Yu. V. Strokin, B. A. Samura, and P. N. Steblyuk, Khim.-Farm. Zh., 15, 59 (1981) [CA 95, 132818 (1981)]. Yu. V. Strokin, I. A. Krasovskii, A. K. Sheinkman, N. A. Klyuev, and R. I. Sinitsina, Khim. Geterotsikl. Soedin., 1267 (1981) [CA 95, 220048 (1981)]. M. Gorczyca, M. Pawlowski, and B. Lucka-Sobstel, Acta. Pol. Pharm., 39, 315 (1982) [CA 99, 139617 (1983)]. M. Tisˇ ler, B. Stanovnik, and Z. Zrimsˇ ek, Heterocycles, 17, 405 (1982). T. Itaya and K. Ogawa, Tetrahedron, 38, 1767 (1982). A. N. Krasovskii, N. M. Turkevich, M. I. Yurchenko, P. M. Kochergin, and I. I. Soroka, Ukr. Khim. Zh. (Russ. Ed.), 514 (1982) [CA 97, 38742 (1982)]. B. A. Priimenko, B. A. Samura, S. N. Garmash, N. A. Klyuev, and N. I. Romanenko, Khim.-Farm. Zh., 17, 160 (1983) [CA 98, 198109 (1983)]. B. A. Priimenko, S. N. Garmash, N. A. Klyuev, N. I. Romanenko, and V. V. Kirichenko, Khim. Prir. Soedin., 32 (1983) [CA 98, 215563 (1983)]. B. Golankiewicz, and W. Folkman, Nucleic Acids Res., 11, 5243 (1983) [CA 100, 7034 (1984)]. M. Hori, T. Kataoka, H. Shimizu, E. Imai, Y. Matsumoto, M. Kawachi, K. Kuratani, H. Ogura, and H. Takanayagi, Heterocycles, 22, 2199 (1984). S. N. Garmash, B. A. Samura, Yu. F. Krylov, B. A. Priimenko, V. V. Kirichenko, and R. I. Katkevich, Khim.-Farm. Zh., 18, 307 (1984) [CA 101, 90861 (1984)].

71TL2725 72B3499 72KGS996 73CPB256 74CPB342 73KFZ(11)14 74KGS693 75JPR745 75KGS1121 75MI1 77PHA558 78JOC1644 78TL2049 79KGS1404 79S581 80JHC583 80JMC1188

80KPS623 81KFZ59 81KGS1267 82MI1 82H(17)405 82T1767 82UKZ514 83KFZ160 83KPS32 83MI1 84H2199 84KFZ307

136 84KGS407 85CPB3113 85FZK(2)54

85JHC105 85MI1 86CPB36 86CPB1328 86H1899 86JHC625 86KFZ1319 86KGS1133

86TL4043 87ACS(B)564 87CPB4372 87EJM243 87JCS(P1)1211

87JMC2013 87JOC2374 87KFZ566

87KGS1105 87KGS1534 88JCS(P1)593 88JMC1351 88JOC382 88KGS534 88KGS1284 88MIP1

88T1273 88TL4129

ALFONZ RYBA´R

[Refs.

S. N. Garmash, B. A. Priimenko, N. A. Klyuev, N. I. Romanenko, and A. K. Sheinkman, Khim. Geterotsikl. Soedin., 407 (1984) [CA 101, 55036 (1984)]. T. Nagamatsu, M. Ukai, F. Yoneda, and D. J. Brown, Chem. Pharm. Bull., 33, 3113 (1985). B. A. Priimenko, B. A. Samura, B. A. Koval, T. A. Slobodyanyuk, S. N. Garmash, N. N. Slobodyanyuk, and V. S. Ponomar, Farm. Zh. (Kiev) (2), 54 (1985) [CA 104, 19554 (1986)]. A. Lefebvre, R. Rips, A. Martine, and Ch. Lespagnol, J. Heterocycl. Chem.,22, 105 (1985). M. Pawlowski, and M. Gorczyca, Acta Pol. Pharm., 42, 4 (1985) [CA 103, 160471 (1985)]. T. Ohsaki, T. Kuriki, T. Ueda, and J. Sakakibara, Chem. Phar. Bull., 34, 36 (1986). M. Hori, T. Kataoka, H. Shimizu, E. Imai, Y. Matsumoto, M. Kawachi, K. Kuratani, and M. Yokomoto, Chem. Pharm. Bull., 34, 1328 (1986). U. Urleb, B. Stanovnik, V. Stibilj, and M. Tisˇ ler, Heterocycles, 24, 1899 (1986). J. Kjellberg and N. G. Johansson, J. Heterocycl. Chem., 23, 105 (1985). N. I. Romanenko, I. V. Fedulova, and V. V. Kirichenko, Khim.-Farm. Zh., 20, 1319 (1986) [CA 106, 213603 (1987)]. N. I. Romanenko, N. A. Klyuev, I. V. Fedulova, B. A. Priimenko, S. N. Garmash, A. Yu. Chervinskii, and A. N. Stepanov, Khim. Geterotsikl. Soedin., 1133 (1986) [CA 106, 176323 (1987)]. T. Itaya, N. Watanabe, and A. Mizutani, Tetrahedron Lett., 27, 4043 (1986). J. Kobe, J. Kjellberg, and N. G. Johansson, Acta Chem. Scand. (Ser. B), 41, 564 (1987). T. Itaya, Chem. Pharm. Bull., 35, 4372 (1987). G. L. Regnier, C. G. Guillonneau, J. L. Duchalt, F. P. Tisserand, G. SaintRomas, and S. M. Holstorp, Eur. J. Med. Chem., 22, 243 (1987). M. Hori, T. Kataoka, H. Shimizu, E. Imai, Y. Matsumoto, M. Kawachi, K. Kuratani, H. Ogura, and H. Takayanagi, J. Chem. Soc. Perkin Trans. 1, 1211 (1987). R. J. Jeﬀerson, J. B. Hunt, and G. A. Jamieson, J. Med. Chem., 30, 2013 (1987). J. T. Kusˇ mierek, D. E. Jensen, S. J. Spengler, R. Stolarski, and B. Singer, J.Org. Chem., 52, 2374 (1987). Yu. V. Strokin, F. S. Zarudii, A. A. Kremzer, N. M. Nasipov, N. V. Chvalyuk, and D. N. Lazareva, Khim.-Farm. Zh., 21, 566 (1987) [CA 107, 190331 (1987)]. S. N. Garmash, B. A. Priimenko, E. A. Skul’skaya, N. A. Klyuev, and N. V. Koval, Khim. Geterotsikl. Soedin., 1105 (1987) [CA 108, 111632 (1988)]. S. N. Garmash, N. V. Koval, B. A. Priimenko, N. A. Klyuev, and E. A. Skul’skaya, Khim. Geterotsikl. Soedin., 1534 (1987) [CA 109, 92613 (1988)]. K. Jenuga, T. Hasegawa, J. Brown, and W. Pﬂeiderer, J. Chem. Soc. Perkin Trans. 1, 593 (1988). J. Boryski, B. Golankiewicz, and E. De Clercq, J. Med. Chem., 31, 1351 (1988). R. S. Hosmane, B. B. Lim, and F. N. Burnett, J. Org. Chem., 53, 382 (1988). S. N. Garmash, Khim. Geterotsikl. Soedin., 534 (1988) [CA 110, 75434 (1989)]. Yu. V. Strokin, and F. A. Khaliullin, Khim. Geterotsikl. Soedin., 1284 (1988) [CA 111, 39296 (1989)]. Newport Pharmaceuticals International, Inc. (J.W. Hadden, L.N. Simon, and A. Giner-Sorola), Pat. Specif. (Aust.) AU 554,372 (1986) [CA 108, 37511 (1988)]. C. Glemarec, J.-C. Wu, G. Remaud, H. Bazin, M. Oivanen, H. Lo¨nnberg, and J. Chattopadhyaya, Tetrahedron, 88, 1283 (1988). T. Itaya, M. Shimomichi, and M. Ozasa, Tetrahedron Lett., 29, 4129 (1988).

137

Refs.]

ANNULATED HETEROCYCLO-PURINES

88UKZ195

S. N. Garmash, Ukr. Khim. Zh. (Russ. Ed.), 54, 195 (1988) [CA 110, 23830 (1989)]. S. N. Garmash, Ukr. Khim. Zh. (Russ. Ed.), 54, 1312 (1988) [CA 112, 7443 (1990)]. T. Itaya, A. Mizutani, M. Takeda, and Ch. Shioyama, Chem. Pharm. Bull., 37, 284 (1989). T. Itaya, A. Mizutani, and N. Watanabe, Chem. Pharm. Bull., 37, 1221 (1989). Nippon Zoki Pharmaceuticals (K. Ienaga, T. Hasegawa, J.B. Desumondo, and F. Uorufugangu), Jpn. Kokai Tokkyo Koho 63,582 (1989) [CA 111, 173917 (1989)]. P. Pecorari, M. Rinaldi, and M. P. Costi, J. Heterocycl. Chem., 26, 1701 (1989). R. Do¨rre and G. Wagner, Pharmazie, 44, 533 (1989). N. I. Romanenko, N. I. Ponomarenko, N. A. Klyuev, B. A. Priimenko, I. V. Fedulova, and N. I. Gnatov, Ukr. Khim. Zh., 55, 1076 (1989) [CA 113, 23830 (1990)]. T. Itaya, M. Morisue, M. Takeda, and Y. Kumazawa, Chem. Pharm. Bull., 38, 2656 (1990). S. N. Garmash, E. A. Skul’skaya, B. A. Priimenko, and N. A. Klyuev, Khim. Geterotsikl. Soedin., 1396 (1990) [CA 114, 143337 (1991)]. N. I. Romanenko, N. A. Klyuev, B. A. Priimenko, and V. I. Serikov, Ukr. Khim. Zh., 56, 215 (1990) [CA 113, 97566 (1990)]. P. Pecorari, M. Rinaldi, and L. Costantino, Farmaco, 46, 899 (1991). B. Golankiewicz, T. Ostrowski, J. Boriski, and E. De Clercq, J. Chem. Soc. Perkin Trans. 1, 589 (1991). J. Boriski, B. Golankiewicz, and E. De Clercq, J. Med. Chem., 34, 2380 (1991). W. J. Chern, G.-S. Lim, Ch.-Sh. Chen, and L. B. Townsend, J. Org. Chem., 56, 4213 (1991). E. N. Dozorova, A. V. Kadusˇ kin, G. A. Bordanova, N. P. Solovjeva, and V. S. Granik, Khim. Geterotsikl. Soedin., 754 (1991) [CA 116, 6334 (1992)]. F. A. Khaliullin, Yu. V. Strokin, and V. A. Kataev, Khim. Geterotsikl. Soedin., 840 (1991) [CA 116, 21018 (1992)]. J. Mahar, G. L. Lukacs, Y. Li, Sh. Hall, and E. Moczydlowski, Toxicon, 29, 53 (1991) [CA 114, 180576 (1991)]. N. Hamamichi, Tetrahedron Lett., 32, 7415 (1991). N. Hamamichi and T. Miyasaka, Chem. Pharm. Bull., 40, 2585 (1992). M. Rinaldi, P. Pecorari, L. Costantino, A. Provvisionato, M. Malagoli, and C. Cermelli, Farmaco Ed. Sci., 47, 1315 (1992). D. B. Nilov, A. V. Kadusˇ kin, S. G. Kalistratov, A. S. Sokolova, I. S. Nikolayeva, V. V. Peters, L. Yu. Krylova, and V. G. Granik, Khim.-Farm. Zh., 26(9–10), 63 (1992) [CA 119, 160226 (1993)]. J. Shimada and F. Suzuki, Tetrahedron Lett., 33, 3151 (1992). R. H. Jin and T. Nishikubo, Tetrahedron Lett., 33, 6307 (1992). P. M. Kochergin, M. Yu. Gromov, E. V. Aleksandrova, and S. Ya. Skachilova, Khim. Geterotsikl. Soedin., 1548 (1993) [CA 122, 31183 (1995)]. F. Gatta, M. R. Del Giudice, A. Borioni, P. A. Borea, S. Dionisottis, and E. Ongini, Eur. J. Med. Chem., 28, 569 (1993). A. F. El Farardy, M. G. Assy, and M. M. Hassanien, Pharmazie, 48, 109 (1993). Y. Ch. Liaw, A. H. J. Wang, G. S. Lin, and J. W. Chern, Acta Crystallogr., Sect.C, 50, 734 (1994) [CA 121, 23294 (1994)]. F. Gatta, M. R. Del Giudice, A. Borioni, and C. Mustazza, J. Heterocycl. Chem., 31, 81 (1994). F. Gatta, M. R. Del Giudice, A. Borioni, C. Mustazza, and C. Fazio, J. Heterocycl. Chem., 31, 1171 (1994).

88UKZ1312 89CPB284 89CPB1221 89JAP(K)1

89JHC1701 89PHA533 89UKZ1076

90CPB2656 90KGS1396 90UKZ215 91FES899 91JCS(P1)589 91JMC2380 91JOC4213 91KGS754 91KGS840 91MI1 91TL7415 92CPB2585 92FES1315 92KFZ(9–10)63

92TL3151 92TL6307 93KGS1548 93EJM569 93PHA109 94AX(C)734 94JHC81 94JHC1171

138 94JMC3187 94JMC3561 94JOC1928 94KFZ(9)33 95JCS(CC)2041 95JCS(P1)15 95JHC457 95JHC1725 95KFZ(2)27 96KFZ(3)49

96KGS265 97JMC3248 97PHA279 97T1595 97TL1979 98CCC407 98CPB1094 98CPB1220 98JHC135 98JMC4958 98JOC4385 98MIP1 98T2941 99BMC7

99CPB1464 99EJM1085 99S655 00CCC1126 00EJO3489 00HCA373 00JOC7697 00ZOK160

ALFONZ RYBA´R

[Refs.

B. Golankiewicz, T. Ostrowski, G. Andrei, R. Snoeck, and E. De Clercq, J. Med. Chem., 37, 3287 (1994). A. B. Reitz, M. G. Goodman, B. L. Pope, D. C. Argentieri, S. C. Bell, L. E. Burr, F. Courmouzis, J. Come, and J. H. Goodman, J. Med. Chem., 37, 3561 (1994). Ch. E. Mu¨ller, J. Org. Chem., 59, 1928 (1994). F.A. Khaliullin, Zh. V. Mironenkova, A. Zh. Gilmanov, E. G. Davletov, and Yu. V. Strokin, Khim.-Farm. Zh., 28(9), 33 (1994) [CA 124, 55873 (1996)]. T. Nagematsu, and H. Yamasaki, J. Chem. Soc., Chem. Commun., 2041 (1995). L. De Napoli, D. Montesarchio, G. Piccialli, C. Santacroce, and M. Varra, J. Chem. Soc. Perkin Trans. 1, 15 (1995). A. P. Freitas, M. F. J. R. P. Proenc¸a, and B. L. Booth, J. Heterocycl. Chem., 32, 457 (1995). M. R. Giudice, A. Boroni, C. Mustazza, and F. Gatta, J. Heterocycl. Chem., 32, 1725 (1995). D. B. Nilov, Khim.-Farm. Zh., 29(2), 27 (1995) [CA 124, 29706 (1996)]. N. I. Romanenko, I. V. Fedulova, B. A. Priimenko, N. A. Klyuev, T. A. Pereverzeva, and B. A. Samura, and E. V. Alexandrova, Khim.-Farm. Zh., 30(3), 49 (1996) [CA 125, 75931 (1996)]. P. M. Kochergin, M. Yu. Gromov, E. V. Alexandrova, and S. Ya. Skachilova, Khim. Geterotsikl. Soedin., 265 (1996) [CA 125, 167910 (1996)]. H. Sawanishi, H. Suzuki, Sh. Yamamoto, Y. Waki, Sh. Kasugai, K. Ohya, N. Suzuki, K.-i. Miyamoto, and K. Takagi, J. Med. Chem., 40, 3248 (1997). M. Pawlowski, J. Katlabi, B. Rys, and E. Szneler, Pharmazie, 52, 279 (1997). J. D. Sutherland and J. N. Whitﬁeld, Tetrahedron, 53, 1595 (1997). T. Itaya, T. Kanai, and T. Iida, Tetrahedron Lett., 38, 1979 (1997). O. Sˇimo, A. Ryba´r, and J. Alfo¨ldi, Collect. Czech. Chem.Commun., 63, 407 (1998). T. Itaya and Y. Hozumi, Chem. Pharm. Bull., 46, 1094 (1998). T. Itaya and T. Kanai, Chem. Pharm. Bull., 46, 1220 (1998). T. Ueda, R. Oh, Sh. Nagai, and Sakakibara, J. Heterocycl. Chem., 35, 135 (1998). M. G. Tutonda, R. W. Buckheit, Jr., V. K. Agrawal, and A. D. Broom, J. Med. Chem., 41, 4958 (1998). H. Maruenda, A. Chenna, L. K. Liem, and B. Singer, J. Org. Chem., 63, 4385 (1998). Childrens Medical Center Corp. (D.S. Kohane, Ch. B. Berde, G.R. Strichartz, and L.S. Langer), PCT Int. Appl. WO 98/51,290 (1998) [CA 130, 17253 (1999)]. J. Zeidler and B. Golankiewicz, Tetrahedron, 98, 2941 (1998). G. D. Ho, L. Silverman, A. Bercovici, C. Puchalski, D. Tulshian, Y. Xia, M. Czarniecki, M. Green, R. Cleven, H. Zhang, and A. Fawzi, Bioorg. Med. Chem. Lett., 9, 7 (1999). T. Itaya, T. Kanai, Sh.-i. Ohyama, Y. Shirasaki, N. Muramoto, and Y. Ono, Chem. Pharm. Bull., 47, 1464 (1999). M. Pawlowski, A. Drabczinska, J. Katlabi, M. Gorczyca, D. Malec, and J. Modzelewski, Eur. J. Med. Chem., 34, 1085 (1999). T. Nagamatsu, H. Yamasaki, T. Akiyama, S. Hara, K. Mori, and H. Kusakabe, Synthesis, 655 (1999). Z. Janeba, A. Holy´, and M. Masoji´dkova, Collect. Czech. Chem. Commun., 65, 1126 (2000). S. Rockitt, H. Duddeck, A. Drabczynsska, and K. Kiec-Kononowicz, Eur. J. Org. Chem., 3489 (2000). T. Goslinski, J. Zeidler, and B. Golankiewicz, Helv. Chim. Acta, 83, 373 (2000). S. Dey and P. Garner, J. Org. Chem., 65, 7697 (2000). E. V. Ratsino and S. I. Radchenko, Russ. J. Gen. Chem., 70, 160 (2000).

139

Refs.]

ANNULATED HETEROCYCLO-PURINES

01CPB188

H. Suzuki, H. Sawanishi, K. Yamamoto, K. Yokogawa, and K.-i. Miyamoto, Chem. Pharm. Bull., 49, 188 (2001). Ch. A. Z. M. Shaifullah and Sh. Yasuyuki, J. Heterocycl. Chem., 38, 743 (2001). B. Golankiewicz, T. Ostrowski, T. Goslinski, P. Januszczyk, J. Zeidler, D. Baranowski, and E. De Clercq, J. Med. Chem., 44, 4284 (2001). Kyowa Hakko Kogyo Co. (K. Ueno, A. Ogawa, Y. Ohta, Y. Nomoto, K. Takasaki, H. Kusaka, H. Yano, Ch. Suzuki, and S. Nakanishi), PCT Int. Appl. WO 01/47,931 (2001) [CA 135, 92647 (2001)]. T. Itaya, T. Kanai, and T. Iida, Chem. Pharm. Bull., 50, 530 (2002). Ch. E. Mu¨ller, M. Thorand, R. Qurishi, M. Diekmann, K. A. Jacobson, W. l. Padgett, and J. W. Daly, J. Med. Chem., 45, 3440 (2002). T. Okamura, Y. Kurogi, H. Nishikawa, H. Fujiwara, and Y. Nagao, J. Med. Chem., 45, 3703 (2002). T. Goslinski, B. Golankiewicz, E. De Clercq, and J. Balzarini, J. Med. Chem., 45, 5052 (2002). K. Li, W. Lin, K. H. Chong, B. M. Moore, and M. B. Doughty, Bioorganic & Medicinal Chem., 10, 507 (2002). The Regents of the University of California (S.B. Prusiner, F.E. Cohen, T.L. James, and K. Kaneko) US pat. 6,365,359 (2002).

01JHC743 01JMC4284 01MIP1

02CPB530 02JMC3440 02JMC3703 02JMC5052 02MI1 02USP1

Pyrazol-3-ones. Part II: Reactions of the Ring Atoms GEORGE VARVOUNIS, YIANNIS FIAMEGOS, and GEORGE PILIDIS University of Ioannina, Department of Chemistry, GR-451 10 Ioannina, Greece

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Acidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. By Reaction with Alkyl Halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Esters of Sulfonic and Carbonic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. With Trimethyloxonium Tetraﬂuoroborate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. With Diazomethane or Trimethylsilylazomethane . . . . . . . . . . . . . . . . . . . . . . . . . E. By the Mannich Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. By the Mitsunobu Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. By Miscellaneous Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Silylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. With Trimethylsilyl Chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. With Acid Chlorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. With Acid Anhydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. By Ketenylidenetriphenylphosphorane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. By the Vilsmeier Formylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Chlorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Bromination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Iodination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Nitrosation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Of 1,2-Dihydro-3H-Pyrazol-3-ones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Of 2,4-Dihydro-3H-Pyrazol-3-ones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. Nitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX. Diazonium Salt Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Diazopyrazol-3-ones, Formation, Coupling and Substitution . . . . . . . . . . . . . . . . . B. Coupling of Pyrazol-3-ones with Aryl Diazonium Salts . . . . . . . . . . . . . . . . . . . . . C. Coupling of Pyrazol-3-ones with 4-Diazo-3-oxo-3,4-Dihydronaphthalene-1-Sulfonic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X. Thiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI. Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. With Aryl Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. With Non-Typical ,-Unsaturated Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . C. With Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. With Nitroso Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. With Aryl Hydrazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. By Conjugate Addition-Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. By Addition-Elimination of Pyrazol-3-ones to Activated Double Bonds . . . . . . . . . H. By Nucleophiles onto 4-(Substituted Methylene)Pyrazol-3-ones . . . . . . . . . . . . . . . XII. Nucleophilic Addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Of Pyrazol-3-ones to Aromatic Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Of Pyrazol-3-ones to Imines and Iminium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . C. Michael Addition of Pyrazol-3-ones to ,-Unsaturated Compounds . . . . . . . . . . . D. By Addition-Elimination to ,-Unsaturated Compounds . . . . . . . . . . . . . . . . . . .

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

142 143 143 143 146 148 149 150 152 153 154 154 155 155 158 160 160 161 161 163 164 168 168 168 169 170 171 171 173

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

178 179 180 180 189 190 196 199 200 202 205 209 209 209 211 213

141 ADVANCES IN HETEROCYCLIC CHEMISTRY VOLUME 87 ISSN: 0065-2725 DOI: 10.1016/S0065-2725(04)87003-X

ß 2004 Elsevier Inc. All rights reserved

142

XIII.

XIV.

XV.

XVI. XVII. XVIII.

[Sec. I

GEORGE VARVOUNIS ET AL. E. Inter- and Intramolecular Addition of Nucleophiles to C-4 of Pyrazol-3-ones . . . . . . F. Michael Additions to Pyrazol-3-ones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. By Grignard Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H. By Secondary Amines or Thiophenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleophilic Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. By Pyrazol-3-ones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. On Mono- or Dihalogenopyrazol-3-ones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Nitroxide Formation via Pyrazol-3-one Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . B. Oxidation of Ring Carbon Atoms Followed by Addition . . . . . . . . . . . . . . . . . . . . C. Oxidative Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. With Ozone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. With Hydrogen Peroxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. With 4-Chlorobenzoic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. With Sodium Metaperiodate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H. With Lead(IV) Acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I. By Atmospheric Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Of 4,4-Dichloropyrazol-3-ones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Of the Carbonyl Group of Pyrazol-3-ones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Reduction of Exocyclic Double Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Radical Addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Ring Cleavage Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Ring Opening/Ring Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. In 18F Isotope Incorporation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

219 221 227 227 228 228 238 240 241 242 243 244 246 246 248 248 249 249 249 249 251 253 257 260 260 262 265 265 266

I. Introduction The present chapter is Part II of a three part series. In Part I (01AHC(80)73) the synthesis and applications of pyrazol-3-ones I and II are described. We now present a comprehensive review of the reactions of the ring atoms (i.e., carbon and nitrogen) of pyrazol-3-ones I and II, since January 1964. The literature covered has been searched up to August 2003. As in Part I, the present work is a follow up of the major work on pyrazolones published by Wiley and Wiley in the ‘‘Chemistry of Heterocyclic Compounds’’ series of monographs (64MI1). In Part III of this series the reactivity of ring substituents of pyrazol-3-ones I and II together with syntheses since 1999, will be presented.

O

N N

H

O

N N

H

H

(I)

(II)

1,2-dihydro-3H-pyrazol-3-one

2,4-dihydro-3H-pyrazol-3-one

Sec. III.A]

REACTIONS OF THE RING ATOMS

143

Following the trend of Part I, throughout Part II all pyrazolones have been named according to the IUPAC recommendations as pyrazol-3-ones and not as pyrazol-5ones. The IUPAC nomenclature numbers the ring clockwise whereas most organic chemists are used to an anti-clockwise numbering. Pyrazol-3-ones are known to be ambient compounds and depending on the solvent in which they are dissolved can exist in several tautomeric forms. Usually is less polar solvents such as chloroform pyrazol-3-one tautomers are dominant, whereas in more polar solvents such as dimethylsulfoxide 3-hydroxypyrazole tautomers are dominant. The most recent review article on this topic has been presented by Katritzky and co-workers (00AHC(76)157).

II. Acidity Pyrazol-3-ones are in general weak acids and can be titrated with strong bases. 2,4-Dihydro-3H-pyrazol-3-ones are stronger acids than 1,2-dihydro-3H-pyrazol-3ones, which are very weak. Titrating several pyrazole-3-ones with perchloric acid in acetic acid derived the most extensive data on basicity. The pKa values range from 1.7 to 3.7, except for 4,4-disubstituted and 4-halogen substituted 2,4-dihydro-3Hpyrazol-3-ones. The 4,4-disubstituted 2,4-dihydro-3H-pyrazol-3-ones are so weak that they are essentially neutral, while the halogenated compounds have pKa values of about 0.8 (64MI1). More recently, the acidity constants of several pyrazolones have been investigated both in the gas phase and aqueous solution by the AM1 method. The AM1/COSMO solvation method was employed in the case of aqueous solution calculations (99JMS(T)125).

III. Alkylation Pyrazol-3-ones are known to be ambident compounds that upon alkylation can give N-alkylated or O- and N-alkylated products, depending on the substrate, the alkylating agent and the reaction conditions.

A. BY REACTION

WITH

ALKYL HALIDES

By reaction with alkyl halides, esters of sulfonic and carbonic acids, trimethyloxonium tetraﬂuoroborate, diazo compounds, Mannich or Mitsunobu conditions or miscellaneous reagents. Methyl iodide is a versatile and eﬀective methylating reagent that can be used at room temperature, at moderate temperatures in a tightly closed vessel or at high temperatures in an autoclave. 2,4-Dihydropyrazol-3-one 1 was methylated at N1 with sodium hydride in boiling 1,4-dioxane followed by methyl iodide at room temperature. 1,2-Dihydropyrazol-3-one 2 was obtained in 59% yield (79AP853) (Scheme 1).

144

[Sec. III.A

GEORGE VARVOUNIS ET AL.

H

H

Me H

Me (i) NaH / 1,4-dioxane / ∆

H O

Me

Me N

O

(ii) MeI

N

H N N

Me

S

S

(1)

(2) Scheme 1

Methylation of N2 of pyrazol-3-one 3 required a weaker base but higher temperature. Thus 3 was heated under reﬂux in acetonitrile containing potassium carbonate and methyl iodide to give 2-methylpyrazol-3-one 4 in 30% yield (96JMC3920) (Scheme 2). Padwa and co-workers (83JOC1069) (Scheme 3) found that 4-diazopyrazol-3-one 5 was stable when methylated by methyl iodide in 95% ethanol containing sodium hydroxide to give 2-methyl-4-diazopyrazol-3-ones 6. Attempted methylation of 2-aminopyrazol-3-ones 7a,b with methyl iodide at room temperature proceeded slowly and it was necessary to operate at higher temperatures, which led to partial deamination of starting material. Thus at 100 C in a sealed tube the reaction gave a mixture of pyrazol-3-ones 8a,b, 9a,b and 10a,b, respectively (81JHC957) (Scheme 4). MeS

MeS

CF3 H N

O

O

N

(3)

(4) Scheme 2

N

N

N

Ph

Ph

(i) 95% EtOH / NaOH O

N N

N N Me

H

N

CF3

H

MeI / K2CO3 / MeCN / ∆

(ii) MeI

O

N N

H

Me

(5)

(6) Scheme 3

Sec. III.A]

145

REACTIONS OF THE RING ATOMS

R1

R1

R2

R2

R1

R2

R1

R2

o

O

N N

MeI / EtOH / 100 C H

N

O

sealed tube

N

+

N

O

N

NH2

NH2 (7)

Me +

O

NH2

(8)

N N

Me

H

(9)

(10)

(a) R1 = Ph, R2 = Me, (b) R1 = Me, R2 = Ph

Scheme 4

Pyrazol-3-one 11 was alkylated with (2-bromoethyl)benzene at 140 C or with n-hexyl, n-decyl, n-dodecyl, or benzyl bromides (01BSCQ459) in reﬂuxing 1,4-dioxane to aﬀord the corresponding 2-alkylpyrazol-3-ones 12 and 13a–d in yields of 45–75% (65ZOR133) (Scheme 5). The structure of compounds 13a–d in CDCl3 was conﬁrmed by NMR spectroscopy. In particular a signal around 172 ppm in the 13C NMR spectra is assigned to the carbonyl carbon, while DEPT 145 spectra and 13C–1H correlation spectra further conﬁrm the C4 methylene entity. Alkylation at N2 of pyrazol-3-one 14 with n-butyl- or n-hexyl bromide took place also by heating in 1,4-dioxane to give 2-alkylpyrazol-3-ones 15a,b, respectively. It was conﬁrmed by NMR studies that, in CDCl3 the pyrazol-3-one 15a,b tautomers are dominant, whereas in DMSO-d6 the pyrazol-5-ol 16a,b tautomers are dominant (99BSCQ367) (Scheme 5). Benzylation of 1,2-dihydropyrazol-3-ones 17a,b with benzyl bromide in reﬂuxing tetrahydrofuran followed by treatment with aqueous sodium hydroxide aﬀorded 1-benzylpyrazol-3-ones 18a,b (81JHC957) (Scheme 6). But when Begtrup (88BSB573) (Scheme 7) treated the pyrazol-3-one 19/pyrazole 20 tautomeric mixture with 4-methoxybenzyl chloride he obtained 5% of Oalkylated pyrazole derivative 21 and 70% of 1-(4-methoxybenzyl)pyrazol-3-one 22. An indirect way of introducing a substituted aminohydroxypropyl group at position 1 of 1,2-dihydropyrazol-3-ones was devised by Holzer, Ecker and co-workers (98JMC4001) (Scheme 8). The method consists of reacting the sodium salt of 4-acylpyrazol-3-ones 23a–l with excess epichlorohydrin and successively Me

Me

Me Ph(CH2)2Br O

N N

140oC

RBr O

(CH2)2Ph (12)

N N

1,4-dioxane / ∆

O

N N

H

R

(11)

(13) Ph

Ph

Ph

RBr O

N N

1,4-dioxane / ∆

O

N N

HO

N N

H

R

R

(14)

(15)

(16)

Scheme 5

(a) R = n-C6H13 (b) R = n-C10H21 (c) R = n-C12H25 (d) R = PhCH2

(a) R = n-C4H9 (b) R = n-C6H13

146

[Sec. III.B

GEORGE VARVOUNIS ET AL.

R

R (i) PhCH 2Br / THF /∆ N

O

N

H

O

(ii) 2N NaOH

N

H

H

(17)

(18)

(a) R = Me (b) R = Ph

CH2Ph

N

Scheme 6

O

MeO

N N Me

(21) 4-MeOC6H5CH2Cl N

O

HO

N

+

N N

Me

Me

(19)

(20)

NaHCO3 / MeOH

OMe

N

O

N Me (22)

Scheme 7 R2

R2

R2 Me

O

Me

O

O

(i) NaH / MeOH O

N N R1 (23)

H (ii)

O

O o Cl / 100 C

N N

Me HO

R R NH /∆ O (25) 2 3

O

N

R3 N R4

N

R1

R1

(24)

(26)

(a) R1= Me, R2= Ph, R3= R4 = i-Pr, (b) R1= R2= Ph, R3= H, R4= n-Pr, (c) R1= R2= Ph, R3= H, R4= i-Pr, (d) R1= R2= Ph, R3= R4 = i-Pr, (e) R1= R2= Ph, R3= H, R4= t-Bu, (f) R1= Ph, R2= 2-thienyl, R3= H, R4= n-Pr, (g) R1= Ph, R2= 2-thienyl, R3= H, R4= i-Pr, (h) R1= Ph, R2= 2-thienyl, R3= H, R4= t-Pr, (i) R1= Ph, R2= (CH2)2Ph, R3= H, R4= n-Pr, (j) R1= Ph, R2= (CH2)2Ph, R3= H, R4= i-Pr, (k) R1= Ph, R2= (CH2)2Ph, R3= H, R4= n-Bu or (l) R1= Ph, R2= (CH2)2Ph, R3= H, R4= t-Bu,

Scheme 8

treating the intermediate epoxides 24a–l with excess appropriate amines 25a–l. The 1-substituted 4-acylpyrazol-3-ones 26a–l were obtained in 14–52% yield. Heating 5-methylpyrazol-3-one 11 with 1-adamantyl bromide 27 at 150 C aﬀorded 2-adamantylpyrazol-3-one 28, whereas at 200 C 4-adamantylpyrazol-3-one 29 was obtained (99BSB735) (Scheme 9).

B. ESTERS OF SULFONIC AND CARBONIC ACIDS A most frequently used method for the methylation of pyrazol-3-ones is stirring at room temperature or heating in an alkaline solution with dimethyl sulfate. Usually a

Sec. III.B]

Br

Br

Me

Me

Me (27)

O

147

REACTIONS OF THE RING ATOMS

N

150oC

N

(27) O

N

N

O

200oC

N

N

H

H

(11)

(29)

(28)

Scheme 9

10% aqueous solution of sodium hydroxide is used. Less frequent is the use of neat dimethyl sulfate at relatively high temperatures. 2-(2-Thienyl)pyrazol-3-one 30 was heated at 150 C in dimethyl sulfate to give the 1-methyl derivative 31 in 60% yield (79AP853) (Scheme 10). Pyrazol-3-ones 32 and 35 were treated with dimethyl sulfate in DMF containing sodium methoxide to aﬀord a mixture of 3-methoxypyrazole 33 and 1-methylpyrazol-3-one 34, or 3-methoxypyrazole 36 and 2-methylpyrazol-3-one 37, respectively (69CPB1467) (Scheme 11). Me

Me o

(MeO)2SO2 / 150 C O

N N

N

O

H

N

Me

S

S (31)

(30) Scheme 10 Me

Me (MeO)2SO2 O

N

H

N

NaOMe / DMF

MeO

N

Me +

N

O

R

R

N N

Me

R N

R= (33)

(32)

(34)

R1

N R2

Me

Me (MeO)2SO2 O

N N

R

NaOMe / DMF

MeO

N N

R

+

O

N N Me

H (35)

Me

(36)

Scheme 11

(37)

R

R1 = R2 = H, Me or MeO

148

[Sec. III.C

GEORGE VARVOUNIS ET AL.

The alkylation of 2-arylpyrazol-3-ones 38a–d or 40 required heating in 10% aqueous sodium hydroxide containing dimethyl sulfate to aﬀord 1-methyl derivatives 39a–d or 1-methyl derivative 41 in excellent yields (75CJC3637, 85JIC54, 89AP351) (Scheme 12). Dimethyl carbonate proved to be an eﬀective methylating agent when pyrazol-3one 42 was heated at 180 C in neat reagent to give pyrazol-3-one 43 in 73% yield and 3-methoxypyrazole 44 in 21% yield. The products were separated by fractional distillation (87CZ83) (Scheme 13). R1

R1

R2

R2

(MeO)2SO2 N

O

N

N

O

NaOH / H2O

N

R

R

(38)

(39)

Me

(a) R = Ph, R1 = 2-aminobenzyl, R2 = Me (b) R = Ph, R1 = 2-aminobenzyl, R2 = Ph (c) R = Ph, R1 = H, R2 = Me, (d) R = 4-MeOC4H6, R1 = H, R2 = Me Ph

Ph

N H

N H

N

Ph

N

Ph

(MeO)2SO2 O

N N

O

NaOH / H2O

N N Me

H (40)

(41) Scheme 12

Me

Me (MeO)2CO

O

N N

H

180oC

O

N N

Me

Me +

MeO

N N

Ph

Ph

Ph

(42)

(43)

(44)

Scheme 13

C. WITH TRIMETHYLOXONIUM TETRAFLUOROBORATE Begtrup (88BSB573) (Scheme 14) methylated the pyrazol-3-one 19/pyrazole 20 tautomeric mixture with trimethyloxonium tetraﬂuoroborate and obtained almost

Sec. III.D]

149

REACTIONS OF THE RING ATOMS Me3OBF4 / NaHCO3 N

O

N

HO

N

N

O

MeNO2 / 24 h

N

N

+

Me

N

MeO

N

Me

Me

Me

Me

(19)

(20)

(45)

(46)

Scheme 14

exclusively the 1-methylpyrazol-3-one 45 in 71% yield and only a trace of isomeric 3-methoxypyrazole 46.

D. WITH DIAZOMETHANE OR TRIMETHYLSILYLAZOMETHANE Adembri et al. (72JHC1219) (Scheme 15) demonstrated the existence of a tautomeric mixture of 2-aminopyrazol-3-ones 47a–c/2-aminopyrazoles 48a–c in diethyl ether by methylation with diazomethane. The products were 2-amino-1methylpyrazol-3-one 49a–c and 2-amino-3-methoxypyrazole 50a–c, respectively. Several years later other workers used the same method to conﬁrm that pyrazol3,5-diones 51a,b/5-hydroxypyrazol-3-ones 52a,b exist as tautomeric mixtures in solution. The reactions with diazomethane took place in a mixture of diethyl ether and methanol and aﬀorded a mixture of the respective pyrazol-3,5-diones 53a,b and 5-methoxypyrazol-3-ones 54a,b. The suitability of these structurally ﬁxed methyl derivatives as model compounds in the study of the tautomeric structures by NMR spectroscopy was investigated (80CB3910) (Scheme 16). Diazomethane reacted nucleophilically at the ,-unsaturated carbonyl entity of 5,50 -dimethyl-2,20 -diphenyl-4,40 -bipyrazole-3,30 (2H,20 H)-dione 55 to give, via intermediate 56, the unstable spiro-cyclopropyldipyrazolone derivative 57 in 47% yield. Upon heating in ethanol 57 isomerized to the 4-[(pyrazol-5-yl)methylene]pyrazol-3one 58. The structure of 58 was assigned unambiguously by X-ray crystallography (89JPR584) (Scheme 17). R1

R2

R1

R1

R2

R2

R1

R2

CH2N2 N

O

HO

N NH2

N

Et2O

N

N

O

N

NH2

+

N

MeO

N

NH2

(48)

(47)

Me

NH2

(49)

(50)

(a) R1 = H, R2 = Ph, (b) R1 = Me, R2 = Ph, (c) R1 = Ph, R2 = Me

Scheme 15 Et

Et

O

Et O

N N

H

O

Et

OH

Et

CH2N2 N N

Et2O / MeOH

Et

O

Et O

N N

Me

+

O

N N

R

R

R

R

(51)

(52)

(53)

(54)

(a) R = H, (b) R = Me

Scheme 16

OMe

Et

150

[Sec. III.E

GEORGE VARVOUNIS ET AL. Ph N

O

N

N

Me Me N N

Ph

CH2 Me

N

CH2N2 O

O H

O N2

Ph

Me

N N

O Me

Et2O

H N

N

O Me

N

N

Ph

Ph

Ph

(56)

(55)

(57) EtOH / ∆

Ph N N Me

Me O H O

N N Ph (58)

Scheme 17

R

R Me

O

R Me

O

Me

O

TMSCHN2 O

N N

H

HBF4

MeO

N N

+

O

N N

Ph

Ph

Ph

(59)

(60)

(61)

Me

(a) R = Me (b) R = Ph (c) R = 2-thienyl (d) R = (CH2)2Ph (e) R = CH=CHPh

Scheme 18

In an eﬀort to obtain selectively 2-methylpyrazoles by methylating 1-arylpyrazol3-ones, Holzer and Plagens (96SP455) (Scheme 18) investigated the use of (trimethylsilyl)diazomethane. Thus pyrazol-3-ones 59a–e were reacted with (trimethylsilyl)diazomethane and 10% aqueous tetraﬂuoroboric acid in dichloromethane to aﬀord mixtures containing 5-methoxypyrazoles 60a–e and 5-methylpyrazol-3-ones 61a–e, in yields ranging from 8 to 58% and 11 to 45%, respectively.

E. BY THE MANNICH REACTION Bhargava et al. (65BCJ912) (Scheme 19) prepared 1-[4-p-tolylthiazol-2-ylaminomethyl]pyrazol-3-one 64 by heating a mixture of pyrazol-3-one 62, 4-p-tolylthiazol-2ylamine 63 and paraformaldehyde in ethanolic hydrogen chloride and then adding ammonia to liberate the free base.

Sec. III.E]

151

REACTIONS OF THE RING ATOMS Me

Me

N S Me

O

Me

N N +

N

EtOH / HCl / ∆

NH2

S

N

H

(CH2O)n

N

O

N

Ph

Ph

(62)

(64)

(63)

Scheme 19

H

N

N

(a) R = Me (b) R = Et (c) R = Ph (d) R = 4-MeC6H4 (e) R = 4-ClC6H4 (f) R = 4-MeOC6H4

N RNH2 / (CH2O)n O

N

R

EtOH / HCl / ∆

N

N

O

N

Ph

Ph

(65)

(66)

Scheme 20

Sammour (72JPR612) (Scheme 20) reported that the Mannich reaction of 5-pyridin-3-ylpyrazol-3-one 65 with primary amines such as the methylamine, ethylamine, aniline, 4-toluidine, 4-chloroaniline or 4-methoxyaniline and paraformaldehyde, gave the corresponding 4-[(alkyl or arylamino)methyl]-5-pyridin-3ylpyrazol-3-one 66 in moderate yields. Mustafa et al. (64T531) (Scheme 21) found that pyrazol-3-one 67 condensed readily with formaldehyde in the presence of piperidine or morpholine to give the corresponding Mannich bases 68a,b. However, when primary amines, namely ethylamine, aniline, 2- or 4-toluidine were used instead, 4-({[(3-oxopyrazol-4-yl)methyl]amino}methyl)-pyrazol-3-ones 69a–d were obtained. More recently formaldehyde or paraformaldehyde in the classical Mannich reaction has been replaced by methylene chloride. Reaction of pyrazol-3-one (antipyrine) 70 with dimethylamine or piperidine in methylenene chloride at 40 C or with morpholine in a 1:1 v/v methylene chloride/acetonitrile mixture at 50 C,

Me

Me

R

35% HCHO / RNH2 O

N N

Ph

/ MeOH

O

N N

H

H

(68)

(67)

35% HCHO piperidine or morpholine

Ph

MeOH

Me R Ph

N H

Me

N N O O

N N

Ph

H (69)

(a) R = Et, (b) R = P h, (c ) R = 2-MeC6H4 (d) R = 4-Me C6H4

(a) R = N(CH2)5, (b ) R = N(CH2CH2)2O

Scheme 21

152

[Sec. III.F

GEORGE VARVOUNIS ET AL. R Me

Me Amines / CH2Cl2 O

N N

Me

or Amines / CH2Cl2 / MeCN

Ph

O

N N

(a) R = N(Et) 2 (b) R = N(CH2)5 (c) R = N(CH2CH2)2O

Me

Ph

(70)

(71)

Scheme 22

Me

Me

PhO2S (CH2O)n / PhSO2Na (72a)

O

N N

O

DMF / AcOH

N

Ph

Ph

(70)

(73) Me

I(Me)3N O

Me

N

N Me

N Me

Me

ArO2S ArSO2Na (72) / DMF / ∆ O

Ph

N N

Me

Ph

(74)

(75) (a) Ar = Ph, (b) Ar = 4-MeC6H4, (c) Ar = 4-ClC6H4 Scheme 23

aﬀorded the corresponding N,N-dialkylaminomethyl derivatives 71a–c in 78, 90 and 63% yield, respectively (93SC817) (Scheme 22). 4-(Arylsulfonyl)pyrazol-3-ones can be synthesized directly from pyrazol-3-ones or indirectly via iodomethane salts of 4-(dimethylamino)methylpyrazol-3-ones. Hellmann and Mu¨ller (65CB638) (Scheme 23) synthesized 4-(phenylsulfonyl)methylpyrazol-3-one 73 by treating pyrazol-3-one 70 with paraformaldehyde and sodium benzenesulﬁnate 72a in DMF with a catalytic amount of acetic acid. Eight years later Messinger (73AP603) reported that the reaction of N,N,N-trimethyl(3-oxopyrazol-3yl)methanaminium iodide 74 with sodium sulﬁnates 72a–c in DMF aﬀorded the corresponding 4-(arylsulfonyl)methylpyrazol-3-ones 75a–c in 82, 67 and 74% yield, respectively.

F. BY THE MITSUNOBU REACTION Holzer and Plagens (97H309) (Scheme 24) studied the alkylation of pyrazol-3-ones 62 and of the tautomeric pyrazol-3-one 78a–d/pyrazol-5-ol 79a–d mixtures by applying the Mitsunobu reaction [triphenylphosphine, diethyl azodicarboxylate (DEAD), alcohol, solvent]. The reactions were performed in various solvents. Using methanol as the alkylating agent the reaction of 62 in dichloromethane or THF,

Sec. III.G]

153

REACTIONS OF THE RING ATOMS Me

Me

Me Ph3P / DEAD N

O

N

O

ROH / solvent

N

N

+

R

N

RO

N

Ph

Ph

Ph

(62)

(76)

(77)

O

O R1

N

O

N

R1

Me

N

N

O

ROH / solvent

R1

Me

Ph3P / DEAD

N

HO

H

O

O

R1

Me

N

R

+

RO

Me N N

Ph

Ph

Ph

Ph

(78)

(79)

(80)

(81)

(a) R = Me, R1 = Ph, (b) R = Me, R1 = 2-thienyl, (c) R = Me, R1 = Bz, (d) R = Me, R1 = Ph, (e) R = Me2CH, R1 = Ph H H H (f) R = Bz, R1 = Ph, (g) R = H

O

H , R1 = Ph

Scheme 24

78a/79a in acetonitrile, chloroform, dichloromethane or THF, 78b/79b in dichloromethane or THF and 78c/79c in benzene, dichloromethane or THF, gave mixtures of the corresponding pyrazol-3-one 76a/pyrazole 77a and pyrazol-3-ones 80a–c/pyrazoles 81a–c, in ratios ranging from 1:1.7 to 1:10.6, respectively. On the other hand the reaction under Mitsunobu conditions of pyrazol-3-one 62 with methanol in benzene, of 62 with propan-2-ol in benzene or THF, 78a/79a with propan-2-ol, benzyl alcohol or 2,3-epoxypropanol in THF or 78b/79b with methanol in benzene, aﬀorded the corresponding O-alkylated pyrazoles 77a, 77e and 81e, f, g, and b as single products.

G. BY MISCELLANEOUS REAGENTS Methylation of pyrazol-3-ones 82a–d with methyl p-toluene sulfonate was possible at 150 C and gave 1-methylpyrazol-3-ones 83a–d in excellent yields (01JHC1065) (Scheme 25). Alkylation of pyrazol-3-one 70 with 4-[morpholin-4-yl-(4-nitrophenyl)methyl]morpholine 84 was performed at room temperature since at higher temperatures polymerization occurred. However the reaction was extremely slow. It took O R1

Me

R1

S OMe O

O

N N

150oC

O

N N

R

R

(82)

(83)

Scheme 25

Me

(a) R = R1 = Ph (b) R = Ph, R1 = 4-ClC6H4 (c) R = Ph, R1 = 4-NO2C6H4 (d) R = 4-NO 2C6H4, R1 = Ph

154

[Sec. IV.A

GEORGE VARVOUNIS ET AL. O2N

O

H

Me O

N N

Me

+

O2N

N

H2O / HCl

C H N

EtOH

Me

N O

O

Ph

N N

Me

Ph O (85)

(84)

(70)

Scheme 26

CO2Me

CO2Me

CO2Me

MeI, (MeO)2SO2, or CH2N2 O

N N

H

O

N N

Me

+

MeO

N N

N

N

N

N

N

N

Cl

Cl

Cl

(86)

(87)

(88)

Scheme 27

6 months for an ethanolic solution of 70 and 84 containing aqueous hydrochloric acid to give 4-[morpholin-4-yl-(4-nitrophenyl)methyl]pyrazol-3-one 85 in 25% yield (64JPR216) (Scheme 26). Szilagyi et al. (83H765) (Scheme 27) compared the methylation of pyrazol-3-one 86 both on N1 and the carbonyl oxygen of the ring using methyl iodide, dimethyl sulfate, or diazomethane. Thus with methyl iodide or dimethyl sulfate the results were similar, 1-methylpyrazol-3-one 87 and methyl 5-methoxypyrazole-3-carboxylate 88 were obtained in a ratio of about 1:5, whereas with diazomethane, compounds 87 and 88 were obtained in a ratio of 5:1. Abarbi et al. (00JOC4618) reacted 3-bromopropene and 2-bromomethylacrylic acid ethyl ester with the Grignard reagent derived from 1,5-dimethyl-3H-5-iodo-2phenylpyrazol-3-one and diisopropyl magnesium, and obtained the corresponding 4-allyl-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one and 2-(1,5-dimethyl-3-oxo2-phenyl-2,3-dihydro-1H-pyrazol-4-ylmethyl)acrylic acid ethyl ester, respectively.

IV. Silylation A. WITH TRIMETHYLSILYL CHLORIDE Trimethylsilylation of 5-methoxypyrazol-3-one 89a or 5-trimethyl-silyloxypyrazol3-one 89b with trimethylsilylchloride in benzene containing triethylamine aﬀorded 5-methoxy-2-trimethylsilyloxypyrazol-3-one 90a and 2,5-di(trimethylsilyloxy)pyrazol-3-one 90b, respectively (80CB3915) (Scheme 28).

Sec. V.A]

155

REACTIONS OF THE RING ATOMS

Et

Et

OR

Et (Me) 3SiCl O

N N

Et 3N / C 6H 6 / ∆

OR

Et O

H

N N Si(Me)3

(89)

(90) (a) R = Me , (b) R = Si (Me)3 Scheme 28

The lactam-lactim structure of these compounds was established not only by conventional 1H and 13C NMR spectroscopy but also by 29Si NMR spectroscopy.

V. Acylation 4-Acylpyrazol-3-ones are the focus of research on potential antifungal agrochemicals and their metal extracting properties.

A. WITH ACID CHLORIDES The outcome of acylation of the ring atoms of pyrazol-3-ones with acid chlorides depends on the type of substitution on the pyrazol-3-one ring. Both C- and Nacylation are possible. With 2-aryl-4-(or 5)-substituted pyrazol-3-ones 91a–c and 93a–c reaction with acid chlorides occurs in 1,4-dioxane with calcium hydroxide. Although C4-acylation occurs in both reactions, the former gives the more stable intramolecularly hydrogen bonded pyrazoles 92a–c when reacted with benzoyl chloride, t-butylacetyl chloride or diphenylacetyl chloride (99POL3041), while the latter gives 4-acylpyrazol-3-ones 94a–c, when reacted with acetyl chloride, triﬂuoroacetyl chloride or benzoyl chloride (99JOM344) (Scheme 29). Acylation at C4 of a 1,2-dihydropyrazol-3-one was also achieved using a 4iodo-1,2,5-trisubstituted derivative on reaction with Grignard reagents. Thus, 4-iodopyrazol-3-one 95 underwent a smooth iodine-magnesium exchange by reaction with diisopropyl magnesium in dichloromethane at 25 C. The resulting 4-diisopropylmagnesium pyrazol-3-one was trapped by transmetallation with copper(I) cyanide lithium chloride complex, leading presumably to the corresponding copper species, followed by treatment with benzoyl chloride to aﬀord the 4-benzoylderivatives 96 (00JOC4618) (Scheme 30). Three examples of N1 acylation of a 1,2-dihydropyrazol-3-one have been reported. Benzoylation of 2-phthalazin-1-ylpyrazol-3-one 97a was accomplished by heating in pyridine containing benzoyl chloride to give 1-benzoylpyrazol-3-one 98a in 55% yield (81PHA471). On the other hand acetylation of pyrazol-3-ones 97b,c occurred by heating in acetic anhydride to aﬀord 1-acetylpyrazol-3-ones 98b,c in excellent yields (91JCS(CC)314, 96T1579) (Scheme 31).

156

[Sec. V.A

GEORGE VARVOUNIS ET AL.

R Me RCOCl / Ca(OH)2 N

O

H

N

Me

O H

1,4-dioxane / ∆

N

Ph

Ph

(91)

(92) R

Me RCOCl / Ca(OH)2

N

O

H

N

1,4-dioxane / ∆

(a) R = Ph (b) R = CH2C(Me)3 (c) R = CH(Ph)2

N

O

H

O O

Me (a) R = Me (b) R = CF3 (c) R = Ph

N N

CF3

CF3

(93)

(94) Scheme 29

O I

Me

Me

Ph o

(i) i-Pr2Mg, CH2Cl2 / -25 C N

O

Me

N

N

O

(ii) CuCN.2LiCl, PhCOCl

N

Ph

Ph

(95)

(96)

Me

Scheme 30

R3

R4

R3

R4

R1 COCl / pyridine / ∆ O

N N

H

O

R2

R1

R2

(97) 1

N N

(98) 2

3

4

1

(a) R = PhCO, R = phthalazin-1-yl, R = Ph, R = H (b) R = MeCO, R2 = 4-NO2 C6 H5, 4 1 2 3 4 R3 = CH2 C(H)(NHR)CO 2Bn, R = Me, (c) R = R = MeCO, R = PhCOS, R = H Scheme 31

Benzoylation of 2,4-dihydro-2,5-disubstituted pyrazol-3-ones at C4 has been performed in the presence of a Lewis acid or a base. Pyrazol-3-one 99a was treated with anhydrous aluminium chloride in carbon disulﬁde and pyrazol-3-one 99b was treated with calcium hydroxide in 1,4-dioxane. Addition of benzoyl chloride followed by dilute hydrochloric acid aﬀorded the corresponding 4-benzoylpyrazol-3-ones

Sec. V.A]

157

REACTIONS OF THE RING ATOMS O R1

O

(i) AlCl3 / CS2 or Ca(OH)2 / 1,4-dioxane

N R

(b) R = Me, R1 = i-Pr

N R (100)

(99) H

O H

Ph

N

Ph O

O

(a) R = R1 = Ph

N

O

(ii) PhCOCl (iii) 2N HCl

N

R1

Ph

Ph

N

(i) Ca(OH)2 / 1,4-dioxane

N

o

N

(ii) PhCOCl / 50 C

Ph

(iii) 2N HCl

O

N

N H

Ph

(101)

O

O O

(102)

Scheme 32

100a,b in 60 and 63% yield, respectively (73IJC1, 91JHC1837) (Scheme 32). Similarly, benzoylation of 2,4-dihydropyrazol-3-one 101 in the presence of calcium hydroxide gave 1,2-dihydro-4-benzoyl-5-benzoylaminopyrazol-3-one 102. An X-ray crystal diﬀraction study of this compound shows that it forms two intramolecular bonds, between the NH of the benzoylamino group and the carbonyl oxygen of the benzoyl group, and between the carbonyl oxygen of the benzoylamino group and the ring NH. Compound 102 is also stabilized by an intramolecular hydrogen bond between the ring NH and the oxygen of a 1,4-dioxane solvent molecule (02JMS175) (Scheme 32). The reaction of pyrazol-3-one 62 and phthaloyl chloride in the presence of calcium hydroxide did not give a product of acyl substitution by two pyrazol-3-one 62 molecules on one phthaloyl chloride molecule. Instead, the reaction proceeded most probably to give the 2-[(5-oxopyrazol-4-yl)-carbonyl]benzoate intermediate 103. Nucleophilic addition of a second molecule of 62 gave the alcohol 104. Addition of dilute hydrochloric acid causes neutralization, tautomerism and dehydration to aﬀord [(pyrazol-4-yl)(5-oxopyrazol-4-ylidene)methyl]benzoic acid 105, in 90% yield (01JCS(D)1790) (Scheme 33). Compound 105 was used as a polydentate ligand and reacted with cyanotin(IV) acceptors to give metal complexes. Organotin(IV) compounds such as these have previously been used in organic synthesis and catalysis (synthesis of polyesters, polyurethanes, cross-linking of silicones, esteriﬁcation, polymerization etc.) and also as PVC heat stabilizers, as a component of aquatic antifouling paints, wood preservatives and biocides. The acylation of pyrazol-3-ones 106a,b with ethyl chloroformate or n-butyl chloroformate in the presence of calcium hydroxide gave the more stable ethyl or nbutyl-5-hydroxypyrazole-4-carboxylates 107a,b and not the expected pyrazol-3-one tautomers 108a,b. On the other hand, pyrazol-3-ones 106c–f, containing an n-octyl or n-dodecyl side chain on N2 of the pyrazol-3-one, reacted with ethyl chloroformate and n-butyl chloroformate under similar conditions to aﬀord surprisingly, ethyl or n-butylpyrazol-5-ylcarbonates 109c–f in moderate yields (95JHC1377) (Scheme 34).

158

[Sec. V.B

GEORGE VARVOUNIS ET AL.

O2C

COCl N

O

Me

O

Me Ca(OH)2 / 1,4-dioxane / ∆

+

O

N

COCl

N N

Ph

Ph

(62)

(103)

(62)

O2C Me H N

Me CO2H

N

Me

N Ph

N

2N HCl

OH

Ph

N

O

O O

N

OH Me

H N N Ph

Ph (105)

(104)

Scheme 33

O

O R1O

Me (i) Ca(OH)2 / 1,4-dioxane

N

O

HO

(ii) R1OCOCl (iii) 2N HCl

N R

1

(106)

(a) R = Ph, R = Et

R1O

Me N N

+

O

Me N N

R

R

(107)

(108)

(b) R = Ph, R1 = (CH2)3Me (i) Ca(OH)2 / 1,4-dioxane (ii) R1OCOCl (iii) 2N HCl Me

O R O

O

(c) R = (CH2)7Me, R1 = Et

N

(d) R = (CH2)7Me, R1 = (CH2)3Me (e) R = (CH2)11Me, R1 = Et

R

(f) R = (CH2)11Me, R1 = (CH2)3Me

1

N

(109)

Scheme 34

B. WITH ACID ANHYDRIDES 1,2-Dihydropyrazol-3-one 110 was triﬂuoroacetylated at C4 and converted into 2,4-dihydropyrazol-3-one 111 by heating in pyridine containing triﬂuoroacetic anhydride (99JOM344) (Scheme 35).

Sec. V.B]

159

REACTIONS OF THE RING ATOMS

O Me (CF3CO)2O / pyridine /∆

N

O

Me

F3C

N

N

O

H

N

CF3

CF3

(110)

(111) Scheme 35

Depending on the substitution of a 2,4-dihydropyrazol-3-one, acylation with acetic anhydride can occur at N2 or C4 (Scheme 36). When 4,4,5-trimethylpyrazol-3one 112 was heated with acetic anhydride under reﬂux the 2-acetyl derivative 113 was obtained in 87% yield (69JOC1717). Surprisingly no acetylation occurred on N2 of 5-methylpyrazol-3-one 114 when heated with acetic anhydride in PPA at 140 C. Instead, acetylation occurred at C4 to give the 4-acetyl derivative 115 in only 35% yield (74CPB207) (Scheme 36). Pyrazol-3-ones 116a–d are converted into the more stable O-alkyl-5-hydroxypyrazole-4-carbothioates 117a–d instead of their tautomeric pyrazol-3-ones 118a–d by treatment with calcium hydroxide and then with O,O-diethyl- or O,O-di-nbutyltrithiotricarbonate in 1,4-dioxane. The yield of the products is 38, 22, 20 and 16% respectively (95JHC1377) (Scheme 37).

Me

N

O

Me

Me

Me

Me

Me

(MeCO)2O / ∆

N

O

N H

N O

Me

(112)

(113)

Me

Me

O Me

o

(MeCO)2O / PPA / 140 C O

N

O

N

N N

H

H

(114)

(115) Scheme 36

160

[Sec. V.D

GEORGE VARVOUNIS ET AL. S

O

S

R1O

Me (i) Ca(OH)2 / 1,4-dioxane

N

HO

(ii) (R1OCS)2S

N

R1O

Me N

Me N

O

N

N

R

R

R

(116)

(117)

(118)

(a) R = Ph, R1 = Et, (b) R = Ph, R1 = (CH2)3Me, (c) R = (CH2)7Me, R1 = Et, (d) R = (CH2)9Me, R1 = (CH2)3Me

Scheme 37

C. BY KETENYLIDENETRIPHENYLPHOSPHORANE Pyrazol-3-ones 97a were heated in tetrahydrofuran with ketenylidenetriphenylphosphorane to aﬀord the corresponding pyrazole-3-one phosphonium salts 119b–f in 44–87% yield. An X-ray single crystal analysis of 119f is presented (00JCS(P1)1723) (Scheme 38). (Ph)3P R3

R4

R4

O Ph3P=C=C=O / THF / ∆

O

N N

H

O

N N

R2

R2

(97)

(119)

(a) R3 = H, R2 = R4 = Me , R2 = H, R4 = Ph, R2 = Me, R4 = Ph, R2 = R4 = Ph or R2 = Me, R4 = CH2CO2Me, (b) R2 = R4 = Me, (c) R2 = H, R4 = Ph, (d) R2 = Me, R4 = Ph, (e) R2 = R4 = Ph, (f) R2 = Me, R4 = CH2CO2Me Scheme 38

D. BY

THE

VILSMEIER FORMYLATION

Seshardi and co-workers (69IJC1006) (Scheme 39) reacted pyrazol-3-ones 120a,b under Vilsmeier conditions in order to study the reactivity of the 5-methyl group, the lactam moiety and the methylene function. It turned out that heating pyrazole3-ones 120a,b with the Vilsmeier complex using DMF as solvent aﬀorded 3chloropyrazole-4-carbaldehydes 121a,b. When pyrazole-3-ones 120b was submitted to the Vilsmeier complex using THF as solvent and the reaction mixture was heated at reﬂux, the 4-dimethylaminoformylidenepyrazol-3-one 123 was obtained in excellent yield. Faster neutralization of the imino nitrogen atom after loss of a proton from intermediate 122 explains why hydrolysis of the iminium ion to aldehyde did not occur.

Sec. VI.A]

161

REACTIONS OF THE RING ATOMS Me

OHC

Me

(i) POCl / DMF /∆ N

O

N

Cl

(ii) H2O / K2CO3

N N

R

R

(120)

(121) (a) R = H, (b) R = NO2

Me (i) POCl3 / DMF / THF /∆ (120b) (ii) H2O / K2CO3

Me N H O

H

H

Me N

N

NO2 (122)

Me

Me2N O

N N

NO2 (123)

Scheme 39

Six years later Wrzeciono and Szostak-Rzepiak (75PHA582) (Scheme 40) repeated the Vilsmeier formylation of compound 120a but neutralized the reaction mixture with a solution of ammonium hydroxide instead of potassium carbonate. They obtained a mixture of products consisting of pyrazole-3-ones 124, 125, 126 and 127/128 in 48, 2, 4 and 5% yield, respectively. Rockley and Summers (81AJC1117) (Scheme 41) presented the only example of a 1,2-dihydropyrazol-3-one that underwent the Vilsmeier reaction. Thus treating pyrazole-3-one 129 with phosphoryl chloride and DMF in chloroform and toluene and heating at 60–65 C aﬀorded 4-formylpyrazol-3-one 130.

VI. Halogenation By far the most frequently encountered reactions of pyrazol-3-ones with halogens are chlorination and bromination. Only one reference refers to the introduction of a ﬂuorine atom whereas two references describe iodinated products.

A. FLUORINATION Diksic and DiRaddo (84TL4885) (Scheme 42) described the preparation of 4-ﬂuoropyrazol-3-one 131a and 18F-labeled 4-ﬂuoropyrazol-3-one 131b by carrying

162

[Sec. VI.A

GEORGE VARVOUNIS ET AL. H NH4 -O

Me N

O

N Ph (126)

H

H Me

Me2N

Me

O

(i) POCl3 / DMF / THF / ∆

H

(120a)

N

O

(ii) H2O / K2CO3

N

O

N

N

Ph

Ph

(124)

(125)

H

H Me

O H

N

O

Me

O

N

O

N

N

Ph

Ph

(128)

(127)

Scheme 40

H Me

Me

O POCl3 / DMF

N

O

N

Me

O

CHCl3 / Toluene / 60 - 65oC

N N

Me

Me

(129)

(130)

Me

Scheme 41

O

N N Ph

HOR Me

R

Me

Me R O

Me

R

H

Me

OH N N

O Me

N N Ph

Ph

(70)

Me

O

N N Ph (131)

(a) R = F, (b) R = 18F

Scheme 42

Me

Sec. VI.B]

REACTIONS OF THE RING ATOMS

163

out the reaction of pyrazol-3-one 70 with hypoﬂuorous acid and 18F-labeled hypoﬂuorous acid at pH 13. Although the yields of the ﬂuoro derivatives were low, 36% for the chemical reaction and 15% for the radiochemical reaction, no detectable side reactions were involved. Even though an ionic mechanism was proposed, the authors cannot exclude a radical mechanism by analogy to the one observed earlier for CF3OF. Diﬂuorination at C4 of compound 70 with concomitant loss of the methyl group at position 1 was observed on reaction with N-ﬂuoro bis[(triﬂuoromethyl)sulfonyl]imide in chloroform. The product 4,4-diﬂuoro-5-methyl-2-phenyl-2,4dihydro-3H-pyrazol-3-one was obtained in 38% yield. A mechanism was proposed (00JFC135).

B. CHLORINATION Monochlorination of 2,4-dihydropyrazol-3-ones by chlorine occurs at position 4 of the ring when this position is unsubstituted or monosubstituted (Scheme 43). The solvent in these reactions can be 1,2-dichloromethane, used for the chlorination of pyrazol-3-ones 132a–e into 4-chloropyrazol-3-ones 133a–e (72JHC1219, 80JA4983), or nitromethane, for the chlorination of 5-methylpyrazol-3-one 132f into 4-chloro-5methylpyrazol-3-one 133f (93BSB735). Because the synthesis of 4-halopyrazol3-ones directly is complicated by the fact that the product is very often the 4,4-dihaloderivative, Spitulnik (85S299) developed a method whereby 4,4-dichloroor 4,4-dibromopyrazol-3-ones are selectively reduced to the monohalo derivatives. By this method 4,4-dichloropyrazol-3-ones 134a–d were reacted with ascorbic acid and excess triethylamine in methanol to give the intermediate 4-chloropyrazole salts 135a–d that were then acidiﬁed to yield the 4-chloropyrazol-3-ones 136a–d in yields of 88–95%. Dichlorination, as mentioned above, occurs readily if position 4 of the pyrazol3-one ring is unsubstituted. Two methods have been reported (Scheme 44). Compounds 137a–c were chlorinated with chlorine, either in dichloromethane at room temperature or in nitromethane at reﬂux temperature. The 4-dichloropyrazol-3ones 138a–c were obtained in good yields (82JOC214, 93BSB735). 1,3-Dichloro-5,5dimethylhydantoin 140 in acetic acid was used to prepared 4,4-dichloropyrazol-3-ones (141a–d) (for a–d see Scheme 43) from pyrazol-3-ones 139a–d (for a–d see Scheme 43) (85S299). Treatment of 2,4-dihydropyrazol-3-ones with phosphoryl oxychloride above 100 C gives 4-chloropyrazoles. Thus pyrazol-3-ones 142a–g were converted into 4chloropyrazoles 143a–g in yields of above 80% (68BSF5019, 79JPR127, 91JHC1837) (Scheme 45). When 4,40 -bipyrazol-3,30 -dione 144 was treated with phosphoryl oxychloride in chloroform at 10–30 C only one of the two rings was chlorinated to give 4-(5-chloropyrazol-4-yl)-pyrazol-3-one 145 in 85% yield (92BCJ1652) (Scheme 46). On heating 5-methylpyrazol-3-one 146 with phosphoryl oxychloride at 200 C a mixture was obtained consisting of 3-chloro-5-methylpyrazole 147 and trimeric compound 148 (94CHE540) (Scheme 47).

164

[Sec. VI.C

GEORGE VARVOUNIS ET AL. R1

R1

Me

H O

Cl

Cl2 / Cl(CH2)2Cl or MeNO2 N N

(d) R = R2 = Me, R1 = Ph

N

(e) R = H, R1 = R2 = Me

R

(132)

(133)

R

(c) R = R1 = Me, R2 = Ph

N

O

R

Cl

(f) R = R1 = H, R2 = Me

Cl

R

Cl

Cl

H+ / H2O

ascorbic acid O

N N

(a) R = H, R1 = Me, R2 = Ph (b) R = H, R1 = Ph, R2 = Me

Me

N

Et3N O

Et3N

O

N

R

H N N

Ar

Ar

Ar

(134)

(135)

(136)

(a) Ar = Ph, R = Me H

H N

N (CH2)12Me

(b) Ar = 2,4,6-Cl3C6H2, R = O

H

(CH2)14Me

O Et

(c) Ar = 2-Cl-4,6-Me2C6H2, R = N

O

H H (d) Ar = 2,4,6-Cl3C6H2, R =

O

N

N O

Et Me

Me

O

H

Me Me

Et

Scheme 43

C. BROMINATION Bromination of 2,4-dihydropyrazol-3-ones unsubstituted or mono substituted at position 4 occurs easily with bromine in solvents such as chloroform, 1,2dichloroethane or acetic acid at room temperature (Scheme 48). Therefore pyrazol-3ones 149a–d react with bromine in chloroform (72JHC1219, 84ZN(B)86), 149e in glacial acetic acid (80JPR679) and 149f in perchloric acid (68BSF5019) to give 4-bromopyrazol-3-ones 150a–f in moderate yields. It was interesting that treatment of 4,40 -pyrazol-3,30 -dione 151 with bromine in glacial acetic acid aﬀorded 4-bromopyrazol-3-one 152, albeit in only 45% yield (94JPR70) (Scheme 49). Addition of bromine occurred readily at the exocyclic alkenyl group of arylmethylene pyrazol-3-ones 153a to give 4-bromo-4-[bromo(2aryl)methyl]-pyrazol-3-ones 154a in yields ranging from 70 to 96% (80JIC212) (Scheme 49).

Sec. VI.C]

165

REACTIONS OF THE RING ATOMS

Cl

Cl2 / CH2Cl2 N

O

R1

Cl

R1

N

O

or Cl 2 / MeNO2

N

N

R

R

(137)

(138)

O

(c) R = H, R1 =

Cl N

Me N

Me

O / MeCO2H

Cl

R

Cl

R

Cl

(140) N

O

(a) R = H, R1 = CO2Me (b) R = H, R1 = CO2Et

N

O

N

N

Ar

Ar

(139)

(141) Scheme 44

R1

R2

H O

R1

R2

POCl3 / 110 - 140 C N

Cl

N

(a) R = R1 = H, R2 = Me (b) R = R1 = H, R2 = Ph

o

N

(c) R = 2,4-(NO2)2C6H3, R1 = H, R2 = Me

N

(d) R = 2,4-(NO2)2C6H3, R1 = H, R2 = Ph

R

R

(e) R = H, R1 = Me, R2 = -N=NPh

(142)

(143)

(f) R = H, R1 = Ph, R2 = -N=NPh (g) R = Me, R1 = COPh, R2 = -CH(Me)2

Scheme 45

Ph Ph

N

O

N

H Me

Me POCl3 / CHCl3

N N

Cl Me

Me

H O

N N

10o - 30oC

Ph

H O

N N Ph

(144)

(145) Scheme 46

4-Bromopyrazol-3-ones 157a–d (for a–d see Scheme 43) have been prepared by Spitulnik (85S299) from 4,4-dibromopyrazol-3-ones 155a–d (for a–d see Scheme 43) in two steps. First reduction with ascorbic acid to give monobromopyrazole salts 156a–d (for a–d see Scheme 43) followed by acidiﬁcation (Scheme 50).

166

[Sec. VI.C

GEORGE VARVOUNIS ET AL.

Me Me

N

Me

N

POCl3 O

N

200oC

N

Cl

N

+

Me

N

H

H

(146)

(147)

N

N

N N Me

(148)

Scheme 47

R1

R1

R2

H

Br2 / CHCl3, Br2 / Cl(CH2)2Cl,

N

O

N

O

Br2 / MeCO2H or Br2 / HClO4

N

R2

Br N

R

R

(149)

(150)

(a) R = H, R1 = Me, R2 = Ph, (b) R = H, R1 = Ph, R2 = Me (c) R = R1 = Me, R2 = Ph, (d) R = R2 = Me, R1 = Ph (e) R = 2,4-(NO2)C6H3, R1 = H, R2 = Me, (f) R = Ph, R1 = H, R2 = Me Scheme 48

H

N

Me H

N

H

Me

Me

Br O

HO O

N

Br2 / MeCO2H

H

(151)

(152) Br

N

R1

H

Me

H

Br2 / MeCO2H

Me

Br N

O

N O

N

H

R1

O

N

O

N

N O

CH2OR

(153)

CH2OR

(154)

(a) R = 2,6-(Me)2C6H3 or 3-Me, 4-i-PrC6H4, R1 = 2-ClC6H4, 3-ClC6H4, 4-ClC6H4, 2-HOC6H4, 3-HOC6H4, 4-HOC6H4, 4-Me2NC6H4 or 4-MeOC6H4 Scheme 49

Sec. VI.C]

167

REACTIONS OF THE RING ATOMS

Br

Br

R

Br

R

Br

H / H2O

ascorbic acid O

N

N

Et3N O

Et3N

N

N

O

N

N

Ar

Ar

(156)

(157)

Ar (155)

R

H

+

Scheme 50

Bromination of 4-unsubstituted 1,2-dihydropyrazol-3-ones is more rare. The reaction takes place with bromine or NBS and ALBN in chloroform. Thus pyrazol3-ones 158a,b were treated with bromine to aﬀord 4-bromopyrazol-3-ones 159a,b in 76 and 77% yield, respectively (89AP351). On the other hand treatment of pyrazol-3one 158c with NBS and AIBN (a,a´-azoisobutyronitrile) gave 4-bromopyrazol-3-one 159c in 73% yield (94SC2133) (Scheme 51). Dibromination of 2,4-dihydropyrazol-3-ones with bromine occurs readily both in water or acetic acid (Scheme 52). Bromination of pyrazol-3-ones 160a–c in water gave 4,4-dibromopyrazol-3-ones 161a–c in high yield (67BSF328, 84S972). In acetic acid pyrazol-3-ones 160a,d,f were also brominated in high yield to give 4,4-dibromo derivatives 161a,e,f where compound 161e is brominated also on the benzene ring (81S72, 93BSB735). 4,4-Dibromopyrazol-3-ones 164a–d (for a–d see Scheme 43) were prepared in high yields by reacting the corresponding pyrazol-3-ones 162a–d (for a–d see Scheme 43) with 1,3-dibromo-5,5-dimethylhydantoin 163 in acetic acid (85S299) (Scheme 53). R1

O

N N

R1

Br Br2 / CHCl3 2

R

or NBS / ALBN

O

N N

R

R

(158)

(159)

R2

(a) R = Ph, R1 = R2 = Me, (b) R = 4-MeOC6H4, R1 = R2 = Me, (c) R = H, R1 = Me, R2 = H Scheme 51

R1 Br2 / H2O or MeCO2H O

N N

R1

Br Br O

N N

R

R

(160)

(161)

Scheme 52

(a) R = H, R1 = Me (b) R = Ph, R1 = Me (c) R = 2,4-(NO2)2C6H3, R1 = Me (d) R = H, R1 = 4-MeOC6H4 (e) R = H, R1 = 3-Br, 4-MeOC6H4 (f) R = H, R1 =

168

[Sec. VII.A

GEORGE VARVOUNIS ET AL.

Br O

O / MeCO2H

Me

N

Me R

N

Br

Br

(163) O

R

Br

N

N

O

N

N

Ar

Ar

(162)

(164) Scheme 53

D. IODINATION Iodination of pyrazol-3-ones has only been reported for 1,2-dihydro derivatives (Scheme 54). Rodriguez and co-workers (97TL8397) reacted pyrazol-3-one 165a with di(pyridine)iodonium(I) tetraﬂuoroborate in dichloromethane and obtained 4-iodopyrazol-3-one 166a in almost quantitative yield. Varvounis and colleagues (01JHC1065) treated pyrazol-3-ones 165b–d with iodine monochloride in acetonitrile and obtained 4-iodopyrazol-3-ones 166b–d in 70, 55 and 75% yield, respectively. R3

R3

I I(Pyridine)2BF4 / CH2Cl2

O

N N

1

R

or ICl / MeCN

O

N N

R2

R2

(165)

(166)

R1

(a) R1 = R3 = Me, R2 = Ph, (b) R1 = Me, R2 = R3 = Ph (c) R1 = Me, R2 = Ph, R3 = 4-NO2C6H4, (d) R1 = R2 = Ph, R3 = Me Scheme 54

VII. Nitrosation A. OF 1,2-DIHYDRO-3H-PYRAZOL-3-ONES Nitrosation of 1-unsubstituted pyrazol-3-ones 167a–j in aqueous hydrochloric acid at 5 C with sodium nitrite aﬀorded the corresponding pyrazol-3-one 4-oximes 169a–j in good yields (65ZOR133) (Scheme 55). The reaction most likely takes place via the intermediate nitroso compound 168 that tautomerises to the product because of the available proton at N1.

Sec. VII.B]

169

REACTIONS OF THE RING ATOMS O R1

R1

N

H

1N HCl / 5oC O

N N

H

O

NaNO2

N N

N

O

H

N R

R

R

(168)

(167) 1

R1

O N

(169)

1

1

1

(a) R = C6H11, R = Me, (b) R = C6H13, R = Me, (c) R = Ph, R = Me, (d) R = 2-MeC6H4, R = Me, (e) R = 4-MeC6H4, R1 = Me, (f) R = 2-MeOC6H4, R1 = Me, (g) R = PhCH2, R1 = Me, (h) R = Ph(CH2)2, R1 = Me, (i) R = H, R1 = Ph, (j) R = Me, R1 = Ph

Scheme 55

Me

O N

Me o

aq. H2SO4 / 5 C O

N N

Me

NaNO2

O

N N

Me

S

S (170)

(171) Scheme 56

On the other hand, nitrosation of methylpyrazol-3-one 170 in aqueous sulfuric acid at 5 C containing sodium nitrite aﬀorded 4-nitrosopyrazol-3-one 171 in 88% yield (79AP853) (Scheme 56).

B. OF 2,4-DIHYDRO-3H-PYRAZOL-3-ONES The prototropic tautomerism between 4-nitrosopyrazol-3-ones 175a–c and 4nitrosopyrazol-5-ols 176a–c, derived from pyrazol-3-ones 172a–c after nitrosation with sodium nitrite in aqueous hydrochloric acid at 5 C, was studied by IR and by 1 H, 13C and 15N NMR spectroscopy (94JHC561) (Scheme 57). It is proposed that reaction occurs via protonation of pyrazol-3-one 172 to give intermediate 1,2dihydropyrazol-3-one 173, which is then nitrosated to 174. The latter tautomerises to the more stable products. From available data it was concluded that in the solid state the equilibrium is shifted towards the NH tautomers 175a–c whereas in the liquid state the OH tautomers 176a–c predominate. The NMR measurements were taken in deuteriochloroform, deuteriopyridine or deuterioacetic acid. The more polar the solvent, the higher the proportion of the NH tautomers 175a–c. To assign the 13C NMR signal sequence in each tautomer, the multiplicity, the approximate coupling constant obtained from the oﬀ-resonance spectra, the chemical shifts and the electronic distribution were considered.

170

[Sec. VIII

GEORGE VARVOUNIS ET AL. O

Me

Me

H

Me

N

o

aq. HCl / 5 C O

N N

NaNO2

O

N H

N

O

N

N H

R

R

R

(172)

(173)

(174) O

O

O

N

Me N N

Me

..

N

H O

H

N N

R

R

(175)

(176)

(a) R = n-C2H5, (b) R = n-C6H4, (c) R = n-C8H17

Scheme 57

VIII. Nitration The nitration of both 1,2-dihydro- and 2,4-dihydropyrazol-3-ones has been reported. The reaction conditions vary from the relatively mild 50% aqueous nitric acid to mixtures of fuming nitric acid and concentrated sulfuric acid. The reactions are performed from 0 C to room temperature. Kovar et al. (81AP532) treated 1,2-dihydro-4-isopropyl-5-methyl-2-phenyl-3Hpyrazol-3-one with fuming nitric acid at room temperature that resulted in at least 27 products of which eight main nitro products were isolated. One of the eight products identiﬁed was 2,4-dihydro-4-isopropyl-5-methyl-4-nitro-2-(2,4-dinitrophenyl)-3Hpyrazol-3-one. Elguero et al. (68BSF5019) (Scheme 58) used concentrated nitric acid for the nitration of pyrazol-3-one 177a and obtained 4-nitropyrazol-3-one 178b in 50% Me

Me

O2N conc. HNO3

O

N N

0oC - RT

O

N N

NO2

NO2

NO2

NO2

(177)

(178)

(a) R = H, R1 = NO2, (b) R = H, R1 = NO2, (c) R = R1 = H, (c) R = NO2, R1 = H Scheme 58

Sec. IX.A]

171

REACTIONS OF THE RING ATOMS

Me

O2N

Me fuming HNO3 / conc. H2SO4 N

O

N

H

O

0oC - RT

N N

Me

Me

(179)

(180)

H

Scheme 59

R1

R1

O2N

(a) R = Ph, R1 = 4-ClC6H4

50% aq. HNO3 O

N N

Me

o

0 C - RT

R (181)

O

N N

Me

(b) R = Ph, R1 = 4-NO2C6H4 (c) R = 4-NO2C6H4, R1 = Ph

R (182)

Scheme 60

yield. Using the same conditions but extended reaction time, Bergman et al. (99T10447) converted pyrazole-3-one 177c into 4-dinitropyrazol-3-one 178d. Pyrazol-3-one 179 was nitrated by Hirota et al. (82JCS(P1)277) (Scheme 59) in a mixture of fuming nitric acid and concentrated sulfuric acid to give 4-nitropyrazol-3one 180 in 43% yield. Varvounis and co-workers (01JHC1065) (Scheme 60) used 50% aqueous nitric acid for the nitration of pyrazol-3-ones 181a–c. The 4-nitro derivatives 182a–c were obtained in 80, 78 and 70% yield, respectively.

IX. Diazonium Salt Coupling A. DIAZOPYRAZOL-3-ONE FORMATION, COUPLING AND SUBSTITUTION 4-Toluenesulfonylazide reacted with two equivalents of each pyrazol-3-one 183a,b in ethanolic sodium hydroxide or triethylamine to aﬀord pyrazol-4,5-dione-4-N(pyrazol-4-yl)hydrazones 186a,b. The reaction occurs via initial formation of diazonium salts 184a,b that couple with a second molecule of the respective pyrazol3-one 181a,b leading to the corresponding azo intermediates 185a,b. Tautomerisation of the latter aﬀorded the stable products 186a,b (73G179) (Scheme 61). 4-Diazopyrazol-3-ones 188 and 192 have been prepared in 69 and 50% yield from the corresponding pyrazol-3-ones 187 and 62 each with one equivalent of 4toluenesulfonylazide and two equivalents of triethylamine. Diazo compound 188 was then methylated by methyl iodide to aﬀord 4-diazo-2-methylpyrazol-3-one 189 in 95% yield (83JOC1069) (Scheme 62). Reaction of 4-diazopyrazol-3-one 189 with methyl acrylate in reﬂuxing toluene gave a mixture containing 50% and 32% of the respective spiro(cyclopropanepyrazol-3-ones) 190 and 191. However, similar

172

[Sec. IX.A

GEORGE VARVOUNIS ET AL.

Cl

R +

N

O

H

R

N N

N

NaOH / EtOH TsN3

N

O

or Et3N / EtOH

(183)

+

N

Ph

Ph

(183)

(184)

Ph N

OH

N R

Ph HN N

N

R N

O

R

N

H

O N N O

N H

R N

N

Ph

Ph

(186)

(185) (a) R = Me, (b) R = Ph

Scheme 61

Ph N

O

N

Et3N / MeOH

Ph

N N

N

O

TsN3 (182)

Ph

N N

(i) NaOH / 95% EtOH (ii) MeI

O

N

N N

H

H

Me

(187)

(188)

(189)

CH2=CHCO2Me Toluene / ∆ MeO2C

N

O

Me Et3N / MeOH O

N N

TsN3

N

+

O

H

Ph N

N

Me

Me

(191)

(190)

Ph

N N O

MeO2C

CO2Me Ph

CH2=CHCO2Me N N

Toluene / ∆

Me

MeO2C O

N N

Ph

Ph

Ph

(62)

(192)

(193)

Scheme 62

Sec. IX.B]

173

REACTIONS OF THE RING ATOMS N S

O

(194)

O

N

Ph

CO2Et

CO2Et

N

1N H2SO4 N3

N N

N N

CO2Et

Et BF4 (195)

N N

O

N N

Ph

Ph

(196)

(197)

Scheme 63

reaction of 4-diazopyrazol-3-one 192 with methyl acrylate was more selective and gave a single product 193 of intermediate stereochemistry (83JOC1069) (Scheme 62). Diazo group transfer onto pyrazole-3-one 194 by aziridinium salt 195 in dilute sulfuric acid gave mesomeric 196/197. This compound exists in quite a high proportion as the diazonium enolate 197. Compound 197 is resistant to acids and thermal stress that agrees with its structure (78H199) (Scheme 63). Diazotization of 4-aminopyrazol-3-one 198 followed by coupling with carbon nucleophiles has been reported by several researchers as a means of synthesizing both acyclic and cyclic 4-substituted derivatives. In all cases diazotization occurs at 0 C with sodium nitrite in concentrated hydrochloric acid. First Elnagdi et al. (82JCS(P1)989) (Scheme 64) showed that diazotized pyrazol-3-one 198 undergoes coupling reactions with malononitrile, ethyl cyanoacetate or 3-aminocrotonitrile in ethanol containing sodium acetate to give hydrazones 202a–c. Although these products could be formulated as the azo-derivatives 200a–c or the azine derivatives 201a–c, these structures were excluded on the basis of both infra-red and 1H NMR spectroscopy. 3-Oxopyrazole-4-diazonium chloride 199 was also coupled with ethyl cyanoacetate dimer 203 to yield the hydrazonodiacetate derivative 204 (82JCS(P1)989) (Scheme 64). Ishizuki et al. (88ACA253) (Scheme 65) prepared for analytical purposes, propane-2-one derivative 205 by coupling 3-oxopyrazole-4-diazonium chloride 199 with two equivalents of acetylacetone, and pentane-2,4-dione derivative 206 by coupling diazonium chloride 199 with one equivalent of acetylacetone. Both reactions were performed at 0 C and in the presence of sodium hydroxide. Slouka and Hejsek (91AP467) (Scheme 66) coupled diazonium salt 199 with ethyl cyanoacetylcarbamate 207 at 0 C in the presence of sodium acetate and obtained the hydrazonocarbamate derivative 208, in 95% yield.

B. COUPLING OF PYRAZOL-3-ONES

WITH

ARYL DIAZONIUM SALTS

This category of coupling reactions involves only 2,4-dihydro-3H-pyrazol-3-ones and the majority of diazonium salts used were diazonium chlorides. Thus pyrazo-3ones 209a–k were coupled with a variety of aryl diazonium chlorides 210a–k at 0 C in aqueous solution containing in certain cases a co-solvent such as methanol, ethanol or pyridine to aﬀord 4-arylazopyrazol-3-ones 211a–k in good to excellent yields (Scheme 67) (72JPR612, 78IJC876, 86IJP40, 87JPS40, 00PJC239, 01JCS (D)1239). In one report (81CCC987) 4-diethylaminobenzenediazonium hydrogen sulfate was used to prepare 4-arylazopyrazol-3-one 211l.

174

[Sec. IX.B

GEORGE VARVOUNIS ET AL. H N H2N

Me

O

0oC

N

Me

NaNO2 / HCl

N N

CN

R

N

Me

O

Cl

N

Me

RCH2CN

N

Me

N

N

O

EtOH / NaOAc

N

Ph

Ph

Ph

(198)

(199)

(200)

CN

CN

R

R N

N

HN (a) R = CN (b) R = CO2Et (c) R = MeCH=N

Me

O

Me

N

Me

N

N Me

O

N Me

N

Ph

Ph

(202)

(201)

CN

H2N

C C CO2Et

EtO2C C N HN H2N (199)

CN

+ EtO2CH2C

Me

EtOH / NaOAc N

O

CO2Et

Me

N Ph

(203)

(204)

Scheme 64

Me N Me

N

O

O

N N

Me

Ph

H Me

Me N

O

N

H N O

Me N N

Me

MeCOCH2COMe H2O / 0oC

MeCOCH2COMe

O N

Me

o

(199)

H2O / 0 C O

N N

Ph

Ph

(205)

(206)

Scheme 65

Me

Sec. IX.B]

175

REACTIONS OF THE RING ATOMS CO2Et CN

H N

N

O

H N

CO2Et (199)

+

Me

MeCOCH2COMe / H2O / 0oC

H N

N

O

N

CN

O

Me

Ph (208)

(207)

Scheme 66

Ar R2

R2

N N o

O

+

N

Ar

N NCl

H2O / co-solvent / 0 C O

N R1

R1

(210)

(209) 1

N N

(211) 2

(a) R = 4-ClC6H4, R = Me, Ar = 4-ClC6H4 (b) R1 = 4-ClC6H4, R2 = Me, Ar = 4-MeC6H4 (c) R1 = 4-NO2C6H4, R2 = Me, Ar = 4-ClC6H4 (d) R1 = 4-NO2C6H4, R2 = Me, Ar = 4-MeC6H4 (e) R1 = Ph, R2 = 3-pyridyl, Ar = Ph, 4-ClC6H4, 4-NO2C6H4, 4-MeC6H4, 4-MeOC6H4 or 4-HOC6H4 R3 N 1

(f) R =

R4

OCH2CO O

R3 = R4 = H, R2 = Me, Ar = 2-MeC6H4, 4-MeC6H4, 4-MeOC6H4, 3-CO2HC6H, 4-CO2HC6H4, 4-BrC6H4, 4-ClC6H4, 2-NO2C6H4, 3-NO2C6H4, 4-NO2C6H4, 2,4-(NO2)2C6H4, or 4-H2NSO2C6H4. R3 = NO2, R4 = H, R2 = Me, Ar = 2-MeC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 2-NO2C6H4, 3-NO2C6H4, 4-NO2C6H4, or 4-H2NSO2C6H4. R3 = H, R4 = H or NO2, R = H or NO2, R2 = Me, Ar = 4-ClC6H4, 4-BrC6H4, 2-MeC6H4, 4-MeC6H4, 3-CO2HC6H4, 4-CO2HC6H4, 2-NO2C6H4, 3-NO2C6H4, 4-NO2C6H4, 2,4-(NO2)2C6H4, 4-MeOC6H4 or 4-H2NSO2C6H4. (g) R1 = Ph, R2 = Me, Ar = 4-MeCOC6H4 (h) R1 = Ph, R2 = Me, Ar = Ph or 4-t-BuC6H4 (i) R1 = H, R2 = Ph, Ar = 4-t-BuC6H4 (j) R1 = R2 = Me, Ar = 4-t-BuC6H4 (k) R1 = 4-t-BuC6H4, R2 = Me, Ar = s-Bu, t-Bu or nonyl (l) R1 = Ph, R2 = Me, Ar = 4-Et2NC6H4

Scheme 67

Coupling pyrazol-3-ones 212a–g with aryl diazonium salts 213a–g gave 4arylhydrazonopyrazol-3-ones 214a–g in moderate to good yields. These compounds are stabilized by intramolecular hydrogen bonding between the hydrazono NH and the oxygen atom of the pyrazol-3-one ring. Diazonium chlorides, tetraﬂuoroborates

176

[Sec. IX.B

GEORGE VARVOUNIS ET AL. Ar

R2 N

O

R2

N N o

Ar

H

0 C

N NX

O

N R1

R1

(213)

(212)

N N

(214)

X = Cl, BF4 or HSO4

(a) R1 = H, Ph or 2,4-(NO 2)2C6H4, R2 = CH2CONHAr', Ar' = Ph, 4-ClC6H4, or 4-MeC6H4, Ar = Ph, 4-ClC6H4, or 4-BrC6H4, (b) R1 = 4-SO3NaC6H4, R2 = Me, Ar = Ph H2NOC N 1

2

(c) R = H or Ph, R = Me or Ph, Ar =

N H Me

(d) R1 = H or Ph, R2 = Me, Ar = N N

Me

N

H OEt S

(e) R1 = H or Ph, R2 = Me, Ar =

O

N Me O

O

(f) R1 =

R2 = n-C3H7, Ar = Ph, 4-CO 2EtC6H4, 4-PhC6H4, 4-CNC6H4,

or N

N

O SO2NH

4-MeC6H4, 4-EtOC6H4,

O

N OMe

N or

SO2NH N

R N (f) R1 = Ph or N

2 N , R = morpholino, R = Me, Ar = 2-NO2C6H4, 4-NO2C6H4, 2,4-(NO2)2C6H4, or 4-MeOC6H4,

R

Scheme 68

and hydrogen sulfates have been used for these coupling reactions (Scheme 68) (79JPR1047, 82JPR955, 82JCS(P1)1811, 91IJC(B)878, 91PS119, 92AF1350, 96JSD176). Diazotisation of 15N-aniline followed by coupling of diazonium salt 216 with pyrazol-3-ones 215a,b gave 4-phenylhydrazono derivatives 217a,b. Through the use of 15N labeling and NMR spectroscopy it was shown that pyrazol-3-ones 217a,b exist entirely in the hydrazone form in deuterated chloroform. In hexadeuterated

Sec. IX.B]

177

REACTIONS OF THE RING ATOMS H N H N

R O

Ph-15N

+

N

NCl

R

N N

0oC

H N

O

N

(215)

N

O

N

(216)

Ph

Ph

R

N

Ph

Ph

(217)

(218)

(a) R = Me, (b) R = NHPh

Scheme 69

dimethyl sulfoxide and pyridine compounds 217a,b exist as a mixture with 4-phenyldiazopyrazol-5-ols 218a,b (69JOC1685) (Scheme 69). Recent work on the coupling of pyrazol-3-ones by Shvekhgeimer and Moreva (00CHE491) (Scheme 70) describe the in situ formation of aryl diazonium salts 220a–c by the reaction of 1H-indole-2,3-dione-3-hydrazone 219a–c with nitrosylsulfuric acid, followed by coupling with pyrazol-3-ones 221d–f to give high yields of 4-arylhydrazonopyrazol-3-ones 222g–o. N NH2 R

R

NaNO2 / H2SO4 / AcOH O N

CN

0-5oC

N

H (219)

N HSO4

(220) Me N

O

N Ar

(a) R = H (b) R = Br (c) R = NO2 (d) Ar = Ph (e) Ar = 4-MeC6H4 (f) Ar = 4-HO 3SC6H4 (g) R = H, Ar = Ph (h) R = Br, Ar = Ph (i) R = NO2, Ar = Ph (j) R = H, Ar = 4-MeC6H4 (k) R = Br, Ar = 4-MeC6H4 (l) R = NO2, Ar = 4-MeC6H4 (m) R = H, Ar = 4-HO 3SC6H4 (n) R = Br, 4-HO 3SC6H4 (o) R = NO2, Ar = 4-HO3SC6H4

(221) R CN Me

N N H O

N N Ar (222)

Scheme 70

178

[Sec. IX.C

GEORGE VARVOUNIS ET AL.

C. COUPLING OF PYRAZOL-3-ONES WITH 4-DIAZO-3-OXO-3, 4-DIHYDRONAPHTHALENE-1-SULFONIC ACID Coupling of pyrazole-3-ones 223a–d with 4-diazo-3-oxo-3,4-dihydronaphthalene1-sulfonic acid 224 in aqueous ethanol with sodium hydrogen carbonate aﬀorded the requisite 4-dihydronaphthalenehydrazonopyrazol-3-ones 225a–d in excellent yield and purity in the majority of cases (01JMC3730) (Scheme 71). HO3S OH SO3H

R1

NaHCO3 / H2O +

N

O

H

EtOH / 60 C

OH

R

N

O

o

N

R1

N N

N R

N2 (224)

(223)

(225)

(a) R1 = H, R = H, Me, t-Bu, Ph, Bz, (CH2)2OH or 2-pyridyl R2

(b) R1 = Me, R =

R2 = H, 2-Cl, 3-Cl, 4-Cl, 2-NO2, 3-NO2, 4-NO2,

2-Me, 3-Me, 4-Me, 3-CF3, 4-CF3, 4-F, 4-I, 4-OCH2Ph, 3,4-(Cl)2, 3,4-(Me)2, 4-CH(Me)2, 3-t-Bu, 4-t-Bu, 4-SO2Me, 3-SO2NHEt, 4-CO2H, 4-SO3H, (3-SO3H, 6-Cl), (4-SO3H, 2,5-(Cl)2 or 4-OH (c) R = 3,4-(Me)2C6H3, R1 = H, t-Bu, Ph, or OEt (d) R = 4-t-BuC6H5, R1 = CO2Et, CO2t-Bu, CO2H or NH2

H

Me

O

N

+

S O

+

PhSH

N

Me

PhS

Me

N

O

Me

N

Ph

Ph

(62)

(227)

DMF p-TSA

(MeCO)2O / DMSO

PhSH

Me S OH Me

Me

H O

N N Ph

Me

Me S

HO .. O H

Me H

Me N

N

Me O

N N Ph

Ph

Me Me

S

Me O

S

Me N N Ph (226)

Scheme 71

Sec. X]

179

REACTIONS OF THE RING ATOMS

X. Thiation Otto reported (71AP505) (Scheme 72) that pyrazol-3-one 62 reacts at ambient temperature with thiophenol in dimethylsulfoxide to aﬀord 4-phenylthiopyrazol-3one 227 in 81% yield. It is interesting that sulfonium ylid 226 was the proposed intermediate since it could be formed by reacting pyrazol-3-one 62 with acetic anhydride in dimethylsulfoxide and could then be converted into product 226 by reacting with thiophenol in N,N-dimethylformamide and a catalytic amount of 4-toluenesulfonic acid. Wendebourg and Hartke (89AP473) (Scheme 72) reacted pyrazol-3-ones 228a,b with dimethylsulfoxide or tetrahydrothiophene 1-oxide in the presence of triﬂuoroacetic acid followed by the addition of lithium perchlorate and obtained sulfonium salts 229c–e. Under similar conditions 1,2-dihydropyrazol-3-ones 231f–i yielded the sulfonium salts 232f–i, which were deprotonated by base to the sulfonium ylides 233f–i. When pyrazol-3-one 228a was reacted with dimethylsulfoxide or tetrahydrothiophene-1-oxide in the presence of triﬂuoroacetic acid without addition of lithium perchlorate, sulfonium ylides 230c,d were obtained. Shermolovich et al. (99RJOC281) (Scheme 73) described the reaction of pyrazol3-one 234 with arylsulfenyl chlorides 235a–c that gave the corresponding 4-arylthiopyrazoles 236a–c as major tautomers and 4-arylthiopyrazol-3-ones 237a–c as minor tautomers. The reaction with phenylsulfenyl chloride required R2 H

S

O

1

R

N

O

N

Ph

R2 S O R3

+

R

(i) CF3CO2H

1

N

O

(ii) LiClO4

R3 O

N

Ph

Ph

(228)

(229) R2

ClO4

R3 O

S R1 CF3CO2H O

Ph

N N

Ph

Ph (230) R2

R2 R3

Me

O

N N

H

+

1

R2 S O R3

S

(i) CF3CO2H (ii) LiClO4

R3

Me

S

Me

base O

N

N H

O

N N

R

R1

R1

(231)

(232)

(233)

(a) R1 = H, (b) R1 = n-C4H9, (c) R1 = H, R2 = R3 = Me, (d) R1 = H, R2 = R3 = (CH2)4, (e) R1 = n-C4H9, R2 = R3 = Me, (f) R1 = R2 = R3 = Me, (g) R1 = Me, R2 = R3 = (CH2)4, (h) R1 = Ph, R2 = R3 = Me, (i) R1 = Ph, R2 = R3 = (CH2)4

Scheme 72

180

[Sec. XI.A

GEORGE VARVOUNIS ET AL. Me

ArS

H

Me

CCl4 / 77 C O

N

+

ArSCl

HO

or C6H6 / 80oC

N (235)

Ph

Me

ArS

o

N

O

N

Ph

Ph (233)

(234)

N N

(237)

(a) Ar = Ph, (b) Ar = 2-NO 2C6H4, (c) Ar = 4-NO2C6H4

Scheme 73

heating in carbon tetrachloride at 77 C whereas reactions with 2- and 4-nitrophenylsulfenyl chlorides were performed in benzene at 80 C.

XI. Condensation These condensations involve position 4 of pyrazol-3-ones and aldehydes, ketones, ,-unsaturated carbonyl compounds, doubly activated methylene compounds containing carbonyl functionalities or nitroso compounds.

A. WITH ARYL ALDEHYDES Since 1964 a large number of reports describe the condensation of 2,4-dihydropyrazol-3-ones with aryl aldehydes. In contrast condensation of 1,2-dihydropyrazol3-ones with aryl aldehydes have been reported on only three occasions. Most 4-arylmethylidenepyrazol-3-ones were isolated as (E/Z)-isomer mixtures. The simplest reaction conditions use heating under reﬂux in ethanol. Zimaity et al. (78IJC876), Ege et al. (83JCS(P1)325) and Ibrahim and Youssef (84CJC2841) have used this method to condense 2,4-dihydropyrazol-3-one 238a–c with a variety of aryl aldehydes 239a–c to give (E/Z)-4-arylmethylidine derivatives 240a–c in over 70% yield (Scheme 74). The electronic spectra of pyrazol-3-ones 240c were recorded on ethanolic solutions and the eﬀect of structure on the electronic spectra were H R2

O

N

+

R3CHO

EtOH / ∆

N R1

R3

R2

(239)

(238)

O

N N R1 (240)

(a) R1 = 4-ClC6H4, R3 = Me or NO2, R2 = 4-MeOC6H4, 4-NO2C6H4, 4-N(Me)2C6H4 or thien-2-yl, (b) R = R1 = Ph, R2 = Me, R3 = Ph, 4-ClC6H4, 4-NO2C6H4, or naphth-2-yl, R1 = 4-MeOC6H4 or 4-NO2C6H4, R2 = Me, R3 = Ph, R1 = R2 = Ph, R3 = naphth-2-yl, (c) R1 = 2,4-(NO2)2C6H3, R3 = Me, R2 = Ph, 2-HOC6H4, 4-HOC6H4, 4-NO2C6H4, 4-ClC6H4 or thien-2-yl

Scheme 74

Sec. XI.A]

181

REACTIONS OF THE RING ATOMS

discussed. The electronic absorption spectra of 240c were also recorded using cyclohexane, diethyl ether, DMF and DMSO and their solvatochromic behavior studied. The longer wavelength band displayed by the 4-hydroxy derivative was assigned to an intramolecular CT transition. The solvated H-bond complexes formed between ethanol or DMF and this compound were investigated. Transition moment (CTL), G and Kf values for these complexes have been determined. In one report the stable (E/Z)-4-[4-(dimethylaminobenzylidene)pyrazol-3-one] perchlorate 242 was isolated after reaction of pyrazol-3-one 241 with 4dimethylaminobenzaldehyde in methanol containing perchloric acid (83M219) (Scheme 75). The condensation occurs by addition of the pyrazol-3-one to the protonated aldehyde followed by the elimination of water. El-Shahawy et al. (88IJC(A)94) prepared (E/Z)-4-(4-dimethylamino)benzylidenepyrazol-3-one 245a by reﬂuxing equimolar ratios of pyrazol-3-one 243a and 4dimethylaminobenzaldehyde 244a in ethanol containing piperidine as catalyst (Scheme 76). The electronic absorption spectra lmax and "max of 245a in diﬀerent solvents and mixed solvents, polar and non-polar have been measured. HMO and PPP calculations have been undertaken and also the electron densities at various positions of the compound have been found by SCF calculations. Singh and H Me

O

N

Me

N

Me

Me2N + Me2N

HClO4 / MeOH

CHO

N

O

N

Me ClO4

Ph

Ph

(241)

(242)

Scheme 75

R2 Me

O

N N

R1

+

R3

CHO R2

(243)

Me

R

EtOH / ∆

O

piperidine cat.

R

H

3

N N R

R1

(245)

(244)

(a) R = Ph, R1 = R2 = H, R3 = N(Me)2, (b) R = Ph, R1 = H, R2 = MeO, R3 = OR4, (c) R = Ph, R1 = H, R2 = OR4, R3 = MeO, (d) R = Ph, R1 = H, R2 = EtO, R3 = OR4, (e) R = Ph, R1 = R2 = H, R3 = OR4, (f) R = Ph, R1 = H, R2 = NO2, R3 = OR4, (g) R = Ph, R1 = OR4, R2 = EtO, R3 = H, (h) R = Ph, R1 = R3 = H, R2 = OR4, (i) R = Ph, R1 = OR4, R2 = R3 = H, R4 = O H AcO H

H AcO

Scheme 76

OAc H H

OAc

182

[Sec. XI.A

GEORGE VARVOUNIS ET AL.

co-workers (88IJC(B)1019) prepared glucosidated (E/Z)-4-arylidenepyrazol-3-ones 245b–i by condensation of pyrazol-3-one 243b–i 2,3,4,6-tetra-O-acetyl--D-glucopyranosidebenzaldehydes 244b–i using the same reaction conditions (Scheme 76). Tietze et al. (88LA9) (Scheme 77) alkylated 2-hydroxybenzaldehyde with 5bromo-2-methylpent-2-ene and 1H-pyrrole-2-carbaldehyde with 1-bromo-3-methylbut-2-ene and obtained the corresponding aryl aldehydes 246 and 248. Condensation of the latter with pyrazol-3-one 262 in acetonitrile containing ethylenediamine diacetate as a catalyst provided (E/Z)-4-{2-[(4-methylpent-3-enyl)oxy]benzylidine}pyrazol-3-one 247 and (E/Z)-4-{[1-(3-methylbut-2-enyl)-1H-pyrrol-2-yl]methylene}pyrazol-3-one 249, in 67 and 99% yield, respectively.

Me

O Br

Ph O

Me

+ HO

(242) CHO

H Me

CHO

N N

H2N(CH2)2NH2 . 2MeCO2H MeCN / R.T.

Me Me (241)

Me

O H

Me

Me

O

N N Ph (242) Br

N H

CHO

N

+

CHO

Me

H2N(CH2)2NH2 . 2MeCO2H MeCN / R.T.

Me Me

Me

(244) Me

Me

H

N

Me

O

N N Ph

(242)

(a) R = Me, (b) R = H

(245)

Scheme 77

Sec. XI.A]

183

REACTIONS OF THE RING ATOMS

A year later Tacconi and co-workers (89T775) (Scheme 78) reported that the condensation of pyrazol-3-one 250 with 2-[(3-methylbut-2-enyl)oxy]benzaldehyde 251 in dichloromethane containing N,N0 -dicyclohexylcarbodiimide as catalyst, aﬀorded (E/Z)-4-{2-[3-methyl(but-2-enyl)oxy]benzylidine}-pyrazol-3-one 252, in only 35% yield. Compounds 247, 249 and 252 underwent intramolecular heteroDiels–Alder reaction at relatively low temperature. When position 2 of a 2,4-dihydropyrazol-3-one is occupied by an electron withdrawing substituent condensation with aryl aldehydes requires heating with glacial acetic acid. Thus pyrazol-3-ones 252a,b (92IJP165, 92PS253) (Scheme 79) were heated at reﬂux in glacial acetic acid with aryl aldehydes 254a,b to aﬀord the respective (E/Z)-4-arylidenepyrazol-3-ones 255a,b in very good yield. Suman and Bahel (80JIC212) (Scheme 80) reported that reaction of 1-acylpyrazol3-ones 256a with arylaldehydes 257a in boiling glacial acetic acid gave (E/Z)-4arylidenepyrazol-3-ones 258a along with bispyrazol-3-one derivatives 259a. Several pyrazol-3-ones 258a were screened and found to possess signiﬁcant antifungal activity. The condensation of pyrazole-3-one 260 with substituted benzaldehydes 261a–d was carried out in the solid state, in the molten state and in chloroform solution at 50 C. Two products, 4-arylidenebispyrazol-3-ones 262 and 4,40 -arylmethylenebispyrazoles 263, were obtained, in varying amounts according to the experimental method used (01CHJC398) (Table 1) (Scheme 81). Me

O H

Me O

CH2Cl2

CHO

+

N

O

N Ph

Me

N

O

C6H11NCNC6H11

N Ph

Me

(252)

(251)

(250)

Scheme 78 H Me N

O

Me

1

+

MeCO2H / ∆

R1

R

CHO

N

O

N N

R

R

(253)

(255)

(254)

(a) R1 = H, R = COCH(Me)O-3,4-(Me)(Cl)C6H3, COCH(Me)O-2,4-(Me)2C6H3 or COCH(Me)O-4-(t-Bu)C6H4, SO2 , R1 = H, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4 or 4-NO2C6H4

(b) R = N OH

Scheme 79

184

[Sec. XI.A

GEORGE VARVOUNIS ET AL. R H Me

O N

Me

Ar

O

N

MeCO2H +

N

O

H

ArCHO

N O

(257)

R

+

N

O

Me

Me Ar

N O

N

O

R

N

(258)

(256)

O

R (259)

(a) R = CH2OC6H3(Me)2-2,6 or CH2OC6H3Me-3-i-Pr-4, Ar = 2-ClC6H4, 3-ClC6H4, 4-ClC6H4, 2-HOC6H4, 3-HOC6H4, 4-HOC6H4, 4-(Me2N)C6H4, 4-MeOC6H4 or PhCH=CH,

Scheme 80

REACTIONS OF (260)

Table 1.

AND

Solid state at RT

(261)

IN THE

SOLID AND MOLTEN STATE AND IN CHCl3

Molten state at 150 C

In CHCl3 at 50 C

Compounds

262

263

262

263

262

263

(a) (b) (c) (d)

4% 0% 3% 0%

80% 87% 70% 92%

94% 84% 89% 79%

0% 5% 0% 8%

46% 32% 28% 61%

33% 52% 49% 21%

R solid state / 22oC, molten state / 150oC

Me

H

N Me

Ar

or CHCl 3 / 50oC N

O

+

ArCHO

O

(261)

R

N O

OH

+

Me

Me Ar

R

(262)

(260)

N

H N

O

N

O

N

HO

N O

R

(263) Cl N R=

N

N

(a) Ar = 2-HO, 5-BrC6H3, (b) Ar = 2-HO, 3-MeOC6H3 (c) Ar = 2-HO, 3-MeO, 5-NO2C6H2, (d) Ar = 2-Cl, 5-NO2C6H3

OH Cl

Scheme 81

Sec. XI.A]

185

REACTIONS OF THE RING ATOMS

Singh and Singh (84JCED355, 91JIC165) (Scheme 82) on the other hand reported that condensation of pyrazol-3-ones 264a,b with aryl aldehydes 265a,b, under the same conditions, yielded (E/Z)-4-arylidenepyrazol-3-ones 266a,b and 4-[(3-oxopyrazol-4-yl) (aryl)methyl]pyrazol-3-ones 267a,b. It is noteworthy that the pyrazol-3one ring of compounds 259 are represented by Suman and Bahel (80JIC212) (Scheme 80) as 1,2-dihydro tautomers whereas the corresponding pyrazol-3-one rings of compounds 267a,b are 2,4-dihydro tautomers. Several workers have found it more convenient to use sodium acetate together with glacial acetic acid. Thus Pathak and Bahel (80JIC1108), Hogal and Pawar (89JIC135), Dwivedi et al. (91JIC515), Zohdi and co-workers (92JCR(S)396) and Zohdi et al. (92JCR(M)3015) (Scheme 83), heated pyrazol-3-ones 268a–e with aryl R2

R3

H R1

4

R

N

O

N R

R1

R3

R4

(266) MeCO2H / ∆

O

R4

+

N

+

CHO

N R4

R (264)

R3

(265) O

R

R2

N H

H

R1

N R1

(a) R = PhCH2, R1 = Me, R2 = R3 = H, R4 = H, NO2, Me2N or MeO (b) R = PhCH2 or benzothiazol-2-yl, R1 = Me, R2 = R4 = H, R3 = NO2 or R2 = R3, R4 = H, NO2, Me2N or MeO, R = R1 = Ph, R2 = R3 = H, R4 = Me2N

O

N N

H

R (267)

Scheme 82 H R1

R1

Ar MeCO2H / ∆

O

N

+

ArCHO

N R

MeCO2Na

O

N N R

(269)

(270)

(268)

(a) R = ArCO, Ar = Ph, PhOCH2, 4-MeC6H4OCH2, 4-ClC6H4OCH2, 4-ClC6H4, 4-(Me)2NC6H4, 2-HOC6H4 or 4-HOC6H4 (b) R = ArCO, Ar = PhCH2, C6H5CH=CH, 2-ClC6H4, 4-NO2C6H4, 3,5-(NO2)2C6H3, 2-HOC6H4, C6H5OCH2, 2-ClC6H4OCH2 or 4-ClC6H4OCH2, R1 = Me Ar = Ph, 4-(Me)2NC6H4, 2-HOC6H4, 3-HOC6H4, 4-HOC6H4 or 4-MeOC6H4 (c) R = Ph or ArCO, Ar = Ph, 2-ClC6H4, 4-ClC6H4, 2,4-(Cl)2C6H3 or 4-Me2NC6H4, R1 = Ar = 4-ClC6H4, 4MeOC6H4 or CF3

Scheme 83

186

[Sec. XI.A

GEORGE VARVOUNIS ET AL.

aldehydes 269a–e in glacial acetic acid containing sodium acetate and obtained (E/ Z)-4-arylidenepyrazol-3-ones 270a–e in variable yields. Tacconi and co-workers (72G491) and Sammour (72JPR612) (Scheme 84) prepared (E/Z)-2-phenyl-4-arylidenepyrazol-3-ones 273a,b by heating pyrazol-3ones 271a,b with aryl aldehydes 272a,b at 180 C. When Abramovitch and co-workers (83JHC1539) condensed pyrazol-3-one 274 with 2-aminobenzaldehyde at 150 C they obtained (E/Z)-4-(2-aminobenzylidene)pyrazol-3-one 275 in 70% yield and 3-acetylquinolinone 276 in 8% yield (Scheme 84). Twelve years later Danel and Tomasik (95PJC1013) (Scheme 85) reported that upon heating pyrazol-3-ones 277a–d with 2-nitrobenzaldehyde at 150 C aﬀorded (E/Z)-4-(2-nitrobenzylidene)pyrazol-3-ones 278a–d and 4-[(5-oxopyrazol-4-yl) (2nitrophenyl)methyl]pyrazol-3-ones 279a–d. It is curious that when pyrazol-3-one 277e was used in this reaction, the only product obtained, and in 70% yield, was (E/Z)-4-(2-nitrobenzylidine)pyrazol-3-one 278e. H R1 180oC N

O

+

R2

R1

R2

CHO

N

O

N

N

Ph

Ph (272)

(271) 1

(273)

2

(a) R = H, Me or Ph, R = H, Me, F, Cl, Br, CO2Me, Me2N, NO2 or MeO (b) R1 = pyridin-3-yl, R2 = Ph, 2-ClC6H4, 4-ClC6H4, 4-NO2C6H4, 4-MeOC6H4 NH2 H Me

O

N

O

Me CHO

o

150 C

Me

+

N

N

NH2

Me

+

N

O

H

(275)

(274)

O

N

Me

(276)

Scheme 84

NO2

O

N N R

R1

O

NO2

(277)

N

+

N

R1

R1

O

N N

R

R

(278)

(279)

(a) R = Ph, R1 = Me, (b) R = R1 = Ph, (c) R = Me, R1 = Ph, (d) R = R1 = Me, (e) R = H, R1 = Me,

Scheme 85

H

N

150oC

+

NO2

N

R1 CHO

O

R H

Sec. XI.A]

187

REACTIONS OF THE RING ATOMS

The condensation of pyrazol-3-one 62 with 2,4,6-trimethylbenzaldehyde 280 as described by Tacconi and co-workers (72G491) gave a mixture of 4-mesitylmethylidenepyrazol-3-ones (E)-281 and (Z)-282 (Scheme 86). These isomers were separated by fractional crystallization and their conﬁguration assigned by NMR spectroscopy. It was established that in the (E)-conﬁguration the methyl group in position 5 lies in the shielding cone of the mesityl ring and therefore occurs further upﬁeld that the corresponding methyl group in the (Z)-conﬁguration. On the other hand the vinylic proton in the (E)-conﬁguration is deshielded by the carbonyl group and appears further downﬁeld than the vinylic proton in the (Z)-conﬁguration. Villemin and Labiad (90SC3213) (Scheme 87) describe the dry condensation of pyrazol-3-one 62 with aromatic aldehydes 283a–d by adsorption on acidic Montmorillonite KSF clay under microwave irradiation (280W) to aﬀord (Z)284a–d and (E)-4-arylmethylidenepyrazol-3-ones 285a–d in 85 (70/30), 77 (68/32), 68 (70/30), 71 (70/30), and 92% (Z/E ratio 54/41), yield and Z/E ratios, respectively. Kirschke et al. (94LA159) (Scheme 88) found that condensation of pyrazol-3-ones 286a–c with benzaldehyde at 120–130 C aﬀorded mixtures of (E/Z)-4-phenylmethylidenepyrazol-3-ones that were separated by chromatography into isomers (E)-287a– c and (Z)-288a–c, respectively, in excellent yields. Me

Me

Me

Me

Me

H

Me Me

H

Me

Me

180oC O

N

+ OHC

N Ph

Me

N

O

(280)

N N

Ph

Ph

(E)-(281)

(Z)-(282)

Me

(62)

Me O

+

N

Scheme 86 H Me

Ar Me

Ar

Me

H

Montmorillonite KSF O

N

ArCHO

+

N

microwaves (283)

Ph

O

N

+

N Ph

(E)-(285)

OMe (a) Ar =

, (b) Ar = O

(d) Ar =

OMe, (c) Ar = OMe

O

NMe2

Scheme 87

N N Ph

(Z)-(284)

(62)

O

NO,2

188

[Sec. XI.A

GEORGE VARVOUNIS ET AL. Ph R1

H R1

H

R1

Ph

120-130oC N

O

+

PhCHO

N

O

N

+

N

O

N

N

Ar

Ar

Ar

(286)

(E)-(287)

(Z)-(288)

(a) Ar = Ph, R1 = EtO, (b) Ar = 4-NO2C6H4, R1 = EtO, (c) Ar = 4-NO2C6H4, R1 = pyrrolidino

Scheme 88

H Me

Me +

N

O

∆ R

N

O

R

O

CHO

O

Ar

N N Ar

(290)

(289)

(291)

(a) Ar = 2-ClC6H4, (b) Ar = 3-ClC6H4, (c) Ar = 4-ClC6H4, (d) R = H, (e) R = NO2, (f) R = H or NO2, Ar = 2ClC6H4, 3-ClC6H4 or 4-ClC6H4

Scheme 89

Wrzeciono et al. (78PHA264) (Scheme 89) presented the only example of condensation between an aromatic heterocyclic aldehyde and a 2,4-dihydropyrazol3-one. Thus reaction of pyrazol-3-ones 289a–c with furan-2-carbaldehydes 290d,e aﬀorded the furfurylidene derivatives 291f,g. Six years later Singh and Singh (84JCED355) (Scheme 90) condensed 2(benzothiazol-2-yl)pyrazol-3-one 292 with aryl aldehydes 293a–d in boiling acetic acid and obtained (E/Z)-4-arylmethylidenepyrazol-3-ones 294a–d in 65, 58, 83 and 69% yield, respectively. The condensation of pyrazole-3-one 295 with aldehyde 296 was found by Timple et al. (82JPR955) (Scheme 91) to work eﬃciently in aqueous sodium hydroxide at room temperature to give (E/Z)-4-(arylmethylidene)pyrazole-3-one 297. H Me

R

MeCO2H / ∆ N

O

N S

Me

1

+

R1

CHO

(293)

N

N

O

N S

N

(294)

(292) 1

1

1

1

(a) R = H, (b) R = NO2, (c) R = Me2N, (d) R = MeO

Scheme 90

Sec. XI.B]

189

REACTIONS OF THE RING ATOMS

NMe2

Me

Me

H aq. NaOH

N

O

Me2N

+

N

CHO

N

O

N

(296) SO3Na

SO3Na

(297)

(295) Scheme 91

Microwave irradiation in the presence of Montmorillonite KSF clay as catalyst has also proved eﬀective in condensations between pyrazol-3-one 62 and various heterocyclic aldehydes. Thus, thiophene-2-carboxaldehyde 298a, 2-furaldehyde 298b and indole-3-carboxaldehyde 298c reacted smoothly under these conditions to give (Z)-299a–c and (E)-2-heteroarylpyrazol-3-ones 300a–c in 89 (80/20), 86 (71/29) and 75% (Z/E ratio 33/67) yield and Z/E-ratios, respectively (90SC3213) (Scheme 92). H Me

R Me

R

Me

H

Montmorillonite KSF O

N

+

RCHO

N Ph

O

microwaves (298)

N

+

N Ph

(a) R =

S

, (b) R =

O

, (c) R =

N N Ph

(Z)-(299)

(62)

O

(E)-(300)

N H

Scheme 92

B. WITH NON-TYPICAL ,-UNSATURATED ALDEHYDES This type of condensation works in competition with the Michael addition but addition occurs preferably at the aldehyde group since the alkene group is connected to an aryl or heteroaryl ring. The ﬁrst of the two reports of this kind of condensation were given by Kamel and Shoeb (64T483) (Scheme 94). The reaction described was between pyrazol-3-one 62 and dibenzo[c,h]xanthen-7-ylideneacetaldehyde 301 in pyridine at room temperature which gave (E/Z)-dibenzo[c,h]xanthen-7-ylideneethylidenepyrazol-3-one 302. In the second report Villemin and Labiad (90SC3213)

190

[Sec. XI.C

GEORGE VARVOUNIS ET AL.

O

O

Me

Me

H pyridine

O

N

+

N

O

Ph

H

H

(62)

N N Ph (E/Z)-(302)

O (301)

O H

H H

H Me

O (62)

+

H

H

Montmorillonite KSF

O

N

O

microwaves

+

N

CHO

H

Me

H

Ph

N N Ph

(4E)-4-(2Z)-(304)

(303)

O

(4E)-4-(2E)-(305)

Scheme 93 Me R2

R2

Me O

O

N N

+

∆ Me

Me

O

N N 1

1

R

R

(306)

(307)

(a) R1 = Ph, R2 = H, (b) R1 = Ph, R2 = Me or Ph, R1 = 4-MeC6H4, R2 = Me, (c) R2 = Ph, R1 = Ph, 2-MeC6H4, 4MeC6H4, 2-ClC6H4, 4-ClC6H4 or 4-BrC6H4, (d) R2 = Me, R1 = Ph, 3-ClC6H4, 4-ClC6H4, 3-NO2C6H4 or 4NO2C6H4, (e) R2 = Ph, R1 = Ph, 4-ClC6H4 or 4-BrC6H4, (f) R2 = Me, R1 = Ph, 4-ClC6H4, 4-BrC6H4, 4-NO2C6H4, 4-MeC6H4 or 4-MeOC6H4,

Scheme 94

(Scheme 93) condensed pyrazol-3-one 62 with 3-(2-furyl)acrolein 303 by adsorption on acidic Montmorillonite KSF clay under microwave irradiation and obtained (4E )-4-[(2Z)-304 and (4E )-4-[(2E )-3-(2-furyl)prop-2-enylidene]pyrazol-3-one 305 in 92% yield and 54/41 Z/E ratio.

C. WITH KETONES All recorded condensations with ketones have taken place at C4 of 2,4dihydropyrazol-3-ones. Reaction even with the simplest ketone, acetone, requires heating at the boiling point. Therefore under these conditions pyrazol-3-ones 306a–f

Sec. XI.C]

191

REACTIONS OF THE RING ATOMS

gave 4-(1-methylethylidene)pyrazol-3-ones 307a–f in near quantitative yields (73BSF2482, 83JCS(P1)325, 83S428, 84BSB1073, 84CPB2146, 86JHC1159) (Scheme 94). Matsugo et al. (85CPB3623) (Schemes 96–98) studied the condensation of pyrazol3-ones 308a–c with cyclopentanone, cyclohexanone or cycloheptanone at reﬂux with or without triethylamine and obtained both predictable and unpredictable results. Thus the reaction of pyrazol-3-ones 308a–c in boiling cyclopentanone aﬀorded 4cyclopentylidenepyrazol-3-ones 309a–c in high yield. However in the presence of triethylamine the above reaction gave completely diﬀerent results. Two products were isolated 11-oxa-2,4-diazaspiro-[4.0.4.1]undec-3-en-1-ones 310a–c and 4cyclopentylpyrazol-3-ones 311a–c. In contrast, the reaction of pyrazol-3-ones 308a–c with cyclohexanone or cycloheptanone in the presence of triethylamine at reﬂux aﬀorded the corresponding 4-cyclohexylpyrazol-3-ones 312a–c and 4cycloheptylpyrazol-3-ones 313a–c. The absence of epoxides is explained by the presence of triethylamine oxide as byproduct. An interesting result was obtained when pyrazol-3-one 314 was reacted with cyclopentanone in the presence of triethylamine at room temperature (Scheme 97). Epoxide 315 and 4-hydroxy-4-(2-oxocyclopentyl)pyrazol-3-one 316 were obtained in 43 and 23% yield, respectively. This reaction may involve initial formation of hydroperoxide 317, dehydration to diketone 318, followed by addition of enolized cyclopentanone to the latter, ﬁnally leading to pyrazol-3-one 316. The reaction of pyrazol-3-ones 308a–c and cyclopentanone catalyzed by triethylamine was further investigated. When the reaction was repeated in the

O

N

O

O

Ph

Ph

∆

N

O

N N

O

N

O

Et3N / ∆

Ph +

N

O

N N

Ar

Ar

Ar

Ar

(309)

(308)

(310)

(311)

/ Et3N /∆

/ Et3N / ∆ O

O

Ph

Ph

O

Ph

N

O

N

N N Ar

Ar

(313)

(312) (a) Ar = Ph, (b) Ar = 4-ClC6H4, (c) Ar = 4-BrC6H4

Scheme 95

192

[Sec. XI.C

GEORGE VARVOUNIS ET AL.

O

O

N

O

Et3N

+

N

O

N N

Ph

Ph

Ar

(314)

(315)

(316)

OOH Ph

O

H O

Ph

Ph HO

N N

O

O

Ph

OH

Ph

- H2O N

N

O

N

N

Ph

Ph

(317)

(318) (a) Ar = Ph, (b) Ar = 4-ClC6H4, (c) Ar = 4-BrC6H4 Scheme 96

HO

O

Ph

Ph H (308)

+

Et3NH+

O Et3N / ∆

O

N

H O

N

N

(309)

N

Ar

Ar

(318)

(319)

(a) Ar = Ph, (b) Ar = 4-ClC6H4, (c) Ar = 4-BrC6H4

Scheme 97

presence of 2,4,6-trimethylphenol as a radical scavenger or under an inert atmosphere using very dry conditions, the outcome of the reaction was unchanged. These and other observations derived from deuterium and O18 labeled NMR experiments lead to a reasonable mechanism for this reaction (Scheme 97). Thus initial formation of adduct 318, protonation to 319 followed by dehydration may give pyrazol-3-ones 309. No satisfactory explanation has been given for the formation of compounds 310 and 311 (Scheme 95). Due et al. (95CHJC520) (Scheme 98) reacted pyrazol-3-one 62 with aromatic ketones 320a–i in the solid state by heating at 120 C to give 4-(diphenylmethylene)321a, (E/Z)-4-[phenyl(pyridin-4-yl)methylene]—321b, (E/Z)-4-[1-(aryl, naphthyl or heteroaryl)ethylidene]—321c–h or (E/Z)-4-[1-(4-{[(E/Z)-1-(4-aminophenyl)ethylidene]amino}phenyl)ethylidene]pyrazol-3-one 321i, in yields ranging from 35 to 78%.

Sec. XI.C]

193

REACTIONS OF THE RING ATOMS

R2 Me

1

+

N

O

R

R O

N

R1

Ph

120oC N

O

R2

N Ph

(320)

(321)

(62)

(a) R1 = R2 = Ph, (b) R1 = Ph, R2 = pyridin-4-yl, (c) R1 = Me, R2 = 4-NO2C6H4, (d) R1 = Me, R2 = 4-NH2C6H4, (e) R1 = Me, R2 = naphthal-2-yl, (f) R1 = Me, R2 = indol-2-yl, (g) R1 = Me, R2 = HO 1

O

O

OH

2

(h) R = Me, R =

Me

(i) R1 = Me, R2 = O

N

Me

O NH2 Scheme 98

In view of the considerable interest given to heterocyclic compounds containing a triﬂuoromethyl group on account of their excellent pharmacological activity, Zohdi et al. (92JCR(S)396, 92JCR(M)3015) (Scheme 99) synthesized, among other compounds, (E/Z)-4-(3-oxo-1,3-diphenylpropylidene)-5-triﬂuoro-methylpyrazol-3one 323 and (E/Z)-[(5-oxopyrazol-4-ylidene)butylidene]pyrazol-3-one 324, required for a medicinal chemistry program. Compounds 323 and 324 were prepared by treating 5-triﬂuoromethylpyrazol-3-one 322 with 1,3-diphenylpropane-1,3-dione and pentane-2,4-dione, respectively, at 140 C. It seems that the steric hindrance in 323 caused by the two phenyl groups prevents further reaction with another molecule of 322. N F3C

Ph

N

O

O

Ph

Me CF3

Ph

CF3 CH2(COPh)2

O

N N

140oC

CF3

F3C CH2(COMe)2

O

N N

140oC

O

N N

Ph

Ph

Ph

(323)

(322)

(324)

Scheme 99

194

[Sec. XI.C

GEORGE VARVOUNIS ET AL. O

H

NHPh

O Me

Me PhHN H

100oC O

N

+

PhNHCO

CONHPh

N

N

O

N

O

Ph

Ph

(62)

(325)

Scheme 100

In one report 3-oxo-N,N0 -diphenylpentanediamide was found to condense with pyrazol-3-one 62 at 100 C to give (E/Z)-3-(5-oxopyrazol-4-yl)-N,N0 -diphenylpent-2enediamide 325 (79JPR1047) (Scheme 100). Joshi et al. (91H1491, 94IJC(B)483) (Scheme 101 to 104) have reported the condensation of pyrazol-3-one 62 with indone-2,3-dione derivatives or 5-ﬂuoro derivative 328 under both thermal and photochemical conditions. Under thermal conditions 62 reacts with indone-2,3-dione in a ratio of 2:1 in boiling ethanol, to give (3E/Z)-3-(5-oxopyrazol-4-ylidene)indol-2-one 326 and spiro(pyrazolopyrazopyrazolo)indolone 327 in 12 and 80% yield, respectively. Under the same reaction conditions 5-ﬂuoroindone-2,3-dione 328 reacted with 62 to give the expected condensation product 329 together with derivative 330. The latter originates from addition of a further molecule of pyrazol-3-one 62 to 329. The analogue of 330 was not isolated in the reaction between 62 and indone-2,3-dione because it intramolecularly cyclized to 327.

H

H

O

+

N

O

N

Ph

Me O

O

EtOH / ∆ N

N Me

O

Me

O

N

N

N

+

N

N N

Ph

H

Me

O

Ph

Ph

(326)

(62)

N

(327)

O F

F

H

O N

H

N

H (328) EtOH /∆

Me

N

O

N O

N N

F

Me O

N

+

Ph O

H H O

Me N N

Ph

Ph

(329)

(330)

Scheme 101

Sec. XI.C]

195

REACTIONS OF THE RING ATOMS

H

N

EtOH / ∆ (62)

O

O

Me

Me

O +

O

O

N

O

or THF / ∆

N

N

Ph

Me

O

N

+

N

(331)

O

(332)

N Me

Ph

(333)

Me O O

N

F (62)

+

O N O

Me

EtOH / ∆ or THF / ∆

Me F

O

N

N N

Me

N

O

Ph

Ph (335)

(334)

Scheme 102

The use of 1-acetyl-2,3-dione 331 as the electrophile in a reaction with 62 gave 45% of condensation product 332 and 17% of pyrazolobenzazepine 333 (Scheme 102). The electronic eﬀect of the acetyl group of 331 has driven the nucleophile to attack C2 of the molecule causing ring opening by cleavage at the amide followed by ring closure and dehydration to 333. The reaction of pyrazol-3-one 62 with 1-acetyl-5ﬂuoroindone-2,3-dione 334 gave curiously only compound 335 in 80% yield. Under photochemical conditions, ultraviolet light in THF solution and under nitrogen, similar products were obtained (Scheme 103). Thus the reaction of 62 and O

O Me

hv (62)

+

(325)

N THF

N

N

H

Ph

+

(326)

+

(327)

(336) HO2C O hv (62)

+

F

N

F

(328)

+

THF O

N H (337)

Scheme 103

(329)

+

(330)

196

[Sec. XI.D

GEORGE VARVOUNIS ET AL.

hv (62)

+

(332)

(331)

+

(333)

THF HO2C O hv +

(62)

(335)

(334)

+

THF

F

N

F O

N O

Me

(338) Scheme 104 Me Ph H2N

Me EtO2C

O

N N

Me

O

O

MeCO2H /∆

+ O

N

Me

N

CO2Et H N

N H EtO2C

CO2Et

O

Me N N

Ph

Ph

(339)

(340)

Me

Scheme 105

325 gave 326, 327 and pyrazolobenzazepine 336, 62 and 328 gave 329, 330 and 2-[(indol-3-ylideneamino)phenyl]oxoacetic acid 337. Furthermore reaction of 62 with 331 and ultraviolet light gave the same products 332 and 333 but in 17 and 40% yield, respectively (Scheme 104). On the other hand, reaction of 62 and 334 gave also the same product 335, in 14% yield together with [indol-3-ylideneamino)-5-ﬂuorophenyl]oxoacetic acid 338 in 37% yield. Metwally and Afsah (84PHA95) (Scheme 105) heated 4-aminopyrazol-3-one 339 with diethyl 2,5-dioxocyclohexane-1,4-dicarboxylate in glacial acetic acid and obtained the diethyl 2,5-di(5-oxopyrazol-4-yl)amino derivative 340. Nucleophilic addition to a ketone by a pyrazole-3-one can also take place via a pyrazolon-4-yl anion generated from a halogen-metal exchange reaction. Akgu¨n and Pindur (84M197) (Scheme 106) reported one such example, namely the addition of pyrazole-3-one lithium salt 342, obtained by treating 4-bromopyrazol-3-one 341 with n-BuLi in THF at 78 C, to benzophenone. The addition product 343 was quenched with tetraﬂuoroboric acid-diethyl ether complex to aﬀord, after loss of water, (3oxopyrazol-4-yl) (diphenyl)methylium tetraﬂuoroborate 344.

D. WITH NITROSO COMPOUNDS 4-Aryliminopyrazol-3-ones are widely employed as color couplers in photography. In an attempt to synthesize (E/Z)-4-phenyliminopyrazol-3-one 345 by heating

Sec. XI.D]

197

REACTIONS OF THE RING ATOMS _ Li+ O Me

Br

Ph

Me

Li

Me Ph

O

N N

PhCOPh

n-BuLi Me

THF / -78oC

N

O

N

Me

N

O

THF / -78oC

Me

N

Ph

Ph

Ph

(341)

(342)

(343)

HBF4.OEt2 -H2O

BF4

_

Ph +

Ph

Me N

O

Me

N Ph (344)

Scheme 106

Ph

Ph N

Me N

O

Me

O N

Me N

O

N

N

Ph

Ph

(345)

(347)

PhNO O

N N

+

60oC

+ Ph

Ph

Me Me

(62) Ph

H N

N

N

N

N Ph O

H

N

Me

O

(346)

O

N N Ph (348)

Scheme 107

pyrazol-3-one and nitrosobenzene in the solid state at 60 C, Tacconi et al. (80JPR674) (Scheme 107) obtained a mixture containing together with (E/Z)-345, 4(pyrazol-4-yl)pyrazol-3-one 346, (E/Z)-(5-oxopyrazol-4-ylidene)-(phenyl)ammoniumolate 347 and (E/Z)-4-[(4-anilinophenyl)imino]pyrazol-3-one 348. The yield of these products was 27, 10, 3 and 2%, respectively. Although the yield of (E/Z)-345

198

[Sec. XI.D

GEORGE VARVOUNIS ET AL.

was only 27% this yield was much higher than other methods and the chromatographic separation of the compound was much easier. Heinisch (88JPR57) and Grigg and co-workers (94T895) and El-Shahawy et al. (88IJC(A)94) (Scheme 109) avoided the side products obtained by Tacconi et al. (80JPR674) (Scheme 108) during the reaction of pyrazol-3-ones 349a–g with Me Me N

R2

R2

N pyridine / ∆

O

Me2N

+

N

N O

O

or EtOH / 78oC

N R1

R1

or EtOH / piperidine / ∆

(350)

N N

(349)

(351)

(a) R1 = H, R2 = Me, (b) R1 = H, R2 = Ph, (c) R1 = Me, R2 = Ph, (d) R1 = Ph, R2 = Me, (e) R1 = R2 = Ph, (f) R1 = 4-MeOC6H4, R2 = Ph, (g) R1 = 4-NO2C6H4, R2 = Ph

Scheme 108

R

H O Br

N

O

EtOH N

Me

..

Me

H +

R

N O

N

Br O

N N Ph

Ph (353) (352)

(354)

R

O N O

Me N N Ph

(a) R = H, (b) R = Me2N, (c) R = PhNH, (d) R = Cl

Scheme 109

(355)

Sec. XI.E]

199

REACTIONS OF THE RING ATOMS

N,N-dimethyl-4-nitrosoaniline 350. Heinisch condensed compounds 349a–e with 350 by heating in dry pyridine and obtained (E/Z)-4-(4-dimethylamino-phenylimino)pyrazol-3-ones 351a–e in good yields. Grigg found that pyrazol-3-ones 349f,g required heating with 350 in absolute ethanol at 78 C to give excellent yields of pyrazol-3-ones 351f,g whereas El-Shahawy who prepared 351d, from 349d and 350, used instead of pyridine as solvent, ethanol with a catalytic amount of piperidine. When 4-bromopyrazo-3-ones condense with arylnitroso compounds the reaction takes a diﬀerent course and gives nitrones. Tacconi et al. (80JPR679) (Scheme 109) demonstrated this by reacting 4-bromopyrazol-3-one 352 with aryl nitroso derivatives 353a–d in ethanol at room temperature to yield nitrones 355a–d, in yields ranging from 55 to 80%. The reaction proceeds via adduct 354, which then loses hydrogen bromide.

E. WITH ARYL HYDRAZINES Condensations by nucleophiles onto the carbonyl group of the pyrazol-3-one ring are rare. The condensation of 1,2-dihydropyrazol-3-one 356 with 2-amino-4-chloro6-hydrazinopyrimidine 357 in ethanol under reﬂux in the presence of a catalytic amount of glacial acetic acid aﬀorded hydrazone 358 in 30% yield. The (E/Z)-5ethylideneaminopyrazol-3-one Schiﬀ bases 359a–c required heating in glacial acetic acid with sodium acetate and 357 in order to give the corresponding hydrazones 360a–c that were obtained in 65, 70 and 60% yield, respectively (92JIC882), (Scheme 110). Me

H2N H2N

Me N

O

N

H2N +

Me

N

NHNH2

N

H

EtOH / ∆

Cl

(356)

(357)

N

N

N Me

Ph

MeCO2H

Ph

N

N H2N

N

Cl (358) Ar

Ar H

H Me

O

N N

N

Me

N

Me

+

(357)

EtOH / ∆ H

MeCO2H

N

N

N

N Me

Ph

Ph N (359) H2N

N

Cl (360)

(a) Ar = 4-ClC6H4, (b) Ar = 4-ClC6H4, (c) Ar = 4-NO2C6H4

Scheme 110

200

[Sec. XI.F

GEORGE VARVOUNIS ET AL.

F. BY CONJUGATE ADDITION-ELIMINATION This type of condensation occurs readily at C4 of 2,4-dihydropyrazol-3-ones. It takes place in two steps: addition of pyrazol-3-one C4 onto an electrophile and then elimination of a neutral molecule to form a double bond. A second elimination of a neutral molecule may occur to form an exocyclic alkene at C4 of the pyrazol-3-one. Tetracyanoethylene has been used as an electrophile by two diﬀerent groups of researchers, Junek et al. (88M993) and Elnagdi and co-workers (89LA1037) (Scheme 111). Reaction with pyrazol-3-ones 361a–c was conducted in reﬂuxing ethanol and the products 2-(3-oxopyrazol-4-ylidene)malononitriles 362a–c, usually deeply coloured, were obtained in over 80% yield. These compounds were further reacted with aliphatic, aromatic and heterocyclic amines. Maquestian et al. (84BSB1073) (Scheme 112) describe the reaction of pyrazol-3ones 363a–e with ethyl 3-aminobut-2-enoate 364 as taking place in two steps, possibly because intermediate 365 is relatively stable. After initial conjugate addition, elimination of ammonia from 365 yields (E/Z) ethyl 3-(5-oxopyrazol-4ylidene)butanoates 366a–e. Cˇiernik and Mistr (66CCC4669) (Scheme 113) studied the addition of bispyrazol3-one derivatives 367a onto salts of heterocyclic quaternary bases 368a and determined that the elimination of ethanediol, N-phenylacetamide or aniline provided bispyrazol-3-ones 369a. The reactions were performed in reﬂuxing ethanol containing triethylamine. The yield was moderate. Two years later Kisˇ a and Hadra´cˇek (68M2365) (Scheme 114) used the same principle to react 2-(triazin-3-yl)pyrazol-3-one 370 with salts of heterocyclic bases 371a–c to obtain pyrazol-3-one derivatives 372a–c, that have been used as merocyanin dyes. Abdel-Latif (91IJC(B)363) (Scheme 115) demonstrated that the reaction of 4bromopyrazol-3-one 373 with ethyl 2-cyano-3-thien-2-ylacrylate 374 in reﬂuxing ethanol containing a catalytic amount of piperidine gave pyrazol-3-one 377 in 50% yield. The ﬁrst step is postulated to give the intermediate 375 followed by elimination

CN R2

O

N N

R2

NC NC

CN

NC

CN

EtOH / ∆

+

O

N N

R1

R1

(361)

(362)

(a) R1 = R2 = Me, (b) R1 = H, R2 = n-Pr, (c) R1 = H, R2 = Ph, (d) R1 = H, R2 = NH2 Scheme 111

Sec. XI.F]

201

REACTIONS OF THE RING ATOMS

O Me

NH2

Me H N

EtOH / ∆

R

N

O

NH2

EtO

Me

EtO

+

N

O

Me

N R

(364)

(365)

(363)

-NH2

O Me

EtO

Me N

O

N R

(a) R = Ph, (b) R = 3-ClC6H4, (c) R = 4-ClC6H4

(366)

(d) R = 3-NO2C6H4, (e) R = 4-NO2C6H4 Scheme 112

Y

Y

N

N Et

O N N N

H C

n

n

H C

X

O

C H

Ph

Y (CH=CH)nZ

+

N

N

Ph

Et3N / ∆

Et

(367)

(368)

X = -(CH2)4 -,

X

EtOH O

N

N

N

N

Ph

Ph

Et

C H O

(369)

or

,

CMe2 or - CH=CHY Se, = O, S,

Z = SEt, N(Ph)COMe or NHPh, n = 0, 1 or 2

Scheme 113

of hydrogen bromide to 376, which tautomerises to ethyl (3-oxopyrazol-4-yl)prop-2enoate 377. Wilde et al. (79JPR495) (Scheme 116) reacted pyrazol-3-ones 378a with diethyl (4-iminocyclohexa-2,5-dienylidene)ammonium salts 379 to aﬀord the addition products 380a that were then oxidized to 4-(4-diethylaminophenylimino)pyrazol-3-one 381.

202

[Sec. XI.G

GEORGE VARVOUNIS ET AL. H

X Me X N

O

EtOH / Et3N / ∆

Me H

Et

CH=CHN

+

N N

COMe

H

N

N Et

N

N

N N

N

N

(371)

Ph

N

O

Ph

Ph

Ph

Ph

(370)

(372)

Scheme 114

N Me NC N N H

Br

S

H O

S

C

Br

EtOH / ∆

+ EtO2C

EtO2C

H O

piperidine

H

Me N

N H

(374)

(373)

(375) -HBr

S

S

H N

NC

C Me

EtO2C

Me EtO2C

O

N N

O

N N

H

H

(377)

(376)

Scheme 115

G. BY ADDITION-ELIMINATION OF PYRAZOL-3-ONES TO ACTIVATED DOUBLE BONDS The introduction of an aminomethylene group into position 4 of 2,4dihydropyrazol-3-ones has been studied by Kreutzberger and Kolter (85AP89, 86AP865) (Scheme 117). The method involves the reaction of electron-deﬁcient 1,3,5-triazine with three equivalents of pyrazol-3-ones 382a,b in ethanol at ambient temperature to give the intermediate tripyrazol-3-one addition products 383a,b. The latter are very unstable and undergo atmospheric oxidative ring cleavage to the (E/Z)-4-aminomethylenepyrazol-3-ones 384a,b.

Sec. XI.G]

203

REACTIONS OF THE RING ATOMS

Et Et

X

N

N

+

N

H

N

Me Y

O

N

alcohol

Et

base

N

H

Ph

Me

X

Et

N

O

N Ph

(379)

(378)

(380)

[O]

Et

-HX

N

N

Me

Et O

N N Ph

(a) X = H, Me, Br, OH, SO3H, SCN, NO2, NO, NH2, NHCOMe, NHCSNH2, NHCOCCl3, or N(CH2CH2)2O

(381)

Scheme 116

Ar N N O

Me Me

O

N N

+

N

N

H

EtOH

N

O Ar

Ar

N

N

H Me

N

N

N

H

N

Me

(382)

O

N Ar

(383) atmospheric oxidation

H Me

H2N O

N N Ar

(a) Ar = 2-EtC6H4, (b) Ar = 4-ClC6H4 Scheme 117

(384)

204

[Sec. XI.G

GEORGE VARVOUNIS ET AL.

Ph S Ph Me

H

Ph

O

N

S ClO4

+

N Ph

N

O

MeCO2Na

N Ph

Ph

(62)

Me

H

MeCO2H

(385)

(386) [O2]

S Me N

O

N Ph (387)

Scheme 118

Wizinger and Angliker (66HCA2046) (Scheme 118) reported the only example of oxidative coupling between a 1,2-dihydropyrazol-3-one and a thiopyranylium salt. The reaction involved heating pyrazol-3-one 62 with 2,6-diphenylthiopyranylium perchlorate 385 in acetic acid and in the presence of sodium acetate to give, after atmospheric oxidation of intermediate 386, 4-(2,6-diphenylthiopyran-4-ylidene)pyrazol-3-one 387. In one report (87TL5165, 89JPS239) (Scheme 119), N-phenylformimidic acid ethyl ester, generated in situ by heating under reﬂux triethyl orthoformate and aniline in Ph

OH O

HC(OEt)3

N N

PhNH2

H N

NHPh

OEt

H

H O

O

N

R1 2

OH

OH N

N N

R1

R1 2

2

R

R

R

(388)

(389)

(390)

(a) R1 = R2 = H, (b) R1 = Me, R2 = H, (c) R1 = R2 = H, (d) R1 = Me, R2 = H, (e) R1 = H, R2 = Cl, (f) R1 = H, R2 = Me

Scheme 119

Sec. XI.H]

205

REACTIONS OF THE RING ATOMS

dry ethanol or toluene, was described to react with pyrazol-3-ones 388a–f to give, via intermediate addition product 389 that loses ethanol, (E/Z)-4-phenylaminomethylenepyrazol-3-ones 390a–f, in good to average yield. When the condensation of two equivalents of pyrazol-3-one 391 was conducted in reﬂuxing triethyl orthoformate without any amino compound, the reaction led to 4[(pyrazol-4-yl)methylene]pyrazol-3-one 393 (85S548) (Scheme 120). The reaction can be envisaged initially to give (E/Z)-4-ethoxymethylene-pyrazol-3-one 392 followed by conjugate addition of 391 to the exocyclic double bond of 392 and by elimination of ethoxide ion to give product ﬁnally. Me

..

.. O

N

H

N HO

OEt H OH O

OH

HC(OEt)3 / ∆

N

(396)

N

N

O

N

Me

Me

(391)

(392)

Me

OH

N N O H OH O

N N Me (393)

Scheme 120

H. BY NUCLEOPHILES ONTO 4-(SUBSTITUTED METHYLENE) PYRAZOL-3-ONES Hydrazones and malononitrile can attack the imine carbon of 4-(arylimino)pyrazol-3-ones resulting in an overall addition–elimination product. Heinisch (88JPR57) (Scheme 121) described the use of several hydrazone derivatives 395a–d,f in their reaction with (Z/E)-4-(arylimino)pyrazol-3-ones 394a-j in concentrated

206

[Sec. XI.H

GEORGE VARVOUNIS ET AL.

NMe2

Me2N NH2 3

3

R O

N .. N H O

R N

+

conc. H2SO4

H2N N C

N R1

NH2

N H

..

N

H

R

2

R2

N N R1

(395)

(394)

(396)

(a) R1 = H, R2 = Ph, R3 = NH2 (b) R1 = H, R2 = Ph, R3 = NMe2

NH2 R3

(c) R1 = H, R2 = Ph, R3 = NHCH2Ph (d) R1 = H, R2 = Ph, R3 = morpholino (e) R1 = Ph, R2 = Me, R3 = NMe2

N N

(f) R1 = Ph, R2 = Me, R3 = morpholino (g) R1 = H, R2 = Ph, R3 = SEt

O

Me N

(h) R1 = Me, R2 = Ph, R3 = SEt

N

(i) R1 = Ph, R2 = Me, R3 = SEt (j) R1 = R2 = Ph, R3 = SEt

Me (397)

Scheme 121

sulfuric acid. It was postulated that in the ﬁrst step hydrazones 395a–d,f add to C4 of pyrazol-3-ones 394a-j to give intermediate addition products 396a–j that lose 4dimethylaminoaniline to aﬀord 4-{(Z/E)-2-[(Z/E)-amino(subsituted)methylidene]hydrazono}-5-oxopyrazoles 397a–j. Hennig et al. (93JPR368) (Scheme 122) described the preparation of deeply colored 4-arylaminocyanomethylenepyrazol-3-ones 403a–g by the reaction of malononitrile with 4-aryliminopyrazol-3-one 398a–g in reﬂuxing ethanol. Initially the reaction is postulated to give intermediate 398 that decomposes to dicyanomethylenepyrazol-3-one 400 together with eliminated anilines 401a–g. Addition of the latter to the exocyclic double bond of intermediate 400 gives 402 that loses hydrogen cyanide to aﬀord the products 403a–g. The reaction of 4,40 -bipyrazolylidene-3,30 -dione 404 with diazomethane was investigated by Hennig et al. (89JPR584) (Scheme 123). The mechanism proposed involves initial attack by diazomethane onto position 4 or 40 of compound 404 to give intermediate inner salt 405. Intramolecular cyclisation of the latter gave dispiroundeca-3,9-diene-1,7-dione 406 in 47% yield. This compound was found to be unstable upon standing at room temperature. When heated in ethanol it quickly isomerized into 4-(pyrazol-4-ylmethylene)pyrazol-3-one 407, whose structure was unambiguously assigned by X-ray crystallography. These reactions are characterized by a two step process in which conjugate addition of nitrogen or carbon nucleophiles 408a–e to 4-(substituted methylene)pyrazol-3-ones 409a–e, is followed by the elimination of a small molecule from

Sec. XI.H]

207

REACTIONS OF THE RING ATOMS CN Me

NC

R

N

O

R

N Ph

H N

CN

Me

N

NC O

EtOH / ∆

(400)

Me

H NCCH2CN

N

O

N

+

N N

Ph

Ph

(398)

(399)

H2N

R

(401)

R

R

CN CN H

Me

N

(a) R = H (b) R = Me (c) R = Cl (d) R = NMe2 (e) R = NEt2 (f) R = NO2 (g) R = OMe

H

H

N

O

Me

N NC O

N

N N

Ph

Ph

(403)

(402)

Scheme 122

Ph

Ph N N

Ph O

ON

N

N

2

N

Me Me

N

CH2 Me

N N Ph (404)

Me Et2O

Me Me

CH2N N O

O

O

N

O

N Ph

N N Ph

(405)

(406)

Ph

N N

Me Me

O H O

N N Ph (407)

Scheme 123

208

[Sec. XI.H

GEORGE VARVOUNIS ET AL. ..

HNu

R4

(408) R3

R

R N

R2

R3

N

O ..

N

Nu

3

..

O

R4

Nu 2

R2

O

N

N N

R1

R1

R1

(409)

(410)

(411) SO2R5

(a) R1 = Ph, R2 = Me, R3 = H, R4 = Me2N, HNu = H2N H2N N

, N Me or H2NC6H4OCH(Me)2 O S (b) R = Ph, R = Me, R = H, R = NHPh, HNu = NH 3, 1-adamantyl or piperidine

where R5 = NH2, N=C(NH2)2, H2NCOMe,H2N 1

2

3

4

(c) R1 = 4-ClC6H4, R2 = Me, R3 = H, R4 = NH2, HNu = piperidine, morpholine or 4-FC6H4NH2 (d) R1 = Ph, R2 = Me, R3 = R4 = CN, HNu = 2-isopropylC6H4NH2, 3-ClC6H4NH2, R1 = Ph, R2 = n-C3H7, R3 = R4 = CN, HNu = PhNH2, 2-MeC6H4NH2, 3-MeC6H4NH2, 2,4-Me2C6H3NH2, 2-MeOC6H4NH2, 4-MeOC6H4NH2,2-isopropylC6H4NH2, 3-ClC6H4NH2, 3,5-(Cl)2C6H3NH2, 4-NO2C6H4NH2, R1 = R2 = Ph, R3 = R4 = CN, HNu = 3-ClC6H4NH2, R1 = Ph, R2 = NH2, R3 = R4 = CN, HNu = PhNH 2, 3-ClC6H4NH2, 3-MeC6H4NH2, 2-MeOC6H4NH2 or 4-MeOC6H4NH2, (e) R1 = Ph, R2 = Me, R3 = R4 = CN, HNu = PhNH2, 2-MeC6H4NH2, 4-MeC6H4NH2, 2-MeOC6H4NH2, 4-MeOC6H4NH2, 2-OHC6H4NH2, 4-OHC6H4NH2, 4-NH2C6H4NH2, 4-NO2C6H4NH2, 2-ClC6H4NH2, 4-ClC6H4NH2, 3-BrC6H4NH2, 4-CO2C6H4NH2, 2-NH2C6H4NH2, 2-SHC6H4NH2, 1- or 2-naphthyl, H2NC4H9, H2NC(Me)3, H2NCH2Ph, piperidine, 2- or 3-aminopyridine, S Ph

N or NH2

N H

N N H

Scheme 124

intermediates 410a–e, to give pyrazol-3-ones 411a–e (75PHA582, 81M369, 86AP865, 88M993, 89LA1037) (Scheme 124). Secondary and tertiary aromatic amines 413a–c and activated phenols 415a,b condense with 4-(dicyanomethylene)pyrazol-3-one 412 followed by hydrogen cyanide elimination to yield compounds 414a–c and 416a–b, respectively (89LA1037) (Scheme 125). R CN

CN

R1 N

Me

PhNR1R2

R

O

N N

N

O

Me

O

N

(412)

(a) R1 = R2 = Me, (b) R1 = R2 = Et, (c) R1 = H, R2 = Et

Scheme 125

N N Ph

Ph

Ph (414)

CN

HO (415)

(413)

2

R

HO Me

NC

(416) (a) R = 2-Me, (b) R = 3-HO

Sec. XII.B]

209

REACTIONS OF THE RING ATOMS

XII. Nucleophilic Addition The reactions described in this section refer to addition of C4 of pyrazol-3-ones onto diﬀerent types of electrophiles to form -bonds. Addition to ,-unsaturated compounds may involve the elimination of small molecules from the electrophile. A rare case would involve a double nucleophilic reaction by the pyrazol-3-one to form a spiro compound.

A. OF PYRAZOL-3-ONES

TO

AROMATIC ALDEHYDES

Zohdi and co-workers (92JCR(S)396, 92JCR(M)3015) (Scheme 126) have reported that reaction of pyrazol-3-one 417 with aldehydes 418a–d in benzene containing acetic acid and piperidine gives the aldol- type products 419a–d in good yields. In the I.R. spectra of the latter the presence of a broad absorption in the region 3400–2400 cm1 and also the absenceof the typical pyrazol-3-one carbonyl absorption at around 1670 cm1 suggests strong intramolecular hydrogen bonding. Nucleophilic addition by a 1,2-dihydropyrazol-3-ones such as Grignard reagent 420 to benzaldehyde gave 4-(hydroxyphenylmethyl)pyrazol-3-one 421 (00JOC4618) (Scheme 127).

B. OF PYRAZOL-3-ONES

TO IMINES AND IMINIUM

SALTS

The hetero-Michael addition of 2,4-dihydropyrazol-3-one 422a–h to trichloroacetaldimine derivatives 423a–h takes place best in apolar aprotic solvents and the Ar CF3 O

O C6H6 / MeCO2H

N

+

ArCHO

N

(418)

Ph

H

H O

piperidine / ∆

CF3 N

N Ph (419)

(417)

(a) Ar = Ph, (b) Ar = 4-MeC6H4, (c) Ar = 4-MeOC6H4, (d) Ar = 4-ClC6H4 Scheme 126

OH Me

i-PrMg

Me

Ph PhCHO

O

N N

O

Me

N N

Ph

Ph

(420)

(421) Scheme 127

Me

210

[Sec. XII.B

GEORGE VARVOUNIS ET AL.

O CCl3

2

R

R1

O

R1

N Cl3C

+

N

R2

N

H

C6H6 / ∆

N

O

N

N

O

R

R

(423) (422)

(424)

(a) R = Ph, R1 = R2 = Me, (b) R = R2 = Ph, R1 = Me, (c) R = Ph, R1 = Me, R2 = EtO, (d) R = Ph, R1 = Et, R2 = Me, (e) R = Ph, R1 = t-Bu, R2 = Me, (f) R = R1 = Ph, R2 = Me, (g) R = R1 = R2 = Ph, (h) R = 2,4,6-Cl3C6H2, R1 = R2 = Me, Scheme 128

2,4,5-trisubstitutedpyrazol-3-ones 424a–h are obtained in 50–90 yields (87S493) (Scheme 128). The addition of 1,2-dihydropyrazol-3-one 425 onto 3-aryltriazin-5(2H)-ones 426a,b required heating at 140 C in acetic anhydride. In the products 427a,b thus obtained, spectroscopic methods showed that addition occurred between C4 of the pyrazolone and C6 of the 1,2,4-triazinone, activated by acetylation at N1 (97JHC1013) (Scheme 129). The reaction of the carbanion of pyrazol-3-one 62 generated by hydroxide ion adds to C-5 of 3-chloro-1-methoxypyridinium perchlorate 428 in DMF and then undergoes base induced ring cleavage to yield the 1,2-dihydropyrazol-3-one 429 in only 33% yield (82AP817) (Scheme 130). The absence of strong base in the reaction between 1,2-dihydropyrazol-3-one 70 and N-methoxy-4-cyanoquinolinium perchlorate 430 in DMF aﬀorded the simple addition product 431 in 70% yield (88AP897) (Scheme 131). The addition of Grignard reagent 420 to imine 432 gave pyrazol-3-one 433 (00JOC4618) (Scheme 132).

R

N H N Me H O

N N Me (425)

Ph

O N

+ Ar

N

N N

o

Ac2O / 140 C O

(426)

O

O Me Me

N

N

Ph (427)

Scheme 129

Me

Sec. XII.C]

211

REACTIONS OF THE RING ATOMS

MeO N Cl Me

OH / DMF

+

N

O

Me

Cl ClO4

N

N

Ph

OMe

(62)

N

O

N

H

Ph

(428)

(429) Scheme 130

Me N

O

Me

N

Me

N CN + ClO4

N

Ph

DMF

MeO O

N Ph

OMe

(70)

N Me

(431)

(430)

Scheme 131

i-PrMg

O

Me N N Ph (420)

Me

Me

N +

N CH2

N

O

N

OCOCF3 (432)

Me

Ph (433)

Scheme 132

C. MICHAEL ADDITION OF PYRAZOL-3-ONES ,-UNSATURATED COMPOUNDS

TO

In this category of compounds 2,4-dihydropyrazol-3-ones are the active methylene compounds that react nucleophilically at C4. A characteristic reaction is the addition of pyrazol-3-ones 434a,b to 2-benzylideneindan-1,3-dione 435 in boiling methanol containing sodium methoxide to give the indan-1,3-dione derivatives 436a,b in 65 and 77% yield, respectively (90PHA255) (Scheme 133). Under analogous conditions pyrazol-3-one 62 and ,-unsaturated ketone 437 gave only 31% of 1,2dihydropyrazol-3-one addition product 438 (97PHA32).

212

[Sec. XII.C

GEORGE VARVOUNIS ET AL.

O O R

Ph

O H

MeOH / ∆

+

N

O

N

N

O

NaOMe

Ph

Ph

R

N Ph

O

(434)

(436)

(435)

O OH O Cl Cl

O

Et O

Me

O

Et O

+

N

H

N Ph

Me OH

N

O

NaOEt

Cl H

EtOH / ∆ N

Cl

O

Ph

(437)

(62)

(438)

Scheme 133

Addition of pyrazol-3-ones 439a,b to 2-(2-oxoindol-3-ylidene)malononitrile 440 gave adduct 441 (82CL1123) (Scheme 134). Ghani (91BCJ2032) (Scheme 135) prepared the 4-oxo-4-(4-methoxyphenyl)butyric acid derivative 443 by heating in benzene pyrazol-3-one 60 with 4-(4-methoxyphenyl)-4-oxobut-2-enoic acid 442. Another example of a Michael addition of a pyrazol-3-one onto ,-unsaturated derivatives is the reaction of compound 444 with arylidenemalononitriles 445a that gave pyrazol-3-one adducts 446a, carried out in boiling methanol containing a catalytic amount of morpholine (83JOU2291) (Scheme 136).

NC

CN

Me

O

N

+

O

N

N

R (439)

MeOH / Et3N

O O

N N R

H (440)

H

CH(CN)2 Me

N

(a) R = H, (b) R = Ph Scheme 134

(441)

Sec. XII.D]

213

REACTIONS OF THE RING ATOMS

OMe

OMe CO2H

O Me

Me C6H6 / ∆

O

N N

+

CO2H

O

Ph

H

N

O

N Ph

H

(443)

(442)

(60)

Scheme 135

H NC Me

O

N N H

Ar

CN

H

CN

MeOH / HN

+

O/ ∆

CN Ar

H H O

Me

N N H

(445)

(446)

(444)

(a) Ar = 2-MeC6H4, 4-MeC6H4, 2-NO2C6H4, 3-NO2C6H4, 4-NO2C6H4, 2-FC6H4, 3-FC6H4, 4-FC6H4, 4-ClC6H4, 3-BrC6H4, 4-BrC6H4, 2-MeOC 6H4, 4-MeOC6H4, 3-HOC6H4, 4-HOC6H4, 4-(Me)2NC6H4, 4-(Et)2NC6H3, 2,4-(MeO)2C6H3 or 3-HO-4-MeOC6H3

Scheme 136

D. BY ADDITION-ELIMINATION TO ,-UNSATURATED COMPOUNDS Abdel-Galil et al. (88BSF658) (Scheme 137) reported that heating pyrazol-3-one 62 with tetracyanoethylene in ethanol gave 2-(3-oxopyrazol-4-yl)-2-(pyrazol-4-yl)malononitrile 449. The reaction initially gives intermediate 447 followed by conjugative addition of a second molecule of pyrazol-3-one 62 to the exocyclic alkene bond of 447 that leads to addition product 448, which then tautomerises to stable product 449. Twelve years later Guard and Steel (01ARK732) (Scheme 138) proved that the reaction of tetracyanoethylene with pyrazol-3-one 62 in boiling ethanol aﬀords spiro{pyrano[2,3-c]pyrazole-4,40 -pyrazo}-30 -one 452 and not malononitrile 447 (Scheme 138) as reported by Abdel-Galil et al. (88BSF658). The structure of 452 was unambiguously assigned by an X-ray crystal structure. Compound 452 was independently proposed by Metwally et al. (91LA961) as the product of the reaction between 447 and 62. For the formation of 452 it was proposed that initially reaction of 62 and tetracyanoethylene gives intermediate 447, as previously, followed by the addition of a second molecule of 62 to C4 of 447. Addition of a carbonyl oxygen to a

214

[Sec. XII.D

GEORGE VARVOUNIS ET AL. Ph

Ph N N

.. O

..

N N

H

Me

O CN

CN Me NC

O

N

NC

CN

NC

CN

+

N

H

Me

Me

NC

EtOH / ∆

N

O

N

O ..

..

Me

N

N

Ph

Ph

Ph

(62)

(447)

(448)

Ph N

OH

N

CN Me

Me NC O

N

N H

Ph (449)

Scheme 137

Ph .. O

..

N N

O

N N

CN

NC

CN

+

EtOH /∆

..

N

Ph

Ph

(62)

(447)

Me

NC O

N

O

H

O.. NC

Me

N NC

N N Ph (450)

Ph

Ph

N N

N

N

O

O Me Me

H2N NC O

Me

N

H

Me CN Me

N

Ph

N N

Me Me

HN NC OH

N N

Ph

Ph

(452)

(451)

Scheme 138

Sec. XII.D]

215

REACTIONS OF THE RING ATOMS

nitrile group in 450 leads to cyclized intermediate 451, which then tautomerizes to spiropyrazolone 452. This type of addition also works for 1,2-dihydropyrazolones as demonstrated by Akgu¨n and Pindur (84M197) (Scheme 139). They described that two equivalents of pyrazol-3-one 70 react with one equivalent of 3-[4-(dimethylamino)phenyl]acrylaldehyde 453 in the presence of tetraﬂuoroboronic acid–diethyl ether complex to aﬀord, via the methylidene intermediate 454 the salt 455. Addition of methanol containing 10% ammonia gave the 4-[1-(3-oxopyrazol-4-yl)-3-phenylprop-2-enyl]pyrazol-3-one 456. The addition-elimination reaction between pyrazol-3-one 457 and (2Z)-2(benzoylamino)-3-(dimethylamino)acrylate 458 gave pyrazol-3-one 459, with loss of dimethylamine (89JHC1273, 91JHC1961, 00SL1077) (Scheme 140). Abarbi et al. (00JOC4618) (Scheme 141) prepared Grignard reagent 420 by treatment of the appropriate 4-iodopyrazol-3-one with diisoropyl magnesium. It then reacted with aliphatic aldehydes 460a–d or cyclopentanone to aﬀord the corresponding 4-(alk-1-enyl)pyrazol-3-ones 461a–d and 4-(cyclopent-1-enyl)pyrazol3-one 462. Orlova and Linerva (66JOU1103) and Pavlova and Samartseva (66JOU1686) (Scheme 142), working independently, heated pyrazol-3-one 62 with diaryl ketones NMe2

H H Me

O

N

N Me

Me

H HBF4 Et2O

+ Me2N

Ph

CH=CHCHO

O

(453)

(70)

N N

Me

Ph

BF4

(454) (70)

NMe2 BF4 Me Me H

Me N Ph

H Me

H

N O O

N N

NMe2

Ph N

OH

N H Me

H MeOH

Me

10% NH4OH

Ph (456)

HO

+ N Me N BF4 Ph (455)

Scheme 139

216

[Sec. XII.D

GEORGE VARVOUNIS ET AL.

H

MeO2C R

R CO2Me

H

PhOCHN

EtOH / ∆

+

N

O

N

O

N

Me2N

N

NHCOPh

Ph

Ph (458)

(457)

(459) Scheme 140

R RCH2CHO

Me

i-PrMg

Me

Me

O

(460) N

O

N

N

O

Me

N

Ph

Ph

(461)

(420)

N

O

Me

Me

N Ph (462)

(a) R = Et, (b) R = n-Pr, (c) R = Octyl, (d) R = (E)-2'-Octenyl

Scheme 141

R

Me

Me

Me

MeO R

O

N

+

H O

O Me Me

MeOH / ∆ O

MeCO2H

N

H

..

H OH

Ph

Ph (62)

N N

463)

(464) -H2O

R Me Me

O Me

O

N N Ph

(a) R = H, (b) R = Cl

(465)

Scheme 142

H

Sec. XII.D]

217

REACTIONS OF THE RING ATOMS

463a,b in methanol containing acetic acid and obtained the 4-(2-benzofuran-1-yl)1,2-dihydropyrazol-3-ones 464a,b. The reaction proceeds by addition of the pyrazol3-one onto the ketone to give intermediate addition products 465 which condensed intramolecularly. In the reaction of 1-acyl-3-aminopyrazol-3-one 466a with ethyl ethoxymethylenecyanoacetate 467a (X ¼ CN) or ethoxymethylenemalononitrile 467a (X ¼ CO2Et) initial addition gives intermediate 468 which then loses ethoxide anion to furnish a tautomeric mixture of pyrazole 469a/pyrazol-3-one 470a. Spectroscopic studies have shown that the pyrazole tautomer predominates almost exclusively (94JHC925) (Scheme 143). Nucleophilic addition to ,-unsaturated compounds by pyrazol-3-ones can occur in an indirect manner. This category of reactions involves ﬁrst condensation of a pyrazol-3-one to an aldehyde or addition–elimination of a pyrazol-3-one to an appropriate ,-unsaturated compound to give an intermediate 4-methylidenepyrazol-3-one derivative, followed by nucleophilic addition of a second molecule of pyrazol-3-one to the latter, to aﬀord methylene or substituted methylenebipyrazol-3ones. Thus reaction of pyrazol-3-ones 471a,b with formaldehyde in the presence of malononitrile can be explained by the formation ﬁrst of methylidene intermediate 472 followed by the addition of a second molecule of 471 to 472 to aﬀord the bipyrazol-3-one adducts 473a,b (83JOU2291, 91JCR(M)1019) (Scheme 144). The reaction of tetracyanoethylene with pyrazol-3-ones 474a,b in ethanol at 40 C is another example of this overall addition reaction and aﬀords the bis(3-oxopyrazol4-yl) (isocyano)acetonitriles 476a,b, via the intermediated condensation adduct 475 (73CB914) (Scheme 145). N C X NH2 NC N

O

N O

NH2

H

H

+

N

O X

R

OEt

N

OEt O

(467)

(466)

R (468) - OEt

X

X CN

CN NH2

H

N

O

(a) X = CN or CO2Et, R = Me, Me2CN, PhCH2, EtO or 4-ClC6H4

N O

R

(470)

Scheme 143

NH2

H

N

HO

N O (469)

R

218

[Sec. XII.D

GEORGE VARVOUNIS ET AL.

R2 1

R

R

CH2(CN)2 / ∆ O

+

N

O

R1

H 2

N

N

O

H

N

R

R

(471)

(472) (471)

O

R

R2

N

H R1

N H 1 R

N

O

(a) R = H, R1 = Me, R2 = Ph, 2-MeC6H4,

N R

2-NO2C6H4, 3-NO2C6H4, 3-NO2C6H4, 1

2

(b) R = Ph, R = Me, R = H

(473) Scheme 144

CN Me

O

N N

Me

NC NC

CN

NC

CN

+

o

EtOH / 140 C O

N N

R

R

(474)

(475) (474) O

R

CN

N

CN Me

N H Me O

N N R

(a) R = Ph, (b) R = 4-MeC6H4

(476) Scheme 145

Sec. XII.E]

219

REACTIONS OF THE RING ATOMS Ph

Ph N N

.. O

..

N N

H

Me

O CN

CN Me NC

O

N N

NC

CN

NC

CN

+

EtOH / ∆ O

Me

NC N

N

O ..

..

Me

H

Me

N

N

Ph

Ph

Ph

(62)

(447)

(477)

Ph N

OH

N

CN Me

Me NC O

N

N H

Ph (478)

Scheme 146

Fifteen years later, Abdel-Galil et al. (88BSF658) (Scheme 146) reported that heating pyrazol-3-one 62 with tetracyanoethylene in ethanol gave 2-(3-oxopyrazol-4yl)-2-(pyrazol-4-yl)malononitrile 478. The reaction initially gives intermediate 447 followed by conjugative addition of a second molecule of pyrazol-3-one 62 to the exocyclic alkene bond of 447 that leads to addition product 477, which then tautomerizes to stable product 478. Reactions of this type also involve 4-arylidenepyrazol-3-ones (or thiones) that have been isolated instead of being formed in situ. Thus pyrazol-3-ones 479a,b were treated with 4-arylidenepyrazol-3-ones 480a in 10% aqueous sodium hydroxide and 4-arylidenepyrazol-3- thiones 480b in boiling ethanol, respectively, to aﬀord in good yield 4,40 -benzylidenebipyrazol-3-ones 481a (69JIC893) and 4,40 -benzylidenebipyrazol-3-thiones 481b (84JIC640) (Scheme 147). The isolation of pyrazolylpyrazol-3-one/bis(pyrazolyl)methane perchlorates 483a was made possible by reaction of the stable benzylidenepyrazol-3-one perchlorate 482a with pyrazol-3-one 70 (83M219) (Scheme 148). Compound 482a was obtained by the reaction of 70 with 4-dimethylaminobenzaldehyde 484a in methanol containing perchloric acid. When this reaction was performed with benzaldehyde 484b or with arylaldehydes 484c,d with less cation stabilizing groups, the result was direct isolation of methane perchlorates 483b–d, respectively.

E. INTER- AND INTRAMOLECULAR ADDITION OF NUCLEOPHILES TO c-4 OF PYRAZOL-3-ONES The addition of chloroacetyl chloride to 4-(4-dimethylamino-phenylimino) pyrazol-3-one 484a,b in dry 1,4-dioxane in the presence of triethylamine was

220

[Sec. XII.E

GEORGE VARVOUNIS ET AL.

R1 N

N

R3 Me +

N

Me

Me

H

N

O

Me

H

10% aq. NaOH

N

X

O R3

O

N

N N

R1

R2

R2

(479)

(480)

(481)

(a) X = O, R1 = R2 = Ph, R3 = Ph, 4-ClC6H4 or 3-NO2C6H4, (b) X = S, R1 = H, R2 = Ph or R1 = R2 = Ph, R3 = Ph, 2-HOC 6H4 or 3-HOC6H4, 4-HOC6H4, 2-NO2C6H4, 3-NO2C6H4, 4-NO2C6H4 or OCH2C6H4 Scheme 147

Me

R

Me N

H O

N

Ph

Me +

N Me

Ph

N OH O

Ph Me

N Me

N

ClO4 R

Me

ClO4

(482)

O

N

N Me

Ph (70)

(70)

+ RCHO

Me HClO4 / MeOH

R

Me N

N Me N

N

(484)

Ph

Me

O O

Ph

H (a) R = 4-(Me)2NC6H4, (b) R = Ph, (c) R = 4-NO2C6H4, (d) R = 3-MeO-4-HOC6H3

ClO4 (483)

Scheme 148

postulated to give adducts 485a,b that cyclized by intramolecular acyl substitution to the spiroazetidinonepyrazol-3-ones 486a,b in 35 and 40% yield, respectively (79JPR870) (Scheme 149) The reduction of 4-[(2-nitrophenyl)methylidene]pyrazol-3-ones 487a,b by sodium borohydride and 10% palladium-on-charcoal in 1,4-dioxane followed by acetic acid treatment, aﬀorded mixtures containing spiroindolepyrazol-3-ones 489a,b and 4-(2-aminobenzyl)pyrazol-3-ones 490a,b (75CJC3645) (Scheme 150). A plausible explanation for the formation of derivatives 489 is concomitant reduction of the

Sec. XII.F]

221

REACTIONS OF THE RING ATOMS NMe2

NMe2

NMe2 O

Me

N

O

O 1,4-dioxane / Et3N

N N

Cl Cl

R1

H O

N

N N

1

R

R1

R2

R2

R2

(484)

(485) 1

Me

Cl

N

O

ClCH2COCl

N

H N HMe

2

(486) 1

2

(a) R = R = H, (b) R = R = NO2

Scheme 149

NO2

H

H R

O

R (i) NaBH4 / 1,4-dioxane 10% Pd-C

N N

O

(ii) MeCO2H

N

.. HO

N N Ph

Ph (487)

(488)

NH2 R

R N

N

O

(a) R = Me, (b) R = Ph

N

+

HO O

N

N

Ph

Ph

(490)

(489)

Scheme 150

exocyclic double bond, considered as part of an ,-unsaturated system, and reduction of the nitro to a nitroso group and then addition of C4 of the pyrazole as an enol to the nitroso group.

F. MICHAEL ADDITIONS

TO

PYRAZOL-3-ONES

Conjugate addition readily occurs onto 4-substituted methylenepyrazol-3-ones since the exocyclic double bond and the carbonyl group of these compounds act as a

222

[Sec. XII.F

GEORGE VARVOUNIS ET AL. R1

H

R1

Ar

Me

Ar

R1 +

N

O

Ar Me

Me

N

MeOH or EtOH

H2C

N

O

NaOH / RT

R2

R2

R2

Ph

N

HO

N

N Ph

Ph

(491)

(492)

(a) Ar = 4-MeC6H4, R1 = R2 = CN, (b) Ar = 4-MeOC6H4, R1 = R2 = CN, (c) Ar = 4-MeC6H4, R1 = R2 = CO2Me, (d) Ar = 4-MeOC6H4, R1 = R2 = CO2Me, (e) Ar = 4-MeC6H4, R1 = R2 = CO2Et, (f) Ar = Ph, R1 = CN, R2 = CONH2, (g) Ar = 4-MeC6H4, R1 = CN, R2 = CONH2, (h) Ar = 4-MeOC6H4, R1 = CN, R2 = CONH2, (i) Ar = Ph, R1 = CN, R2 = CO2Et, (j) Ar = 4-MeC6H4, R1 = CN, R2 = COEt

Scheme 151

typical ,-unsaturated group. Initial addition by a nucleophile may be followed by an intramolecular addition or substitution to give a spiropyrazol-3-one. The reaction of (E/Z)-4-arylidenepyrazol-3-ones 491a–c with reactive methylene compounds such as diethyl or dimethyl malonate, ethyl cyanoacetate or cyanoacetamide in alcoholic solution containing sodium hydroxide aﬀorded the corresponding addition products 492c–j. These adducts were found to be almost exclusively enol tautomers (79AP478) (Scheme 151). Metwally et al. (91LA961) (Scheme 152) reacted 4-(dicyanomethylene)pyrazol3-one 447 with malononitrile 493a or ethyl cyanoacetate 493b in dichloromethane CN

NC Me

NC

R +

N

O

N

N C

CH2Cl2 / Et3N / ∆

H2C

CN Me

R

CN

Ph

O

N N

H N Me

R H O

N N

Ph

Ph

(494)

(495)

(493) (447) Me R1

(a) R = CN, (b) R = CO2Et

N

O

N

H2C R2

H2N

Ph (62)

(497)

Me R NH2

NH2 O

CNMe

R1

O

CN Me

O Me

N

Ph N

N

N

Ph

N N Ph (496)

N R2 O

O

N Ph

(499)

(498)

Scheme 152

(c) R1 = Me, R2 = CO2Et (d) R1 = Me, R2 = CO2Et

Sec. XII.F]

223

REACTIONS OF THE RING ATOMS

containing triethylamine and obtained stable spiropyrazol-3-ones 496a,b. The formation of these adducts was explained by a 1,2-addition pathway where initial addition of the carbanionic compound on the exocyclic double bond gives intermediate 494 which cyclises to 495 and then tautomerises. In the case of active methylene derivatives capable of enolization, such as ethyl acetoacetate 497c (R1 ¼ MeCO, R2 ¼ CO2Et), acetylacetone 497d (R1 ¼ R2 ¼ MeCO) and pyrazol3-one 62, reaction with 447 aﬀorded, as sole products, the spiro-pyrazol-3-ones 498c,d and 499, respectively. Matsugo and Takamizawa (86JHC1159) (Scheme 153) treated 4-(1-methylethylidene)pyrazol-3-ones 500a,b with acetone in reﬂuxing triethylamine and obtained the addition products 501a,b in 80 and 77% yield respectively. However pyrazol-3one 500c under the same conditions gave the spiropyrazol-3-one derivative 505 in 63% yield. The formation of 505 can be explained by the initial addition of acetone carbanion to the exocyclic double bond to give 3-hydroxypyrazol 502, nucleophilic addition of C4 of the latter to a second molecule of acetone leading to 503, enolisation of 503 to 504 and intramolecular condensation to 505. Me

O

Me Me

Me

Me H

H Me2CO / Et3N / Ä

H Me O

N

O

N

R

O

Me N

Me Me

N

Me Me Me

O

N N

R

(a) R = Cl, (b) R = Br, (c) R = NO2

NO2

(501)

(500)

(505) Me2CO / Et3N / ∆ R = NO2

-H2O

Me Me

O

Me

Me

C O Me Me

HO Me

..

.. O

N

Me Me

Me

Me

Et3N

Me O

N

O

N N

CH2 H2O

Me Me O

Me Me Me N N

O

H

NO2 (502)

NO2 (503)

Scheme 153

NO2 (504)

224

[Sec. XII.F

GEORGE VARVOUNIS ET AL. R3

R2

R3

R3

N

CN

N 1

R2

R

3 NC

R

CN 1

R

NC

N

-HCN

R2

R

CN R1

4 NC

N

HO

N

N

Ph

Ph

(506)

(511)

hv / EtOH or Me2CO

hv / EtOH or Me2CO

or DMF / 100oC

or DMF / 100oC

-HCN

R4

CN

R2 R1

R2

N

R2

N

O

Ph (508)

R4

(510)

(507) N

HO

N

CN N

R1

N R3

O

R3

N

O

N

N N

Ph

Ph

(509)

(512) (a) R1 = Me, (b) R1 = Ph, (c) R1 = Me, R2 = R3 = H, (d) R1 = R2 = Me, R3 = H, (e) R1 = R3 = Me, R2 = H, (f) R1 = R2 = R3 = Me, (g) R1 = Ph, R2 = R3 = Me, (h) R1 = Me, R2 = R3 = R4 H, (i) R1 = R2 = Me, R3 = R4 = H, (j) R1 = Me, R2 = H, R3 = R4 = Me, (k) R1 = R2 = R3 = R4 = Me, (l) R1 = Ph, R2 = Me, R3 = R4 H

Scheme 153 (Continued)

The addition of indoles 507c–h and pyrroles 510i–m to 4-(dicyanomethylene) pyrazol-3-ones 506a,b gives (pyrazol-4-yl)(indolyl or pyrrol-3-yl)malononitriles 509c–h and 511i–m, respectively. Malononitriles 508c–h and 511i–m were subjected to either photolysis in ethanol or acetone, or thermolysis in DMF at 100 C to yield, after elimination of hydrocyanic acid, (E/Z)-4-methylenepyrazol-3-ones 509c–h and 512i–m, respectively. An NMR study of compounds 509d and 512i,j showed that they exist as E/Z isomer mixtures. The ratio of E/Z isomers was found to be about 70/30. UV–VIS data of several compounds are discussed by means of AM1 and INDO/S-CI calculations. An X-ray crystallographic analysis of compounds 509a is presented (92LA7) (Scheme 154). In another example of the use of indole as the nucleophile, solid reactions between 4-arylidenepyrazol-3-ones 513a–k and excess indole were carried out by grinding the reactants and allowing the reaction to proceed at room temperature. The 1-(3-indolyl)-1-(pyrazole-4-yl)methanes 514a–k were obtained in 41–67% yield (99JHC697) (Scheme 154). Junek et al. (92M581) (Scheme 155) demonstrated that the reaction of N,N0 -diphenyldiaza-18-crown-6 515 with pyrazol-3-one 447 in acetic acid at 40 C aﬀorded addition product 515 which could be converted into the

Sec. XII.F]

225

REACTIONS OF THE RING ATOMS

H

N

H

H Me

Me

Ar

Ar +

N

O

N

HO

N

N

N

Ph

Ph

H

(514)

(513)

(a) Ar = Ph, (b) Ar = 4-FC6H4, (c) Ar = 4-ClC6H4, (d) Ar = 4-BrC6H4, (e) Ar = 4-IC6H4, (f) Ar = 4-BzOC6H4, (g) Ar = 4-MeC6H4, (h) Ar = 4-MeOC6H4, (i) Ar = 4-NO2C6H4, (j)Ar = 4-NO2C6H4, (k) 4-HO, 3-MeOC6H3 Scheme 154

CN Me

NC N

Ph

O

O

O

O

N Ph +

O

N N Ph

(515) (447) MeCO2H / 40oC Me CN

Me CN

N

N

N

CN

Ph

O

O

O

O

N

N

N

CN

Ph O

O (516) MeOH / Hg / ∆ -2HCN

NC N

Me N

N

O

O

O

O

CN N

Me O

O

N Ph

Ph (517) Scheme 155

N

226

[Sec. XII.F

GEORGE VARVOUNIS ET AL.

N

N Ar Me

O

Ar Me

Ar

(519) N

O

O

N

H

N N

Me (521)

MeCN /∆

N

O

N

O

MeCN / ∆

N N

Ph

Ph

Ph

(520)

(518)

(522)

(519) NO2

MeCN /∆

(519) or (521)

N

O

Ar

Ar

Me

N

MeCN

N N

N

Ph X (523)

Me

Me

O

N N

MeCN / ∆

N

O

Ph

Ph (524)

N

X (525)

Scheme 156

(E/Z)-diphenyldiaza-18-crown-6-bispyrazolideneacetonitrile 517 by heating in methanol containing mercury. Abdel-Rahman and Abdel-Ghany published two papers (89SC1987, 91SC1281) concerning the reaction of (E/Z)-arylmethylidenepyrazol-3-ones with enamines (Scheme 156). In the ﬁrst paper, reaction of pyrazol-3-ones 518a,b,d with 1-morpholinocyclohexene 519 in reﬂuxing acetonitrile was described to give the less substituted alkylated enamines 520a,b,d. On the other hand, the more substituted alkylated enamines 522a–d and 523 were formed when pyrazol-3-ones 518a–d reacted under the same conditions with 1-piperidinocyclohexene 521 or when 518c was reacted with 519. In the second paper, the reaction of pyrazol-3-ones 518a–d with enamines 519 and 521 in acetonitrile at room temperature aﬀorded the Diels–Alder type dihydropyran adducts 525e,f. Upon heating in acetonitrile, 518e,f gave the Michael-type adducts 520a–d and 522a–d, respectively. It was therefore proposed that the reaction of 518 with either 519 or 521 in reﬂuxing acetonitrile proceeds via zwitterionic intermediate 524 that leads to products 525a–d. Further evidence of an intermediate 524 was obtained by the reaction of adducts 525e,f with tetracyanoethylene in reﬂuxing acetonitrile (Scheme 157, for e,f see Scheme 156). It was proposed that products 527e,f are derived from ring opening of 525 to 524, nucleophilic addition of the carbanionic form of 524 to tetracyanoethylene and intramolecular cyclization of intermediate 526 to aﬀord pyrazol-3-one derivatives 527e,f.

Sec. XII.H]

227

REACTIONS OF THE RING ATOMS

X N NC

Ar

CN

Me NC (525)

CN (524)

MeCN / ∆

X

N C

O CN

NC

CN

N N Ph

X

N

N NC

Ar Me

NC NC O

NC

Ar

CN

Me

N

NC

CN N Ph

NC O

N N Ph

(526)

(527) Scheme 157

G. BY GRIGNARD REAGENTS The addition of aliphatic and aromatic Grignard reagents 529a to (E/Z)-4arylidenepyrazol-3-ones 528b was reported by Afsah and co-workers (78IJC876) (Scheme 158) to aﬀord 4-diaryl(or arylalkyl)methylpyrazol-3-ones 530c–k in yields ranging from 64–73%.

H. BY SECONDARY AMINES OR THIOPHENOLS The additive behavior of the exocyclic double bond in position 4 of (E/Z)4-arylidenepyrazol-3-ones 532a–c was investigated with secondary amines and thiophenols. Thus reaction with piperidine, morpholine, thiophenol or 4-methylthiophenol gave the corresponding addition products 533d–f, in good yields (72JPR612, 78IJC876) (Scheme 159). 1,5-Diphenyl- or 1,5-difuran-2-yl-penta-1,4-dien-3-one 463a,b furnished the spiropyrazol-3-ones 464a,b by Michael addition with pyrazol-3-one 62 (99JCEN61) (Scheme 160).

228

[Sec. XIII.A

GEORGE VARVOUNIS ET AL.

H

H

Ar

Me

Ar

Me R

N

O

+

N

R1MgX

Et2O

N

O

N

(529)

R

R

(528)

(530)

(a) R1 = Me, Ph or cyclopentyl, (b) R = Cl, Ar = 4-MeOC6H4, 4-NO2C6H4, 4-Me2NC6H4, benzo[1,3]dioxol-5-yl or thien-2-yl, (c) R = Cl, R1 = Me, Ar = 4-MeOC6H4 (d) R = Cl, R1 = Me, Ar = 4-NO2C6H, 4, (e) R = Cl, R1 = Me, Ar = 4-Me2NC6H4 (f) R = Me, Ar = thien-2-yl, (g) R = Cl, R1 = Ph, Ar = 4-MeOC 6H4 (h) R = Cl, R1 = Ph, Ar = 4-NO 2C6, (i) R = Cl, R1 = Ph, Ar = benzo[1,3]dioxol-5-yl (j) R = Cl, R1 = Ph, Ar = 4-Me 2NC6H4, (k) R = Cl, R1 = cyclopentyl, Ar = 4-MeOC6H4 Scheme 158

H

H R

Ar

Ar R

2

R amines or thiophenols O

N N

benzene

O

N N

R1

R1

(532)

(533)

(a) R = Me, R1 = Cl, Ar = 4-MeOC6H4, (b) R = Me, R1 = Cl, Ar = 4-NO 2C6H4, (c) R = pyrid-3-yl, R1 = H, Ar = 4-MeOC6H4, (d) R = Me, R1 = Cl, R2 = piperidino, (e) R = Me, R1 = NO2, R2 = morpholino, Ar = 4-MeOC6H4, (f) R = pyrid-3-yl, R1 = H, Ar = 4-MeOC6H4, R2 = piperidino, morpholino, thiophenol or 4-methylthiophenol Scheme 159

XIII. Nucleophilic Substitution A. BY PYRAZOL-3-ONES Under appropriate conditions 1,2-unsubstituted 1,2-dihydro- and 2,4-unsubstituted 2,4-dihydropyrazol-3-ones take part in nucleophilic substitutions at N2. In 2,4dihydropyrazol-3-ones substituted at N1 nucleophilic substitution occurs at C4 as

Sec. XIII.A]

229

REACTIONS OF THE RING ATOMS O

Ar Me

Me ArCH=CHC(O)CH=CHAr

+

N

O

MeOH / Et3N Ar O

N (463)

Ph

N

N

Ph (a) R = Ph, (b) R = 2-Furyl

(60)

(464)

Scheme 160

R1 N N Br

Me N

N

Me

R

H O

O

2

+

Me2Co / Et3N /∆ O

N

R2 O

N

N N

R

R1

R

(535)

(536)

(537)

(a) R = R1 = Ph, R2 = Me, (b) R = Ph, R1 = H, R2 = Me, (c) R = R2 = Ph, R1 = 4-NO2C6H4, (d) R = R2 = Ph, R1 = H, (e) R = R2 = Ph, R1 = 2,4-(NO2)2C6H3, (f) R = Ph, R2 = Me, R1 = 2,4-(NO2)2C6H3, (g) R = Ph, R2 = Me, R1 = CONH2, (h) R = Ph, R2 = Me, R1 = 2,4-(NH2)2C6H3, (i) R = R1 = H, R2 = Me, (j) R = H, R1 = Ph, R2 = Me, (k) R = H, R1 = 4-NO2C6H4, R2 = Ph, (l) R = R1 = H, R2 = Ph, (m) R = H, R1 = 2,4-(NO2)2C6H3, R2 = Ph, (n) R = H, R1 = 2,4-(NO2)2C6H3, R2 = Me, (o) R = H, R1 = CONH2, R2 = Me, (p) R = H, R1 = 2,4-(NH2)2C6H3, R2 = Me Scheme 161

long as there is at least one hydrogen atom in that position. Nayak and Mittra (80JIC643) (Scheme 161) prepared 4,40 -bipyrazole-3,30 -diones 537a–p by reacting 4-bromopyrazol-3-ones 535a–p with pyrazol-3-ones 536a–p in reﬂuxing ethanol containing triethylamine. All these compounds were screened against the the rice blast pathogen Pyricularia oryzae and the brown leaf spot pathogen Helminthosporin oryzae to ﬁnd that most exhibit signiﬁcant fungicidal activity comparable to standard fungicides. Reaction of the carbanion of pyrazol-3-thione 539 with 4-bromopyrazol-3-one 538 in ethanolic sodium ethoxide aﬀorded 5-thioxo-4,40 -bipyrazol-30 -one 540 (83JIC679) (Scheme 162). On the other hand reaction of one equivalent of 4,40 -dibromopyrazol3-one 541 with two equivalents of 539 under the same reaction conditions yielded 5,500 -dithioxo-4,40 ,40 ,400 -terpyrazol-30 -one 542. Nucleophilic aromatic substitution of activated aryl halides has been reported for both 1,2-dihydro and 2,4-dihydropyrazol-3-ones. With 2-ﬂuorobenzonitrile 544 pyrazol-3-one 543 required heating at 100 C for 16 h in dimethyl sulfoxide in the

230

[Sec. XIII.A

GEORGE VARVOUNIS ET AL.

Ph N N Me

H

Me

R

S Me

Me

R

Br NaOEt / EtOH

+

N

O

S

N

N

Ph

Ph

(538)

(539)

N

O

N

N Ph (540)

(a) R = H, (b) R = NO Ph N

S

Me

N N Ph Me

N Br

Me

Me

Br +

N

O

S

N

NaOEt / EtOH

N

H H

Me

S N

O

N

N

Ph

Ph

Ph

(541)

(539a)

(542) Scheme 162

presence of powered potassium carbonate to give 2-(benzo-2-nitrile)pyrazol-3-one 545 in only 47% yield (94SC123) (Scheme 163). 1-Fluoro-2,4-dinitrobenzene 547 reacted similarly with pyrazol-3-ones 546a–g to give substitution products 548a–g (68BSF5019) (Scheme 164). Both 1,2-dihydro- and 2,4-dihydropyrazol-3-ones are known to substitute the chlorine atom of aliphatic and heterocyclic chloro imines and aliphatic trihalogenomethylimines. Nucleophilic substitution of 2-chlorobenzo[1,3]thiazole 550 by C-2 of 1,2-dihydropyrazol-3-one 549 requires heating at 120 C in DMF with a strong base such as sodium hydride. The product 551 was obtained in only 22% yield (88JHC543) (Scheme 165). The reaction of 2-unsubstituted pyrazol-3-one 552 with 1-chloropropane1,2-dione 1-(N-phenylhydrazone) 553 requires heating in ethanol containing triethylamine to give pyrazol-3-one 554 (84BCJ1650). Under similar conditions F

Me

Me CN

O

N N H

H

DMSO / K2CO3

+

100oC

O

N N

H CN

(544)

(543) (545) Scheme 163

Sec. XIII.A]

231

REACTIONS OF THE RING ATOMS

R1

R2

R1

F NO2

N

O

DMSO / K2Co3

+

100°C

N H

R2 N

O

N NO2

NO2

(546) (547) NO2 (548) (a) R1 = R2 = H, (b) R1 = H, R2 = Me, (c) R1 = Me, R2 = H, (d) R1 = R2 = Me, (e) R1 = H, R2 = Ph, (f) R1 = NO2, R2 = Me, (g) R1 = Br, R2 = Me Scheme 164

Me

Me S O

N N H

H

+

Cl N (550)

DMF / NaH 120oC

N

O

N S

H

N

(549)

(551) Scheme 165

pyrazol-3-one 62 displaced the triﬂuoromethyl group of 3,3,3-triﬂuoro-2-[(2,2,2triﬂuoroacetyl)imino]propanoate 555 to give the 4-substituted methyl triﬂuoroacetyliminoacetate derivative 556 (89IZV2131) (Scheme 166). Under acidic conditions the hydroxyl group of 2-(t-butyl)-5,5-dimethyl-4-(4methylphenyl)-2,5-dihydrofuran-2-ol 557, 9H-xanthen-9-ol 559a, 9H-thioxanthen9-ol 559b was displaced by C4 of pyrazol-3-one 62 in reﬂuxing methanol or ethanol to give the corresponding pyrazol-3-one derivatives 558 and 560a,b in 70, 91, and 76% yield, respectively (66JGU215, 80JHC1339, 82JHC437). The reaction worked equally well with 4-aminopyrazol-3-one 561 and either 559a or 559b to give 4-substituted pyrazol-3-ones 562a,b in 84 and 61% yield, respectively (80JHC1339, 82JHC437) (Scheme 167). One year later Okabayashi and co workers (83CPB3718) (Scheme 168) obtain an X-ray crystal structure of 560b and established that it was a diﬀerent tautomeric form than that previously assigned in the liquid state. In the solid state 560b was found to be in the ‘‘N–H’’ tautomeric form 563 where the molecules are linked by an intermolecular hydrogen bond between N–H and C¼O groups. Tetraglucose 565 was derivatised with pyrazol-3-one 564 by dissolving it in methanol containing sodium hydroxide and heating in a sealed tube at 70 C.

232 Me

O

[Sec. XIII.A

GEORGE VARVOUNIS ET AL.

Me

O

N

+

N

N

Me

EtOH / Et3N / ∆

NHPh

N

O

N

Cl

H

PhHN (553)

(552)

N

COMe

(554) F3C

Me

O

O +

N

CF3

F3C

N

OMe

N

N O H

EtOH / Et3N / ∆

O O

Ph

N N Ph

(555)

(62)

CO2Me Me

(556)

Scheme 166 Me Me

O

C(Me)3 Me

Me

Me N

Me

+

N

MeOH / MeCO2H / ∆

OH

O O

O

Me

Me

C(Me)3

N N Ph

Ph

(558)

(557)

(62)

X OH

Me MeOH / MeCO2H / ∆

+

(62)

O X

N N Ph

(559) (560)

X NH2

NH2 O

N

+

(559)

MeOH / MeCO2H / ∆ O

N

N N

Ph

Ph

(561)

(562) (a) X = O, (b) X = S

Scheme 167

Sec. XIII.A]

233

REACTIONS OF THE RING ATOMS

S Me N

O

N

H

Ph (563) Scheme 168

The pyrazol-3-one labeled sugar derivative 566 was obtained in quantitative yield (99JMAS502) (Scheme 169). A mass spectrometric study of this product using ESIMS and ESI-MS/MS revealed that in comparison with tetraglucose, the labeling process increases the positive mode ESI sensitivity by a factor of 10. This derivatisation also made the fragmentation pattern easier to interpret than for tetraglucose itself, owing to the dominant reducing end-containing fragment ions. 2,4-Dihydropyrazol-3-ones bearing a hydroxyethyl side-chain at C4 can undergo intramolecular substitution of the hydroxyl group at the same position to give a spiropyrazol-3-one. On the other hand, the hydroxyethyl group of 1,2dihydropyrazol-3-ones was converted into a bromoethyl group before cyclization. Me MeOH / NaOH N

O

N

+

H

tetraglucose (565)

Ph (564) H OH HO

HO HO

H H

OH HO

H

HO

HO HO

H H

OH

H OH HO

O HO

H H

H H OH

OH O HO

N

Me H OH

H

H O Me

OH

H O N

N

Ph (566) Scheme 169

N Ph

H

234

[Sec. XIII.A

GEORGE VARVOUNIS ET AL.

Thus heating 4-(2-hydroxyethyl)pyrazol-3-ones 567a–d in concentrated sulfuric acid at 80–90 C gave the corresponding spiropyrazol-3-ones 568a–d (84CZ285). 4-(2Hydroxyethyl)pyrazol-3-ones 569a,b were converted into the corresponding 4-(2bromoethyl) derivatives 570a,b by heating at 80 C with 62% hydrobromic acid. Addition of 570a,b to DMSO containing potassium carbonate at room temperature aﬀorded the respective spiro compounds 571a,b. This experiment was also done directly in an NMR tube with hexadeuterated DMSO and base (99EJMC967) (Scheme 170). A noteworthy reaction is the overall substitution of the aldehyde group of C4 of pyrazole-3-one 572 by C4 of a second molecule of 573. The reaction took place in a methanolic solution of sodium borohydride and led to pyrazol-4-ylmethylenepyrazol-3-one 575 (75LA2293) (Scheme 171). The mechanism proposed by the authors consists of deprotonation of 433 and addition to a neutral molecule of the same compound to give intermediate 573 after loss of hydroxide ion. Further loss of formaldehyde results in the allene 574, which is reduced to pyrazol4-ylmethylenepyrazol-3-one 575. An interesting reaction between pyrazol-3-one 62 and N,N0 -diphenylformamidine 576 has appeared in a patent (69GEP1800581) (Scheme 172). The reaction took place by heating these compounds in a mixture of acetaldehyde and triethylamine and gave, in excellent yield, (E/Z)-4-[3-(pyrazol-4-yl)prop-2-enylidene]pyrazol-3-one 581. The proposed mechanism suggests initial substitution and loss of aniline, addition of acetaldehyde to the ,-moiety of pyrazol-3-one, loss of aniline from 578 to a 3-(5oxo-pyrazol-4-ylidene)propionaldehyde 579c, addition of a second molecule of 62 to HO Me

Me H2SO4, 80 - 90oC O

N

O

N

N N

R1

R1 2

2

R

R

(567)

(568)

(a) R1 = H, R2 = Cl, (b) R1 = R2 = Cl, (c) R1 = H, R2 = NO2, (d) R1 = H, R2 = Me Br

HO

Me

Me

O

N N

H

80oC

Me DMSO

62% HBr O

N N

H HBr

K2CO3

O

N N

R

R

R

(569)

(570)

(571)

(a) R = H, (b) R = Me

Scheme 170

Sec. XIII.A]

235

REACTIONS OF THE RING ATOMS Ph

N

N

CHO Me H O

CHO Me NaBH4

N N

+

N

O

MeOH

(572)

CHO Me N

O

N

Ph

Me

O H

N Ph

Ph

(573)

(572)

Ph N O H CH2O

+

NaOH

O

N

Ph

Me H

O

Me N

N

N

Me

N

Me

C

NaBH4 O

N N

Ph

Ph

(575)

(574)

Scheme 171

the aldehyde group of the latter, and elimination of water followed by tautomerism to aﬀord 581. Compounds such as 581 have found application as photographic sensitizers and as dyes for polyamide ﬁbers. Twelve years later Rockley and Summers(81AJC1117) (Scheme 173) limited the above reaction to the substitution and isolated several 4-(arylmethylidene)pyrazol3-ones 584 by heating pyrazol-3-ones 582 and N,N0 -diarylformamidines 583 at 170–180 C. Pyrazol-3-one 62 is also known to attack C4 of 4-aryliminopyrazol-3-one 585. Compounds such as 585 known as azomethine dyes react with pyrazol-3-one 62 and lose 4-dimethylaminoaniline to give the proposed intermediate 586. Addition of a second molecule of 62 yields the 4,40 -bis(5-hydroxy-1H-pyrazol-4-yl)pyrazol-3-one 587. The reaction takes place in reﬂuxing methanol but upon heating 587 at 140 C, loss of a pyrazole molecule and tautomerism leads to compound 588 (88JPR435) (Scheme 174). Nucleophilic attack by N2 of pyrazol-3-ones 589a–e on chloramines displaced chloride anion to give 2-aminopyrazol-3-ones 590a–e in good yields (81JHC957) (Scheme 175). Several reports describe the reaction of pyrazol-3-ones with amidines and iminium salts where the group displaced is an amine. Nucleophilic substitution of ammonia by 2,5-dimethylpyrazol-3-one 591 attack on benzamidine hydrochloride 592 requires 220 C to give via addition intermediate 593 4-[imino(phenyl)methyl]pyrazol-3-one

236

[Sec. XIII.A

GEORGE VARVOUNIS ET AL. NHPh Me Ph

O

Me

H

N

+

N

H

N

N

O

Ph

+

PhNH2

N

H

Ph

(576)

(577)

Ph (62)

N

MeCHO / Et3N / ∆

Ph N N Me

O H

H

OHC

HO

H

H

Me

H (62)

N

O

NHPh

OHC Me

O

N

H

- PhNH2

N

Me

H

N

O

N

N

Ph

Ph

Ph

(580)

(579)

(578)

-H2O N Me

Ph

N

OH

H H

Me

H

O

N N Ph (581)

Scheme 172

H

Ar Me

O

N N

Me

N Ar +

H

o

N

N

170-180 C

H O

Ar

N N

R

H

R

(582)

(583)

(584)

+

PhNH2

(a) R = H, Ar = Ph, (b) R = Me, Ar = Ph, (c) R = H, Ar = 2-ClC6H4, (d) R = Me, Ar = 2-ClC6H4, (e) R = H, Ar = 3-ClC6H4, (f) R = Me, Ar = 3-ClC6H4, (g) R = H, Ar = 4-ClC6H4, (h) R = Me, Ar = 4-ClC6H4

Scheme 173

Sec. XIII.A]

237

REACTIONS OF THE RING ATOMS Ph N

O

N Me

O

N

Me2N

N

+

Me N

O

N

Me Me

MeOH / ∆

N

O

N

N

Ph

Ph

Ph

(62)

(585)

(586) (62)

Ph Ph

N N

N

HO Me

O

N Me

H

140oC N

O

Me Me

N

Me Ph

N N

OHO

N

N

Ph

Ph

(588)

(587)

Scheme 174

R2

O

R3 N N

R1

R2 +

NH2Cl

R3

Et2O / DMF

Na

O

N N

R1

NH2 (589)

(590)

(a) R1 = R3 = Me, R2 = Ph, (b) R1 = R2 = Me, R3 = Ph (c) R1 = Me, R2 = R3 = Me, (d) R1 = Bz, R2 = Ph, R3 = Me, (e) R1 = Bz, R2 = Me, R3 = Ph Scheme 175

594 in 60% yield. The compound is stabilized by intramolecular hydrogen bonding (73CB332) (Scheme 176). On the other hand 2,4-dihydropyrazol-3-one 595 under similar reaction conditions attacks acetamidine hydrochloride 596 to give (E/Z)-4-(1-aminoethylidene)pyrazol3-one 598 in 63% yield (74CPB207) (Scheme 177). The adduct 597, formed initially in this reaction, must be losing ammonia via an elimination process involving H4. On the other hand, in the analogous adduct 593 (Scheme 176), proton loss from C4 follows neutralisation of the positive change on N1, whereas loss of ammonia is triggered by lone-pair conjugation from the neutral amino group.

238

[Sec. XIII.B

GEORGE VARVOUNIS ET AL.

H

Me

N

.. Ph NH2 H ClH3N

NH3Cl

Ph Me

o

O

N N

H

Me

-NH3

200 C

+

O (592)

(591)

N N

H HH

Me

N H O

N

H

N

Me

Me

(593)

(594)

Scheme 176

Me NH2 H

Me NH3Cl O

N N H

NH2 Me

ClH3N +

Me

Me

210oC

Me

O NH (596)

(595)

N N

O

N N

H

H

(597)

(598)

Scheme 177

The reaction of pyrazol-3-one 62 with iminium salts is similar to the above addition–elimination process involving pyrazol-3-one C4/H4. In the ﬁrst example, two equivalents of pyrazol-3-one 62 react with iminium perchlorate 599 in tetrahydrofuran containing sodium hydride to aﬀord the (E/Z)-bipyrazol-3-one derivative 600 in only 32% yield (82AG559). Without the use of basic conditions one equivalent of 62 reacted with iminium chloride 601 in acetonitrile to give (Z)-4-(3,3dichloroprop-2-enylidene)pyrazol-3-one 602 in 84% yield (97S573) (Scheme 178). In the reaction of pyrazol-3-ones with imines, alkoxide groups have also been displaced from heterocyclic derivatives. Thus the reaction of 10-thia-8-azabenzo[a]azulene 603 with pyrazol-3-one 62 in reﬂuxing ethanol aﬀorded pyrazol-3-one derivative 604 in 42% yield (73AP531). When the electrophile used was 2-nbutoxyazepine 605 reaction with 62 took a diﬀerent path in the elimination step. Loss of n-butanol from adduct 606 gave 4-(azepin-2-ylidene)pyrazol-3-one 607 in 62% yield (88T3309) (Scheme 179). Reaction of 62 with dithiobenzoic acid 608 in 50% methanol containing sodium hydroxide gave 609 by a manner analogous to the reaction leading to compound 607 in Scheme 179. The yield of 613 was very low (18%) (81JCS(P1)2948) (Scheme 180). The reaction of 5-hydroxypyrazol-3-ones 610a,b with diaryldisulﬁdes 611a,b in DMF with potassium carbonate and bubbling air aﬀorded the corresponding 4-phenylthiopyrazol-3-ones 612a–c in moderate yields (00JHC911) (Scheme 181). The arylthiolate anions were recovered as starting disulﬁdes after air oxidation.

B. ON MONO-

OR

DIHALOGENOPYRAZOL-3-ONES

Halogens at positions 4 of pyrazol-3-ones can be displaced by both aliphatic and heterocyclic carbon and nitrogen nucleophiles and can be oxidized by lead(II)

Sec. XIII.B]

239

REACTIONS OF THE RING ATOMS

Ph N

N

O

Me

H

PPh3 Me N

O

Me

H PPh3

NaH / THF

NMe2

Me2N

+

N

O

N

N

2ClO4

Ph

Ph

(599) (600)

(62) Cl Cl H

+

(62)

Me

H

Cl Cl

MeCN

N

N

O

N

O

Cl

Ph

(601)

(602) Scheme 178

N O

N

S

Me EtOH / ∆

+

N N

S

O OEt

Ph

N N Ph

(62)

(603)

(604)

N H

N H H Me (62)

EtOH / ∆

+

Me

H

N n-BuO

n-BuO O

N N Ph

(605)

(606)

Scheme 179

Me - n-BuOH O

N N Ph (607)

240

[Sec. XIV

GEORGE VARVOUNIS ET AL.

Ph S

Me

SH

+

N

O

Me

S H

MeOH / NaOH

N

O

N Ph

N Ph

(608)

(609)

(62) Scheme 180

OH

S

OH atmospheric O2 O

N N

Ph

+

R

ArSSAr

DMF / 90- 95oC

O

N N

Ph

+

ArS

R

(611)

(612)

(610) (a) R = H, Ar = Ph, (b) R = Ar = Ph, (c) R = Ph, Ar = 4-ClC6H4

Scheme 181

acetate. 4-Bromopyrazol-3-one 613 was treated with acetylacetone 614a, diethyl malonate 614b or ethyl acetoacetate 614c in an ethanolic solution of sodium ethoxide to aﬀord in good yield the corresponding 4-substituted derivatives 615a–c (84ZN(B)86). When the reaction was repeated between 613 and pyrazol-3-thione 616a,b, 617a,b was obtained. The same reaction conditions allowed 4,40 dibromopyrazol-3-one 618 and two equivalents of 616 to react and give 619 (83JIC679) (Scheme 182). The reaction with nitrogen nucleophiles such as sodium azide works very well with 4,4-dichloro-3-one 620 and 4,4-dibromopyrazol-3-ones 622 in boiling ethanol and give high yields (91%) of 4,4-diazopyrazol-3-ones 621a,b (76TL2513, 80ZC437). Heterocyclic amines 624a required reﬂuxing in ethanolic sodium hydroxide in order to displace bromide ion from 4-bromopyrazol-3-ones 623a and give 4-thiazolidine derivatives 625a. Some of these derivatives exhibited signiﬁcant antifungal activity against the pathogens P. oryzae and H. oryzae (84JIC77) (Scheme 183). 4,4-Dibromopyrazol-3-ones 626a,b were treated with lead(II) acetate in acetic acid to aﬀord pyrazol-3,4-diones 628a,b. The reaction is believed to occur through initial nucleophilic substitution of both bromine atoms by acetate ion to give an intermediate 4,4-diacetoxypyrazol-3-one 627a, which is unstable and loses acetic anhydride (84S972) (Scheme 184).

XIV. Oxidation Depending on the substitution of the pyrazol-3-one ring, oxidation can lead to pyrazol-3-one radicals, carbonyl group formation on the ring or oxidative coupling.

Sec. XIV.A]

241

REACTIONS OF THE RING ATOMS

H Me

Br

Me

R1 R1CH2R2

+

N

O

R2

EtOH / NaOEt

N

O

N

N

(614)

Ph

Ph

(613)

(615)

(a) R1 = R2 = MeCO, (b) R1 = R2 = CO2Et, (c) R1 = MeCO, R2 = CO2Et Ph N N S

Me Me

Me

R

R (613)

EtOH / NaOEt +

N

S

N

O

N

N Ph

Ph (616)

(617) (a) R = H, R = N=O N

Me S

Ph

N

Ph

N Br

MeS

N

Me

Br O

N

+

(616)

EtOH / NaOEt

N Ph

Me

O

N N Ph

(481)

(482) Scheme 182

Furthermore, pyrazol-3-ones have been oxidized by a variety of oxidizing agents such as ozone in oxygen, hydrogen peroxide solution, 3-chloroperbenzoic acid, aqueous sodium periodate, lead(IV) acetate with boron triﬂuoride etherate, or atmospheric oxidation. The reactions lead mainly to epoxidation of an alkene or imine functionality and cleavage of the pyrazol-3-one ring.

A. NITROXIDE FORMATION

VIA

PYRAZOL-3-ONE RADICALS

Omelka et al. (93JPR435) (Scheme 185) oxidized pyrazol-3-ones 629a–k with lead(IV) oxide in benzene, 4-nitrobenzenoic acid in benzene or Co(II)-acetylacetone t-butylhydroperoxide mixture. The resulting pyrazol-3-one radicals 630a–k were detected by ERS spectroscopy directly, or after trapping with nitrosobenzene as phenyl nitroxides. Thus oxidation of pyrazol-3-ones 629b–e,j with lead(IV) oxide in

242

[Sec. XIV.B

GEORGE VARVOUNIS ET AL.

Cl

N3

Me

Cl

NaN3 / EtOH N

O

N

Me

Br

NaN3 / EtOH

N

O

Br

Me

N3

N

O

N

N

Ph

R1

R1

(620)

(621)

(622)

(a) R1 = Ph or 4-BrC6H4, R2 = Me, Ph 4-NO2C6H4 or NH2, (b) R1 = Ph, R2 = Me R1 H

S R1 Br

Me

S S

N

O

N

N

H +

O

N

S

H O

N N

H

R

(624)

(625)

R (623)

EtOH / NaOH / ∆

O Me

(a) R = H or Ph, R1 = Ph, 4-MeOC6H4, 2-NO2C6H4, 3-NO2C6H4, 4-NO2C6H4, 2-HOC6H4, 3-HOC6H4, 4-HOC6H4, 2-HO-4-MeOC6H3, OC6H4, 4-CH2=CHC6H4 or 4-(Me)2NC6H4 Scheme 183

Br

O

OAc Me

Me

Br

Pb(OAc)2 / AcOH N

AcO O

N R (626)

N N

Me

O -(MeCO)2O O

N N

R

R

(627)

(628)

(a) R = H, (b) R = Ph

Scheme 184

the presence of nitrobenzene aﬀorded phenyl nitroxides 631b–e,j. Under the same reaction conditions pyrazol-3-one 629h gave nitroxide 632 and pyrazol-3-ones 629f,g,h gave nitroxides 633f,g,k.

B. OXIDATION OF RING CARBON ATOMS FOLLOWED BY ADDITION The oxidation of pyrazol-3-ones 634a–c with 30% hydrogen peroxide in glacial acetic acid led to the 4,40 -bipyrazolyl-3,30 -dione 636a–c in 66, 38, and 96% yield respectively. The reaction occurs via oxidation to pyrazol-3,4-diones 635a–c

Sec. XIV.C]

243

REACTIONS OF THE RING ATOMS Ph

O

N

Me

1

R

N

O

N R (631)

or 4-NO2C6H4CO2H / C6H6

R1

Me

Ph

C6H5NO

PbO2 / C6H6 R1

or CoII -MeCOCH2COMe /

N O Me

Me

t-BuO2H / C6H6 O

N N

N

O

H

O

N

N N

R

R

H

(629)

(630)

(632)

H

C6H5NO R1

O

Me Ph

N N R

O

(633) 1

1

1

(a) R = Ph, R = H, (b) R = Ph, R = Me, (c) R = Ph, R = Et, (d) R = Ph, R1 = n-Pr, (e) R = Ph, R1 = i-Pr, (f) R = R1 = Ph, (g) R = H, R1 = Me, (h) R = H, R1 = Ph, (i) R = R1 = H, (j) R = o-tolyl, R1 = Me, (k) R = o-tolyl, R1 = Ph,

Scheme 185

followed by addition of the corresponding pyrazol-3-one 634 to the appropriate intermediate 635 (94JPR70) (Scheme 186).

C. OXIDATIVE COUPLING Slow air oxidation of 4,5-dialkylpyrazol-3-ones 637a–f gave a mixture consisting of 4-hydroxypyrazol-3-ones 638a–f resulting from the oxidation of H4 and chiral forms 639a–f and 640a–f resulting from oxidative coupling of the starting material at C4 (72ACS3685) (Scheme 187). Mittra and Rout (69JIC893) and Mittra and co-workers (83JIC679) have oxidized 4,40 -benzylidenebipyrazol-3-ones 641a–c and 643 by reaction with iodine and potassium iodide in 20% aqueous sodium hydroxide (Scheme 188). The corresponding oxidation products bipyrazolonecyclopropanes 642a–c and dipyrazolonepyrazolthionecyclopropane 644 were isolated in good yields. Furthermore Mittra and co-workers (83JIC679) used the same reaction conditions to oxidize 50 -thioxo4,40 -bipyrazolyl-3-one into 50 -thioxo-4,40 -bipyrazolyliden-3-one (Scheme 188).

244

[Sec. XIV.D

GEORGE VARVOUNIS ET AL. R

N N O

Me H2O2 / MeCO2H N

O

N

O N

O

N

N

R

R

(635)

(636)

R (634)

H

634

N

O

Me Me

O

Me

(a) R = H, (b) R = Ph, (c) R = CONH2

Scheme 186

R1

R1 N N

N

3

R

2

R

R2

3

O

3

R

R2

HO O

N N

air oxidation O

N

+

N

R R R3 2

O

N N

R3 +

N O 3

R2 O

R2 R N N

R1

R1

R1

R1

(637)

(638)

(639)

(640)

(a) R1 = H, R2 = Bz, R3 = Me, (b) R1 = Me, R2 = Bz, R3 = Me, (c) R1 = R3 = Ph, R2 = Me, (d) R1 = Ph, R2 = R3 = Me, (e) R1 = Ph, R2 = n-Bu, R3 = Me, (f) R1 = Ph, R2 = Bz, R3 = Me

Scheme 187

Pfeiﬀer et al. (92JPR365) (Scheme 189) demonstrated that oxidative coupling of pyrazol-3-one 62 with (3H-thiazol-2-ylidene)hydrazine 648a–f gave 4-[(3H-thiazol-2ylidene)hydrazono]pyrazol-3-one 649a–f by two methods. In the ﬁrst method potassium hexacyanoferrate was used as oxidant with hydrazones 648a–f as free bases. In the second method peroxidase and 30% aqueous hydrogen peroxide were used as oxidants with hydrochloric salts of hydrazones 648a–f. Aqueous DMF was the solvent in both cases. The yields of 649a–f by both methods were nearly quantitative.

D. WITH OZONE Harnish et al. (69JOC1687) (Scheme 190) introduced a dilute stream of ozone and oxygen into a methylene chloride solution of pyrazol-3-one azomethine 650 and obtained major reaction products 651a–d, and minor reaction products 652e,f and 653g,h.

Sec. XIV.D]

245

REACTIONS OF THE RING ATOMS

Ph N

Ph

O

N

N N

Ar Me H

I2 / KI / 20% aq. NaOH

Ar H

N

O

Me Me

O

Me

N

N

O

N

Ph

Ph

(641)

(642)

(a) Ar = Ph, (b) Ar = 4-ClC6H4, (c) Ar = 3-NO2C6H4 Ph N

Me

S

N

Me

N Ph Me

N H H

Me

Ph I2 / KI / 20% aq. NaOH

S N

O

N

S

Ph

N

Me S

N N

N

O Me

N

N

Ph

Ph

(643)

(644)

Ph N N

Ph

Me

N

Me

N

S Me

Me

H

S

I2 / KI / 20% aq. NaOH N

O

N

O

N

N

Ph

Ph

(645)

(646) Scheme 188 R2 R1 R2

Me

S

R3

N N

N O

+

N

R1

N Ph

S

N

R3

N

NH2

Me

K3[Fe(CN)6] O

or peroxidase / H2O2

N N Ph

(648)

(62)

(649) 1

3

2

1

2

3

1

2

3

(a) R = R = Me, R = Ph, (b) R = Me, R = R = Ph, (c) R = R = Ph, R = Me, (d) R1 = R2 = R3 = Ph, (e) R1 = R2 = Ph, R3 = i-Pr, (f) R2 = R3 = Me, R1 = CO2Et

Scheme 189

246

R1

Me Me

[Sec. XIV.F

GEORGE VARVOUNIS ET AL. 2 N R

N

N

Me

N

R1 N

R2 R

Me

O

N

Me

N

Me

O

O3 / O2 / CH2Cl2 O

N

O

N

N

+

N

O

N

N

+

O

N N

Ph

Ph

Ph

Ph

(650)

(651)

(652)

(653)

(a) R1 = R2 = Me, (b) R1 = H, R2 = Me, (c) R1 = H, R2 = CHO, (d) R1 = Me, R2 = CHO, (e) R1 = H, R2 = Me, (f) R1 = Me, R2 = CHO, (g) R = NO2, (h) R = NH2

Scheme 190

E. WITH HYDROGEN PEROXIDE Nye and Tany (73CJC338) (Scheme 191) oxidized 2,4-dihydropyrazol-3-one 654 with 30% hydrogen peroxide in methanol at C4 to give 4-hydroxypyrazol-3-one 655, in 76% yield. Ph

O

Ph

Ph

H N N

30% / H2O2 / H2O MeOH

Ph

HO O

N N

Me

Ph

(654)

(655) Scheme 191

Oxidation of 4-(substituted methylene)pyrazol-3-ones 656a–n with 30% hydrogen peroxide in methanolic sodium hydroxide aﬀorded the 1-oxa-5,6-diazaspiro[2,4]hept-6-ene-4-ones 657a–n in good yields The conformation of 657m was determined by X-ray crystallography and found to have the (2R, 3R) conﬁguration. Similar geometry was assigned to compound 657l, however the conﬁguration of 657n was assigned (2S,3R) (83JCS(P1)325) (Scheme 192).

F. WITH 4-CHLOROBENZOIC ACID Oxidative cleavage of pyrazol-4,5-dione-4-[N-(pyrazol-4-yl)]hydrazone 658 occurred when this compound was oxidized with 4-chloroperbenzoic acid (73G179) (Scheme 193) to give pyrazole diazonium salt 659 in 72% yield, oxadiazol-5-one 660 in 0,5% yield, hydrazone derivative 661 in 10% yield and the bispyrazole 662 in 17% yield. Oxidation of hydrazone 663 under similar conditions

Sec. XIV.F]

247

REACTIONS OF THE RING ATOMS

R4

R4 2

3

R

R

3

R

R2

O

30% H2O2 / H2O N

O

O

NaOH / MeOH

N

N N

R1

R1

(656)

(657)

(a) R1 = Ph, R2 = R3 = R4 = Me, (b) R1 = R2 = Ph, R3 = R4 = Me, (c) R1 = 4-MeOC6H4, R2 = R3 = R4 = Me, (d) R1 = R4 = Ph, R2 = Me,R3 = H, (e) R1 = R2 = R4 = Ph, R3 = H, (f) R1 = 4-MeOC6H4, R2 = Me, R3 = H, R4 = Ph, (g) R1 = 4-NO2C6H4, R2 = Me, R3 = H, R4 = Ph, (h) R1 = Ph, R2 = Me, R3 = H, R4 = 4-Cl2C6H4, (i) R1 = Ph, R2 = Me, R3 = H, R4 = 4-NO2C6H4, (j) R1 = Ph, R2 = Me, R3 = H, R4 = 2-naphthyl, (k) R1 = R2 = Ph, R3 = H, R4 = 2-naphthyl, (l) R1 = R3 = Ph, R2 = EtO, R4 = H, (m) R1 = 4-NO2C6H4, R2 = EtO, R3 = Ph, R4 = H, (n) R1 = 4-NO2C6H4, R2 = pyrrolidino, R3 = Ph, R4 = H Scheme 192

N N Ph N

OH

+

N

CO3H

N N

Ph

O N

O

N

Ph

Ph

O

Ph

Ph

Ph

N N

(660)

(659) Cl

H N

O

CHCl3

N Ph

Ph

Ph

N (658)

O

N

N

N N N

Ph

O Ph

Ph Ph N

O

+

N

O

N N

Ph

Ph

(661)

(662)

Ph N

OH

CO3H

N Me

N N N

N

Me

Ph Br2 / CHCl3

Cl

H O

N N

O

N N

Ph

Ph

(663)

(664)

Scheme 193

(658)

(661)

248

[Sec. XIV.H

GEORGE VARVOUNIS ET AL. R2 1

R

N

Me NaIO4 / H2O N

O

Me

N

Me

N

N

N

MeOH O

Ph

R1

O

Ph

R2

O

(666)

(665)

(a) R1 = R2 = H, (b) R1 = H, R2 = Me, (c) R1 = R2 = Me, (d) R1 = H, R2 = i-Pr, R

Me

Me NaIO4 / H2O

N

O

Me

N

Me

N

MeOH O

Ph (667)

O R

N Ph

O

(688) R = H, Me, Et, i-Pr or OH

Scheme 194

gave pyrazol-3-one diazonium salt 664 in 63% yield. The other components of this reaction were not identiﬁed. A more selective oxidation of hydrazone 658 took place when bromine in chloroform was used. Hydrazone derivatives 661 was obtained in about 90% yield (Scheme 193).

G. WITH SODIUM METAPERIODATE Sodium metaperiodate in aqueous methanolic solution oxidatively cleaved pyrazol-3-ones 665a–d into 666a–d in 64–98% yield. Under the same conditions pyrazol-3-ones 667a–e were cleaved to give the respective 668a–e in 49–94% yield (88AP551) (Scheme 194).

H. WITH LEAD(IV) ACETATE Gillman et al. (94SC2133) (Scheme 195) found a convenient method to prepare methyl 2-bromo-2,3-butadienoate 670 via oxidative ring cleavage of H

Me

Br

Pb(OAc)4 O

N N

H

BF3OEt / MeOH

H

H C

MeO

Br O

(669)

(670) Scheme 195

Sec. XV.B]

249

REACTIONS OF THE RING ATOMS

H

N H

Me SH O

S

atmospheric O2 NH

O

N

N N

Ph

Ph

(671)

(672) Scheme 196

4-bromopyrazol-3-one 669 using lead(IV) acetate and boron triﬂuoride etherate in 59% yield. Compounds such as 670 are valuable building blocks for the synthesis of 2-aryl and 2-alkenyl substituted alka-2,3-dienoates via palladium-catalysed crosscoupling reactions.

I. BY ATMOSPHERIC OXIDATION Coutts et al. (76CJC993) (Scheme 196) managed to convert pyrazol-3-one 671 into spiro compound 672 by subjecting an ethanolic solution of 671 to atmospheric oxidation for 48 h. Compound 672 was obtained in 33% yield.

XV. Reduction Reductions aﬀecting the ring atoms of a pyrazol-3-one are of two types. Selective reductions of a dichloromethyl group into a chloromethyl group and the reduction of the lactam carbonyl into either a methylene group or a secondary alcohol. Exocyclic double bonds at C4 of pyrazol-3-ones such as imino groups of oximes and various alkenyl derivatives are prone to reduction under relatively mild conditions.

A. OF 4,4-DICHLOROPYRAZOL-3-ONES Selective reduction of 4,4-dichloropyrazol-3-ones 673 has been accomplished in a two-step process involving ﬁrst reaction with triethyl phosphite followed by alkaline hydrolysis of the intermediate phosphate ester 674. 4-chloropyrazol-3-ones 675 were obtained in yields ranging from 60–80% (77USP4021445) (Scheme 197).

B. OF THE CARBONYL GROUP OF Pyrazol-3-ONES Abdel-Hamid and co-workers (91BCJ3713, 91BSF884) (Scheme 198) studied the kinetics of the chemical and electrochemical reduction of 4-(arylmethylene)-pyrazol3-ones 676a,b and 4,4-dimethylpyrazol-3-one 681. The study was conducted in

250 Cl

R1

Cl O

[Sec. XV.B

GEORGE VARVOUNIS ET AL.

(EtO)3P

N

R1

Cl OEt

O

(i) HO- / H2O

P EtO

N

O

R

R1

Cl

N

N

O

(ii) H+ / H2O

N

N R

R

(673)

(675)

(674) R = CH2CF3, Ph or 2,4,6-(Cl)3C6H2, R1 = NH2, Me or 4-ClC6H4NH

Scheme 197

R

R

Me

H

N N

Me

H H Al H O

Et2O

N Ph

(676)

(677)

N

O

N

Ph

Me

H

H

AlH3 O

R

H

N

Al H

Ph (678)

(a) R = OMe, (b) R = Br R

Me

Me

Me

Me O

Me

Me N N

AlH3 Et2O

Me

H

N

N

N

N

R

Me

H H

N N

Ph

Ph

Ph

Ph

(681)

(682)

(680)

(679)

Scheme 198

tetraethylammonium perchlorate and DMF solution using a hanging dropping mercury electrode. The products exhibited two diﬀusion-controlled irreversible mono electronic CV waves. Both waves follow ErevCirr kinetics and are attributed to pyrazoles 680a,b and 682, where reduction of the carbonyl group selectively occurred. Chemical reduction of pyrazol-3-ones 676a,b and 681 was carried out by aluminium hydride in diethyl ether. Selective reduction of the carbonyl group also occurred to give pyrazoles 680a,b and 682 in 50, 80 and 22% yield, respectively. In the proposed mechanism for this reduction, coordination is ﬁrst assumed to occur between the carbonyl oxygen and the aluminium followed by intramolecular hydride

Sec. XV.C] Me

Me

R

Me

NaBH4 / t-BuOH N

O

251

REACTIONS OF THE RING ATOMS

N O

Me H

N N

HO O

Ar

R

Ar

(a) R = Me, Ar = Ph (b) R = H, Ar = 4-MeC6H4 (c) R = Me, Ar = 4-MeC6H4 (d) R = Me, Ar = 4-ClC6H4 (e) R = Ph, Ar = 4-MeC6H4

(684)

(683)

Scheme 199

transfer in 677 and hydrolysis of 678, and ﬁnally hydride addition to cation 679 to give 680. Intermediate 677 must play an important stabilizing role facilitating the reduction. Mitikidou and Stephanidou-Stephanatou (91JHC49) (Scheme 199) managed to reduce the ring carbonyl group of 1-acylpyrazol-3-ones 683a–e into the corresponding alcohols 684a–e by reaction with sodium borohydride in t-butanol.

C. REDUCTION

OF

EXOCYCLIC DOUBLE BONDS

Khaikin et al. (65ZOR133) (Scheme 200) reduced thirteen (E/Z)-pyrazol-3-one-4oximes 685a,b by catalytic hydrogenation in ethanol at 40–50 C using Raney nickel catalyst, and obtain fairly good yields of the corresponding 4-aminopyrazol-3-one hydrochlorides 686a,b. Coutts et al. (75CJC3637) and Wrzeciono et al. (78PHA264) (Scheme 201) reduced the respective 4-[(2-nitrophenyl)methylidene]pyrazol-3-ones 687a–c and 4-[(2-furfuryl)methylidene]pyrazol-3-ones 687d–i with sodium borohydride in 1,4-dioxane and obtained the corresponding pyrazol-3-ones 688a–i in moderate to good yields. Compounds 688d–i exhibited signiﬁcant antibacterial action against Escherichia coli K12.J5, Salmonella panama Nr. 73 and Staphylococcus aureus 209P strains. In an attempt to synthesize 4-phenylmethylidene-3-phenyliminopyrazoles 691 Tomasik and co-workers (01ARK63) (Scheme 202), condensed 4-phenylmethylidenepyrazol-3-ones 689 (R ¼ Me or MeO) with anilines 690a–p under various HO R2

N

R2

HCl.H2N Raney Ni / H2

O

N N

EtOH / 40-50oC

O

N N

R1

R1

(685)

(686)

(a) R2 = Me, R = C6H11, C6H13, PhCH2, Ph(CH2)2, Ph, 2-MeC6H4, 4-MeC6H4 or 2-MeOC6H4, (b) R2 = Ph, R1 = H or Me Scheme 200

252

[Sec. XV.C

GEORGE VARVOUNIS ET AL.

H R1

2

R

O

R1

R2 NaBH4 / 1,4-dioxane

N

O

N

N N

Ar

Ar

(687)

(688)

(a) R1 = Me, R2 = 2-NO2C6H4, Ar = Ph, (b) R1 = Ar = Ph, R2 = 2-NO2C6H4, (c) R1 = Me, R2 = 2-NO2-5-ClC6H3, (d) R1 = Me, R2 = furfur-2-yl, Ar = 2-ClC6H4, (e) R1 = Me, R2 = furfur-2-yl, Ar = 3-ClC6H4, (f) R1 = Me, R2 = furfur-2-yl, Ar = 4-ClC6H4, (g) R1 = Me, R2 = 5-NO2furfur-2-yl, Ar = 2-ClC6H4, (h) R1 = Me, R2 = 5-NO2furfur-2-yl, Ar = 3-ClC6H4, (i) R1 = Me, R2 = 5-NO2furfur-2-yl, Ar = 4-ClC6H4, Scheme 201

R1

R1 O

N

R2

NH2

Me

Me

+

N

N

N

N

Ph

R2

Ph

(689)

(690)

(691)

R1

R1

Me

Me R2

(689) N N

+

N Ph

O

N N Ph (692)

(693)

(a) R1 = R2 = MeO, (b) R1 = MeO, R2 = H, (c) R1 = MeO, R2 = Me, (d) R1 = MeO, R2 = t-Bu, (e) R1 = MeO, R2 = F, (f) R1 = MeO, R2 = Cl, (g) R1 = MeO, R2 = Br, (h) R1 = Me, R2 = H, (i) R1 = R2 = Me, (j) R1 = Me, R2 = Et, (k) R1 = Me, R2 = n-Bu, (l) R1 = Me, R2 = F, (m) R1 = Me, R2 = Cl, (n) R1 = Me, R2 = Br, (o) R1 = Me, R2 = MeO, (p) R1 = Me, R2 = PhO

Scheme 202

Sec. XVI]

253

REACTIONS OF THE RING ATOMS

conditions such as heating in the presence of anhydrous zinc chloride, with phosphorus pentoxide in xylene or in ethylene glycol. The resulting products were 4-benzylpyrazol-3-one 692 (R1 ¼ Me or MeO) and pyrazolo[3,4-b]quinolines 693a–p in a ratio of 1:1. It was suggested that pyrazol-3-ones 689 acted as oxidants on the initially formed pyrazoles 691 that led to products 692.

XVI. Cycloaddition Pyrazol-3-one derivatives have taken part in both 1,3-dipolar cycloaddition and Diels–Alder reactions. The 1,3-dipolar cycloaddition between (Z)-pyrazol-3-ones 694a–g with an excess of ethyl vinyl ether gave the pyrazol-3-one-4-spiro-3isoxazolidines 695a–g, in nearly quantitative yield (82G483) (Scheme 203). The kinetics of this reaction was studied by quantitative spectroscopic analysis. The rate of reaction increases with the electron-withdrawing character of the substituent on the aromatic ring and a linear relationship is obtained between log k and p constants. The LUMO nitrone–HOMO vinyl ether is taken as the dominant interaction. Tacconi and co-workers (79JCS(P1)856) (Scheme 204) describe the [4 þ 2] and [2 þ 2] cycloaddition of 4-arylidenepyrazol-3-ones 696a–d and 697e–m with N,N0 diethylaminomethylacetylene. Pyrazol-3-ones 696a–d have an (E)-conﬁguration and pyrazol-3-ones 697e–k have a (Z)-conﬁguration. The reaction was performed in cooled benzene and gave a mixture of two products, pyrano[2,3-c]pyrazoles 698a–k via a [4 þ 2] cycloaddition and (4Z,20 E)-4-(1-diethylamino-2-methyl-3-arylpropenylidene)pyrazol-3-ones 670a–k via a [2 þ 2] cycloaddition to give intermediate spirocyclobutenepyrazol-3-ones 699, followed by electrocyclic ring opening. Both products were obtained in almost quantitative yield and could be separated by fractional crystallization or column chromatography. Righetti and co-workers (85TL3137, 88T5229) (Scheme 205) studied the thermal reaction between 4-arylidenepyrazol-3-ones and 2,3-dimethylbutadiene with the purpose of evaluating the electronic and conﬁgurational factors that aﬀect the R

R

H Me

O N

N N

N

EtO H

O

O Me

H

+

O OEt

N N

Ph

Ph

(694)

(695)

(a) R = H, (b) R = Me (c) R = Cl, (d) R = Br, (e) R = I, (f) R = NO2, (g) R = CO2Me Scheme 203

254

[Sec. XVI

GEORGE VARVOUNIS ET AL. R2

R2

Me Et2N

O

H 1

1

R

H

R

R2

R1 N N Ph

Et2NCCMe O

N N

or

O

N

(698)

N

Ph

Ph

(696)

(697)

R2

R2

(a) R1 = R2 = H, (b) R1 = H, R2 = Br (c) R1 = H, R2 = NMe2, (d) R1 = H, R2 = NO2, (e) R1 = Me, R2 = H, (f) R1 = Me, R2 = Br, (g) R1 = Me, R2 = NMe2, (h) R1 = Me, R2 = NO2, (i) R1 = Ph, R2 = H, (j) R1 = Ph, R2 = Br, (k) R1 = Me, R2 = NMe2, (l) R1 = Me, R2 = NO2

Me

2' 1

R Et2N O

3'

Me

Me

N N

Et2N O

R1

1'

N N

Ph

Ph

(699)

(670)

Scheme 204

reactivity, as well as the inﬂuence of various catalysts on both reactivity and selectivity. The solvent for the thermal reactions was benzene and the temperature 80 or 120 C. Thermal reaction of (E)-4-arylidenepyrazol-3-ones 671a–c, with R2 ¼ H or an electron-withdrawing group on the arylidene substituent and 2,3dimethylbutadiene 672 at 80 C gave a mixture of Diels–Alder adducts 673a–c in 90% yield and heterodiene adducts 674a–c in 10% yield. (E)-4-Arylidenepyrazol-3-ones 671d,e with electron-releasing groups on the arylidene substituent react with 672 at 120 C to give Diels–Alder adducts 673d,e as single products in 90 and 97% yield, respectively. The reaction of (Z)-4-arylidenepyrazol-3-ones 675f,g,i,j with 672 at 80 C gave both Diels–Alder adducts 673f,g,i,j and 676f,g,i,j and heterodiene adducts 674f,g,i,j and 677f,g,i,j. The yield of adducts 673f,g,i,j are 73,48, 40 and 40%, of adducts 674f,g,i,j 8, 6, 20 and 20%, of adducts 676f,g,i,j 14, 40, 25 and 25% and of adducts 677f,g,i,j 2, 4, 10 and 10%, respectively. Interestingly, (Z)-4-arylidenepyrazol-3-ones 675h,k and 672 at 120 C gave a mixture of Diels–Alder adducts 673h,k in 85 and 52% yield and 676h,k in 9 and 43% yield, without any trace of heterodiene adducts. The reasoning given by the authors for the outcome of these reactions is the following. Electron-releasing substituted pyrazol-3-ones (E)-671d,e, and (Z)-675h,k, (Scheme 205) did not yield dihydropyran derivatives because at 120 C they underwent [3.3] sigmatropic rearrangement to become spirocyclohexene derivatives. The reactions of (E)-pyrazol-3-ones 671a–c were stereospeciﬁc as explained by the Diels–Alder reactions occurring with retention of conﬁguration of the dieniphile, and the heterodiene reactions occurring through a stabilized endo transition state.

Sec. XVI]

R2

R2

H

R1

H O

255

REACTIONS OF THE RING ATOMS

Me

H

(672)

H R1

Me

+

N

O

Me

O

Me

N

N N

Ph

Ph

(673)

(674)

H

(E)-(671)

H

R1

C6H6 / ∆

Me

Ph

H

Me

H

+

N N

R2

R2 R2 H

H

H Me

1

R

R2

R1 Me

C6H6 / ∆ O

N

+

(672)

Me

N Ph (Z)-(675) C6H6 / ∆

(E)-(671d,e)

(Z)-(675f,g,i,j)

(Z)-(675h,k)

+

+

+

H

R1

(672) C6H6 / ∆

O

N

Me

+

N

N

O

N

Ph

Ph

(676)

(677)

(673d,e) (679f,g,i,j)

+

(674f,g,i,j)

(676f,g,i,j)

+

(677f,g,i,j)

(672)

C6H6 / ∆ (672)

(673h,k)

+

(676h,k)

(a) R1 = R2 = H, (b) R1 = H, R2 = NO2 (c) R1 = H, R2 = CN, (d) R1 = H, R2 = OMe, (e) R1 = H, R2 = NMe2, (f) R1 = Me, R2 = H, (g) R1 = Me, R2 = NO2, (h) R1 = Me, R2 = NMe2, (i) R1 = Ph, R2 = H, (j) R1 = Ph, R2 = NO2, (k) R1 = Ph, R2 = NMe2

Scheme 205

The reactions of (Z)-pyrazol-3-ones 675f–k were not stereospeciﬁc since both diastereoisomers 673 and 676 and 674 and 677 were obtained. The thermal reaction of both (E)- and (Z)-4-arylidenepyrazol-3-ones 671 and 675 with 672 was inﬂuenced dramatically in the presence of acids. For example, in the reaction 671a with 672a not only the rate was found to increase dramatically in the presence of AlCl3 or TiCl4 (4 h at room temperature) but also the chemoselectivity was changed since the diene adduct 673a was the only product, in 95 and 90% yield, respectively. The same occurred with (E)-4-arylidenepyrazol-3-ones 671b–d and 672, AlCl3 acting more eﬃciently than other catalysts (TiCl4 or CF3CO2H) since single products 673b–d were obtained in about 95% yield. With (Z)-arylidenepyrazol-3ones 675 the reaction with 672 in the presence of various acids catalysts was not as chemoselective. The reaction with the highest chemoselectivity was between

256

[Sec. XVI

GEORGE VARVOUNIS ET AL.

(Z)-benzylidenepyrazol-3-one 675f and 672 in the presence of AlCl3 that gave a mixture containing 92% of 673 and 3% of 676. Diels–Alder adducts of pyrazol-3-ones 678a,b were obtained by reaction with Nchlorosulfenylphthalimide in chloroform at 70 C. The predicted intermediate 679 was then treated with either cyclopenta-1,3-diene or 2,3-dimethylbuta-1,3-diene in a mixture of pyridine and dichloromethane at room temperature. The corresponding spiropyrazol-3-ones 680a,b and 681a,b were obtained in good yields (00CHE152) (Scheme 206). The products of Diels–Alder reactions of polyﬂuoroalkylidenepyrazol-3-ones 682a,b with 2,3-dimethylbutadiene and cyclopentadiene at room temperature and in the absence of catalysts are spiropyrazol-3-ones 683a,b and 684, respectively (00JFC111) (Scheme 207). The presence of a polyﬂuoroalkyl substituent at the exocyclic carbon bond of compounds 682a,b increases its activity in reactions with dienes. The presence of four chiral carbon atoms in 684 caused complication in the 1 H and 19F NMR spectra. Comparison of integrated intensities of the signals led the authors to conclude that one of the six possible pairs of diastereomers exists in more than 80%. The formation of only one pair of diastereomers has been observed in the case of compounds 683a,b.

O NSCl / Et3N / CH2Cl2

R

O

S

R

O

N

O

-70 to 0oC

N

N N

Ph

Ph

(678)

(679)

Me

pyridine, CH2Cl2

Me

H S H O

pyridine / CH2Cl2

R N N

Me

Me

Ph R

(680)

S O

N N Ph (681)

Scheme 206

Sec. XVII]

257

REACTIONS OF THE RING ATOMS

Me H

Me

R

Me

Me R

Me

N

O

H

N

O

N

Me R

Me

H

N

O

N

N

Ph

Ph

Ph

(683)

(682)

(684)

(a) R = CF3, (b) R = (CF2)4H, (c) R = CF3, (d) R = (CF2)4H, (e) R = (CF2)4H

Scheme 207

XVII. Photolysis The photo transformation of pyrazol-3-ones proceeds through one or more of a variety of pathways involving rearrangement, ring cleavage, fragmentation, oxidation, and solvolysis, and depends on the experimental conditions employed. A common feature in nearly all of these reactions was the ﬁssion of the ring N–N bond of the pyrazol-3-one ring. In some cases polymeric material was obtained. One of the ﬁrst reports on the photolysis of pyrazol-3-ones was in 1969 by Reisch and Fitzek (69TL271) (Scheme 208). Pyrazol-3-one 685 was photolysed in water to give 4-hydroxypyrazol-3-one 686. Irradiation of the latter in the presence of an equimolar amount of aqueous dimethylamine led to the formation of 2-hydroxy-N1, 2-dimethyl-N3-phenylmalonamide 687 and 2-(methylamino)propanoyl-(phenyl)carbamic acid 688. Pyrazol-3-one 689 was irradiated for 140 h in methanol by light from a high pressure immersion Hg lamp to give 2,2-dimethoxy-3-oxo-Nphenylbutanamide 690 in 50% yield. Five years later Reisch and Fitzek (74AP211) (Scheme 209) published another report on the photolysis of pyrazol-3-ones. Irradiation of 4-aminopyrazol-3-one 691

Me Me O

N

Me

O

N N

Ph

Ph

(685)

(686)

Me

H2O

O

O

N N

hv / 140 h Me

Me2NH / MeOH

Me

MeO O

NH

Ph

Ph

(689)

(690)

Scheme 208

N H

HO O

MeO

Me

MeO

Me

Me hv / Me2NH

hv / H2O N

O

Me

HO

Me

N

NH

Me

Me +

NH

HO O

NH

Ph

Ph

(687)

(688)

258

H

H

Me H

N

N

Me O O

N N

Ph

(692)

Me

H2N O

[Sec. XVII

GEORGE VARVOUNIS ET AL.

N

Me hv / H2O

Ph

Me Ph N

H (691)

Me

O H O

O

+

Me

Me Me N

N

Ph

H

O

H

O

Ph N

(694)

N H O H O (693)

H2N O

Ph

Ph N N

hv / H2O

H

N

N

Me

H hv / H2O Ph

Me O

Ph

NH2 + Ph

NH

O

N

N O

O

Ph

(695)

H

O

N

Ph

H

(698)

(697)

(696)

Scheme 209

in aqueous solution gave 694 in addition to 692 and 693, the characteristic photolysis products of pyrazol-3-ones. Intermediate 696 was isolated after irradiating 4aminopyrazol-3-one 695 in water. Compound 696 upon further irradiation fragments into N-phenylethanediamide 697 and N,N0 -diphenylethanediamide 698. When Cardy and Poquet (81T2279) (Scheme 210) irradiated at 300nm pyrazol-3ones 699a–c in methanol, cleavage occurred between the two nitrogen atoms to give the corresponding 2-methoxy-N-methyl(or phenyl)-3-methyliminobutanamides 700a–c. When the substituent at position 4 is an electronegative group, the product is stabilised. The STO/3G ab initio calculations were used to study the photo cleavage and the inﬂuence of the C4 substituent, giving evidence of a mechanism which involves triplet excited states of the ,* type.

R2

R2

Me hv / 300nm

O

N N

Me

Me N H

MeO O

NH

R1

R1

(699)

(700)

(a) R1 = Me, R2 = H, (b) R1 = R2 = Me (c) R1 = Ph, R2 = H, NH2, NMe2, OH or OMe Scheme 210

Me

Sec. XVII]

259

REACTIONS OF THE RING ATOMS

R1 N N

CO2Me C C

R2

H

(Z)-(704)

R2

N2 hv / MeOH

+

hv / MeOH N

O

R1 N N

R2

..

H

O

Me O

N

O

N

Me

N

R2 N N

R1

R1

R1

(701)

(702)

(703)

C C R2

CO2Me

(Z)-(705) polymeric material 1

2

1

2

1

2

1

2

(a) R = Ph, R = Me, (b) R = R = Ph, (c) R = Me, R = Ph, (d) R = 4-MeOC6H4, R = Me

Scheme 211

Photolysis of 4-diazopyrazol-3-one 701a in acetone was attempted by Griﬃn and co-workers (84CJC2456) (Scheme 211, 212) in order to see whether carbene 702, a postulated intermediate, may be intercepted by acetone to give oxirane 703a. However no isolable products and no chromatographic evidence for the formation of 703a was obtained, apart from polymeric material. On the other hand photolysis of 4-diazopyrazol-3-ones 701a,b,e in methanol gave a mixture of stereoisomeric (Z)and (E)-arylazoalkenoic acids esters 704a,b,e and 705a,b,e, as well as polymeric material. The photolysis of 4-diazopyrazol-3-one 701c in methanol gave methyl (Z)3-methylazo-3-phenylpropenoate. Two proposed mechanisms account for the formation of open-chain azoesters 704 and 705. The initially formed carbene 702 has zwitterionic character, as depicted by resonance forms 706 and 707 (Scheme 212). Concerted or non-concerted R2 C C O N N R1

R2 (708)

(702)

R2 C C O N N R1

O

N N

+

Scheme 212

N N R1

(706)

(707)

(703)

(E)-(705)

O

R1

MeOH MeOH

(Z)-(704)

R2

+

260

GEORGE VARVOUNIS ET AL.

[Sec. XVIII.A

nucleophilic attack and protonation of 702 in methanol results in the formation of (Z)-azoester 704 but fails to account for the presence of (E)-isomer 705, unless it is assumed that rotation of the carbonyl function about the C4-C5 axis is possible in the transition state. In an alternative mechanism carbene 702 undergoes ring opening to ketene 708, which subsequently is intercepted by methanol to give (Z)-704 and (E)-705. The formation of (Z)-azoester 704c exclusively by irradiating 4-diazopyrazol-3-one 701c points to a direct attack of the nucleophilic solvent on carbene 702. A study of the absorption spectra of the species generated upon steadystate photolyses in glasses at 77K, in solution at 296K and by laser and lamp ﬂash photolysis experiments, suggests that a long-lived heterocyclic intermediate such as a carbene or its valence isomer, as well as a ketene generated by ring opening, are precursors to the esters. Marciniec (85PHA30) (Scheme 213) studied the photostability of eight pyrazol3-ones that are important pharmaceuticals. These compounds are phenazone 709 aminophenazone 715, propylphenazone 719, nifenazone, morazone, noramidopyrine, 4-aminophenazone and isopropylaminophenazone. The reactions were done in a photoreactor with U.V. irradiation at 254 nm in an atmosphere of nitrogen or air. A total of 24 decomposition products were isolated by thin-layer chromatography and identiﬁed by u.v. and i.r. spectroscopy, mass spectrometry, and elemental analysis. The products of photochemical decomposition were compounds derived from the ﬁssion of the N–N pyrazol-3-one bond and then rearrangement, formation of a smaller ring of further ﬁssion, as well as compounds where oxidation had occurred and the pyrazol-3-one ring had remained intact. A representative number of reactions for three of the eight pyrazo-3-ones is shown in Scheme 213. Ram and co-workers (81TL2213) (Scheme 214) studied the photo transformations of 2-benzylpyrazol-3-ones 721a–e and found that benzyl migrations had occurred onto the intact pyrazol-3-one ring. The irradiation of 721a–e was done at 254 nm in a nitrogen atmosphere with methanol solvent. The photoproducts were isolated by thick-layer chromatography and identiﬁed by u.v., i.r. and 1H n.m.r. spectroscopy. The identiﬁed products were benzyloxypyrazoles 722a–e in 18–25% yield obtained by N2 to O-benzyl migration, the betaines 723b,c by N2 to C4 benzyl migration or the hydroxypyrazoles 724a,d,e in 18–25% yield by N2 to C4 benzyl migration followed by phototropic shift, and the hydroxypyrazoles 725a–e in 16–32% yield by the fragmentation followed by hydrogen abstraction, along with dibenzyl 726 in every case except 721d. The authors propose a free radical mechanism involving the homolysis of the N–CH2Ph bond and subsequent reactions of the radicals thus produced.

XVIII. Miscellaneous Reactions A. RADICAL ADDITION This type of reaction was exempliﬁed (96T1443) (Scheme 215) by treatment of 4-arylidenepyrazol-3-ones 728a–j with equimolar amounts of 1,2-phenylenediamine

Sec. XVIII.A]

261

REACTIONS OF THE RING ATOMS Me

Ph

H

N

N

Me

O (711) hv / 3 h H2O / N2 OHH Me2N N

O

Me Me

N

hv / 25 min Me

H2O / N2

hv / 8 h O

N N

Ph

Ph

(710)

(709)

Me

NC

H2O / N2 (712)

hv / 5 h H2O / air

hv / 30 min H2O / air

HO

Me

O H

N

N

O

H

N

Ph

Ph

(713)

N

Ph

Me

hv / 5 min

Me

H2O / N2

N

(714) Me2N

NMe2

O

Me

NMe2

O

Me

hv / 16 min O

Me

N N

Me

O

H2O / N2

Ph

Ph (715)

(716)

O

N N Me (718)

hv / 3 h H2O / air OHH Me2N O

Me N N

Me

Me2HC

Me hv / 6 min

O

N N

Ph

Ph

(717)

(719)

Me

H2O / N2

CHMe2 N

O N

Ph

Me

Me

(720)

Scheme 213

and 1.5 molar excess of the appropriate arylaldehyde 727a–j. The reaction took place in reﬂuxing ethanol and gave reduced 4-substituted pyrazol-3-ones 729a,b,e,g and/or 4,40 -linked bipyrazol-3-ones 730a–d,f–j in moderate to good yields. A radical mechanism was proposed where the initiation process occurs via a single electron transfer, with the formation of an anion radical, which undergoes a proton transfer from the benzimidazoline ion radical, rapidly evolving reaction products.

262 R2

O

[Sec. XVIII.B

GEORGE VARVOUNIS ET AL. R2

R3 N N

R1

R3 N

O

N

R1

Ph

Ph (721)

hv / MeOH Ph R2 Ph

O

R3 N N

R1

+

O

N N

R1

(723)

(722)

R2

R3

R2

+

R3 N

HO

N (725)

Ph

R1

+ Ph (726)

R2 = H

R3

Ph HO

N

N R1

(724)

Scheme 214

B. RING CLEAVAGE REACTIONS The pyrazol-3-one ring in these reactions is attacked by nucleophilic species at the carbonyl group or electrophilic species at a ring carbon. Subsequent ring opening by amide bond fracture may give stable compounds, or, ring closure may follow leading to a diﬀerent ring structure. Thus addition of pyrazol-3-one 731 to aqueous potassium hydroxide at 35–40 C aﬀorded the decarboxylated 1,1-dinitroacetone potassium salt 733. The mechanism is believed to proceed via nucleophilic attack of hydroxide ion on the amide carbonyl, cleavage of the amide bond, followed by decarboxylation of the intermediate carboxylate 732 (99T10447) (Scheme 216). Phenyliodonium diacetate or iodosobenzene react electrophilically with 5-substituted pyrazol-3-ones 734a–h in methanol at 23 C to yield, after fragmentative loss of molecular dinitrogen, methyl 2-alkynoates 740a–h (89T1605) (Scheme 217). However, 5-methyl-4-unsubstituted pyrazol-3-ones 740a–d under similar conditions yielded methyl-2,3-allenic esters 744a–d (Scheme 218). The yields from these two reactions range between 57 and 66%. The proposed mechanism for the synthesis of methyl 2-alkynoates 739a–h involves generation of the tricoordinate a species (dimethoxyiodo)benzene, electrophilic addition of (dimethoxyiodo)benzene to give 735, loss of methanol to form an intermediate ylide 736, ligand transfer of a second molecule of (dimethoxyiodo)benzene to give 737 and then reductive elimination of iodobenzene to form intermediate 738, and ﬁnally, oxidative

Sec. XVIII.B]

263

REACTIONS OF THE RING ATOMS Ph

Ar O

Ph

H NH2 +

H

N

Ar

(727)

Ph N

.

H N

H

N

Ar

Ph

+

N Ph

O

N

Ph

N

+

N

H N

N N

+ N

Ar

H

Ph

Ar O

.

Ph Ar

N O

Ph

Ar

Ph

.

Ph

H

O

(728)

H

.

O

N ArCHO

NH2

Ph

N N

N N

Ph

Ph

(729)

(730)

(a) R = Ph, (b) R = 3-MeC6H4, (c) R = 4-MeC6H4, (d) R = 2-MeOC6H4, (e) R = 3-MeOC6H4, (f) R =4-MeOC6H4, (g) R = 2-EtOC6H4, (h) R = 3-ClC6H4, (i) R = 4-ClC6H4, (j) R = 2,4,6-(Me)3C6H2

Scheme 215

NO2 Me O2N O

N N

NO2 (731)

NO2

NO2 Me KOH / H2O 35 - 40oC

O2N

- CO2

O2C N HN

NO2 (732)

K O2N

M e HN

N

NO2 (733)

Scheme 216

nucleophilic addition of methanol to carbonyl carbon of 738 followed by reductive elimination of molecular dinitrogen to yield methyl alkynoate 739. The reaction of 5-methyl-4-substituted pyrazol-3-ones 740a–d under similar conditions may be explained by an analogous mechanism (Scheme 218). After formation of intermediate 741, which due to C4 substitution of the pyrazol-3-one

264

[Sec. XVIII.B

GEORGE VARVOUNIS ET AL. Ph H

Ph N

O

N

H

+

MeO

I

R

I -MeOH

N

O

OMe

Ph

OMe R

I

R

N

H

H

(734)

(735)

N

HO

H

N (736)

PhI(OMe)2

PhI(OAc)2 + MeOH (PhIO)n + MeOH

Ph

Ph I

R

OMe

- N2 R

C C CO2Me - PhI (739)

- MeO Ph

N O N .. MeOH

-PhI

I

R

I

N

O

N (737)

(738) (a) R = Me, (b) R = Et, (c) R = CO2Me, (d) R = CH2CO2Me, (e) R = Ph, (f) R = 4-ClC6H4, (g) R = 4-MeC6H4, (d) R = 4-MeOC6H4

Scheme 217

Ph R

R

Ph O

N N

H

+

MeO

I

OMe

O

Ph

OMe Me

I

Me

PhI(OMe)2 N N

OMe Me

I

H

MeO R Ph

O

N N

H

H

H

(740)

(741)

(742) - PhI - MeOH

Ph H

R

-PhI -MeOH

C C C H (a) R = Me, (b) R = Et, (c) R = CH2COMe, (d) R = Bz

CO2Me (744)

-N2

OMeH C H I

R O N .. MeOH

N

(743)

Scheme 218

ring cannot form an ylide, a second molecule of (dimethoxyiodo)benzene adds to intermediate 741 to give 742, which then undergoes reductive elimination of iodobenzene through the loss of a proton from the methyl or methylene group at C5, leading to intermediate 743. Addition of methanol to the latter yields methyl 2,3-alkadienoates 744a–d.

Sec. XVIII.D]

265

REACTIONS OF THE RING ATOMS

C. RING OPENING/RING CLOSURE Ring opening of pyrazol-3-one ring followed by ring closure has been achieved (97LA159) (Scheme 219) by heating at reﬂux a solution of spiropyrazol-3-one 745 in methanolic sodium methoxide. The reaction aﬀorded methyl (4S,5S)-4-hydroxypyrazol-4-carboxylate 747, whose structure was determined by X-ray crystallography. The proposed mechanism involves initial attack of methoxide ion on the carbonyl carbon of 745 causing ring opening to give intermediate hydrazono-ester 746, followed by ring closure as depicted, to give pyrazole 747. 18

D. IN

F ISOTOPE INCORPORATION

Pyrazol-3-one 748 was ﬂuorinated with acetyl hypoﬂuorite in chloroform to give meso-hexestrol dimethyl ether 749 and pyrazole-3-one 750 (86BSF861) (Scheme 220). Meso-hexestrol in an important estrogenic hormone therapy agent.

H Ph O

O

H

N MeO Na

OH

N

Ph MeO2C .. N HN

N N

O

H

MeO2C Ph

∆

N N

H

NO2

NO2

NO2

(746)

(745)

N

(747)

Scheme 219

Et MeO

OMe Et

Et MeO

F

OMe

(749)

Me

Et

AcOF / CHCl3 O

N N

+

Me

Ph

AcO

Me

(748) O

N N

Me

Ph (750)

Scheme 220

266

GEORGE VARVOUNIS ET AL.

[Refs.

With this method a ﬂuorine atom can be attached to an activated aromatic ring, eﬀectively by displacement of the pyrazol-3-one moiety M750. This method is suitable for incorporation of the important 18F isotope into biologically interesting compounds, for position emitting tomography (PET) studies.

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269

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270 90SC3213 91AP467 91BCJ2032 91BCJ3713 91BSF884 91H1491 91IJC(B)363 94IJC(B)483 91IJC(B)878 91JCR(M)1019 91JCS(CC)314 91JHC49 91JHC1837 91JHC1961 91JIC165 91JIC515 91LA961 91PS119 91SC1281 92AF1350 92BCJ1652 92IJP165 92JCR(M)3015 92JCR(S)396 92JIC882 92JPR365 92LA7 92M581 92PS253 93BSB735 93JPR368 93JPR435 93SC817 94CHE540

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Refs.] 94JHC561 94JHC925 94JPR70 94LA159 94SC123 94SC2133 94T895 95CHJC520 95JHC1377 95PJC1013 96JMC3920 96JSD176 96SP455 96T1443 96T1579 97H309 97JHC1013 97LA159 97PHA32 97S573 97TL8397 98JMC4001 99BSCQ367 99EJMC967

99JCEN61 99JHC697 99JMAS502 99JMS(T)125 99JOM344 99POL3041 99RJOC281 99T10447 00AHC(76)157 00CHE152

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272 00CHE491 00JCS(P1)1732 00JFC111 00JFC135 00JHC911 00JOC4618 00PJC239 00SL1077 01AHC(80)73 01ARK32 01ARK63 01BSCQ459 01CHJC398 01JCS(D)1239 01JCS(D)1790 01JHC1065 01JMC3730

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Fluorine-Containing Heterocycles. Part II. Synthesis of Perﬂuoroalkyl Heterocycles from Carbonyl Compounds GEORGII G. FURIN Novosibirsk Institute of Organic Chemistry, Siberian Division of the Russian Academy of Sciences, 630090 Novosibirsk, Russia

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. From Hexaﬂuoroacetone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Elimination of Triethyl Phosphate Occurs on Heating or Photolysis . . . . . . . . . . . . III. From Perﬂuoroalkyl-Containing -Diketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. From Other Carbonyl-Containing Compounds with Perﬂuoroalkyl Groups . . . . . . . . . . V. The Synthesis of Oxygen-Containing Heterocycles by Intramolecular Cyclizations in Antimony Pentaﬂuoride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. New Strategy of Heterocyclic Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Intramolecular Nucleophilic Cyclizations with Annulated Fluorinated Heterocyclic Rings VIII. Innovations in the Use of Rearrangements in Heterocyclic Syntheses . . . . . . . . . . . . . . . IX. Polyﬂuoro-2,3-Epoxyalkanes in the Synthesis of Heterocyclic Compounds . . . . . . . . . . . X. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

273 275 280 288 316 334 342 344 361 364 372 372

This chapter is a continuation from Part I of this review of ﬂuorine-containing heterocycles recently published (03AHC(86)129). Part II deals with the synthesis of ﬂuorine-containing heterocycles by condensations of two or more precursors. Major attention is paid to the use of mono- and 1,3-dicarbonyl substrates, and their nitrogen analogs.

I. Introduction Condensation of two or more molecules with speciﬁc functional groups is a key method for the synthesis of heterocyclic compounds in general. This approach is also widely practiced for the synthesis of heterocycles with perﬂuoroalkyl groups (88M1, 93M2, 95CEN39, 97UK1985, 00H1411, 81UK325), one of the most important areas of ﬂuoroorganic chemistry. Heterocyclic compounds containing perﬂuoroalkyl substituents have attracted much attention due to their remarkable biological activity, speciﬁc chemical reactivity, and physical properties. In particular, perﬂuoroalkylated six-membered heterocycles have important applications in medicinal (87T3123, 89T1409, 88JCS(P1)1837), agricultural (93PCTWO11112, 90JOC2872, 90JOC2964, 90EurP353187), host–guest chemistry (95H521), and in the chemistry of laser dyes (95IJPAP431, 87T3123). Among nitrogen-containing heterocycles, azoles and pyrimidines play a major role because of their biological activity. Many azoles are useful in the preparation of 273 ADVANCES IN HETEROCYCLIC CHEMISTRY VOLUME 87 ISSN: 0065-2725 DOI: 10.1016/S0065-2725(04)87004-1

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drugs and agrochemicals. Triﬂuoromethyl-containing azoles and pyrimidines are of great interest from the viewpoint of their potential biological activity induced by the introduction of ﬂuorine atoms; these compounds have recently been extensively studied (98ZOR411, 01CGS1232, 01ZOR915). Fluorinated azoles often exhibit increased biological activity, leading to the development of eﬀective synthetic procedures for such heterocycles (87GERP3632291). For example, it has been found that addition of a polyﬂuorinated benzene ring to an azole increases the biological activity of the azole. This has stimulated syntheses and production of herbicides, plant growth regulators, and defoliants. Fluoroalkyl derivatives of pyrazole have also generated intense interest. They exhibit antibacterial, antiviral, fungicidal, herbicidal, insecticidal, pain-relieving, and other useful properties (92JFC(56)141, 91EUP418845, 98JOC2550, 94JCS(P1)2161, 90JAP(K)02129171, 87GEP3713744, 88EUP295117, 82CanP1130808). Also, they play an important part in the creation of pesticides and pharmaceuticals with a broad spectrum of applications (85JFC333). Perﬂuorinated heterocyclic compounds are used in medicine as eﬀective oxygen carriers and artiﬁcial blood components. Pyrimidines, a widespread class of natural bases, are pharmaceuticals with pronounced antiviral (88JMC144), gastroantisecretory (89H985), diuretic (90AF1349), antimalarial (88CL819), and anti-HIV-1 activities (89JMC2507, 92JMC337). As is known, the presence of ﬂuorine in the molecule enhances the physiological activity of compounds relative to their nonﬂuorinated analogs (87T3123). The interest in the syntheses of new ﬂuorinated heterocyclic compounds is therefore not surprising. A wide variety of unusual gem-(triﬂuoromethyl)-substituted ﬁve- and sixmembered heterocyclic compounds are readily obtained by condensation of hexaﬂuoroacetone with nitriles, isonitriles, and orthoformates, or by condensation of ﬂuorine-containing 1,3-dicarbonyl compounds with alkylenediamines and polyethylenepolyamines (79M3, 83ZN769, 82CB2494, 97ZOR1418). This methodology leads to the synthesis of heterocyclic compounds with triﬂuoromethyl groups from readily available hexaﬂuoroacetone and its derivatives Scheme 1). However, this technique is not always eﬀective. Substrates with perﬂuoroalkyl groups may not be readily available, or they may be toxic and inconvenient to handle. Therefore, for the syntheses of heterocyclic compounds, it is recommended to choose simple accessible substrates. -Diketones and -ketoesters have recently become accessible substances that hold much promise as substrates in such processes. Lithium salts of -diketones and regioisomeric -aminovinylketones, -aminovinylthiones, ,-enones, and their halogen derivatives are being actively

CF3 O

150 oC

F3C F3C

+ (CH3O)3CH

OCH 3 OCH 3

O

O

F3C

CF3

CF3 Scheme 1

CF3

+ CH3O

OH CF3

Sec. II]

275

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

applied (00H1411, 84ZOR1964, 89M4, 96IZV2278, 86IZV123, 93IZV2134, 99ZOR106, 99IZV1279, 96IZV1493, 97RusP2100345, 96BCZ93). ,-Unsaturated triﬂuoromethylketones are also becoming increasingly important as materials for the syntheses of heterocycles with a triﬂuoromethyl group (99UK483).

II. From Hexafluoroacetone Hexaﬂuoroacetones, an accessible starting material, has found practical application in the syntheses of cyclic and heterocyclic systems due to the high reactivity of its C ¼ O group (Scheme 2). The utility of this compound in organic synthesis considerably expanded the possibility of synthesizing derivatives with two triﬂuoromethyl groups. The general Scheme 3 is as follows. At ﬁrst, hexaﬂuoroacetone is converted into an intermediate (generally, a 1,3dipole), which then undergoes cycloaddition under the action of binucleophilic reagents. This approach opens up new synthetic possibilities and oﬀers a new methodology for the syntheses of ﬁve-membered heterocyclic compounds. The Scheme 4 illustrates the general synthetic potentialities in reactions with -amino azines. As described in the following sections, condensations of hexaﬂuoroacetone with various amines frequently give hetero-1,3-dienes as intermediates, used in the syntheses of heterocycles. Treatment of hexaﬂuoroacetone with 4,4-dibromobut-2-ene oxide and propargyl alcohol (91JFC(52)159) or ethylbromohydrin catalyzed by Bu4NBr yields ﬂuorinated 1,3-dioxolanes (Scheme 5) (93JOC972). CF3

CF3

O CF3 Scheme 2

CF3 XH

O

(CF 3)2C

a -b=c

F3C F3C

H X

a

CF3

c b - HCF 3

F3C X a

c b

Scheme 3

276

[Sec. II

GEORGII G. FURIN

CH3 N N N

N

H 3C

F

F

N

N

N

F

CF3

CF3

N CF3 SnCl 2

CF3 N

N

O

N

NH2

N

CF3 F

N

F3C

CF3

CF3

N

N

F

H3C

N

H 3C

N

CF3

N N

F

CF3

Scheme 4

O

H

CH3

CH 2OH

H

O

O

O

HgO F3 C

BrH2C

O

CH2Br

O CF3

F 3C

CF3

H

H CF3

H

CF3

O

O

O

180 oC, 6 h, Bu 4NBr F3 C H

O

CH2 Br

125 oC, 5 h , Bu 4NBr

CF3 76 %

H

H

Br O F3C

O CF 3 95 %

Scheme 5

Cyanoformamidines, exhibiting nucleophilic and electrophilic properties in the 1,3-positions, react with hexaﬂuoroacetone forming ﬁve-membered heterocycles (86CB2127). This ability to form ﬁve-membered heterocycles is the major characteristic of hexaﬂuoroacetone, which is also inherent in some perﬂuorinated and partially ﬂuorinated ketones, aldehydes, and imines in their reactions with -functional derivatives of carboxylic acids, as well as -amino, -N-alkylamino,

Sec. II]

277

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

-N-arylamino (60JA2288, 66CB1461), -hydroxy (66CB2880), and -mercapto (87JFC(35)87) derivatives of acids (Scheme 6). Applying this strategy to !-carboxy--amino acids, a preparatively simple regioselective carboxyl group activation is possible (91CZ77). The eﬃciency of this method was demonstrated by a two-step synthesis of aspartame (Scheme 7) (90CZ249). Protection of the -amino group and activation of the -carboxylic group is accomplished in only one step. Deprotection of the -amino group occurs during aminolysis. 1,3,4-Oxadiazoles are obtained from diaryl and arylmethyl diazomethanes when hexa- or pentaﬂuoroacetone is added at 20 C (Scheme 8) (78JA4260). The reactions of hexaﬂuoroacetone with trimethylsilyl ethers of enols form 4,4-bis(triﬂuoromethyl)-1-oxabuta-1,3-dienes (92JPC311). When heated in the presence of tin(II) chloride, the latter are transformed into 4,4-diﬂuoro-3-triﬂuoromethylbut-3-en-1-one. Subsequent treatment with sodium hydride leads to 2-ﬂuoro-3-triﬂuoromethylfuran, while with phosphorus pentasulﬁde the product is 2-ﬂuoro-3-triﬂuoromethylthiophene (92JCS(CC)348). Partially ﬂuorinated 1-oxopenta-1,4-diene, derived from hexaﬂuoroacetone, is employed as an intermediate in the syntheses of ﬂuorinated furans (92JCS(CC)349) and thiophenes (92JFC(58)380) (Scheme 9). Interaction between hexaﬂuoroacetone and various trivalent phosphorus derivatives forms ﬁve-membered ring 1 (Scheme 10); the reaction involves two

O

O

H

CF3

DMSO +

R

CF3

O

COOH 20 o C

XH

CF3 R

X

CF3

X = NH, NMe, O, S Scheme 6

CF3 O

1) O H

NH2

H

CF3

HOOC COOH

O

NH

F3C

CF3

COCl

2) SOCl 2

Scheme 7

CF3 O

Ph +

CF3

Ph

+ N _ N

pentane

Ph

-15 - -20 oC

Ph

N N CF3 O 95 %

Scheme 8

CF3

278

[Sec. II

GEORGII G. FURIN

CF3

NaH

CF3

R1

CF3

O

O

F

O

F2C CF3

CF3

R1

P 2S 5 R1

S

F

Scheme 9

F3C F3C

CF3 O

+

PR3

CF3 CF3

O

CF3

R

P R 1

O R

Scheme 10

hexa-ﬂuoroacetone molecules ([2 þ 2 þ 1] cycloaddition) (78CB890, 78CB2077, 79CB2380, 81IZV1592, 83CJC2264, 87ZOB1910, 88ZN(D)196, 89CB1465, 90JFC(48)99). Hexaﬂuoroacetone and triﬂuoromethyl isocyanate react to give a system of bicyclic ﬁve-membered heterocycles 2 (87AGF921, 81AHC1) (Scheme 11). From isothiocyanatodialkylphosphites and hexaﬂuoroacetone one btains a 1 : 1 adduct-bicyclic phosphorane 3 (87AGE921) (Scheme 12). At the ﬁrst stage, the reaction forms betaine 4, cyclizing into imide 5. The latter experiences an electrophilic attack by another hexaﬂuoroacetone molecule, forming bicyclic phosphorane 3. It is believed (87AGE921) that the strain in the trigonal bipyramid of the phosphorane is minimal when the two rings are axial equatorial and have an equatorial nitrogen. The activating eﬀect of the CF3 group in hexaﬂuoroacetone imines makes it possible to prepare ﬂuorinated oxazoles, thiazoles, and imidazoles using tin(II) chloride as a catalyst (82CB2494) (Scheme 13). The ﬁrst stage of the reaction is a [4 þ 1] cycloaddition of SnCl2 at room temperature, forming hetero-1,3-diene 6 in a quantitative yield. In solution,

F3C

CF3

N

CF3 + CF3N

O

C

F3C

CF3 2 Scheme 11

N

CF3

N

CF3

N CF3

Sec. II]

279

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

CF3 O

RO

RO +

P

CF3

N=C=S

+ P

N=C=S O

RO F3 C

RO

_

CF3

4 CF3

CF3

O S

N

RO P RO

O

RO RO

CF3

O

CF3

O

CF3

P N

CF3

S

F3C

5

CF3

3 Scheme 12

Ar

F3C

SnCl 2

N

X (CF 3)2C

N

F

X

Ar

X = O, S, NR Scheme 13

cycloadduct 6 is only stable at 20 C; above this temperature, ring cleavage into 1,X-dipolar compound 7 takes place. If triﬂuoromethyl substituents are present, the allyl anion eliminates the ﬂuoride ion to form a four-coordination center on tin. Elimination of SnFClþ 2 creates conditions for the generation of a heteropentadienyl anion, which undergoes electrocyclization, eliminating the ﬂuoride ion to form heterocycle 8 (Scheme 14). R R

SnCl X

(CF 3)2C

F3C

SnCl 2

7

R

R

N

N X

CF 2

X + SnCl 2

F3C

6

X = O, S, NR

F3C

N _

F3C

X

F3C

N

R

N

SnFCl 2

R

_

N X

F3C

X

F3C F

F

F 8

Scheme 14

In this reaction, tin is oxidized to the tetravalent state (Sn þ 2 ! Sn þ 4).

280

[Sec. II.A

GEORGII G. FURIN

R

R O

F3C

+ P(OMe) 3

N

(CF 3)2C

N

F3C

P

O

OMe OMe 10

MeO 9 R F3C

CF 3

N_

R

F2C

+ O P OMe MeO OMe

N

F3C

R

CF 3 N O

_

R

N_

R

F2C

OMe OMe O P OMe F

N

O

F3C

O

F3C F

F F 11

Scheme 15

Transition metal compounds can be replaced by other substances, for example, by phosphites. Thus, 2-substituted 4-triﬂuoromethyl-5-ﬂuoro-1,3-oxazole-2,4-dienes 9 were obtained by the reaction of 4,4-bis(triﬂuoromethyl)-N-acylimine 10 with trimethylphosphite (71CB1826, 74CB1448). The reaction occurs via the intermediate formation of 5-substituted 3,3-bis(triﬂuoromethyl)-2,2-dihydro-1,4,2-oxazaphospharol-4-ene 11 (Scheme 15).

A. ELIMINATION OF TRIETHYL PHOSPHATE OCCURS ON HEATING OR PHOTOLYSIS In the presence of nitrobenzene, a [3 þ 2] cycloaddition takes place, forming stereoisomers: 5,5-bis(triﬂuoromethyl)-2,3-diaryl-1,2,4-oxadiazol-3-in 12 and 3,3bis(triﬂuoromethyl)-1,5-diaryl-1,2,4-oxadiazol-4-in 13 (77CB605) (Scheme 16). At the same time, stable oxazaphospholenes 15 are formed by reactions of hexaﬂuoroacetone N-acylimines 14 with chlorine-containing compounds of trivalent phosphorus (92JFC(58)345, 91DOK619, 92JFC(58)375, 95IZV1809, 89IZV1213, 91IZV239) (Scheme 17). Under the action of tin(II) chloride, the initial products, hetero-1,3-dienes, undergo an amidine skeletal rearrangement into a terminal oleﬁn, giving a heterocycle (82JFC(20)813, 84ZN(B)1442).

Sec. II.A]

281

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

R N F3C

[

O

P F3C OMe MeO OMe 11

_ (CF 3)2C

+ N

CR

PhNO

]

R

R F3C

N

F3C

O

N

+ Ph

N

F 3C

O

F3C

N Ph 13

12 Scheme 16

R1 CF 3 O

O

CF3

RPCl 2

O

+ R1

N

(CF 3) 2C

SO 2

NH2 14 R1 O N

P

F3C

CF 3

O R

15 R = Me, EtO R1 = Me, Et, EtO, CF3, CH(CF 3) 2 Scheme 17

A Diels–Alder reaction between hexaﬂuoropropane-2-imine and 2,3-dimethylbutadiene at 100 C gives an adduct in excellent yield (65JOC1398) (Scheme 18). The reaction of epichlorohydrin with hexaﬂuoroacetone in the presence of catalytic amounts of Bu4NBr aﬀords 2,2-bis(triﬂuoromethyl)-4(bromomethyl)-1,3dioxolane 16, which on further treatment with KOH yields 2,2-bis(triﬂuoromethyl)4-methylene-1,3-dioxolane 17 (92JPK311) (Scheme 19). The [4 þ 1] cycloaddition of 4,4-bis(triﬂuoromethyl)-1,3-diazabuta-1,3-diene 18, obtained by a reaction of hexaﬂuoroacetone with an amidine in the presence of a dehydrating agent, to an isonitrile gives 5-(butylimino)-1-(2,6-dimethyl-phenyl)-2phenyl-4,4-bis(triﬂuoromethyl)-2-imidazoline 19 in the form of Z and E isomers (92JFC(58)345) (Scheme 20). Heating with hydrazines leads to bis(triﬂuoromethyl)-substituted 1,2,4-triazolines 20a and 20b, which undergo heteroaromatization into 5-triﬂuoromethyl-1,2,4thiazole 21 in the presence of azobisisobutyronitrile (AIBN) (88CZ109) (Scheme 21).

282

[Sec. II.A

GEORGII G. FURIN

CF3 HN

+ 100°C, 18 h

CF3

F 3C NH

F3C

74 % Scheme 18

RF O

HO

O

CH 2CH2Cl

+ ClCH 2CH2 OH RF

RF

O

RF

O

RF R F CH2 Br

CF3 O

+

H H

CF3

Bu4NBr

CH2Cl

O

O

O

F 3C

CF3

F3C

CF 3

125°C, 5 h

H

O

KOH O

17

16 95 % Scheme 19

CF3 O

Ph +

CF3

N R`

+ R2 N

Ph

POCl 3

_ C

N NH2

pyridine

R`

N

C(CF3) 2 MeCN

18 Ph F 3C

N N

F 3C

R`

R2 19

R1

R2

Yield, %

2,6-(CH3 )2 C6 H3

t-Bu

79

2,4,6-(CH3 )3 C6 H2

t-Bu

77

2,6-(CH3 )2 C6 H3

2,6-(CH3 )2 C6 H3

98

2,4,6-(CH3 )3 C6 H2

2,4,6-(CH3 )3 C6 H2

93

Ph

Bu

92

65:35

Ph

C6 H5 CH2

93

74:26

Ph

c-C6 H11

87

55:45

Scheme 20

Sec. II.A]

283

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

R1 + R3 NHNH2

N N

(CF3 ) 2C

CF3

H

CF3

N

R2

N

R1

N

R3

20a AlBN 140°C

CF3

CF3

N R1

CF3

N N N

R3

N

R1

N

R3

H 20b

21 Scheme 21

4,4-Bis(triﬂuoromethyl)-1,3-diazabuta-1,3-diene 18 reacts with cyanamide, acetonitrile, and benzonitrile to give [4 þ 2] cycloadducts, 1,4-dihydro-1,3,5-triazines 22 (84CZ205). With electron-deﬁcient nitriles (triﬂuoroacetonitrile, trichloroacetonitrile, and 4-chlorophenylaza-nitrile) the six-membered heterocycle undergoes a skeletal rearrangement forming 23 (Scheme 22). The reactions of 4,4-bis(triﬂuoromethyl)-substituted 1,3-diazabuta-1,3-diene with acetylene and its derivatives yield [4 þ 2] cycloadducts, 4,4-bis-(triﬂuoromethyl)-1,4-dihydropyrimidine derivatives (83CZ271) (Scheme 23). In the reaction F3 C

CF3

N

N N

Ph Ph

C8H 9 22

C 8H 9 N

(CF3)2C

R

+ R-CN

R = NMe2 (73 %), Me (63 %), Ph (68 %)

N

F3 C

CF 3

N

N

C 8H9

R

Me

N Ph 23 R = CF3 (80 %), CCl3 (25 %),

C8H9 =

N Me

Scheme 22

N

Cl (16 %)

284

[Sec. II.A

GEORGII G. FURIN F 3C CH 3

N(CH3) 2

CF3 CH3

N

20°C, 6 h

N

Ph

NMe 2

C9H11 80 % MeOOC

COOMe

CF 3

F 3C

100°C, 3 day

COOMe

N N

Ph

COOMe

C9 H11 10 %

18

CF3

CF3

F 3C Ph

H

N Ph

N

Ph

C9H11

C9H11

7%

47 % CF3

F3 C H

N

Ph

Ph

CF 3

COOMe

H

N

+

14O°C, 24 h

CF3

COOMe N

CF3

H

N

+

120°C, 48 h N

Ph

Ph

CF 3 CF3

COOMe

C9H11

Ph R` = C9 H11

N

COOMe

N Ph

N

H

C9H11

Scheme 23

of phenylacetylene and methyl acetylenecarboxylic ester, the product is (Z)-5benzylidene-1-(2,6-dimethylphenyl)-2-phenyl-4,4-bis(triﬂuoromethyl)-2-imidazoline, whose structure is conﬁrmed by X-ray analysis (83CZ274). The [2 þ 4] cycloadditions of ,-unsaturated carbonyl compounds and nitriles to 4,4-bis(triﬂuoromethyl)-substituted hetero-1,3-dienes give heterocyclic compounds. The [4 þ 2] cycloaddition of hetero-1,3-diene to methylvinylketone is highly selective when the process is conducted in the presence of equimolar amounts of 4-dimethylaminopyridine. 3-Triﬂuoromethyl-1,2,4-triazoles 24 were obtained in good yields by the interaction of hexaﬂuoroacetone imines 25 with HN3 (Scheme 24).

Sec. II.A]

285

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

R (CF3) 2C

F3C

+ HN3

N

X

F3C

X

R

N3 X = O, S, NR`

- N2

25 CF3

R

CF3

CF3

N X

NH

N - HCF3 R

N X 24

Scheme 24

Using hexaﬂuoroacetone azine in reactions with oleﬁns aﬀords 5,5-bis(triﬂuoromethyl)-1H-3-pyrazolines 25, whose thermolysis yields 3-triﬂuoro-methylpyrazoles 26 (82JFC(19)437) (Scheme 25). Triﬂuoromethyl derivatives of azomethine imines are eﬀective 1,3-dipoles in reactions with unsaturated compounds. Thus, RCH ¼ CHR type oleﬁns and azinehexaﬂuoroacetone react to form azomethineimine, transformed into 1H-3pyrazoline (75JCS(P1)538, 79T389) (Scheme 26). Heating the latter with AIBN leads to triﬂuoromethyl derivatives of pyrazole (82JFC(19)437) (Scheme 26). Hexaﬂuoroacetone azine reacts with two equivalents of terminal oleﬁns (71JCS(C)2404) and with acetylene derivatives (75TL1125), forming 1,5-diazabicyclo[3.3.0]octenes and 1,5-diazabicyclo[3.3.0]octa-2,6-dienes 27, respectively (Scheme 27). The cycloaddition involves two [3 þ 2] processes. The structure of azamethineimine is conﬁrmed by X-ray analysis data (74AGE475).

N (CF3)2C

C(CF3)2

R2

R1

CHR2

R1CH

N

F3C

+ _ N N

C(CF3)2

F 3C R1 F3C

R2 R1 N NH

CH(CF3)2 F3C

F3C

F3C

25 R1 - CF3

R2

F3C

R2 N NH

CH(CF3)2

26 Scheme 25

N N

CH(CF3)2

286

[Sec. II.A

GEORGII G. FURIN

R4 O

F3C

CF3

N

O

R3 CH R2

R H X R3

R2 R X (CF3) 2C

N R2

X = O, S, NR

R`CH

F3C

CF3

N

N

H CN R3

X

R

R2 Scheme 26

N (CF3) 2C

C(CF3)2 H

CF3 CF3 _ H + N N

R

N

R

CF3

F3C CF3

R

R

F3C N N R

F3C

CF3

27 Scheme 27

Similar reactions were reported to take place between this intermediate and ethylene (71JCS(C)2404), acetylene (75TL1125), terminal alkenes with alkyl, aryl, and geminal dialkyl groups (74AGE475, 75CB1460, 75JCS(P1)1902, 82JFC(19)589), dienes (75JCS(P1)1411), cyclic alkenes (79T389), vinyl ethers (82LA853), alkoxyacetylenes (79LA133), and acrylonitrile (82LA845). Triﬂuoroacetaldehyde azine, prepared from triﬂuoroacetaldehyde hydrate and hydrazine monohydrate, reacts with triethylamine in methanol to give the 1,4-dihydro-1,2,4,5-tetrazine derivatives 28, whose structure is conﬁrmed by X-ray analysis (95BCJ2085) (Scheme 28).

Sec. II.A]

287

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

CF3

CF3CH N CF3CH

CHCF3

N

N

CH3OH + Et3N

N 20°C, 1 day

N N

F3C

CH2CF3 28 14.2 %

Scheme 28

The low yield of the product is the result of polymerization of the substrate (formation of a trimer and longer cyclic systems). Hexaﬂuoroacetone alkoxycarbonylimines 29, exhibiting biphilic properties, act as 1,3-heterodienes or as dienophiles in [2 þ 4] cycloadditions. With cyclopentadiene they react as dienophiles forming [2 þ 4] cycloadducts, for example, 2-alkoxycarbonyl-3,3-bis(triﬂuormethyl)-2-azabicyclo[2.2.1]hept-5-ene 30 (95IZV1809) (Scheme 29). With cyanoguanidines and cyanamides compound 29 behaves as a 1,3-heterodiene forming heterocyclic compounds. These reactions lead to the formation of a [2 þ 4] cycloadduct as the sole product. The [2 þ 4] cycloaddition (formation of a compound of type 31) is only possible for dienophiles possessing suﬃciently strong donor properties, as illustrated by reactions with various compounds containing a nitrile group (Scheme 30). The reaction of hexaﬂuoroacetone alkoxycarbonylimine with diethyl cyanamide is exothermic with N-cyanomorpholine at 20 C. It takes 5–7 h, and with chloroacetonitrile or acetonitrile no reaction occurred over 3 days at 130–140 C. Condensation of 2-acetyloxiranes with ethyl perﬂuoroalkanoates gives 2,3dihydro-3-hydroxy-6-perﬂuoroalkyl-4H-pyran-4-ones, which on dehydration form 5-substituted 2-perﬂuoroalkyl-4H-pyran-4-ones (98T2819) (Scheme 31). The dehydration of hydroxy dihydropyranones intermediates was performed by the action of a slight excess of thionyl chloride in dry pyridine. The above reactions are easy to perform and have wide synthetic potential. These advantages, along with the accessibility of substrates, make them very useful.

COOR

COOR (CF3)2C

N

+

N

Et 2O 80°C, 5 h

CF3 CF 30

R = Me (70 %), Et (68 %), Pr n (63.8 %), Pri (53.1 %), iC5H11 (41.1 %), PhCH2 (64.3 %) Scheme 29

288

[Sec. III

GEORGII G. FURIN

COOR` (CF3) 2C

N

R 2N

CF3

N

CF3

+ R 2N-CN

O

N OR` 31

R 2N =

N, R` = Me (83.6 %), Et (85,7 %), iPr (78.4 %), iC5H 11 (70.4 %)

R2N = Et2N, R2N = O

R` = Et (73.3 %), iPr (84.2 %) N,

R` = Et (78.0 %), iPr (74.5 %)

Scheme 30

O i PrONa or t BuOK

R2 CH3

O

R2 HO

R1

R2

O

O

RF

O

Cl

]

S O

RF

O

R2

R2

O

O

SOCl2, pyridine

+ R FCO2Et

R1

[ Cl

O

pyridine

+ R1

O

RF

R1

O

RF

R1 61-79 %

RF = CF3, C 3F7 R1 = H, R2 = Me; R 1 = H, R 2= Ph; R1=R2 = Me Scheme 31

III. From Perfluoroalkyl-Containing b-Diketones The strong electron-withdrawing character of the polyﬂuoroalkyl substituent causes increased activity of the carbonyl group of the ketone towards nucleophilic reagents. The interaction of ﬂuorinated 1,3-diketones with polynucleophilic reagents is of great theoretical interest (reactivity studies) and from a synthetic viewpoint. 1,3-Dicarbonyl compounds react in their enol form giving [4 þ 2] cycloadducts (85CZ185). For example, acetylacetone, acetoacetic ester, and chloroacetoacetic ester react with 4,4-bis(triﬂuoromethyl)-1,3-diazabuta-1,3-diene giving 6-hydro-4,4bis(triﬂuoromethyl)-1,4,5,6-tetrahydropyrimidine derivatives 32 (Scheme 32).

Sec. III]

289

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

R2 O

R1

Ph N (CF 3)2C

R3

N

+

N

R2

R3 O

Me

CF3R

F3C

O

O H N

Ph

R

OH

3

O R2 1

32

Me ,

R1 =

Me Me

Me

Scheme 32

Perﬂuorocarbonyl compounds, obtained by the interaction of (triﬂuoromethyl)trimethylsilane with diacetyl ﬂuorides FC(O)(CF2)nC(O)F (n ¼ 2, 3) in the presence of KF, exhibit high reactivity with nucleophiles, for example, with water, giving cyclic diols 33 due to intramolecular cyclization (93IC5079) (Scheme 33). The structure of cis (n ¼ 3) and trans (n ¼ 2) diols 33 was conﬁrmed by X-ray analysis. In the presence of metal carbonates, for example Na2CO3 in diglyme at 80 C over 1 h, perﬂuoro-2,7-dimethyl-3,6-dioxasuberic diﬂuoride 34 (83CZ274) aﬀords perﬂuoro-2,7-dimethyl-3,6-dioxacycloheptanone 35 (92JPP04,316576) which then was irradiated with UV light at 70 C for 190 h to give 81% of perﬂuoro-2,3dimethyl-1,4-dioxane 36 (92JPP04, 316577) (Scheme 34). These compounds are useful as solvents, heating media and insulating liquids. In contrast, cyclic 1,3-diketones such as cyclohexane-1,3-dione having no stable OH O intramolecular hydrogen bonds in the enol form, react with 4,4-bis(triﬂuoromethyl)-1,3-diazabuta-1,3-diene forming a mixture of 4,4-bis(tri-ﬂuoromethyl)-1,4-dihydropyrimidine 37 and 4,4-bis(triﬂuoromethyl)-4H-1,3-oxazine 38 (85CZ185) (Scheme 35).

F

(CF 2)n O

n = 2, 3

F O

CF3SiMe 3

F3C

KF PhCN

(CF2)n O

F3 C

O

O

HO (CF2)n 33 Scheme 33

CF3

CF3 OH

H2O

290

[Sec. III

GEORGII G. FURIN O F F3C F

F

O

O

O

O O

F

O

F F F

F CF3

F F

M 2 CO3

F

O

O

F3C

O

CF3 O 35

34

CF3

F CF3

36

Scheme 34

O R`

Ph

F 3C O

(CF3)2C

CF3 O

N NH N

O

O

Ph

R`

OH CF3 O

F 3C N Ph

Me R` =

N

+ N

CF3O

F 3C

Ph

O

R` 37

38

63 %

24 %

Me 65 %

24 %

Me Me

Me

Scheme 35

However, ﬂuoroalkyl-containing 1,3-diketones interact with ethylene diamine to give only N,N0 -ethylenebis(aminovinylketones) (75AJC1517, 70JINC1895, 81ZVKO105, 78AJC765). It was shown (91JFC(56)325, 91JFC(56)297, 91IZV890) that with ﬂuorine atoms introduced into the alkyl fragments of the 1,3-diketone, the latter reacts with ethylenediamine monohydroperchlorate, producing 2,3-dihydro1H-1,4-diazepine monohydroperchlorates. Neutralization with an alkali gives free bases, for example, 2,3-dihydro-5,7-bis(triﬂuoromethyl)-1,4-diazepine 39 (Scheme 36).

Sec. III]

291

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

RF

R

RF

R

+ H 2NCH 2CH2NH2 HClO4 HN

HO

O

+ _ NH ClO4

R = Me, R F = CF 3 (76 %), H(CF2) 2 (59 %) R = Ph, R F = CF 3 (68 %), H(CF2) 2 (51 %) R = tBu, RF = H(CF2) 2 (71 %) RF HN

R N 39 75-95 %

Scheme 36

The nature of the substituents in the 1,3-diketone determines the identity of the ﬁnal products. In the case of RF ¼ CF3, acidic salts were not isolable; the reaction gave only free bases due to the lowered basicity of 1,4-diazepines products having CF3 electron-acceptor substituents and their greater thermodynamic stability than their corresponding conjugate acids. Protonated salts are isolated from more basic nonﬂuorinated products. In the reactions of ,-unsaturated ketones with ethylene-diamine perchlorate 1,4-diazepine salts are by-products of tetra-azamacrocycle formation. But for 1,3-diketones the formation of 1,4-diazepines is the main reaction route irrespective of the nature of the dicarbonyl fragment. Interaction of acetylacetone with ethylenediamine leads to macrocyclic complexes (97T5847, 97JFC(86)127), whereas hexaﬂuoroacetylacetone gives unstable N,N0 ethylenebis(aminovinyl)-ketones, which can be transformed into the corresponding 1,4-diazepines (98KGS634). While nonﬂuorinated 1,3-diketones on Cu þ 2 and Ni þ 2 matrices form N,N0 ethylenebis-(aminovinylketone) chelates in their reactions with ethylenediamine, ﬂuorinated 1,3-diketones give 2,3-dihydro-1H-1,4-diazepines 39 via the intermediate formation of metal chelates. The reactions of the copper salts of -ketoesters and -diketones with hydrazine hydrate and phenylhydrazine lead to the corresponding pyrazoles in moderate yields that may be increased by performing the reactions in the presence of bases (Scheme 37). The structure of the product (RF ¼ CF3, R ¼ Ph) is conﬁrmed by X-ray analysis (90IZV640). The thionation of perﬂuoroalkyl -diketones RCOCH2COMe [R ¼ CHF2, C4F9, (CF2)nH, n ¼ 2, 4] or their Cu þ 2 chelates by the SPS2 anion formed in situ from P4S10 and K2CO3 gave perﬂuoroalkylthiopyrans (92SL195). The reactions between 2-polyﬂuoroacylcyclohexanones 40 and methylhydrazine or phenylhydrazine exclusively yields 3-CF3 pyrazoles (01CJC183). When the chain length of the polyﬂuorinated substituent in the RFCO group increases, 5-RFpyrazoles are isolated. The reaction of 2-(triﬂuoroacetyl)cyclohexanone with hydrazinopyridine gives 5-hydroxypyrazoline, an intermediate in the formation of

292

[Sec. III

GEORGII G. FURIN

R1

OEt

R1

R2 NHNH 2 HCl O

O

N N

NaOH,H2O

Cu/2

OH

R2 R1 = HCF2, R 2 = H; R1 = CF3 , R2 = H; R1 = CF3 , R2 = Ph; R1 = C 4F9, R2 = H; R1 = C 4F9, R 2 = Ph

R1

Me

R1

R2 NHNH 2 HCl O

O

N N

NaOH,H 2O

Cu/2

Me

R2 R1 = CF 3, R2 = H; R1 = CF3, R 2 = Ph; R1 = C 6F13, R2 = H

Scheme 37

5-CF3-pyrazoles. The regiochemistry of the condensation is probably controlled by the nucleophilicity of the terminal nitrogen in the monosubstituted hydrazines and by the steric requirements of the RF group in the 1,3-diketones (01CJC183). Compounds 40 react with guanidine, urea, thiourea, methylisothiourea, guanylthiourea by Lewis-acid catalysis (00S1738) and with thiosemicarbazide, semicarbazide (99IZV361) in the presence of triethylamine to form the corresponding 5,6-oligomethylenepyrimidines and 3-hydroxy-2(thio)-carbamoyl-3-polyﬂuoroalkyl-3,3a,4,5,6,7-hexahydro-2H-indazoles 41, respectively (Scheme 38). The structure of 41 (thio) is conﬁrmed by X-ray analysis. Similarly, asymmetrical perﬂuoroalkyl-containing 1,3-diketones with semi- and thiosemicarbazydes give 5-hydroxy-5-polyﬂuoroakyl-2-pyrazolines (00ZOR1180) (Scheme 39). Hexaﬂuoroacetylacetone reacts with ethylenediamine to give an unstable N,N0 ethylene-bis(aminovinyl ketone), which can be converted to the corresponding H RF OH X

NHNH 2 X

N

+ N

RF

NH2 O

NH2

O 41

40

RF

CHF 2 CF3 H(CF2 )2 C4F9 C6 F13 C8 F17 CF3 C6 F13 C8 F17

X

S

Yield, % 51

S

S

S

S

S

O

O

O

50

68

75

76

54

40 44

30

Scheme 38

Sec. III]

293

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

NHNH 2 RF

R O

R iPrOH

+ X

HO NH2

O

RF

N

N

O

NH2

R F = HCF2, CF3, (CF2)2H, C3F7, C4F9, C8F17 R = Me, Et, t Bu, Ph, (CF 2)2H X = O, S Scheme 39

1,4-diazepine (70JINC1895). In contrast, ﬂuoroalkylated 1,3-diketones react with ethylenediamine monohydroperchlorate (100–120 C, 8–10 h) to form 2,3-dihydro-7ﬂuoroalkyl-1H-1,4-diazepines monohydroperchlorates, intermediates which then with concentrated alcoholic KOH (pH 10–11) prepare 2,3-dihydro-7-ﬂuoroalkyl-1H1,4-diazepines 42 (81ZVKO105, 91JFC(56)325, 91IZV2088) (Scheme 40). Lithium salts of ﬂuorinated -diketones are new ﬂuorine-containing synthons. They are used in the syntheses of ﬂuorinated pyrazoles, 5-hydroxy-2-isoxazolines, 2-aminopyrimidines, and 1,5-benzo- and 1,5-naphthodiazepines (98ZOR411). Thus, in reactions of lithium salts of ﬂuorinated 1,3-diketones with hydrazine (86DAN1133), guanidine, and thiourea (87GEP3603291) hydrochlorides, and 3-aminopyrazoles (02IZV332) the products are hydroxypyrazolines or mixtures of regioisomeric pyrazoles, pyrimidines, and (7-poly-ﬂuoroalkyl)pyrazolo[1,5-a] pyrimidines 43, 44, and 45 respectively (Scheme 41). The structure of 3-bromo-2methyl-5-phenyl-7-triﬂuoromethylpyrazo-lo[1,5-a]pyrimidines was established by X-ray diﬀaction (02IZV332). Interaction between the alkaline salts of ﬂuorinated -diketones and orthophenylenediamine and ortho-diaminonaphthalene forms the corresponding 2-diﬂuoromethyl-4-phenyl-3H-benzo[b]-1,4-diazepines and 2-diﬂuoro-methyl-4phenyl-3H-naphtho[2,3-b]-1,4-diazepines (87GEP3603291) (Scheme 42). The synthesis of some ﬂuorine-containing polycyclic compounds involves intramolecular cyclization. Thus, heating quinoxalone, obtained by the reaction of the copper chelate of ethyl pentaﬂuorobenzoylpyruvate with ortho-aminophenol in dimethylsulfoxide or DMSO–NEt3 leads to the product of intramolecular

RF H2N

NH 2 HClO4

+ OH

O

RF OEt 1) 100-120 °C 8-10 h HN 2) KOH (alcohol)

O NH

RF = CF3 (58 %), H(CF2 ) 4 (78 %)

42 Scheme 40

294

[Sec. III

GEORGII G. FURIN

NH H 2N

HCl

RF

R

NH 2 N

N

MeOH NH2 43 S

RF

RF

C(NH2) 2

R

R N OLi

N

O SH 44

N NH R1

X

NH2

R

N X

R1

AcOH, reflux, 10 h

N

N RF

45 52-87 % R = Ph, Me R1 = H, Me, Br, COOEt RF = CF3 , HCF2 , C4F9 Scheme 41

(H2NOH)2 H2SO4

RF

MeOH

H2NNHR`

HO

R O N

RF

R N N

MeOH R` RF

R

NH2 RF

OLi

O

N NH2 N R NH2 RF N NH2 N R Scheme 42

Sec. III]

295

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

cyclization, 1,2,3,4-tetraﬂuoro-7,8-dihydro-5H-1,4-dihydroquinolino-[1,2-a] quinoxaline-5,7-dione (97ZOR1418) (Scheme 43). It was assumed that the ﬁnal reaction proceeds by the SNAr mechanism. 2-Perﬂuoroalkylbenzothiazoles are obtained by the reaction of 2-aminothiophenol with ﬂuorinated -diketones or -chloro--(triﬂuoromethyl)-acrolein (91TL643). With hydroxylamine, the products are 5-hydroxy-2-isoxazolines (87GEP3603291). Asymmetric ﬂuorine-containing -diketones (01IZV643, 94JFC(67)87) on interaction with 2-cyanoacetamide in the presence KF give 3-cyano-2-pyridones in useful yields only with short polyﬂuoroalkyl chains (CF2H, CF3); the yield of the tetraﬂuoroethyl derivative was only 20%, and the octaﬂuorobutyl 4% (Scheme 44). The reactions of -diketones with -aminocrotonitrile in boiling ethanol gives 3-cyano-2,6-dimethyl-4-triﬂuoromethylpyridine (yield 66%) (97S1321) (Scheme 45). 1-Benzylsulfonyl-hexaﬂuoropentan-2-one reacts with phthalimidosulfenyl chloride at room temperature in chloroform giving a stable phthalimidothio derivative (Scheme 46). Decomposition of these compound in the presence of 1,3dienes as trapping reagents for the unstable -thioxoketone has allowed a number of NH2 C6F5

COOEt O

O

O C6F5 NH

OH O

MeOH

HN

Cu/2 64 % F Et3N, DMSO (5:1)

O

F O N

F

NH

F

30-32 %

Scheme 43

RF

R2

O

R1

RF O

+

KF, i PrOH

NC NH2

O

reflux, 10 h

R2

R1

CN

NH 20-89 %

RF = CF2H, CF 3, (CF2) 2H, (CF2)4 R1 = Ph, 4-FC6H4, 4-BrC 6H4, 4-MeC6H4, 4-ClC6H 4, 2-thienyl _ R2 = H, R1 + R 2 = (CH2)3 _ , _ (CH2)4_ Scheme 44

O

296

[Sec. III

GEORGII G. FURIN

CF3 R1

NH2

CF 3

R2 reflux

+ O

O

8h

R2

R1

CH 3

N

R1

R2

Yield, %

CN

80

CN

66

4-CH3 C6 H4

CN

80

4-CH3OC6 H4

CN

79

4-ClC 6 H4

CN

82

2-Furyl

CN

74

2-Pyridyl

CN

82

Me

COOEt

70

Ph

COOEt

72

2-Furyl

COOEt

73

2-Pyridyl

COOEt

78

cyclohexyl

COOEt

80

Solvent EtOH

Ph Me

MeCN

CH3

Scheme 45 SNPhth

S 56 oC

PhthNSC l H(CF2 )3

H(CF2 )3 SO2CH2 Ph

]

SO2CH2 Ph

- PhthNH

O

O

[ H(CF2)3

SO2 CH2 Ph

20 oC

O

O

Phth =

S

SO2 CH2Ph

O

(CF2)3 H

H Ph O

H O O

S

SO2 CH2Ph

O

(CF2)3 H

H

O

n-BuO

Scheme 46

S

SO2 CH2Ph

O

(CF2)3 H

Sec. III]

297

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

new polyﬂuoroalkyl ketones to be obtained they contain the thiin moiety in the position (02JFC(115)175). Reactions proceed with regioselectivity and diastereoselectivity. Thus, in the case of cyclopenta-1,3-diene the product consists of two diastereomers in the ratio 2.4 : 1. 1,3-Amino vinylimine, for example 2-amino-4-iminoperﬂuoropent-2-ene obtained from perﬂuoropent-2-ene and ammonia, is an azo analogue of heptaﬂuoroacetylacetone. These compounds react with ethylenediamine in alcohol to give 2,3-dihydro-6-ﬂuoro-5,7-bis(triﬂuoromethyl)-1H-1,4-diazepine 46 (Scheme 47). The reaction with diethylenetriamine gives a nontrivial product—1,9-bis(triﬂuoromethyl)3,4,6,7-tetrahydro-2H-pyrazino-[1,2-a]pyrazine 47 (93IZV1773, 94JFC(69)25), identiﬁed by X-ray analysis (94JFC(69)25). In the latter case, the reaction occurs via intermediate macrocycle 48, which undergoes intramolecular nucleophilic substitution of ﬂuorine by the amino group of the ethylenediamine fragment, showing the synthetic utility of analogous ﬂuoroalkyl-containing 1,3-aminovinylketones. The reactions of polyﬂuorinated imidoylamidines with anhydrides (99IZV2195) and perﬂuorocarboxylic acid halides (85M6) are general processes forming pyrimidenes (Scheme 48). 2-Amino-4-iminoperﬂuoropent-2-ene, analogous in structure to the above imidoylamidines, interacts with anhydrides and perﬂuorocarboxylic acid chlorides forming 2,4,6-tris(perﬂuoroalkyl)-5-ﬂuoropyrimidines (99IZV2195). It is thought that pyrimidine formation is a two-step process including acylation of the imino enamine and further dehydration of this intermediate acyl derivative leading to ring closure. Pyrazoles are obtained by [3 þ 2] condensation of -diketones with hydrazine and its derivatives (96M7). The same applies to the synthesis of ﬂuorinated pyrazoles and F F3 C

CF3

H2NCH2 CH2NH2 N

MeOH

F

46 65 %

CF3

F3 C

NH

F NH 2 NH

F 3C (H2 NCH2CH2 )2NH

N

[

MeOH

CF3 NH

]

NH 48 F 3C

H

N

F 3C

CF3 N

N

NH N

N 47 44 % Scheme 47

CF3

298

[Sec. III

GEORGII G. FURIN

F CF3

F3C

(RCO)2O

N

N

RF = CF 3 F F3C

RF RF

R = CF 3 (71.3 %), C2F5 (73 %), C3F7 (88 %) F

F

NH2 NH RCOX

CF3

[

RF N

N

H R

X

RF

CF3

]

N

N

H

OH

R 36-88 %

RF = CF3; R = CF3, C2 F5, C3 F7, C6 F13 R F = CF3; R = Me, Et, tBu R F = C2F5 ; R = Me X = Hal, OCOR Scheme 48

pyrimidines. Here, 1,3-bifunctional ﬂuorinated synthetic units are employed; they are introduced in [3 þ 2] and [3 þ 3] cyclizations between the 1,3-bifunctional compounds and the binucleophilic reagents representing hydrazines and amidines, respectively (85M6). 1,3-Bifunctional compounds include ﬂuoro-1,3-diketones (98JOC2550), ﬂuorinated acetylacetylenes (89TL2049, 90JFC(48)123), and -triﬂuoroacetyllactams (93TL5075). Thus, 2-ﬂuoro-1,3-diketones RC(O)CHFC (O)R0 (R, R0 ¼ Ph, CF3; Ph, Ph; Me, Me; Me, 4-NO2C6H4) react with phenylhydrazine forming high yields of pyrazoles (94JFC(69)25, 92JFC(56)141). Fluorine-containing 2-oximino-1,3-oxo ethers 49 react with ortho-phenylenediamine in methanol, benzene, or toluene, giving substituted quinoxalines 50 and 51 rather than the expected 1,5-benzodiazepinones or benzimidazoles (98ZOR405) (Scheme 49). Although both 50 and 51 have a quinoxaline structure, they are formed by diamine condensation at diﬀerent carbonyl groups of the starting 1,3-dicarbonyl compound, which depends on the size of the ﬂuoroalkyl substituent. The nucleophilic reagent attacks the sterically less hindered carbon atom of the carbonyl group. The reaction of 1,1,1-triﬂuoro-3-hydroxyimino-4-phenyl-2,4-butanedione in diethyl ether gives rise to 2-hydroxy-3-hydroximino-4-phenyl-2-triﬂuoromethyl-2,3dihydro-1H-1,5-benzodiazepine 52 (yield 75%) (Scheme 50). In methanol there results a cleavage of the latter and the formation of 3-triﬂuoromethyl quinoxalin-2one (98ZOR405). When heated in a vacuum or boiled in toluene, compound 52 is stable against dehydration and does not lose a water molecule. Compound 49 containing a triﬂuoromethyl group (RF ¼ CF3) and hydrazine hydrate give 3-hydroxy-2-hydroximino-4,4,4 hydrazide-triﬂuorobutanoyl hydrazide

Sec. III]

299

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES O N

NH2

OH

RF = C 4 F 9

N

NH2

OEt O

OH

50 79 %

N RF

RF

RF

N

MeOH

O

EtOOC

49

N 70 % RF

R F = CF3

N

O N N

H

NH 2 51 69 %

Scheme 49

NH2 OH NH2

Ph Et 2O O

OH

N

N CF3

H

CF3 N

N

O

OH Ph

49

52 Scheme 50

53 and 3-hydroxy-4-hydroximino-3-triﬂuoromethylpyrazolidin-5-one 54 (97ZOR442, 97JFC(84)107) (Scheme 51). Compound 54 is easily dehydrated on heating to 70 C, forming pyrazolinone 55. In the case of RF ¼ C4F9, heterocycle 56 is formed as the sole product. It has been shown (98JFC(92)101) that the reaction of hydrazine in Et2O and hydroxylamine hydrochlorides in CH3OH in the presence of NaOAc with ethyl-2-( para-methoxyphenyl)-hydrazone-4,4,4-triﬂuoro-2,3-dioxobutanoate 57, obtained by reactions of 1,3-ketoesters with aryldiazonium chloride, gives 3-nonaﬂuorobutyl-4( para-methoxyphenyl)hydrazonepyrazolin-5-one 58 and 3-ﬂuoromethyl-4( para-methoxyphenyl)hydrazonepyrazolin-5-one 59, respectively (98JFC(92)101) (Scheme 52). Fluorine-containing 2-arylhydrazone-1,2,3-diketo esters, 2-arylhydrazones of 1,2,3-triketones and 3-arylhydrazone-1,2,3,4-triketo esters may serve as key precursors to a variety of novel heterocycles and react with binucleophiles (85UK1997, 81UK325, 94ZOR1225). Thus, the 1,2,3-triketones arylhydrazones react with hydrazine hydrate, phenylhydrazine, thiosemicarbazide, and hydroxylamine hydrochloride to form the substituted pyrazoles and isoxazoline (98JFC(92)101, 98IZV673) (Scheme 53).

300

[Sec. III

GEORGII G. FURIN N H2 NNH2 H 2 O

HO C4 F9

RF = C 4 F9

OH

OH O

NH NH

N RF

56 83 %

OEt

OH

OH O

N

N

O

H2 NNH2 H 2O

49 RF = CF 3

HO F3 C

O + NH NH

F3C

NHNH2

HO OH

53 16 %

54 68 %

N

O

OH O

F3C N NH 55 89 %

Scheme 51

X

X H2NNH 2 H2O

N

Et2 O CF 20 oC, 10 min 4 9 RF = C 4F 9

NH

RF

N

H O

N NH 58 (79 %) X

R O

N

O 57

H2NOH HCl NaOAc/MeOH reflux, 3 h RF = CF 3

N

N

F 3C

H O

N O 59 (80 %) RF = CF3, X = OMe, R = OEt; RF = C 4F9, X = OMe, R = OMe Scheme 52

Sec. III]

301

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

C6H4 X-4 N N Me

NH2NHPh H(CF2) 2 NaOAc/MeOH reflux, 2 h

C6H4 X-4 N

NH

H(CF2) 2

Me O

N N Ph X = OMe (82%) C6H4 -X-4 N

HO

O

N Me

H(CF2 ) 2 NH2NHC(S)NH 2

HN N NH 2

C6H6 :DMSO (3:1) heater for 50 h

S X = OMe (84%)

Scheme 53

Hexaﬂuoroacetylacetone reacts with urea and thiourea to yield 4,6-bis(hydroxy)4,6-bis(triﬂuoromethyl)hexahydropyrimidine-2-one and -2-thione (01ZOR915, 00JFC(103)17), respectively (Scheme 54). The dehydration of the products and also the reaction of unsymmetric ﬂuoroalkylcontaining 1,3-diketones with urea and thiourea aﬀord substituted pyrimidines. The condensation of ﬂuorinated 3-oxoesters or 1,3-diketones with benzaldehyde and urea or thiourea result in the diastereoselective formation of 4-ﬂuoroalkyl-4hydroxy-2-oxo(thioxo)-6-phenylhexahydropyrimidine-5-carboxylates from which by dehydration under acetic conditions the corresponding 6-ﬂuoroalkyl-2oxo(thioxo)-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates were obtained (01ZOR915, 00JFC(103)17) (Scheme 55).

NH 2

OH

O

OH

HO

X R2

R1

NH2 EtOH reflux, 2 h

R1

N O

R1=R2 = CF3 (68 %) R1= H(CF2 )2 , R2 = Ph (52%)

NH X

HN

PhCH3 n-TsOH reflux, 2 h

R2 HN

R2

R1

X=O

R2

R1 X=S N

N

SH R1 =R2 = CF3 (62 %) R1= H(CF2) 2, R2= Ph (37%) Scheme 54

302

[Sec. III

GEORGII G. FURIN

NH 2 R

X R

RF OH

NH 2 PhCHO EtOH

O

R

Ph n-TsOH NH

X

NH

O

NH

O HO

Ph

PhCH3 reflux, 6 h

RF

NH

X

RF RF

HCF2 H(CF2 )2 C3F7 C4F9 CF3 H(CF2 ) 2 H(CF2) 2 CF3 CF3

R

OEt

OMe

X

O

O

OMe OEt O,S

O,S

OEt S

Ph

Me

Me

Ph

O,S

O

O

O,S

Scheme 55

Addition of a reactive group to the 2 position of the 1,3-dicarbonyl compound expands the traditional synthetic utility of these substances since their reactions with binucleophilic reagents form both the expected (benzodiazepine heterocycles) and the unexpected (quinoxalines) products. Thus, in the presence of Rh2(OAc)4, ethyl-2-diazoﬂuoroacetoacetate, obtained by the reaction of ethylﬂuoroalkylacetoacetate with perﬂuoroalkane-sulfonylazide, reacts with nitriles giving 5-ﬂuoroalkyl-substituted 1,3-oxazoles (00JFC(103)139) (Scheme 56). The reactions of pentaﬂuorobenzoylpyruvic acid with N-nucleophiles primarily involve the -carbonyl group; however, intramolecular cyclization replacing the ortho-ﬂuorine atom in the aromatic ring is also possible, giving new types of heterocycles. This kind of cyclization is not characteristic of the nonﬂuorinated hydrocarbon analogs. Pentaﬂuorobenzoylpyruvic acid is transformed by amines into the corresponding enamines, whose subsequent cyclization forms N-substituted 4-quinolone-2carboxylic acids. Thus, treatment of pentaﬂuorobenzoylpyruvate with gaseous or aqueous ammonia aﬀords chromone (yield 64%) (94JFC(69)119, 94IZV299) (Scheme 57). Pentaﬂuorobenzoylpyruvic acid reacts at the C3 center with various binucleophiles, this reaction being the basic method for the synthesis of ﬂuorinated chromones, quinolones, cynolones, and pyrazines. It was shown (95ZOR266, 99JFC(96)87) that copper chelates of pentaﬂuorobenzoylpyruvic esters react with dinucleophiles (hydrazine hydrochloride,

O

COOEt

RF

O Rh2(OAc)4

RF

OEt

+ RCN 80-90°C

O

N2

N R

R F = CF3, ClC3F6, C5F11 R = Ph, 3-MeC6H4, CH2Ph, ClCH 2, CH Scheme 56

CHCH 3

Sec. III]

303

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

C6F5

COOH O

NH 3

O

OH

C6F5

O F

_ + COO NH 4

[

OH

O

O

F

F

F O

F

_ + COO NH 4

] O

F

F

COOH

F Scheme 57

phenylhydrazine, hydroxylamine hydrochloride, 1,2-ethylenedi-amine, 1,2-phenylenediamine, 2-aminophenol) to form heterocyclic compounds (Scheme 58). The reaction occurs at the -diketone fragment and forms 5-ﬂuoro-3-ethoxycarbonylalkylpyrazoles 60. The reactions with ortho-phenylenediamine give pyrimidines 61. Formation of these products instead of the expected 5-hydroxypyrazolines seems to be caused by the presence of the copper cation, not only orienting the reagent molecules, but also facilitating water elimination

RNHNH2 HCl

RF

COOEt N N R 60

NH2

R = H, R F = CF3 (72 %), C4F9 (75 %), C6F 5 (67 %) R = Ph, R F = CF3 (70 %) O RF

RF

COOEt O

O

NH2

NH O

MeOH reflux, 4 h

HN

Cu/2 61 RF = CF 3 (63 %), C4F 9 (53 %), C6F 5 (59 %)

1) H2NOH HCl 2) H+ , H2O

RF

COOH O N

RF = C6F5 (25-30 %) Scheme 58

304

[Sec. III

GEORGII G. FURIN

(by means of coordination) from the intermediates. In the case of hydroxylamine hydrochloride, the product is 5-pentaﬂuorophenyl-isoxazole-3-carboxylic acid (99JFC(96)87). At the same time, polyﬂuoroacylpyruvic acid itself reacts with hydrazine hydrate and phenylhydrazine at the -dicarbonyl fragment and forms stable 5-hydroxy-3alkoxycarbonyl-5-polyﬂuoroalkylpyrazolines 62 (92ZOR1380) (Scheme 59). Bornyl polyﬂuoroacylpyruvate and hydrazine hydrate give 3-bornyloxycarbonyl-5ﬂuoroalkylpyrazoles. Treatment of aryl(aroyl)pyruvic acid ester metal chelates with ortho-phenylenediamine and ethylenediamine is accompanied by an attack at the -ketoester fragment, forming quinoxalones and piperazinones, respectively (95ZOR266, 99JFC(96)87) (Scheme 60). In the case of -aminoalcohols, ﬁve-membered heterocycles are formed (Scheme 61). The reaction of the pentaﬂuorobenzoylpyruvic acid with primary amines (aniline, isopropylamine, cyclohexylamine) yields addition-elimination products at the C(2) center, 2-alkylamino(anilino)-2-pentaﬂuorobenzoylacrylic acids. In an alkaline medium, these compound undergo cyclisation and nucleophilic replacement of the

HO R`NHNH2 MeOH, 20 °C

COOR

RF

N N

R` 62 RF = CHF 2, R = Et, R` = H (67 %); RF = CF 3, R = Me, R` = H (77 %); RF = C 4F9, R = Et, R` = H (69 %); RF = CF 3, R = Me, R` = Ph (73%)

NH2 RF

COOR O

OH

NH2

O RF

MeOH

NH O

HN

RF = CHF 2 (68 %), CF 3 (75 %), C4F9 (57 %) H 2NNH2 H2 O MeOH

RF

COOBorn HN N 61-68 %

RF = CF 3, C4F9 Scheme 59

Sec. III]

305

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

O H2 NCH2CH 2NH 2

R NH

MeOH, 20°C

HN

O

R = CF3 , C 4F 9, CHF 2, C 6F5 COOR1

R O

NH 2

R1 = Me, Et

NH 2

OH

O R NH HN

O

MeOH

R = CF 3, C 4F 9, CHF2 , C 6 F5 Scheme 60

F3C

COOEt

H2NCH2CH2CH2OH O R1

R2

H2N

OH

NH

F3C CF3

O

O CH2COOEt

COOEt NH R1

R2 COOH F3C HS

NH2

S

COOEt NH COOH

Scheme 61

ﬂuorine atom at the C(7) atom by the hydroxy group to form 5,6,8-triﬂuoro-7hydroxy-1-R-4-quinolone-2-carboxylic acids (94IZV299, 94JFC(69)119) (Scheme 62). The reaction of pentaﬂuorobenzoylpyruvic acid (as well as the reaction of aroylpyruvic acid) with ethanolamine in dioxane yields 3-pentaﬂuorobenzoylmethylenemorpholin-2-one. Due to the presence of ortho-ﬂuorine in the aromatic ring, the latter is capable of further cyclization forming 4-oxo-7,8,9,10-tetraﬂuoro-1,2,4, 5-tetrahydro[1,4]oxazino[4,3-a]-4-quinolone (94JFC(69)119, 94IZV279) (Scheme 63).

306

[Sec. III

GEORGII G. FURIN F COOH H2 NR

C6F5 O

_ COO

C6F5 O

OH

F

KOH, H2O

+ NH2 R

O

90-95°C

N

HO

47-78 %

F

R = iPr, Ph, cyclo-C6H11

COOH

R 75 %

Scheme 62

O COOH H2 NCH2CH2OH C6F5

C6F5 OH

O

O

dioxane reflux

O

DMSO

NH 46 % F

O

F O

N

F

O

F 46 % Scheme 63

Alkaline hydrolysis opens the lactone ring to form 1-(2-hydroxyethyl)-5,6,7, 8-tetraﬂuoro-4-quinolone-2-carboxylic acid. Interaction between ethyl pentaﬂuorobenzoylpyruvate and ortho-aminophenol (or its hydrochloride) in alcohol gives 3-pentaﬂuorobenzoylmethylidene-2H-1,4-benzooxazin-2-one (99JFC(96)87, 96ZOR1386); in the reaction with ortho-aminothiophenol hydrochloride, the product is 3-pentaﬂuoro-benzoyl-methylidene-2H-1,4benzothiazin-4-one (00ZOR700) (Scheme 64). Ethyl pentaﬂuorobenzoylpyruvate was used as the starting compound for the synthesis of derivatives of ﬂuoroquinolone (01JFC(108)187) (Scheme 65). Thus, the copper chelate of these compound was treated with triethylorthoformate in the presence of acetic anhydride to form -ethoxymethylene-substituted ethyl pentaﬂuorobenzoylpyruvate, which reacts with various amines (ammonia, methylamine, ethylamine, cyclopropylamine, n-hexylamine, and o-toluidine) to form acyclic precursors of quinolones—ethyl-4-alkylamino-2-oxo-3-pentaﬂuorobenzoylbut-3-enoates (91ZVKO447, 01IZV689, 00IZV1234). These compounds in the presence of triethylamine upon heating in a dry aprotic solvent (toluene, chloroform) undergo intramolecular cyclization to form the corresponding 3-ethoxalyl-5,6,7, 8-tetraﬂuoroquinolones. The cyclization proceeds through intramolecular substitution of the ortho-ﬂuorine atom in the pentaﬂuorophenyl substituent by the amino group.

Sec. III]

307

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

NH2

O C6 F5

C6 F5

NH

O

ROH, 20°C

O

O

O

OH

COOEt

H 33-51 % R = Me, Et, iPr O

NH 2 HCl C6 F5 C6F 5

COOEt

O

O

O

S

SH

NH

ROH, 20°C

Cu/2 18-32 % Scheme 64

OEt

H C6F5

COOEt HC(OEt)3

1) RNH2, EtOH COOEt

C 6F5 OH

O

Ac 2O reflux, 2 h

O

2) Et3 N, toluene reflux, 15 min

O 83 %

F

O

O

F COOEt F

N F

R

R = H (63%), Me (75%), Et (91%), C6 H13 (85%), cyclo-Pr (74%), 2-MeC6 H4 (75%) Scheme 65

Thus, aryl(aroyl)pyruvic esters can interact with N-dinucleophiles not only at the -diketone but also at the -ketoester fragments (93IZV858, 90IZV561, 58CCI189, 78KGS407, 64LA136). The reactions of ﬂuorinated -diketones with urea (59JOC113, 69SWP293341, 71USP3580913, 53JA4091) in basic (59JOC113) or acid (53JA4091) solvents or with thiourea in the presence of sodium methoxide, or with guanidine carbonate (53JA4091) and carboxylic acid amidines lead to uracils, thiouracils, isocytosines, and 2-substituted hydroxypyrimidines, respectively (Scheme 66). Triﬂuoroacetoacetic ester reacts with hydrazine hydrate to form 3-hydroxy5(3)-ﬂuoroalkylpyrazoles 63 (68JCS(C)1507, 81JOC1532, 85IZV144). With

308

[Sec. III

GEORGII G. FURIN

NH2

X

Y

O

R

NHR1

NH

N

R1

X RF

Y

OEt NH O

O

X

R2

OH

R NH2 HCl N

N R2

R = CF3 , X = H, R1 = H, Y = O (20 %) [59JOC113]; R = CH2 F, X = H, R1 = H, Y = O (73 %)

S (67 %) [53JA4091];

1

R = CH3 , X = F, R = Ar, Y = O [69SWP293341,71USP3580913] Scheme 66

2-imino-thiazolidine, the products are thiazolinopyrimidines; and with amino alcohols it gives 2-triﬂuoromethyl-2 carbethoxymethylperhydrooxazine or the corresponding oxazoline. Finally, with cysteine, the product is 4-carboxy-2triﬂuoromethyl-2-carbethoxymethylthiazolidine (Scheme 67). Ethyl 4,4,4-triﬂuoroacetoacetate and 3-bromo-1,1,1-triﬂuoroacetone react in the presence of KH in dimethyl sulfoxide at room temperature to form ethyl 2,4-bis(triﬂuoromethyl)4-hydroxydihydro-3-furanate (97JFC(81)123) (Scheme 68).

RF H 2NNH 2 H 2O

HO

N NH 63 20-98 %

RF

OR O

NH2

O

RF NH2

N

NH O RF = CF3, C 3 F7, C 4F9 , H(CF2)n (n = 1, 2, 4) Scheme 67

Sec. III]

309

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

O Br

O

F3 C

HO F3 C

COOEt

COOEt F 3C

KH, DMSO, 20°C

CF3

O

Scheme 68

Ethyl pentaﬂuorobenzoylacetic ester undergoes cyclization into 1-oxo-3pentaﬂuorophenyl-1H-pyrano[4,3-b]6,7,8,9-tetraﬂuorochromone (92IZV2186) (Scheme 69). The reaction with ethyl orthoformate aﬀords ethyl 2-ethoxymethylidenepentaﬂuorobenzoylacetate, which on heating undergoes cyclization into 3ethoxycarbonyl-5,6,7,8-tetraﬂuorochromone (93JFC(65)37, 93IZV362). The reactions of triﬂuoroacetoacetate with anilines in the presence of sulfuric or polyphosphoric acid lead to the formation of a six-membered heterocycle, oxyquinoline 64 (73JMC319, 68JMC267, 76USP3953453, 73JMC337, 80USP4202981, 77JHC1109) (Scheme 70).

F O

O

F

[ C6F5

O

COOEt ] F

- EtOH HO

O F

HO C6F 5

O

O

C6F5

C6F 5

37 %

OEt O

O F OEt

H CH(OEt)3

C6F5

F

COOEt

OEt F O

O 81 %

O F

Scheme 69

CF 3 CF3

PhNH 2

O CH2COOEt

O

H2SO4

N 64

Scheme 70

OH

62 %

310

[Sec. III

GEORGII G. FURIN

These reactions indicate that the O-, N-, and S-nucleophiles attack the C(1) carbonyl carbon, although in the case of N-nucleophiles the attack may be preceded by formation of a salt with ﬂuorine-containing -ketoesters. If the -position is occupied by a chlorine atom, possessing higher leaving ability compared to ﬂuorine, the reaction follows alternate routes, forming ethyl 2-amino-4triﬂuoromethyl-thiazolecarboxylic ester in the case of thiourea (72BrP290841, 81USP4308391) and ﬁve-membered heterocyclic compounds in the case of formamidine and urethane (76USP3950353, 91USP4303439) (Scheme 71). Bis--diketones 65 containing perﬂuoroalkyl groups are obtained by condensation of acetonylacetone with perﬂuorocarboxylic esters in the presence of lithium methoxide (95IZV2289, 98ZOR371) (Scheme 72). Reaction of compound 65 with binucleophiles such as hydrazine, phenylhydrazine, or hydroxylamine, leads to bis-heterocyclic compounds 66 and 67 (95IZV762) (Scheme 73). Dehydration of bis(5-hydroxy-2-isoxazolines) occurs readily and forms isoxazoles 68. The reaction of 2-amino-4-phenyl-1,1,1-triﬂuoromethylbut-2-en-4-one 69 with acetophenone forms 2,4-diphenyl-6-(triﬂuoromethyl)-pyridine 70 (yield 24%) (96IZV2278) (Scheme 74). S EtOOC

H 2N

N

NH2 EtOH

F3C

NH2

S

O Cl

F3C

H 2N

F3C

OEt O

COOEt

H N

H2O

O

NH O F3C

H2N OR

COOEt

HN

O

150°C O Scheme 71

O

O

O

1) LiH, R FCOOMe, THF 2) H+ / H2O

O

O

RF

RF 65

RF = C4F9, C6F13 Scheme 72

O

Sec. III]

311

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

MeOH

R

R

RNHNH2 HCl

N N

N N RF

Y

RF

66, 67 32-90 % O

O

O

O

Y

RF

R = H, Ph RF = CF 3, C 4F 9, C 6F 13 _ Y = CH 2 CH2_ , 1,4-phenylene, 2-pyrilidene

RF

65 H2NOH HCl LiH / MeOH

RF

N O

O N Y

HO

RF OH

68 67-89 % RF = CF 3, C 4 F9, C 6 F13, _ _ Y = CH 2CH2 , 1,4-phenylene, 2-pyrilidene

Scheme 73

CH 3 Ph

O F3C

Ph O

C 6H5

NH 2

Ph

69

N

CF3

70

Scheme 74

The reaction of 2-amino-4-methyl-1,1,1-triﬂuoromethyl-2-butene-4-one with thiosemicarbazide forms 5-hydroxy-5-triﬂuoromethyl-2-pyrazoline, and with derivatives 3-amine-1,2,4-triazoles forms derivatives triazolo[1,5-a]pyrimidine (02IZV332) (Scheme 75). The derivatives of a new condensed triazabicyclo-[5.3.0]dec-4-ene system with a nodal nitrogen atom (7-triﬂuoromethyl-5-phenyl-1,4,8-triazabicyclo[5.3.0]dec-4-ene 72) are obtained in reactions of aminoenones 71 with diethylenetriamine (room temperature, no solvent, 4–7 days) (yield 64–74% for the triﬂuoromethyl substituent and 23–33% for tetraﬂuoroethyl) (99IZV1410) (Scheme 76). In this case, diethylenetriamine acts as a trinucleophile; its interaction with amino enone 71 involves double nucleophilic addition at the -carbon, forming ammonia, and an attack at the carbonyl group, liberating water. The reaction takes place when the compound contains a polyﬂuoroalkyl substituent, not only enhancing the electrophilicity of the -carbon atom, but also stabilizing the imidazolidine ring. The interaction of regioisomeric -aminovinylthiones 73 with Lawessons reagent forms 3,5-2-thioxo-1,3,2-thiazaphosphorine and 3,5-2-thioxo-1,3,2-oxazaphosphorine 74 (88SL107) (Scheme 77).

312

[Sec. III

GEORGII G. FURIN

H2 N

NHNH2

HO Me

CF3

S

N N

S CF3

NH 2 60 %

Me O

N

CH 3COOH R1

NH 2

NH2

N N H

N

N R1 N

Me

N CF3

60-65 % R1 = MeS, H Scheme 75

Ar

RF O

Ar

RF

(H2 NCH2CH2 )2NH 20°C, 7 days

NH 2

NH N

71

N 72

Ar Ph Ph RF CF3 HCF2CF2 Yield, % 74 33

2-C 4H3S CF3 64

Scheme 76

Ar S

R1

Ar

S P

P S

S R1

R2

R2 NH2 S

NH2 O

73 Ar S

Ar

S P

P S

S

R1

R S

P

S

Ar 74

Scheme 77

N

2-C 4 H3 HCF 2 CF 25

Sec. III]

313

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

When treated with hydroxylamine, -aminovinylketones 75 give 5-amino-5ﬂuoroalkyl-2-isoxazoline 76, while -aminovinylketones 77 yield 3-hydroxy-5ﬂuoroalkyl-2-isoxazoline 78; treatment of 77 with hydrazine hydrate and phenylhydrazine leads to pyrazole and mixture pyrazole and 5-hydroxy-2pyrazoline corresponding (96IZV1306) (Scheme 78). Condensation between ethylene diamine and -amino--polyﬂuoroalkyl-vinylketones 75 containing at two electrophilic centers, an amino group and a ﬂuoroalkyl substituent, follows two routes (Scheme 79). Either 2,3-dihydro-1H-1,4-diazepines 79, existing in its imino enamine form and generated by two nucleophilic attacks at the -carbon and the carbonyl group, or 2,2-substituted imidazolines (81IZV455, 98KGS847, 99IZV546) are formed. The latter are only formed under kinetic control conditions and are converted into the more stable dihydrodiazepines on boiling in ethanol for 3–6 h. The reaction of 3-amino-1-phenyl- and 3-amino-1(thien-2-yl)-4,4,4-tri-ﬂuorobut2-en-1-ones with 1,2-diaminopropane and 1,2-diamino-3,3,3-triﬂuoropropane under kinetic control conditions (room temperature, 20 h) forms a mixture of cis and trans isomers of imidazolines, one of which prevails (isomer ratio 9 : 1) (99IZV2135,

RF

R

(H2NOH)2 H2SO4

RF

R

NH 2

N O NH2 O

76 60-65 %

75

RF = CF3, H(CF2)2, C3F7 R = Me, Et, tBu, Ph RF

(H2NOH)2 H2SO4 R N O

NaOH

OH

78 55-65 %

RF

RF = CF3, H(CF2)2, C3F7 R = Me, Et, tBu R1 = H, Ph

R NHR1

O 77

H2NNH2 H2O

RF

MeOH, BF3 Et2 O

RF

R

N N

N N

H

H 40-60 %

PhHNNH2

R

RF

MeOH, BF3 Et2O

HO R

N N

R

RF +

N N Ph

Ph 20 %

30 %

RF = H(CF2 )2 , R = Me, R1 = Ph; RF = H(CF2 )2 , R = Et, R1 = H; RF = CF3, R = Me, R1 = Ph; RF = CF3 , R = Me, R1 = H;

Scheme 78

314

[Sec. III

GEORGII G. FURIN

RF R

NH HN

O

R

RF O

EtOH H2NCH2CH2NH2

NH2 R

75

RF N

NH 79

R = C4H3S, RF = CF3; R = C4H3S, RF = H(CF2)2; R = Ph, RF = CF3; R = Ph, RF = H(CF2)2 Scheme 79

X H 2N Ar

CF3 O

NH2

CF3 Ar

NH O

NH2

HN

X

Ar = Ph, 2-C 4H3S X = Me, CF 3 Scheme 80

99IZV2234) (Scheme 80). The available data, however, do not permit an unambiguous conclusion about the conﬁguration of the major and minor isomers. It was shown (00IZV1432) that the reactions of aminoenones with diethylenetriamine lead to a condensed system, triazabicyclo[5.3.0]dec-4-ene, with a nodal nitrogen atom (Scheme 81). Diethylentriamine acts as a trinucleophile. Its interaction with amino enones includes double nucleophilic addition on atom C with elimination of ammonia and attack on the carbonyl group accompanying by loss of a molecule of water. Successful reaction is promoted by the presence of poluﬂuoroalkyl substituents that not only increase the electrophility of atom C, but also stabilizes the imidazoline ring. 3-Amino-1-aryl-4,4,4-triﬂuoro-2-buten-1-ones react with 2-aminoethanol at room temperature in the absence of solvent over 2–3 days to give only aminoenones in 46–75% yield (98MC83) (Scheme 82). It is surprising that the thiophene analogue of aminoenones (3-amino-1(2-thienyl)-4,4,4-triﬂuoro-2-buten-1-one) reacts with 2-aminoethanol to form 2(2-thenoyl-methyl)-2-triﬂuoromethyloxazolidine.

Sec. III]

315

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

Ar

R F (H2NCH2CH 2)2NH

Ar O

20°C, 4-7 days

NH 2

RF

[ O

NH

NH2

NH Ar

Ar O

NH

N

]

N

[

RF

NH 2

RF

]

N

HN

RF = CF3, H(CF 2)2 Ar = Ph, 2-C 4 H3 S, 2-C4H3 O, 4-XC6H4 (X = Me, Cl, Br, NO 2, MeO) Scheme 81

X

CF3 OH

N

O H X

CF3

NH2CH2CH2OH

X = Ph, 4-MeC 6H4, 3-NO 2C6H4, 4-ClC6H4, 4-BrC6H4

O

NH2

CF3 O

S O X=

HN (77 %)

S Scheme 82

The reactions of ﬂuorine-containing -aminocrotonic ethers 80 and isocyanates lead to ﬂuorinated uracils 81 (72JHC513, 76TL243, 76BrP1427945, 76ZOR949, 81BCJ3221, 80JHC1413, 77FrP2335566, 99IZV2195) (Scheme 83). These examples demonstrate the eﬃciency of using labile multiple bonds in functional groups for constructing heterocyclic rings. An important factor governing this process is the ﬂuorine eﬀect on the properties of such groups.

O F3C

OEt NH 2 O

R

N

C

O

MeONa, DMSO

80

R N O

R = Ph, 4-ClC6H4, C 5H11, 3,4-dichlorobiphenyl Scheme 83

NH CF3 81 20-70 %

316

[Sec. IV

GEORGII G. FURIN

When a methyl ketone or cyclohexanone phenylhydrazone is treated with triﬂuoroacetimidoyl iodide 82 in the presence of excess sodium hydride, [1 þ 4] cyclization into 5-triﬂuoromethylpyrazoles 83 and 84, respectively, takes place (97SL679) (Scheme 84). -Ketoesters react with methylhydrazine with formation of ﬁve-membered heterocycles (93JHC49) (Scheme 85). Oxidation of bis-hydrazones of aliphatic polyﬂuorinated -dicarbonyl compounds with SO2Cl2 or bromine forms isomeric 1-amino-1,2,3-triazoles, one of which was identiﬁed by X-ray analysis (96JFC(79)45) (Scheme 86). Oxidation of polyﬂuoroalkyl-substituted glyoxal dihydrazones gives only one isomer. Me N R

R NHPh N

F3C

N Ph

I

83 57-72 %

N Ar

N

CF3

NHPh

82 N

F3C

N Ph

84 50-62 % Scheme 84

MeNHNH2

F3C

F3C

COOEt Me

O

N N

OH

Scheme 85

IV. From Other Carbonyl-Containing Compounds with Perfluoroalkyl Groups Compounds with a carbonyl group conjugated to the double bond are conventionally called Michael acceptors. The Michael reaction is a route to a carbon–carbon bond. A nucleophile adds to a Michael acceptor. Together with nucleophilic addition at the carbonyl group, this is the ﬁrst step of Robinson’s cyclization, which is an excellent method for the preparation of medium-sized (and especially six-membered) rings.

Sec. IV]

317

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

RF H 2N

R

N

N

[

_ N

NH2 RF

R

+ N

N

R

NH2

]

RF N

H2N

N

N

R = CF3 (77 %) RF

R

[

_ N

+ N

RF

N

RF NH 2

]

R

N

H 2N

N N

H

HN

N N

RF = C2F5, R = H (70 %); RF = HCF2CF2, R = H (80 %) Scheme 86

In a ﬂuorocarbon chain containing multiple bonds, the carbonyl group possesses high reactivity and is involved in the formation of heterocyclic systems induced by binucleophilic reagents. The mutual arrangement of the C ¼ O group and the double bond may diﬀer between molecules, which leads to diversity of heterocyclic compounds. Below we consider some examples of such substrates. The C ¼ O group is directly bonded at the multiple bond. Some compounds, for example, -chloro-perﬂuorovinylaldehydes are eﬀective building blocks for the synthesis of heterocycles with a perﬂuoroalkyl group. Thus, thiophenes 85 are formed by reaction of -chloro-perﬂuorovinylaldehyde 86 with Na2S and benzyl bromide (99JFC(94)91, 95JFC(70)121) (Scheme 87).

RF

CHO

Cl

Ar

PhCH 2S

CHO

+ Na2S + PhCH2Br RF

Ar Ar

Ph

S 85

Scheme 87

RF

318

[Sec. IV

GEORGII G. FURIN

In the case of the reactions of compound 87 with anilines, the products are quinolines 88 (95JPR34) (Scheme 88). The reaction with para-phenylenediamine produces 2,6-bis(perﬂuoroalkyl)-1,5diazaanthracene 89, while with ortho-phenylenediamine the initial product is benzodiazepine salt 90, stable at 35 C. At elevated temperatures the salt is transformed into benzimidazole perchlorate 91 (Scheme 89). The reaction of compound 86 with phenylhydrazine in the presence of triethylamine, guanidine, and ammonium thiocyanate forms heterocyclic compounds with two heteroatoms (99JFC(94)91) (Scheme 90). Reaction conditions play an important role. For example, when performed in diethyl ether in the presence of triethylamine, the reaction of -chloro-triﬂuoromethylenone 92 with phenylhydrazine yields substituted pyrazole 93; in acetic acid, the product is the isomeric pyrazole 94 (97JFC(84)145) (Scheme 91). 5,5,5-Triﬂuoro-4-triﬂuoromethylpent-3-en-2-one is versatile and highly reactive and provides new substances with interesting properties. Thus, it reacts with p-toluenesulfonylhydrazine and 2,4,6-triisopropylbenzenesulfonylhydrazine in

NH 2 OHC

CF3 F3C

R

N

Cl

R

R

Cl

N CF3

F3C

88

CHO 87

R = OH, COOH, OMe, CF3, COCH3 Scheme 88

H2N

NH2

Ar

F 3C Cl

N N

RF Ar

Ar

89 NH2

RF

CHO

RF NH2

NH

NH Ar

+ N H 90

Scheme 89

+ N

_ ClO4

H 91

_ ClO4

Sec. IV]

319

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

Ar RNHNH2, Et3N N

EtOH

R 64 %

HN NH 2 HNO3

Ar

H 2N Cl

CF3

N

EtOH

Ar

N N

F3C

NH2

39 % F3C

Ar

CHO NH4SCN

86

N

CF3

S 56 % N3

NaN3 DMF

Ar

Ar

F3C

- CO

CHO

NH N N

F3C

68 % Scheme 90

CF3 Et3N Et2O

Ph

O Cl

Ph

PhNHNH2

N N Ph 93 NHPh

F3C 92

Cl AcOH F3C

Ph

N Ph

F3C

N N Ph 94

Scheme 91

acetonitrile under acidic conditions to give the corresponding 1,1,1-triﬂuoro2(triﬂuoromethyl)-4(p-poluenesulfonylhydrazone)pent-2-ene and 1,1,1-triﬂuoro2(triﬂuoro-methyl)-4-(20 ,40 ,60 -triisopropylbenzene sulfonylhydrazone)-pent-2-ene in almost quantitative yields (99JFC(97)115) (Scheme 92). X-ray structures of these compound are provided. Treatment of the compound with sodium hydroxide in a two phase system gives 5-methyl-3,3-bis(triﬂuoromethyl)-3H-pyrazole.

320

[Sec. IV

GEORGII G. FURIN

X X Y

SO2NHNH2

O CH3

X

NH S N O X

CF3 CF3

X = H, Y = CH3 X = Y = CH(CH 3)2

CH3 CF3

O

CF3

Na2CO 3

CF3

Et 2O

CF3

Y

CH3 N

CH3

N

50 %

O

F

CH3

O

CH2COOCH3 THF,RT, 20 h

CF3

COOCH3 O

CH3 58 %

Scheme 92

The conversion of 5,5,5-triﬂuoro-4-triﬂuoromethylpent-3-en-2-one with methyl acetoacetate in the presence of sodium hydride opens a new reaction pathway for the preparation of molecules which might show some biological and medical activities. The ﬁrst step of this reaction is the anti-Michael addition of the nucleophile (-metallated ester) to the 3-position of 5,5,5-triﬂuoro-4-triﬂuoromethylpent-3-en-2one. In the next step metallation in the -position yields the enolate which attacks nucleophilically the oleﬁnic CF2-carbon forming 4-acetyl-2-ﬂuoro-6-methyl-5methoxy-carbonyl-3-triﬂuoromethylpyran by ﬂuoride elimination. The nucleophilic addition of ammonium dithiocarbamate to 5,5,5-triﬂuoro-4triﬂuoromethyl-pent-3-en-2-one follows a Michael analog addition. The presence of two gemminal highly electronegative CF3 groups dominates the regioselectivity. This 1,3-anti-Michael addition results in the synthesis of the new 2-mercapto-4-methyl5(2,2,2-triﬂuoro-1-triﬂuoro-methylethyl)-1,3-thiazole derivatives (02JFC(117)185) (Scheme 93). These compounds exhibits thiol-thione tautomerism; thus, 2-mercapto-1,3-thiadiazoles exist predominately in the thione form (2-thione-4-methyl5(2,2,2-triﬂuoro-1-triﬂuoromethyl-ethyl)-1,3-thiazoline. The dominance of the thione over the thiol form depends on a combination of diﬀerent factors, among them the diﬀerence in p-electron energy. X-ray structures of these compound are provided. When ortho-phenylenediamine reacts with ﬂuoroalkyl-containing ,-dibromoketones 95, dihydroazirinoquinoxalinones 96 (96ZOR320) result. The reaction with ethyl ,-dibromo--ﬂuoroalkylcarboxylic esters 97 yields 2-oxo-1-polyﬂuoroalkyl1,1a,2,3-tetrahydroazirino[1,2-a]-quinoxalines 98 (96IZV3026) (Scheme 94).

Sec. IV]

321

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

NH2 CH3 CF3 CF3

HO

CF3

SNH2 O

CH3

CH3

S

hexane overnight

O+ NH2

S

S

S

CF3

NH

CF3 CF3

SH CH3 HCl

CF3

N

CF3 S

NH S

SH

S

CF3

CF3

37 %

Scheme 93

Br R

RF Br

RF

O

N

95 N 96 45-65 % NH2 NH 2

Et3N

RF = C 4F 9, R = Ph; RF = CHF 2CF2, R = 4-ClC 6H4

Br

MeOH RF

OEt Br

O

RF N

97 reflux, 3 h

NH

O

98 RF = CHF 2, C 6F 13 Scheme 94

When the substrate contains a triﬂuoromethyl substituent, the reaction is anomalous and forms a bis-aziridinylketone. This is probably explained by factors other than steric eﬀects. For example, the electron-accepting inﬂuence of the CF3 group sharply accelerates dehydrobromination relative to dehydration and leads to a three-membered ring (96IZV3026, 95IZV1599, 96IZV2795) (Scheme 95). On the other hand, dihydroazirinoquinoxalines are also prepared from a substrate with a triﬂuoromethyl group by using a -ﬂuoroalkyl-,-dichloropropionic ester. Thus, the reaction of ortho-phenylenediamine with an ,dichloroketone produces 1-triﬂuoromethyl-2-phenyl-1,1a-dihydroazirino[1,2-a] quinoxaline (99ZOR106, 96IZV3026, 99ZOR100) (Scheme 96).

322

[Sec. IV

GEORGII G. FURIN

Ph

O NH2 Br NH2

N

Et 3N, MeOH

N

Ph

F3C Br

O

CF3 CF3

Ph

O

68 % Scheme 95

NH2

CF3

Cl NH2

N

Et3N, MeOH

N

Ph

F3C Cl

O

Ph

13.6 %

O

O CF3 EtO 99

O CF3

CF3

O

O

100

101

Scheme 96

Many publications are devoted to the use of compounds with one triﬂuoromethyl group in the syntheses of heterocycles: 4-ethoxy-1,1,1-triﬂuoro-3-buten-2-one 99 and -alkoxy enones 100 (95JHC739, 95JHC731, 96JHC1223, 96JHC1, 95S1491, 93JHC1159, 91JBCS118, 95JHC735, 97JHC509, 98JHC451, 99JHC45, 96TL9155, 99JFC(99)177). The use of -alkyl--methoxyvinyltriﬂuoromethylketones aﬀords various heterocycles with a CF3 group (95JHC739). Thus, cyclocondensation has been performed with hydroxylamine, semicarbazide, thiosemicarbazide, phenylhydrazine, and urea. In the case of a reaction with amines only the 3-membered heterocyclic aziridine (96IZV2795) is produced (Scheme 97). The presence of a triﬂuoromethyl group can lead to the formation of dihydroazirineqinoxalines with ortho-diamines. Thus, ortho-phenylendiamine with an ,-dichloroketone gives 1-triﬂuoromethyl-2-phenyl-1,1a-dihydroazirino [1,2-a]quinoxaline (99ZOR106, 95IZV1599, 96IZV2795) (Scheme 98). A signiﬁcant number of studies are devoted to the synthesis of compounds with one triﬂuoromethyl group such as 4-ethoxy-1,1,1-triﬂuoro-3-buten-2-one 99 and -alkoxy-substituted enones 100 (95JHC739, 99JFC(99)177).

Sec. IV]

323

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

O

Br RF

RNH2

OEt

RF NHR

MeOH Br

N

O R 65.1-73.2 %

R F = CF3, H(CF 2)2 R = Me, C6H13, PhCH2 Scheme 97

NH2

CF3

Cl F3C

Ph Cl

NH2

N

Et 3N, MeOH

N

O

Ph

13.6 % Scheme 98

Using -alkyl--methoxyvinyl triﬂuoromethyl ketones allows the preparation of various heterocyclic compounds with a CF3-group (95JHC739, 99JFC(99)177). Often carried out by cyclocondensation with hydroxylamine, semicarbazide, thiosemicarbazide, phenylhydrazine, and urea (Scheme 99). -Alkoxyvinyl halomethyl ketones, diethylaminomethylene hexaﬂuoromethylacetone [Et2NCH ¼ C(COCF3)2] and -diketones are intermediates in the syntheses of ﬁve-, six-, and seven-membered heterocycles (for example, a series of CF3-substituted pyridines, pyrazoles, and quinolines) (95JHC739). ,-Unsaturated ketones with a CF3 group are of interest as reagents in the syntheses of various heterocyclic compounds (99JFC(99)177, 01JFC(107)107, 00SC677, 01JFC(108)51. 00T7267, 00PCTWO6382). These mainly include 1,1,1-triﬂuoro-4-ethoxy-3-butene-2-one, 3-triﬂuoroacetyl-3,4-dihydro-2H-pyran, and 3-triﬂuoroacetyl-2,3-dihydrofuran. Thus, it has been shown (01JFC(107)107, 00SC677, 01JFC(108)51, 00T7267) that 4-ethoxy-1,1,1-triﬂuoro-3-butene-2-one is a convenient reagent for synthesis of pyrimidines with a CF3 group (Scheme 100). 4-Ethoxy-1,1,1-triﬂuoro-3-butene-2-one and 3-triﬂuoroacetyl-3,4-dihydro-2Hpyran react with phenylhydrazine in ethanol, forming the corresponding triﬂuoromethyl derivatives of pyrazole (01JFC(107)107). Under the same reaction condition treatment these compound with pentaﬂuorophenyl hydrazine or tetraﬂuorophenyl hydrazine did not give the expected N-ﬂuorinated phenyl pyrazole, it give undehydrated products—5-hydroxy-1-pentaﬂuorophenyl-5triﬂuoromethyl-4,5-dihydropyrazole (the molecular structure was identiﬁed by X-ray analysis) (01JFC(107)107) (Scheme 101).

324

[Sec. IV

GEORGII G. FURIN

S F3C

N

N

H2NNH 1) PhNHNH 2 HO EtOH, , 3 h NH2 F3C 2) H 2SO 4, CH2Cl2 MeOH, 20°C, 24 h S 40°C, 2 h

Ph 75 %

N

N NH 2

79 % O

OMe O

NH 2

F3 C

H2NNH

O NH2 MeOH, , 20 h

H2NOH, C 5H5N MeOH, 45-50°C, 16 h

NH2 MeOH, 55°C, 24 h

CF3 HN

HO F3C

N HO O

F3C

O

N O

65 %

62 %

N

N

NH2 67 %

Scheme 99

N N

CF3

NH2

CF3

HCONH2

X

F3C

NH 4Cl

O EtOCH

N

NH2 HX

N

H X = O, S, NH Scheme 100

Cyclocondensation of (3 þ 2) compounds of type 99 with hydrazine and methylhydrazine leads to pyrazoles (93JHC1159) (Scheme 102). The interaction of compound 102 with hydroxylamine forms isoxazolines 103 (70JINC1895, 93JHC389, 90ZOR1877, 99JHC837, 91S483), which are dehydrated by P2O5 or concentrated sulfuric acid to give isoxazoles 104 (99KGS395, 97JCS(P1)1581) (Scheme 103). In reactions with N-methylhydroxylamine hydrochloride, the product is a 3-isoxazoline derivative (99JHC837) (Scheme 104). In essentially neutral solvents (in the presence of sodium acetate), the reaction forms a mixture of oxime and isoxazoline. In basic solvents, isoxazoline derivatives are obtained as the sole products. Reactions of compound 99 with aldehyde tert-butylhydrazones lead to 4-triﬂuoroacetyl-pyrazoles 105 (87POL2169). Triﬂuoromethylpyrimidines are

Sec. IV]

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

COCF3

ArNHNH2

F3C

EtOH , 24 h

EtO

N

HO

325

N

Ar Ar = C6F5 (80 %), 4-HC 6F4 (72 %) COCF3 ArNHNH2

( )n

HO ( )n

EtOH , 24 h

O

F3C

N N

HO

Ar n = 1, Ar = C 6F5 (71 %); 4-HC 6F4 (70 %); n = 2, Ar = C 6F5 (46 %); 4-HC 6F4 (55 %) Scheme 101

R2

R1

R4NHNH 2 EtOH ,2h

OR3

R2

F3C

N

N

R4

O

R1 R2

CF3

R1

F3C

N N

HO

R4

R1

R2

R3

R4

H

H

Et

H

H

Me

Et

Me

Me

H

Me

Ph

Scheme 102

obtained when 99 is allowed to react with formamide in the presence of NH4Cl, with urea compounds (91CGS502), and with isothiuronium salts (95JHC735) (Scheme 105). Reactions with aromatic binucleophiles form fused ring heterocycles (00T7267). Thus, when the reaction is performed with 2-aminothiophenol, compound 99 is converted into 2-triﬂuoroacetyl-4H-1,4-benzothiazine (identiﬁed by X-ray crystallography) (Scheme 106). In the case of thioethanolamine hydrochloride, the product is 2-triﬂuoroacetyl-4H-1,4-thiazine.

326

[Sec. IV

GEORGII G. FURIN

O R3

CF3

R 1O

OH

N

2) NH 4Cl / H2O

R2

R2

R3 1) H2NOH EtONa / EtOH O

CF3

103 68-97 %

102

P2O5 R2

R3 N

F 3C

O 104 68 %

Scheme 103

R2

OR

O

R1

R2

R1

MeNHOH HCl K2CO3 HO MeOH, 0°C, 4 h

F3C

CF3

N O

Me

_

_

R = Me, R1R2 = (CH2) 4 (85 %) R = Me, R1 = Ph, R2 = Me (87 %) Scheme 104

NH 2 CF3

X NH 2 EtOH, HCl 20°C, 48 h NHBut F 3C

OEt O 99

RCH

N

N N

XH

X = O, S, NH O R

F 3C

MeCN, AcOH 20°C, 48-140 h

N

N

But 105 R = Et, Ar CF3 HCONH 2 N NH4 Cl 160°C, 2 h Scheme 105

N

Sec. IV]

327

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

NH 2

O

OH

S

SH

S

CF3

DMSO 100°C, 12 h

CF3

NH

N

32 % 99

O O H2NCH 2CH2SH HCl

S

CF3 K2 CO3

HS(CH 2)2 NH

CF3

DMSO 80°C, 24 h

NH

Scheme 106

With 2-aminophenol, no reaction takes place even at 120 C in dimethylsulfoxide. The reaction with guanidine hydrochloride in tert-butanol in the presence of KOCMe3 forms 6-triﬂuoromethyl-2-amino-4-hydroxypyrimidine (yield 49%) (00PCTWO6382). Semicarbazide and its derivatives including thiosemicarbazide react with 2-polyﬂuoroacyl-cyclohexanones, giving exclusively hydroxy-pyrazolines (99IZV361) (Scheme 107). The choice between the two isomeric possible forms, F and X, was made based on an X-ray investigation (for the derivative with the n-C6F13 substituent). The reactions of polyﬂuoroalkylcyclohexanones with ortho-phenylene diamine form 2-polyﬂuoroalkylbenzimidazoles (99IZV562) (Scheme 108). Compounds 100 and 101 also react with 2-aminothiophenol, forming 3-(2,2,3-2Hbenzothiazolyl)-2-(triﬂuoromethyl)tetrahydrofuran-2-ol and 3-(2,2,3-2H-benzothiazolyl)-2-(triﬂuoromethyl)tetrahydro-2H-pyran-2-ol, respectively (Scheme 109). The structure of the latter is conﬁrmed by X-ray analysis (00T7267).

H

RF OH X

NH 2

O + RF

O

N

X NHNH2

N

NH2

F or RF

RF = HCF2, CF3, H(CF2)2, n-C4F9, n-C 6F 13, n-C8F17 X = O, S

N N HO X X

Scheme 107

NH 2

328

[Sec. IV

GEORGII G. FURIN

NH2 N

NH2

O

RF MeOH, AcOH, 72 h RF

NH

O

RF = CF3, H(CF 2)2, HCF2, n-C6F 13 Scheme 108

O CF3

HO NH2

CF3

( )n

PhMe

NH

20°C, 24 h

S

O

+

O

SH

( )n

n = 2 (74 %) n = 3 (70 %)

n = 2 (100) n = 3 (101) Scheme 109

The reaction scheme may be represented as follows (Scheme 110): O CF3 ( )n O

HS

O

HS

+ F3C

H2N

HO

NH ( )n

CF3 HO O NH ( )n

HO

O S

SH

CF3

NH ( )n

Scheme 110

The reactions between 4-amino-1,2,4-triazoles and 2-polyﬂuoroacylcycloalkanone lithium salt form polycyclic nitrogen-containing heterocycles with polyﬂuoroalkyl substituents (99IZV562) (Scheme 111). Five-membered nitrogen-containing heterocycles may be synthesized from N,N-diethylaminomethylene-1,1,1,5,5,5-hexaﬂuoro-acetylacetone (93TL7737) (Scheme 112). N,N-Diethylaminomethylene-1,1,1,5,5,5-hexaﬂuoroacetylacetone reacts with ureas to form pyrimidine derivatives (93TL7737) (Scheme 113). 4-Alkyl(aryl)-1,1,1-triﬂuoro-4-methoxyalk-3-en-2-one reacts with aminoguanidine bicarbonate, giving 6-alkyl(aryl)-2[3-alkyl(aryl)-5-triﬂuoro-methyl-5-hydroxy-4,5dihydro-1H-pyrazol-1-yl]-4-triﬂuoromethylpyrimidine. The latter is converted into

Sec. IV]

329

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

RF

N

N

N

NH2

N N

N

N

35-40 % RF

N NH R1 O Li+ O

_

N N

NH2

N

R1

N

N 40-60 %

RF

N NH R2

NH2

RF

X

N N

R2

N X 50-70 %

RF = CF3, H(CF2)2 R1 = Me, SMe, H R 2 = Me X = Br Scheme 111

6-alkyl(aryl)-2[3-alkyl(aryl)-5-triﬂuoro-methyl-1H-pyrazol-1-yl]-4-triﬂuoromethylpyrimidine by reaction with concentrated sulfuric acid in methylene chloride (93TL7737). Heating compound 101 with diethylamine yields a mixture of two products, one of which is a pyrone derivative (99MC671) (Scheme 114). If a compound contains an arylamino group at the multiple bond, heating this compound with TiCl4 leads to six-membered heterocyclic compounds (93TL7737). -Ethoxyvinyl triﬂuoromethyl ketone reacts with cyclohexyl isocyanide, forming 2,5-dihydrofuran derivative 106, whereas ,-diethoxyvinyltriﬂuoromethylketone 107 under the same conditions isomerizes into ester 108 (77IZV2061) (Scheme 115). Reactions with thioacetate and 2-thiolethyleneamine give thiazole 109 and thiazepine 110, respectively (92JFC(58)134) (Scheme 116). The reactions of butoxy(triﬂuoromethyl)enone 111 with 1,2-diamines (orthophenylene diamine and 1,2-ethylenediamine) lead to 1,5-diazepines 112 and 113; with ortho-aminophenol or ortho-aminothiophenol, the products are 1,5-oxazepines or 1,5-thiazepines 114, respectively (98KGS634, 96TL2845) (Scheme 117). Good results were obtained by using microwave (W) radiation. At the same time, in boiling xylene, the condensation leads to a mixture of products. -Alkoxyvinyl triﬂuoromethyl ketones and -aryl--methoxyvinyl triﬂuoromethyl ketones, prepared from the respective acetophenone dimethyl-acetals by reaction with triﬂuoroacetic anhydride, undergo cyclocondensation with thiosemicarbazide

330

[Sec. IV

GEORGII G. FURIN

O F3C

H2 NNH2 H2O 20 oC, 4 h

F3 C

NH

N

96 % O

CF3 NEt2

O O

O

PhNHNH2 F 3C 20°C, 4 h

F3C

F 3C

N

CF3

N + F3 C

N

Ph 75 %

MeCN, 70°C, 4 h

Ph

25 % O

PhCH 2NHCH2COOEt

N

O

F3C

CF3 N

EtOOC

CH 2Ph

O F 3C

EtOOC

CF3 N CH2 Ph 96 %

Scheme 112

O O CF3

CF3 R2

N N

N

HO N

R1

F3C NMe2

79 % R1

R2

NMe2 NMe 2 NMe 2 NMe2 OMe

COCF3 COOH COOMe COCF3 COCF3

Yield, % 85 85 65 Scheme 113

F3C

N N

NMe2

Sec. IV]

331

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

O CF3 O

O

H

NEt 2

CF3

Et 2NH 101

NEt2

(CH2) 3OH 80°C, 12 h

Et2N

H OH O

CF3

R C(COCF3 )2 H NH R

NH

NH

PhNH N O CF3 O

O CF3

F3 C F 3C CF3

Heterocycle

NH

F3C

N

HO

N N

Yield, %

96

60

90

100

Scheme 114

OEt

N EtO

C

O

F 3C

N

O

20°C, 3 days CF3 99

106 54 % N

C F3C

OEt O

OEt

CF3

20°C, 2 month EtOOC

CF3 OEt 108 70 %

107 Scheme 115

332

[Sec. IV

GEORGII G. FURIN

R2 CF3

HSCH2COOEt NaH

Cl

R3

R2

R3

F3C

O

COOEt

S 109 R2

R2 R1

F3C

H2NCH2CH2SH

R1

F3C N

S Cl

O 110 Scheme 116

R1

NH2

R2

NH2

R1

NH X

R2

N CF3 112 73-93 %

O CF3 W t BuO

X

NH

H2NCH2CH 2NH2

X

xylene 8-25 min

N CF3

R3

NH2 YP

113 73-77 % R3

NH X Y

X = COCF3 R1 = H, Me; R 2 = H, Me, Cl, NO 2, COPh;R3 = H, Cl

OH

CF3 114 71-89 %

Y = O, S Scheme 117

and semicarbazide, giving new 5-(1-thiosemicarba-zido)-2-pyrazoline-1-thiocarboxamide and 2-pyrazoline-1-carboxamide, respectively (99IZV361) (Scheme 118). Boiling with sulfuric acid gave 3-aryl(alkyl)-5-triﬂuoromethyl-1H-pyrazoles (98JFC(92)23). Isoxazolines and isoxazoles were obtained in good yields by the interaction of acetylenic ketones 114 with hydroxylamine; the regioselectivity of the reaction depends on reaction conditions. Thus, when treated with hydroxylamine in alkaline

Sec. IV]

333

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

S OR

O

R2

NH2 F3C

R1 R2

R1

H2NNH F3C

N N

HO

MeOH 20°C, 20-24 h

S

NH2

73-96 % H 2SO4 ,4h R2

F3C

R1 N NH

57-76 % R

Et Me Me Me Me

R1 H R2 H

Me

Me

Me H Ph 4-MeC6H4 4-BrC6H4 4-NO 2C6H4 H Me H H H H Scheme 118

media, ketone 114 is converted into isoxazoline 115, whose dehydration on heating in benzene gives the corresponding isoxazole 116 (99KGS395) (Scheme 119). In acid solvents, the initial product is an oxime, whose cyclization on boiling in benzene leads to an isomer of isoxazole 116. It seems that the possibility of aromatization has a critical eﬀect on the reaction route. If aromatization is impossible, oxime formation seems to be preferable. -Ethoxy(phenoxy)substituted enones 117 are eﬀective heterodienes; in the reverse Diels–Alder reaction, they react with vinyl ethers, giving 3,4-dihydro-2H-pyranes 118, while with dihydrofuran they give derivative 119 (89S215) (Scheme 120). The interaction of -alkoxy enones 120 with enaminonitriles leads to pyridines with CF3 groups 121 (95JHC543) (Scheme 121). The reaction of 2,2-diaminohexaﬂuoropropane with an equimolar amount of glyoxal forms cis-2,4,6,8-tetraazabicyclo[3.3.0]-octane 122; with an excess of glyoxal, imidazolidine 123 is formed (87JOC1113) (Scheme 122). ,-Dibromoketones 124 react with hydrazines in the presence of triethylamine in methanol, forming ﬂuorine-containing pyrazoles 125 (96ZOR320, 94IZV282, 96RusP2054416, 96IZV3026) (Scheme 123). Khomutov et al. developed eﬀective universal methods for the syntheses of 3-ﬂuoroalkyl-2-aziridinylketones from ﬂuorine-containing ,-enones (94IZV282) (Scheme 124). The reaction of -bromo-,-enones with ammonia or amines proved to be a more universal synthetic method, permitting a wide variation of substituents at the nitrogen atom of the aziridine ring (94IZV282).

334

[Sec. V

GEORGII G. FURIN H2NOH MeONa / MeOH

N O C8H17

reflux, 2 h

OH CF3

115 C 6H 6 reflux

O

N O

C8H17 CF3

C8H17

114

CF3 116 64 %

H2NOH, AcOH 10 % HCl 20°C, 15 h

N

OH

C8H17 CF3 C6H6 O N C8H17

CF3 80 %

Scheme 119

OR1 CF3

OR2 O

O

R2O CF3

118 72-100 % R1O

80°C, 30 h

OEt

117 O F3C R1 = Et, Ph R2 = Alk, Ph

O

O

119 68 %

Scheme 120

V. The Synthesis of Oxygen-Containing Heterocycles by Intramolecular Cyclizations in Antimony Pentafluoride In the series of unsaturated perﬂuorinated compounds, the C–F bond is extremely stable. At the same time, German et al. found that the CF3 group of the

Sec. V]

335

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

R1

O R2O

R2O

CF3

R1

CN

MeCN

+ X

CN

reflux, 2 h

X

121 68-95 %

120

X= N

N

F3C

,N

Y Y = O, NMe, NCOOEt Scheme 121

R1

R

O

O

H

H

F3C

N

N

CF3

F3C

N

N

CF3 R2

R3

(CF3)2C(NH2) 2 +

122 R RO

RO

N

CF3

N

CF3

R 123

R - R3 = H (87 %); R = R2 = H, R1 = R3 = NO2; R = H, R1 - R3 = NO2; R - R3 = NO2 Scheme 122

Br RF

R

R`NHNH 2

RF

R N N

Et 3N, MeOH Br

R`

O

125

124 Scheme 123

unsaturated ﬂuorocarbon chain of perﬂuoroaliphatic compounds is involved in the formation of new chemical bonds (83IZV2765). They showed that if the molecule contains fragments capable of generating secondary carbenium ions and if the reaction is catalyzed by a powerful electrophilic acid such as SbF5, the CF3 group in the skeleton of a saturated perﬂuoroaliphatic compound can act as a functional

336

[Sec. V

GEORGII G. FURIN

O RF

R1NH2

Ph

RF

Ph 1) Br2

RF

Ph N

2) R1NH2 NHR1 O

O

R1 68-87 % RF = CF3, C6F13, C8F17, H(CF2)4, H(CF2) 6 R1 = n-C6H13, (CH2)2OH, C4H9, H, Me Scheme 124

group that can be involved in electrophilic perﬂuoroalkylation reactions. This peculiarity was employed in the design of methods for the syntheses of perﬂuorinated oxygen-containing heterocyclic compounds from ketones, -diketones, and oleﬁn -oxides. These reactions involve the terminal CF3 group and the oxygen atom of the carbonyl group at the opposite end of the molecule when the ring-forming chain contains ﬁve carbon atoms (91JFC(54)77). Thus, on heating perﬂuoro-4methylpentan-2-one in SbF5, one obtains perﬂuoro-2,4-dimethyltetrahydrofuran 126 in a high yield (Scheme 125). The proposed reaction scheme involves coordination of SbF5 (or perﬂuorobenzyl cation) at the carbonyl oxygen and isomerization of the initially generated secondary carbenium ion into the primary ion as a result of ﬂuoride migration with subsequent reaction of the carbocationic center with the nucleophilic fragment of the molecule. The during force of the isomerization is presumably a transition from the secondary carbocation, destabilized by two electron-accepting ﬂuoroalkyl groups, to the more stable primary carbenium ion due to the interaction of the vacant p orbital of the carbon atom with lone electron pairs of the geminal ﬂuorine atoms.

O SbF5 F 3C

CF2CF(CF 3)2

100°C, 7 h F3 C + F 2C

CF3

[ (CF3)2CFCF 2

+ _ OSbF5

F - SbF5 F3 C F O

CF3

126 84 % Scheme 125

CF3 CF2

]

F _ OSbF5

Sec. V]

337

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

The nature of the catalyst also plays an important role in these processes. Thus, cyclization of perﬂuoropentan-2-one in SbF5 leads to perﬂuoro-2-methyloxolane 127 with a yield of 2–3%, whereas using a SbF5–C6F5CF3 system increases the yield of the target product to 76% (Scheme 126). Note that the reaction does not occur when the structure of the starting ketone precludes formation of an oxolane ring. Thus, heating perﬂuoro-2-methylpentan-3-one, perﬂuoro-2,6,6-trimethylheptan-3-one, and perﬂuorooctan-2-one in SbF5 (150–170 C, 20–30 h) did not end with the formation of a heterocycle. Nevertheless, in the series of saturated perﬂuorinated oxygen-containing compounds, cyclizations of this kind induced by strong Lewis acids, such as carbocations or SbF5, are general reactions. Electrophilic cyclizations of perﬂuoroketones possibly form either perﬂuorooxetanes or perﬂuorooxolanes. In fact, oxolanes are the sole products of this reaction. It was concluded (91JFC(54)77) that electrophilic cyclizations of saturated perﬂuoroaliphatic ketones under these conditions involve the CF3 group in only those instances that lead to formation of ﬁve-membered rings. The tendency toward formation of ﬁve-membered rings is especially conspicuous in the case of intramolecular electrophilic cyclizations of perﬂuoro--diketones in the presence of SbF5. Thus, when heated in SbF5, perﬂuorinated -diketones RFC(O)C(O)CF3 give substituted perﬂuorooxolan-3-ones or 2-triﬂuoromethylacetylperﬂuorooxolane (RF ¼ C3F7) (Scheme 127). The structures of the starting diketones suggests the possibility of forming rings with diﬀerent numbers of atoms (four-, ﬁve-, or six-membered). However, there is a clear-cut tendency toward formation of a ﬁve-membered ring with the carbonyl oxygen atom and a group with a required number of linear carbon atoms involving a terminal CF3 group. Depending on the structure of the perﬂuoroalkyl radical, the carbonyl group not O C6F5CF 3 / SbF5 F3C

CF2CF 2CF 3

F O

100°C, 13 h

CF 3

127 76 % Scheme 126

O

O

R

CF3

O

SbF5 F3C

R C2 F5

R` F O

R`

Condition

F2

o

150 C, 8 h o

Yield, (%) 83

CF(CF3 )2

FCF3 70 C, 6 h

81

C(CF3 )3

(CF3 )2 100o C, 9 h

80

Scheme 127

338

[Sec. V

GEORGII G. FURIN

involved in the cyclization enters the ring (oxolanes) or stays outside (acyloxolanes). If this rule is violated, no cyclization takes place. For example, under comparable conditions (150 C, 16 h), perﬂuoroocta-2,3-dione fails to undergo cyclization, whereas under more stringent conditions, pronounced decomposition takes place. Isomerization of perﬂuoro-2-methyloxan-3-one 128 (the hypothetical product of cyclization of perﬂuorohexa-2,3-dione) into perﬂuoro-2-acyloxolane 129 is a further illustration of the high thermodynamic stability of oxolanes (Scheme 128). If a compound contains a carbonyl group at a double bond, the reaction with SbF5 forms a ﬁve-membered heterocycle. Thus, heating perﬂuoro-3-isopropyl-4methylbut-3-en-2-one 130 (according to 19F NMR data, the conformer ratio is 1:6 at 20 C) in SbF5 at 100 C is accompanied by electrophilic cyclization forming perﬂuoro-3-isopropyl-2,4-dimethyl-2,5-dihydrofuran 131 (91JFC(54)77, 90IZV2183) (Scheme 129). An essential condition for this reaction is the presence of a triﬂuoromethyl group in the -position with respect to the carbonyl group of the vinylketone. The reaction starts with ﬂuoride anion elimination, and the generated C cation attacks the carbonyl oxygen, forming a cyclic cation D, captured by the

O F

X

O O

F3C

CF3

128

O

SbF 5 100°C, 96 %

CF2CF2CF3 SbF5 120°C, 24 h

O

F O

CF3 129 65 % Scheme 128

CF(CF3 )2 (CF3 )2C O

F3C

SbF5 100°C

CF(CF3)2 _ O SbF 6

+ F2C

F 3C 130

F3C C F3 C

CF(CF3 )2

F3 C

F F

+

F F

O

CF3

D Scheme 129

CF(CF3)2

O

CF3 F

131 76 %

Sec. V]

339

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

F 3C

CF(CF3) 2

C2F 5

O

C2F 5

CF3

F

SbF5 C2F 5

C2F 5

O

F

_ F

CF 3

F

F

C2F5

C2F 5

C2F 5

134

133

132

C2F5

O

Scheme 130

ﬂuoride ion to give compound 131. Likewise, heating perﬂuoro-4,6-dimethylhept-4en-3-one 132 in SbF5 yields perﬂuoro-2,2,4-trimethyl-5-ethyl-2,5-dihydrofuran 133, which is subsequently transformed into thermodynamically more stable perﬂuoro-2ethyl-3,5,5-trimethyl-4,5-dihydrofuran 134 (Scheme 130). Under the action of cesium ﬂuoride, perﬂuoro-4-methylpent-3-en-2-one, which does not form stable enolates, cyclizes into perﬂuoro-2,4-dimethyl-2,5-dihydrofuran 136. Analogously, when treated with SbF5, 136 cyclizes into 2,5-dihydrofuran (83IZV2765) (Scheme 131). The opening of the epoxide ring under the action of SbF5 and HF–SbF5 leads to perﬂuorinated tertiary alcohols or perﬂuoroketones, depending on the structure of -oxides and the electrophile used. Therefore, oxides can be converted into the corresponding perﬂuorinated oxolane 137 (90IZV2183, 91IZV2611). For example, heating perﬂuoro-2-methylpent-3-ene oxide in SbF5 aﬀords a (1:1) mixture of perﬂuoro-2,4-dimethyloxolane 138 and perﬂuoroethylisopropylketone 139 (Scheme 132).

CsF F 3C

diglume 100°C, 2 h

F (CF3)2C

F

F

O

SbF5

F3C

F

89 %

F

O

CF3

86 %

136

135 Scheme 131

F3 C X F3 C F

C2 F5 F

O

CF(CF3 )2 O 137

F

F 3C

O

SbF5 200°C, 10 h

F O 138 50 %

Scheme 132

+ CF3

C2 F5

CF(CF3)2

139 50 %

340

[Sec. V

GEORGII G. FURIN

Isomerization of -oxides can give either an oxetane or an oxolane. It appears, however, that the reaction follows the route leading to substituted perﬂuorooxolanes. Other perﬂuoroepoxides also undergo this reaction. Thus, the reaction of perﬂuoro-2-methyl-2-pentene oxide with octaﬂuoroisobutylene in the presence of SbF5 gives perﬂuoro-2,2-dimethyloxolane 140 (yield 15%) (Scheme 133). A similar result was obtained when this oxide was heated with a catalytic amount of octaﬂuorotoluene in the presence of SbF5 (yield 85%). In the absence of octaﬂuorotoluene or octaﬂuoroisobutylene oxide, even heating to 300 C did not give compound 140. Other oxygen-containing derivatives can also undergo this reaction. For example, vicinal bis(ﬂuorosulfato)perﬂuoroalkanes 141 undergo partial scission under the action of the ﬂuoride ion (from SbF5), giving -ﬂuorosulfatoperﬂuoroketone 142 and isomeric cyclic perﬂuoroalkene sulfate 143 as major reaction products (90IZV2048, 90IZV2057) (Scheme 134). Prolonged heating of the compound with SbF5 leads to -diketones (90IZV2063). At the same time, in the presence of the perﬂuorobenzyl cation, the product is the corresponding oxolane 144. It has been shown (90IZV2063) that severad bis(ﬂuorosulfato)perﬂuoro-alkanes 145 and ketoﬂuorosulfatoperﬂuoroalkanes 146 heated in SbF5 give the corresponding perﬂuorooxolanones 147 with high yields (Scheme 135). Cyclization occurs by cleavage of the C–F bond at the end of the saturated ﬂuorocarbon chain. Burger et al. (83JFC(27)327) showed that the reaction of SbF5 with perﬂuorotrimethylamine

CF3 (CF3) 2C

CF2

F3C

[

O

SbF 5, 100°C

F3C

O

F

CF2

_ Sb2F11 + CFC2F5

CF3 C6F5CF3

]

F

F F 3C

C2F5

F3C

_ Sb 2F11 + CFC2F5

F 3C

[

O

SbF5 100°C, 6 h

140

F C 6F5 F

CF3 F 3C

_ Sb2F 11 + CF2CF2CF2

O

F C 6F5 F

Scheme 133

]

Sec. V]

341

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

F

F3C

_

+

F3C FSO2O

F3C

FSO2O

O S

C2F5

O O 143 41 %

142 37 %

C2F 5

C2F5

O

F

F3C

F

F3C F3C

O

O

OSO2F

C6F5CF3 / SbF5

141 100°C, 6 h

CF3

F O

CF3

144 87 % Scheme 134

F

OSO2F

RF

CF3 RF = CF3 (86 %)

F3C F3C

100°C, 6 h

O

F

OSO 2F

RF

F3C

CF3

F3C F3C

CF3 RF

O

SbF5

145

F O 147

150°C, 12 h

OSO 2F

RF = F (82 %), CF3 (86 %)

F 146 Scheme 135

forms tetraﬂuoromethane and a salt of ﬂuorinated s-triazine, whose hydrolysis yields 6,6-diﬂuoro-1,5-bis(triﬂuoromethyl)-[1,3,5]triazine-2,4-dione (Scheme 136). The same compound is prepared by electrophilic trimerization of perﬂuoro-2azapropene induced by SbF5 and a subsequent reaction with water (83IZV476).

F

F SbF5

F3C

(CF3)3N - CF4

N

N

SbnF5n+1

+ N

F

CF3 F

H 2O

F3C O

F

F

N

N NH

CF3

1) SbF5

O

2) H2O

F3C N

Scheme 136

CF2

342

[Sec. VI

GEORGII G. FURIN

C4F9

[ SbF5 ] (C4F9)3N

C3F7CF

N

100°C, 4 h

C3F 7 KSCN MeCN 45°C, 5 h

N C4F9

N=C=S

Scheme 137

The ﬁrst reaction occurs by dealkylation, which forms perﬂuoro-2-azapropene, subsequently trimerized by SbF5. In linear and cyclic perﬂuorotrialkylamines, SbF5 promotes splitting at the C–N bond, which forms the corresponding perﬂuoroazaalkenes (Scheme 137). Because the ﬂuorine atom at the C ¼ N bond is extremely labile, the latter are eﬀective intermediates for the syntheses of various derivatives, leading to various heterocyclic compounds in reactions with binucleophilic agents. Another approach uses derivatives, in particular, those containing N ¼ C ¼ S groups, which are readily obtained by reaction of sodium thiocyanate with this compound. Several examples of using heterocyclic compounds are given in Chapter 3. Thus, new intramolecular cyclization reactions of perﬂuorinated mono- and dicarbonyl compounds induced by strong electrophiles have demonstrated the possibility of processes involving nonactivated CF3 groups in unsaturated ﬂuoroaliphatic chains. These reactions have no analogs in ﬂuoroorganic chemistry. Development of this approach will hopefully lead to new data on the synthesis of heterocyclic compounds and to nontrivial synthetic procedures.

VI. New Strategy of Heterocyclic Design Free-radical reactions have begun to ﬁnd increasingly wide application in synthetic chemistry. Because of their high stereoselectivity, some of them are very appealing. At the same time, many such processes have serious limitations since they use iodine-containing systems as substrates. Nevertheless, radical cyclization has become a known technique of both cyclic and heterocyclic system design. For most reactions involving radical intermediates, it is required that the radical precursor and the carbon site of radical cyclization be present in the same substrate. Using a radical generated separately, however, seems to be more eﬃcient. In its reaction with a substrate, this radical gives a new radical center, which is responsible for further cyclization. This is the essence of the new strategy of heterocyclic design. Based on this approach, the synthesis of ﬂuorine-containing heterocyclic compounds can use one of two possibilities. The ﬁrst is the introduction of a perﬂuoroalkyl group together with a radical site into the substrate. The second is the use of a substrate with the above radical and generation of a new radical by addition at an unsaturated group. Some examples of such reactions are given below. In one example, accessible perﬂuoroalkyl iodides were employed as sources of perﬂuoroalkyl radicals. Irradiation, thermal treatment, or the use of a catalyst lead

Sec. VI]

343

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

R

R RF

I Na2S2O4 - NaHCO 3 + RF I O

MeCN - H 2O

O

O

O 148

R

RF

Yield,%

E:Z

H

CF3

44

32:68

H

Cl(CF2 )2

47

60:40

H

Cl(CF2 )4

50

52:48

Me

CF3

80

95:5

Me

Cl(CF2 )2

83

>97:3

Me

Cl(CF2 )4

82

>97:3

n-C8 H17

Cl(CF2 )2

92

>97:3

Scheme 138

to homolytic splitting of the C–I bond. If a molecule contains multiple bonds, a new radical center is generated by the action of the perﬂuoroalkyl radical. If there are two multiple bonds, RF and I fragments add at the oleﬁnic bond, and a ﬁve-membered heterocycle 148 is formed (this process is highly regioselective) (95T2639) (Scheme 138). In this case, the strategy is generation of a radical center with initial C–I bond cleavage and further cyclization involving this center and the multiple bond as a donor. For example, polyﬂuoroalkylated 3-iodoalkyliden-2-(3H)dihydrofuranone is obtained by generation of a perﬂuoroalkyl radical initiated by reaction of RFI with Na2S2O4 with subsequent formation of a ﬁve-membered heterocycle. This reaction is highly regioselective (95T2639). Analogously, perﬂuoroalkylation of N-allyl-2-propynamide and N-allyl-2-butynamide under the action of perﬂuoroalkyl iodides in the presence of Na2S2O4–NaHCO3 forms perﬂuoroalkyl derivatives of 3-alkylidene-2(3H)-pyrrolidone 149 and the product of addition at a double bond 150 (95T2639, 94TL613) (Scheme 139). Cyclization by the intermediate radical is eﬀectively used for the formation of cyclic systems (91CRV1237). Due to the presence of a C–I bond in the substrate molecule, cyclization can occur by generation of a radical center by C–I bond cleavage. Thus, the triﬂuoroacetimidoyl radical, generated photochemically or thermochemically from iodine and tellurium derivatives, reacts with a multiple bond by the action of Bu3SnH–AIBN, forming indoles 151 or quinolines 152 (93TL7933) (Scheme 141). If the CF3 group lies at a multiple bond (compound 153), heterocycle-forming cyclization also takes place (Scheme 142).

344

[Sec. VII

GEORGII G. FURIN

R1

Na 2S 2O4 - NaHCO3 + RFI O

R1

R1

MeCN - H2O

N

I

RF

I RF

+ O

N

R2

O

R2 150

R2 149

R1

R2

RF

Yield, %

N

E:Z

149 150 Me Me

Cl(CF2 )2

53

19

>97:3 >97:3

Me Bn

Cl(CF2 )2

50

35

Me Bn

Cl(CF2 )4

49

29 >97:3

Prn

Bn

Cl(CF2 )2

41

23 >97:3

n

Pr

Bn

Cl(CF2 )4 43

27 >97:3

H

MeCO Cl(CF2 )2 46

0

52:48

Me PhCO Cl(CF2 )2 70

0

>97:3

Me PhCO Cl(CF2 )4 60

0

>97:3

CF3

72

0

>97:3

Cl(CF2 )4

83

0

>97:3

Me

OTs

CH3 OTs

Scheme 139

VII. Intramolecular Nucleophilic Cyclizations with Annulated Fluorinated Heterocyclic Rings Intramolecular cyclizations involving the ﬂuorine atoms of the benzene ring and the multiple bonds of perﬂuorooleﬁns as induced by heteronucleophiles, as well as by condensations involving several molecules with suitable functional groups, are key methods for the synthesis of various heterocyclic compounds. While condensation as a method of synthesis of ﬂuorinated heterocycles is well known and well characterized, intramolecular nucleophilic cyclization is a new technique, permitting one to obtain perﬂuoroalkyl derivatives of heterocyclic compounds. Due to the presence of ﬂuorine atoms in the starting benzene molecules, cyclizations occur by elimination of ortho-ﬂuorine atoms (74FCR115). In view of their high electronegativity, ﬂuorine atoms accumulated in the benzene ring substantially increase the electrophilicity of the carbon atoms. This creates conditions for high mobility of the ﬂuorine atoms of polyﬂuorinated aromatic compounds in nucleophilic substitution reactions and hence for intramolecular nucleophilic cyclizations by the elimination of the ﬂuorine atom ortho to the

Sec. VII]

345

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES R1 I

RFI R1

RF N

O

R1

R2 RF

+ RF O

N

N

O

R2

R2

R1

RF

O

N R2 R FI I

R1

RF

O

N R2

Scheme 140

iniziator

X N

Y

R1

R1

]

[ N

CF3

R1

CF3 NH

CF3

151 R X iniziator N F3C

R

[ F 3C

Ar

H

]

N Ar

N 152

X = I, TeAr, N

NCPh 3

Y = H 2, O Scheme 141

CF3

346

[Sec. VII

GEORGII G. FURIN

CF3 CHPh

CF3 CHPh

X = Ph + O CF3

I

O

O

81 %

Bu3SnH X AIBN

5%

CF 3 CH 2Ph

CF3 CH2 Ph

153 + X = PhCH

CH

O 70 %

O 5%

Scheme 142

functional group having a nucleophilic center. There are many examples of these reactions, which formed the basis of one of the most important and general methods for the synthesis of ﬂuorine-containing condensed heterocyclic compounds. In these reactions, ﬂuorinated derivatives of benzene and binucleophilic reagents serve as substrates. Work is still in progress to synthesize heterocyclic compounds by this procedure, especially in connection with drug synthesis. We cite only a few such examples. It was reported (94IC415) that the reactions of 2,2,3,3 tetraﬂuorobutyleneglycol triethylsilyl ether with 1,4-dibromotetraﬂuorobenzene, tetrabromoethane, and oxalyl ﬂuoride form oxygen-containing heterocycles (Scheme 143). Adamson et al. (92JFC(58)300) showed that 1,2,3,4-tetraﬂuoroacridines 154 are formed in quantitative yields in reactions of pentaﬂuorobenzaldehyde with substituted anilines at room temperature (Scheme 144). 2,3-Diphenyl-4,5,6,7-tetraﬂuorobenzofuran is formed in a reaction of hexaﬂuorobenzene with phenyl benzyl ketone in the presence of sodium hydride (79BCJ2657) (Scheme 145). The reaction involves intramolecular nucleophilic cyclization of the generated O-nucleophile due to tautomerization of the intermediate ketone. The reaction of iodobenzene with pentaﬂuoroaniline in the presence of 3% PdCl2(PPh3)2 and 1.2 equivalent of 1,8-diazabicyclo[5.4.0]undec-7-ene in N,N-dimethylacetamide in the presence of carbonmonoxide forms 2-aryl-4,5,6,7-tetraﬂuorobenzoxazole (92JOC6351) (Scheme 146). The reaction probably occurs via the intermediate formation of a palladium complex and N-pentaﬂuoro-phenylbenzamide. Weak nucleophiles, generated from the corresponding derivatives of acetic and hydroxamic acids under the action of bases (KF, K2CO3), replace the ortho-ﬂuorine atoms of the benzene ring by the intramolecular nucleophilic cyclization mechanism. This yields the corresponding heterocyclic compounds (155 and 156) (81BCJ3447, 93ZOR2416) (Scheme 147). It has been shown (81BCJ3447, 93ZOR2416) that 5,8bis(vinylthio)-6,7-diﬂuoro-2,3-dihydro-1,4-benzoxazine is formed by the reaction of 3,6-bis(vinylthio)-1,2,4,5-tetraﬂuorobenzene with aminoethanol in dimethylformamide in the presence of NaOH at 50 C.

Sec. VII]

347

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

O

O

F

F

O

O

O

O

F F

Br2CHCHBr2

F F F F O

O

O

O

F F F F

F F Me 3SiOCH2(CF 2)2CH2SiMe 3

Br F

F

F

F Br

Br F

O

O

F F

O

O

F

F F F F

Br Scheme 143

CHC6F 5 C6F5CHO + R

NH2

R

N

F R

NH2

F

R

F

N F 154

R = OMe, Me, CMe 3 , H, F, Br Scheme 144

In 1967, two reactions that proceeded by the intramolecular cyclization mechanism and led to ﬂuorinated benzo[b]thiophenes were carried out. The ﬁrst is based on the reaction of the lithium salt of pentaﬂuorothiophenol and diethyl acetylenedicarboxylic ether (67JCS(C)1225) (Scheme 148). Here the intermediate species is a carbanion. In the second process, the starting compound is a benzylidene rhodanine derivative, giving benzo[b]thiophene carboxylic acid 157 in alkaline media. This reaction occurs via the intermediate S-nucleophile (Scheme 149).

348

[Sec. VII

GEORGII G. FURIN

PhCOCH2Ph C6F6

O

Ph

[

C6F5

OH

Ph

Ph

]

C6F5

NaH

H

Ph

F

Ph

F Ph O

F F 49 % Scheme 145

F

O PdCl 2(PPh3) [ Ph

PhI DMAc / CO

C6 F5NH 2

F

N

F

O

Ph +

PdI ] 155-160°C, 16 h

F 62 % O +

Ph NHC6F5 43 %

Scheme 146

Subsequently, these processes were extended to polyﬂuoronaphthalene derivatives. Thus, the reaction of lithium 1,3,4,5,6,7,8-heptaﬂuoro-2-naphthalene thiolate with dimethyl acetylenedicarboxylic ester yields isomeric dimethyl hexaﬂuoronaphtho[b]thiophenedicarboxylic esters 158 and 159 (in a ratio of 8 : 92) (89JFC(43)393, 90JFC(50)229) (Scheme 150). The ﬂuorinated derivative of 2-naphthoryl thiocyanate, obtained by condensation of 1,3,4,5,6,7,8-heptaﬂuoronapthalene-2-aldehyde with rhodanine, is converted by alkali into a mixture of isomeric methyl hexaﬂuoronaphtho-[b]thiophenecarboxylic acids 160 and 161 (in a ratio of 22 : 78) (90JFC(50)229, 91JFC(53)339) (Scheme 151). In a similar process, 1,3,4,5,7,8-hexaﬂuoro-6-isoquinolinethiol and 2,3,5,6,7,8-hexaﬂuoro-4-quinolinethiol gave dimethyl 4,5,6,8,9-pentaﬂuoro-thieno[3,2-f ]isoquinoline-1,2-dicarboxylic ester and dimethyl 4,5,6,8,9-pentaﬂuorothieno[2,3-g]isoquinoline-1,2-dicarboxylic ester, respectively (94JFC(67)143).

Sec. VII]

349

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

F KF

F

O

F

O

C6F5OCH 2COOH DMF

O

F 155 F O

F

O

F

O NH

K2CO3

C6F 5OCH2

O DMF

NHOH

F 156 Scheme 147

C6F5S C6F5SLi + EtOOC

_

[

COOEt

EtOOC

] COOEt

F

COOEt

F COOEt S

F F 49 %

Scheme 148

H

F

O

C6F5

_ HO NH S

H+ _ -F

S

F COOH S

F F 157

Scheme 149

(Pentaﬂuorobenzyl)benzylketone reacts with sodium hydride in dimethylformamide to form 2-benzyl-4,5,6,7-tetraﬂuorobenzo[b]furan 162 via the O-nucleophile (81JCS(P1)1417) (Scheme 152). The interaction between hexaﬂuorobenzene and vinylthiol in alkalies leads to the formation of tetrathio- derivative 163 (82JFC(20)173) (Scheme 153).

350

[Sec. VII

GEORGII G. FURIN

F

F

F

F

SH

F

F

F

COOMe

F

1) n-BuLi

COOMe +

F

2) MeOOC

COOMe F

S

F

F

F

158 F F

F S

F

+

COOMe F COOMe

F 159 Scheme 150

O

F

NH

F CHO

F

F

F F

F

F

S

F

S

COOH +

KOH - H2O 100°C

S

F F

F

F

160 F F

F S

F

COOH

+ F F 161 Scheme 151

The reagent ratio 1 : 2 leads to a disubstituted product, which reacts with aminoethanol in an alkaline solvent to give 5,8-bis(vinylthio)-6,7-diﬂuoro-2,3dihydro-1,4-benzoxazine 164 along with other products (92ZOR1463) (Scheme 154). The formation of compound 165 is possibly explained by a Smiles type rearrangement. When heated at 100 C in dimethylformamide, N-(2,3,4,5,6-pentaﬂuorobenzylidene)-20 -hydroxyaniline is converted into 1,2,3,4-tetraﬂuorodibenz-[b,f ] [1,4]-oxazepine 166, formed in a quantitative yield (87JFC(36)93) (Scheme 155).

Sec. VII]

351

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

O Na - DMF C6F5CH2

CH2Ph

reflux

H

CH2Ph

[

]

_ O

C6F5 F F

CH2Ph O

F

F 162 73 % Scheme 152

F S

_

Na +

S

S

S

S

C6F6 + 4 F 163 Scheme 153

S F

S F H2NCH2CH2OH

F

F S

F

S O

F

F

F

NH

+

NaOH, DMF, 50°C

NH

F S

164 27 %

S

165

OH

Scheme 154

A similar procedure gave 1,2,3,4-tetraﬂuoro-10,11-dihydrobenz[b,f ][1,4]-oxazepine 168, and octaﬂuorodibenzoxazepine 169 (Scheme 156). Although the nitrogen of the N ¼ S ¼ N group has low nucleophilicity, an intramolecular cyclization can occur in the presence of a catalyst (ﬂuoride ion). Thus, heating of 1-pentaﬂuorophenyl-3-trimethylsilyl-1,3-diaza-2-thiaallene 170 in acetonitrile in the presence of cesium ﬂuoride leads to 4,5,6,7-tetraﬂuoro-2,1,3thiadiazole 171 (90JFC(50)359) (Scheme 157). It is assumed that 171 is formed via the intermediate pentacoordinated silicon anion, which is further transformed into the N-nucleophile with elimination of trimethylﬂuorosilane.

352

[Sec. VII

GEORGII G. FURIN NH 2

C6F5

H

F

N

OH

F

DMF

C6F5CHO

100°C

OH

N O

F F

90 %

166 99 %

Scheme 155

F NH

F

C6F5

NH

F

OH

O F 167 85 % F

N

C6F5

KF, DMF 100°C

OH

F

N

F

O F 168 80 %

F F

F N

C6F5

DMF 100°C

F

OH

F

N

F

F

F F

O F

F 169 93 %

F

Scheme 156

The regioselective eﬀect of the ﬂuoride ion on intramolecular nucleophilic cyclization has also been demonstrated for heptaﬂuoronaphthylsulfur diimide (94HAC561, 92POL1137). The reaction of the latter leads to a mixture of 4,5,6,7,8,9hexaﬂuoronaphtho[1,2-c][1,2,5]thiadiazole, whose structure was established from X-ray diﬀraction, and 4,5,6,7,8,9-hexaﬂuoronaphtho-[2,3-c][1,2,5]thiadiazole (in the ratio 94 : 6) (94HAC561) (Scheme 158). A similar reaction of 1-pentaﬂuorophenyl-4-trimethylsilyl-2,4-diaza-1,3-dithia2,3-butadiene 172 aﬀorded 5,6,7,8-tetraﬂuoro-1,3,2,4-benzo-dithiadiazole 173

Sec. VII]

353

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

F

F

F N=S=NSiM 3

X

CsF

X

N

F

N

MeC F

F

S + Me3SiF

F 171

170 X = H, Br, F, CF3 , Me Scheme 157

F

F

F

F

N

F

S

N

MeCN

F F

S N

F

CsF

SiMe3

N

F

F F

F

F

Scheme 158

S

N

S

F

F

F

F

N

F

SiMe3 CsF MeCN

F

S

F

N

N S

F

F 172

173 54 % Scheme 159

(92POL1137) (Scheme 159). The stereochemistry of this compound is conﬁrmed by X-ray diﬀraction analysis and 19F NMR spectroscopy. Heating benzoxazinone under the same conditions leads to 4,5,6-tetraﬂuoro-3Hpyrido[3,2,1-k]phenoxazin-3-one (97ZOR1418) (Scheme 160). To construct [i, j ]-annelated quinolonecarboxylic acids, Nosova et al. (97ZOR1556, 96MC15, 97MC109, 98ZOR436, 98MC131, 99ZOR1447, 99ZOR1729, 01ZOR604) developed a method based on intramolecular cyclizations of the 3-hydrazido derivatives of 2-polyﬂuorobenzoylacrylic acids. In these tricyclic systems, the quinolone skeleton is annulated to the six-membered oxadiazine or thiadiazine ring. They may be regarded as analogs of ophloxacin and marbophloxacin known antibacterial agents with antitumour activity (00PCJ19). The objective of the study was to determinate the antitumour activity of new [ij ]annelated ﬂuoroquinolones and derivatives of a new heterocyclic system of

354

[Sec. VII

GEORGII G. FURIN

O

O

F

C6 F5

DMSO NH

F

[

O

O

F

F

]

O

80-90°C

N

F

F

O

N

O

F

O

F

O

F

O

+ _

O

F N

F

O

O

F

N

F

O F 17-55 %

Scheme 160

O

F F

R

COOEt

N NHNH2

+ F

F

OEt

X

R

F 174

175 F

O

F

O F

COOEt

COOEt

F

F F

F

NH N

NH

F

R

R

R

N X

X 176

N N

R

177

X = NMe, R = F, H X = H, R = NO 2, Br X = S, R =H Scheme 161

benzimidazo[1,2-a]-pyrazolo[1,5-c]quinazoline (00PCJ19). A number of ethyl 3(benzazol-2-yl)hydrazino-2-polyﬂuoro-benzoylacrylic esters 176 were synthesized by the interaction of acrylates 174 with 2-hydrazino-benzazoles 175 in toluene (97ZOR1556) (Scheme 161). The ability of these compounds to undergo amine-imine tautomerization led to cyclizations with [i, j ]-annulation of quinolines by the

Sec. VII]

355

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

F

O

F

F COOEt

S

O COOEt

F

+ F

F

OEt

R

NHNH2

F

F

F 174

F 179

178

NH R

NH S

O

F

COOEt

F N

F S

N R 180

Scheme 162

triazine ring (96MC15, 97MC109). The reaction was performed in acetonitrile in the presence of HF scavengers such as diazobicycloundec-7-ene (DBU), KF, and triethylbenzylammonium chloride (TEBA). Condensed quinolones 177 were obtained from acrylates 176 only in the presence of DBU (yield 10–70%) (98ZOR436). The acrylates synthesized from acrylate 174 and semicarbazide 178 are boiled in benzene or toluene for 1–2 h; this gives 2R-9, 10-diﬂuoro-7-oxo-7H-1,3,4thiadiazino[6.5.4-i, j ]quinoline-6-carboxylic esters 180 (yields 40–60%) (98MC131, 99ZOR1447, 99ZOR1729, 01ZOR604) (Scheme 162). Cyclization of benzoyl acrylates 174 to condensed ﬂuoroquinolones 180 takes place via intermediates 179, which are not always isolated because of the fast closure of the thiadiazine ring. The structure of tricyclic ﬂuoroquinoline 180 (R ¼ thiomorpholin-1-yl) was established by X-ray analysis. The reactions of 2-aminoazoles with ethyl 2-polyﬂuorobenzoyl-3-ethoxyacrylates in ethanol lead to 3-azolylamino-2-polyﬂuorobenzoyl-acrylates. Further cyclization of acrylates in boiling acetonitrile in the presence of potassium ﬂuoride depends on the nature of the X and Y groups (01ZOR604). Cyclization of ethyl 2-pentaﬂuorobenzoyl-3(pyrazol-3-yl)aminoacrylate (X ¼ N, Y ¼ F) gives ethyl 4-oxo-1-(pyrazol-3-yl)-5,6,7,8-tetraﬂuoro-1,4-dihydroquinoline-3carboxylic ester, whereas cyclization of the tetraﬂuoro-benzoyl analog (X ¼ CH, Y ¼ H; X ¼ N, Y ¼ H) with 3-aminopyrazole yields 7-tetraﬂuorophenyl-6-ethoxycarbonylpyrazolo[1,5-a]pyrimidine; in the case of 3-amino-1,2,4-triazole, the product is 7-tetraﬂuorophenyl-6-ethoxycarbonyl-1,2,4-triazolo[1,5-a]pyrimidine (01ZOR604).

356

[Sec. VII

GEORGII G. FURIN

Y

O COOEt

F N

F N N

X

An attempt to perform further cyclization of 1-substituted quinolone using a stronger binding agent for HF (DBU) did not lead to the desired result. Lipunova et al. (01ZOR604) explained the diﬃculty of this cyclization by the high strain of the condensed system (Scheme 163). The reaction of the acrylate (Y ¼ H) with a derivative of 1-amino1,2,3-triazole in ethanol gives a mixture of 3-(1,2,3-triazol-1-yl)-aminoacrylate and ethyl 1-(5-hydroxy-4-ethoxycarbonyl-1,2,3-triazol-1-yl)-4-oxo-6,7,8-triﬂuoro-1,4dihydroquinoline-3-carboxylic ester, whereas heating this mixture in benzene leads to quinolone as the sole product (01ZOR604) (Scheme 164).

Y

O COOEt

F F

F

OEt

Y

X

H2N

NH N EtOH 18-20°C, 3 h

O COOEt

F F

NH

F F

F Y = H, F

NH N

X

71 - 82 %

Y KF

O COOEt

F

MeCN , 2-4 h F

N F NH

X N X = CH, Y = F (70 %) COOEt

NH KF MeCN , 2h

OH

[X

COOEt

N

N N F

F F F

Scheme 163

] X

N N F

F F

F X = CH (74 %), N (60 %)

Sec. VII]

357

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

ONa F

O

H2 N COOEt

F F

F

OEt

N N N

EtOH, 18-20°C, 2 h

O

F

COOEt

COOEt

F F

F

F

F

NH N N

F

O

N

ONa

COOEt COOEt

F F

N F

N N

N

OH COOEt

50 % Scheme 164

Cyclization of benzoyl acrylates 179 into condensed ﬂuoroqinolones 180 proceeds through intermediates 179 which were not always possible to isolate because of rapid cyclization to the thiadiazine. The structure of the tricyclic ﬂuoroquinolone 180 (R ¼ thiomorpholin-1-yl) was established on the X-ray data. The reaction of 2-mercaptobenzimidazole with pentaﬂuorobenzoyl chloride forms 1,2,3,4-tetraﬂuoro-12H-benzimidazo[2,1-b][1,3]benzo-thiazin-1,2-one (yield 50%), whose structure was conﬁrmed by X-ray data (94JOC7688) (Scheme 165). The formation of a heterocyclic system by intramolecular elimination of the ortho-ﬂuorine atom of an aromatic ring was demonstrated by the reaction of pentaﬂuorobenzoyl chloride with 2-imidazolidinethione or 2-mercaptoimidazole, forming 6,7,8,9-tetraﬂuoro-2,3-dihydro-5H-imidazo-[2,1-b][1,3]-benzothiazin-5-one (yield 54%) and 6,7,8,9-tetraﬂuoro-5H-imidazo[2,1-b][1,3]benzothiazin-5-one (yield 48%) (94JOC7688) (Scheme 166). If the starting nucleophilic agent has an S ¼ C–N triad, the cyclization involves the nucleophilic centers on sulfur and nitrogen atoms. Thus, the interaction between pentaﬂuorobenzoyl chloride and pyrimidine-2-thione 181 forms tetraﬂuorobenzothiazinopyrimidinone 182 (94JOC7688) (Scheme 167). Ethyl acetoacetate was acylated with 3,4,5-triﬂuoro-2,6-dimethoxybenzoyl chloride to give ethyl 3-oxo-2(3,4,5-triﬂuoro-2,6-dimethoxybenzoyl)butyrate (01IZV1090), preparated as in (01MC76). The compound was used for the synthesis of 6,7,8-triﬂuoro-5-hydroxy-2-methylchromone (Scheme 168). The reaction of 2,3,4,5,6-pentaﬂuorobenzyl bromide and 2-mercaptobenzimidazole initially forms the product of substitution of the bromine atom by the sulfur atom to give [2(pentaﬂuorophenyl)methyl]thio)-1H-benzimidazole 183, yield 87%. The latter is cyclized by NaH in tetrahydrofuran to give tetraﬂuorobenzimidazobenzothiazine 184 (yield 95%) (94JOC7688) (Scheme 169).

358

[Sec. VII

GEORGII G. FURIN

O N

C6F5

SH N

NH

S

C6F5COCl N

pyridine, 0°C, 5 min

C6F 5

O

, 30 min

F

F

O F N S

F

Scheme 165

F

NH S NH

O

F N

Et3N, MeCN , 30 min

F

N

S F 54 %

C6F5COCl N

F

SH

O

F

NH

N Et3N, MeCN , 30 min

F

S

N

F 48 % Scheme 166

Thus, numerous examples suggest a general concept for the synthesis of polyﬂuorinated ﬁve- to seven-membered benzoheterocycles using intramolecular cyclization that occurs by elimination of an ortho-ﬂuorine atom of the benzene ring under the action of a heteronucleophile. The reactions may occur by nucleophilic attack of the second nucleophilic center of the binucleophile at the ortho-ﬂuorine atom of the aromatic ring as in the usual SNAr mechanism. However, an alternative mechanism is an attack of the ipsocarbon atom at the second nucleophilic center, generating an intermediate

Sec. VII]

359

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

NH O NH 181 C6F5COCl

F

S

F

N

n-BuLi, THF 0°C, 10 min

N

S

F F

182 91 % Scheme 167

F O F

OMe OEt

Me COCl

F

Mg(OEt)2 EtO F

+ OH

F

F

MeO

Me

O

OMe

O OX

OMe

X = H (80%), Cu (80%) OH

O

F

40% HBr 120°C, 6 h

O

F F

76 % Scheme 168

N SH N

NH

SCH2C6F5

C6F5CH 2Br NH

NaOH, THF

183 87 % F

F

F

F N S N 184 95 % Scheme 169

NaH, THF , 1h

Me

360

[Sec. VII

GEORGII G. FURIN

Y

F F

O

F

F

NH DMF

F

O

Cl

N

Cl

O

+ Cl

F F 187 Y = H (12 h) Me (3 h)

F

N

Y F 185

F

80 % 90 %

10 % 5%

Y 186

Scheme 170

benzenonium anion as in an intermediate Meisenheimer complex (79ZOR1107). Further transformation of the anion leads to a cyclization product. With hexaﬂuorobenzene as a substrate, no other mechanisms can be found because of the high symmetry of the product. Thus, the reaction of hexaﬂuorobenzene with ortho-aminophenol in the presence of alkali, leading to 1,2,3,4-tetraﬂuorophenoxazine, was studied by several authors (67ZOB1285, 84IZVS113). Gerasimova et al. (94JFC(66)69) tried to determine the mechanism of this reaction using pentaﬂuorochlorobenzene as a substrate. It was found that the reaction of pentaﬂuorochlorobenzene with ortho-aminophenol and ortho-N-methyl-aminophenol leads to two isomeric phenoxazines, 185 and 186, via the intermediate 187 of monosubstitution of the ﬂuorine atom in the substrate (Scheme 170). The ratio between the isomeric phenoxazine products suggests that the main route of cyclization is a direct attack of the second nucleophilic center at the ortho-carbon atom of the aromatic ring; an alternative route is a Smiles type rearrangement (70M9). Therefore, the following route of cyclization was proposed (Scheme 171).

F F

Y

NH

F F

O

_

[ X

X

F

F

O

O

F

+ N F

X

F

F

F

N

_

Y H

F

] Y

H+

X = F, Cl Y = H, Me, Ac F

F X

O

F

N F

Y Scheme 171

F

X -F

_ N

F F

Y

_ O

Sec. VIII]

361

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

The mechanism of intramolecular cyclizations cannot yet be interpreted unambiguously, more experimental data is needed for an unambiguous conclusion.

VIII. Innovations in the Use of Rearrangements in Heterocyclic Syntheses For a number of rearrangements, the presence of ﬂuorine atoms in a benzene ring makes it possible to obtain heterocyclic compounds. These processes occur by the mechanism of intramolecular cyclization that involves ortho-ﬂuorine atoms. Thus, thermolysis (365 C) of pentaﬂuorophenylallyl ether 188 (71TL2377) leads to a Claisen rearrangement forming 2,5-dienone 189. However, when boiled in dimethylformamide in the presence of potassium ﬂuoride, this ether is converted into 5,6,7,8-tetraﬂuorochromane 190 (Scheme 172). This speciﬁc behavior of some polyﬂuorinated benzenes underlies the new methodology for the synthesis of heterocycles with a condensed polyﬂuorinated benzene ring. An important role is played by the ﬂuoride ion. As follows from the data (83JFC(22)483), the reaction initially forms the product of a Claisen rearrangement. The reaction of the latter with potassium ﬂuoride in dimethylformamide gives an O-nucleophilic reagent, which undergoes intramolecular cyclization into 5,6,7,8-tetraﬂuorochromane (81JCS(P1)1417). In the case of the sulfur F

F KF DMF

F

F

F

O

F KF F

O F

F

F F C6F5O O

F

188

F 190 O

O 365°C

F

F F

F F

F

F

F

F F 189

Scheme 172

362

[Sec. VIII

GEORGII G. FURIN

F

F C6F5SCH2CH

CH 2

F

F

PhNEt 2

Me +

reflux 24 h

S

F

F

F 193 40 %

F 192 30 %

191

S

Scheme 173

F 370°C C6F5OCH 2

F CH2R

R F

O

F 194 R = F (8 %), Ph (28 %), 2,5-Me 2C6H3 (21 %) Scheme 174

derivative, 2,3,4,5,6-pentaﬂuorophenylprop-2-enyl sulﬁde 191, the ortho-ﬂuorine of the benzene ring is eliminated to form a mixture of 4,5,6,7-tetraﬂuoro-2,3dihydro-2-methyl-1-benzothiophene 192 and 5,6,7,8-tetraﬂuorothiochromane 193 (81JCS(P1)1659) (Scheme 173). If the substrate contains a triple bond (pentaﬂuorophenylprop-2-ynyl ether), the reaction under the same conditions forms exclusively a ﬁve-membered ring (2-ﬂuoromethyl-4,5,6,7-tetraﬂuorobenz[b]furan 194 (yield 8%) (81JCS(P1)1417)) (Scheme 174). The yield of the target product is slightly increased by conducting the reaction in para-xylene. The radical scheme is suggested (Scheme 175). Intermediate 195 of the Claisen rearrangement undergoes homolytic ﬁssion at the aliphatic C–F bond and gives a radical center at the oxygen atom. Then radical cyclization takes place, and cyclic product 196 reacts with a ﬂuorine atom, giving compound 194. 1,3,4,5,6,7,8-Heptaﬂuoro-2-naphthylprop-2-ynyl ether and its thio analog exhibit a similar behavior (85JCS(P1)2643). Benzene, para-xylene, and freon-113 were used as solvents. This method was employed to synthesize 2-benzyl4,5,6,7,8,9-hexaﬂuoronaphtho[2,1-b]furan 197, 2-(2,5-dimethyl-benzyl)-4,5,6,7,8, 9-hexaﬂuoronaphtho[2,1-b]furan 198 (81JCS(P1)1417), 4,5,6,7-tetraﬂuoro-2-ﬂuoromethylbenzo[b]thiophene 199 (85JCS(P1)2643), and 4,5,6,7,8,9-hexaﬂuoro-2-ﬂuoromethylnaphtho[2,1-b]thiophene 200 (85JCS(P1)2643) (Scheme 176). Other derivatives behave in a diﬀerent way. Thus, pyrolysis of pentaﬂuorophenylpropionate in vacuum (quartz tube, 640 C/0.01 torr) gives 4,5,6,7,8pentaﬂuorocyclohepta[b]furan-2-one 201 in 8% yield (91JFC(53)339) (Scheme 177).

Sec. VIII]

363

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

F F C6F5OCH2

F

H F

O F 195

F

F

F

F

F

O

F

O

F F

F F

F

F

F

CH2

CH2F

O

F

O

F

F

F 194

196 Scheme 175

F F

F

C6H6 21 h F

F 197 64 % F

F

F F

F

CH2Ph O

F F

O

H

F

F

F p-(CH3)2C6H4 20 h

F

Me

Me

F O

F F

198 73 % Scheme 176

The mechanism of this reaction involves carbene formation by an acetylenemethylene rearrangement. Boiling pentaﬂuorophenyl- and 1,3,4,5,6,7,8-heptaﬂuoro-2-naphthylhydra-zones of some ketones in tetralin leads to the derivatives of 4,5,6,7-tetra-ﬂuoroindole 202 and 4,5,6,7,8,9-hexaﬂuorobenz[e]indole 203, respectively (83JCS(P1)821,

364

[Sec. IX

GEORGII G. FURIN

H

F

F F

640°C

F

F

0.01 torr O

F

]

[

O

F

F

F

F

O

O

F O

O

F F

F

F

201 8 % Scheme 177

F Me

F R

N R

C6 F5NH

F F 202

R = H, Ph

F

NH

NH

F

F

R1

F

F

F N

F R2

R3 R1

F F

NH

F

F

F

NH2

F

F

+

F F

F F 203

R1 R1 R1 R1 R1 R1

Ph, R2

F

F 204

R3

= = H, = Me (37, 21 %) = 4-MeC6H4, R2 = H, R3 = Me (41, 12 %) = Ph, R2 = Me, R3 = Et (34, 19 %) = Ph, R2 = Ph, R3 = CH2Ph (42, 0 %) = Ph, R2 = H, R3 = Me (20, 17 %) = H, R2 = Ph, R3 = CH2Ph (24, 8 %) Scheme 178

84JFC(26)77) (Scheme 178). These compounds are typically formed in Fischer’s indole-forming reactions, which occur by an ortho-benzidine rearrangement.

IX. Polyfluoro-2,3-epoxyalkanes in the Synthesis of Heterocyclic Compounds Polyﬂuoro-2,3-epoxyalkanes easily react with ﬂuoride-ion, to give a convenient method of synthesis of perﬂuorinated ketones. Internal ﬂuorooxiranes are known to react with nucleophilic reagents (LiAlH4, NH3, NEt3, F) resulting in the formation of regioisomeric ring-opened products (Scheme 179).

Sec. IX]

365

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

_ O

RF F

RF

RF RF CF2

F

O

RF -F

O

_

CF2RF

F RF = CF3, C2F5, -(CF2)3-, -(CF2) 4Scheme 179

Steric factors seems to control the regiochemistry (Scheme 180). RF

a O

C2F5

_ F3C F

RF O

F

F b

CF2RF ` O CF3

RF

route a

route b

Yield, %

CF3

-

-

92.5

C2 F5

55

45

91.6

C3 F 7 74

26

89.4

C5 F11 77

23

93.4

0

92.0

i-C3 F7 100

Scheme 180

Polyﬂuoro-2,3-epoxyalkanes are a convenient building block for the construction of heterocyclic systems. Nucleophilic attack on the central carbon of the epoxide ring of polyﬂuoro-2,3-epoxyalkanes gives rise to amides or ethers of the corresponding acids. Further reaction of a second nucleophile with the C ¼ O may follow. So, orthoaminophenole and polyﬂuoro-2,3-epoxypropane in the presence triethylamine give 2-(pentaﬂuoroethyl)benzoxazole (90IZV2338) (Scheme 181). The intermediate pentaﬂuoropropenyl ﬂuoride reacts with ortho-aminophenol, giving a ﬁve-membered heterocycle. In the absence of base, for example in dioxane, a six-membered heterocycle-3(triﬂuoromethyl)-2H-1,4-benzoxazin-2-one forms (90IZV2338). Here the initial attack of the nitrogen nucleophile occurs on the central carbon atom followed by cyclization under the action of the oxygen nucleophilic center. A similar picture emerges in the reaction of polyﬂuoro-2,3epoxypropane with ortho-phenylenediamine, ortho-aminothiophenole and anthranilic acid with the formation of 3-(triﬂuoromethyl)-2(1H)-qinoxalinone, 2-ﬂuoro-2 (triﬂuoromethyl)-2,3-dihydro-1,4-benzothiazin-3-one and 2-(pentaﬂuoroethyl)-4H3,1-benzoxazin-4-one accordingly (90IZV2338). Results for other ortho-diamines are in Table 1 (92JOC5630) (Scheme 182).

366

[Sec. IX

GEORGII G. FURIN

X

Et3N

N C2F5

MeCN F3 C F

F O

O

NH 2

X = H (84 %)

+

F OH X dioxane

N

CF3

O

O

X = H (66 %), Me (76 %), Cl (83 %) Scheme 181

Table 1. Products of the reactions of hexaﬂuoro-2,3-epoxypropane with ortho-diamines (92JOC5630) Solvent (time, h; temperature, C

Reagent

Product

NH2

Yield, % CF3

N

CH2Cl2 (12, 23)

96

NH2

NH

O

O

O NH2

Ph

Et2O (12, 23)

CF3

N

Ph

NH2

NH

O

NH

O

71

O Ph

13 N

NH2

N

CF3 CF3

CH2Cl2 (12, 23) N

NH2

3 N

NH NH

N

NH

O CF 3 F

31

O

N C2 F5 N

NH

6

Sec. IX]

367

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

NH2 NH 2

CF3

N NH

NH2

O

84 % F

S F3C

F

F

F

O

SH NH 2

CF3 NH

O

26 % COOH

C2F5

N O O 89 %

Scheme 182

Terminal ﬂuorooxiranes have a strongly pronounced polarization that promotes their reactions with nucleophilic reagents. So, polyﬂuoro-2,3-epoxyalkanes in reaction with bifunctional nucleophilic reagents (ethylenediamine, 2-aminoethanol) as opposed to hexaﬂuoro-2,3-epoxypropene form 2,3-bis(triﬂuoromethyl)-1,5,6trihydro-1,4-diazin-2-ol and 2,3-bis(triﬂuoromethyl)-5,6-dihydro-1,4-oxazin-2-ol, respectively (97ZOR299, 98JFC(87)49). The initial attack is by an amino group on the epoxide with the formation of adduct 205. Then elimination of two molecules of HF gives 3-imino-2-butanones 206 which cyclizes (Scheme 183). In the case of unsymmertic polyﬂuoro-2,3-epoxyalkanes, mixtures regioisomeric heterocyclic compounds have been obtained. 2,3-Benzosubstituted 1,4-hetero-cyclic compounds (01JFC(108)1) result from the interaction of 3-chloropentaﬂuoro-2,3-epoxypropane and benzene-1,2-diamine, 2-aminophenol, naphthalene-1,8-diamine. They give 3-(chlorodiﬂuoromethyl)quinazolin-2(1H)-one, 3-(chlorodiﬂuoromethyl)-benzoxazin-2(1H)-one and 3-(chlorodiﬂuoromethyl)-1,4-naphtho [1,8a, 8-e, f ] diazepin-2 (1H)-one accordingly (01JFC(108)1) (Scheme 184). The interaction of polyﬂuoro-2,3-epoxyalkanes with thiourea results in 2-amino-5ﬂuoro-4-hydroxy-4,5-di(polyﬂuoroalkyl)1,3-thiazolines (99MC231, 00JFC(104)155, 00ZOR887). It is established, that octaﬂuoro-2,3-epoxybutane, dodecaﬂuoro-2,3epoxyhexane and 6-hydroundeca-ﬂuoro-2,3-epoxyhexane do not react with thiourea under conditions described for the terminal ﬂuorooxiranes (00JFC(104)155), probably for steric reasons. Reactions could be carried out only at increased temperature (70–90 C, sealed tube in the case of oxiranes) using as solvent MeOH, DMSO, or DMF. As a result, heterocyclic compounds, 2-amino-5-ﬂuoro-4-hydroxy4,5-bis(polyﬂuoroalkyl)-1,3-thiazolines 207a,b; 208a,b, were obtained (99MC231, 00JFC(104)155, 00ZOR887) (Scheme 185). The molecular structure of the E-isomers of 2-amino-5-ﬂuoro-4-hydroxy-4,5-bis(triﬂuoromethyl)-1,3-thiazoline and of

368

[Sec. IX

GEORGII G. FURIN

F F 3C

RF

F

O

F

H + H 2 NCH2CH2 XH

X

CF3

+ N H H

F

_ O CF3

205 CF3

F 3C

CF3

N N

O

OH

- 2HF

X

CF3

XH 206

RF = CF 3, H(CF 2)3, C 3F 7, C 5F 11 X = NH (20 %), O (45 %) Scheme 183

YH

NH2

F

F F

NH2

NH2

Y

O

N

CClF2

Y = NH (77 %), O (62.1 %)

CClF2 O NH

O

N

CClF2

19.1 % Scheme 184

2-amino-5-ﬂuoro-5-heptaﬂuoropropyl-4-hydroxy-4-triﬂuoromethyl-1,3-thiazoline has been established by X-ray crystallography (00JFC(104)155). Symmetrical octaﬂuoro-2,3-epoxybutane (E : Z ¼ 90 : 10) reacting with thiourea gave one regioisomer, namely 2-amino-5-ﬂuoro-4-hydroxy-4,5-bis(triﬂuoromethyl)1,3-thiazoline 209 (Scheme 186). A similar reaction of asymmetrical polyﬂuoro-2,3-epoxyalkanes gave mixtures of regioisomers 207a, and 208a, which apparently arose from the initial nucleophilic attack on the carbon atoms C-3 (Path A) and C-2 (Path B) of the epoxide ring (99MC231, 00JFC(104)155, 00ZOR887). The interaction of thiosemicarbazide with symmetrical oxirane (octaﬂuoro-2, 3-epoxybutane, E : Z ¼ 90 : 10) was carried out in DMSO at elevated temperatures

Sec. IX]

_ O H+

F

[

369

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

RF

F CF3 NH2

S

]

Nu

Path A S=C(NH2)2

_ H+ O

Path B S=C(NH2) 2

RF

F

F RF

[

CF3 S

O

HN

NH - HF

- HF RF

RF

OH

F

F

HO

CF3 S

]

H2N

CF3

F

F

CF3 N

N

S NH2

NH2

208a,b

207a,b

RF = C3 F7 a, H(CF2 )3 b Scheme 185

_ F3C F

CF3 O

F

S=C(NH2)2 F3C

F

O

S

F NH

CF3

MeCN

F

OH CF3

S

NH

F3C - HF

H2N

NH

F

OH CF3

S

N

F3C

NH2 209 Scheme 186

(60–75 C) produce 2-amino-1,3,4-thiadiazines 210a and products of their rearrangement—3-amino-2-iminothiazolidines, 2-hydrazinothiazolines or even pyrazole derivatives (00JFC(104)155) (Scheme 187). The interaction of thiosemicarbazide with dodecaﬂuoro-2,3-epoxy-hexane (E: Z ¼ 90 : 10) and 6-hydroundecaﬂuoro-2,3-epoxyhexane (E : Z ¼ 85 : 15) was carried out in DMSO at elevated temperatures (60–75 C) gave compex mixture containing

370

[Sec. IX

GEORGII G. FURIN S

CF3 OH

F F

F

H2N

CF3

CF3

NHNH2

CF3 S

NH

DMSO, 60-75°C

O

CF3

F +

CF3

S

N

OH

S

+

N

NH2

N N

H2N

F

OH CF3

CF3

NHNH2

H

Scheme 187

regioisomers 210b,c and 212b,c in E-forms as major products, those in Z-form as minor products (00JFC(104)155, 00ZOR887) [formation of end-products occurs, apparently, in result hydrolytic splittings of connection N4–C5 intermediate thiadiazines and the subsequent short circuit in thizoline cycles at participation imines nitrogen] (Scheme 188). The reaction of (1S,4S)- and racemic camphor thiosemicarbazone [(1S,4S)- and rac-CTSC] leads to the formation of trans- and cis-isomers of (1S,4S)- or racemic camphor 50 -ﬂuoro-40 -hydroxy-40 ,50 -di(perﬂuoroalkyl)-10 ,30 -thiazolinyl-20 -hydrazones 211a–c and 213b,c (Scheme 189). The molecular structure of the two diastereomers (1S,4S,40 R,50 R)- and (1S,4S,40 S,50 S)- of 211a has been established by X-ray crystallography (03JFC(120)41). This result can be explained by a considerable contribution of the SN2 type of nucleophilic substitution both to the epoxide ring

F

O

RF

[

S

_ H+ F CF3 NH2

Nu

Path A

]

F

CF3

Path B

[

CF3

H2N

]

S N

O

N

F

RF

F

RF

N H

H+ _ FO

N

H

H

H

S -HF F

CF3

RF

[

-HF H2N

NHNH2 HO

OH S

H

N

]

[

N H

H

F N

S

]

N

H

N

N

H

F

CF3

RF

H

HO RF

OH S

CF3

RF

N

S

NHNH2

CF3 F N NHNH2

210a-c

210a, 212b,c

RF = CF 3 (210a ), C 3F7 (210b, 212b ), H(CF2) 3 (210c,212b,c )

Scheme 188

Sec. IX]

371

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES R`F

OH

F S

N

H

R`F S

O

Path G

N

NH

N

Path D

S

-HF N

OH

F

R``F

F

N

R``F

F

R`F

R``F

-HF

N

N H

NH2

211a -c

211a, 213b,c R`F = CF3 ; R``F = CF3 211a R`F = C 2F5 ; R``F = C 2F5 211b , 213b R`F = CF3; R``F = CF3CF2CF2 211c, 213c

Scheme 189

opening and to the thiazoline cyclization states, that cause conﬁguration inversion at both the epoxide carbon atoms (03JFC(120)41). As a result, the starting oxirane and the resulting thiazoline have the same (trans- or cis-) conﬁguration. The ring opening of unsymmetrical dodecaﬂuoro-2,3-epoxyhexane with (1S,4S)CTSC under the same conditions occurred in both possible directions (paths G and D) to give regioisomeric (1S,4S)-camphor thiazolinylhdrazones 211c, 213c (44:56) consisting of mixtures of trans- and cis-isomers. Similarly, the interaction of hexaﬂuoro-2,3-epoxypropane with benzimidazolin-2thione and 4,5-diphenylimidazolin-2-thione result in imidazolones 214 and 215 which are of pharmacologic (80BCSJ1694) interest (Scheme 190). Ph

NH

Ph

O

Ph

SH N

CF3

N Ph

F

214

F

F3C O

F

F

S

N

N

CF3 SH

NH

O

F

N

S

F

NH N N O 215

Scheme 190

S CF3 F

372

GEORGII G. FURIN

[Refs.

Thus, Chupakhin et al. have developed an approach to synthesis of functionalised 1,3-thiazolines with two ﬂuoroalkyl substituents, which are of interest as biologically active compounds and new convenient building blocks for complex heterocyclic systems.

X. Conclusions The foregoing treatment evidences extensive interest in the development of new methods and approaches to the synthesis of ﬂuorine-containing heterocyclic compounds and the application of speciﬁc features of perﬂuorinated organic compounds, especially perﬂuorooleﬁns and polyﬂuoroaromatic compounds. Signiﬁcantly, these approaches use accessible and inexpensive starting materials. Recent developments of ﬂuoroorganic chemistry have led to the discovery of new ﬂuorine-containing heterocyclic compounds with unique structures, many of which exhibit speciﬁc biological activity and eﬃcacy in medicinal and pesticide applications. One of the problems of ﬂuoroorganic synthesis is the high cost of ﬂuorine incorporation into organic molecules. But in view of the unique properties of ﬂuoroorganic compounds imparted by ﬂuorine, progress in ﬂuoroorganic chemistry and technology must lower the cost of ﬂuorine introduction into organic compounds and expand ﬂuorine applications.

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Refs.] 73JCS(P1)429 73JMC319 73JMC337 74AGE475 74FCR115 74CB1448 75CB1460 75AJC1517 75JCS(P1)538 75JCS(P1)1411 75JCS(P1)1902 75TL1125 76BrP1427945 76TL243 76USP3950353 76USP3953453 76ZOR949 77BCSJ2164 77CB605 77FrP2335566 77JHC1109 77IZV2061 78AJC765 78CB890 78CB2077 78JA4260 78KGS407

79CB2380 79BCJ2657 79LA133 79M3 79T389 79ZOR1107 80BCSJ1694 80JHC1413

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

373

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374 80USP4202981 81AHC1 81BCJ3221 81BCJ3447 81JCS(P1)1417 81JCS(P1)1659 81JOC1532 81IZV455 81IZV1592

81ZVKO105

81M5

81UK325 81USP4308391 82CanP1130808 82CB2494 82JFC(19)437 82JFC(19)589 82JFC(20)173 82JFC(20)813 82LA845 82LA853 82UK1287 83CJC2264 83JFC(20)813 83JFC(22)483 83JFC(27)327 83JCS(P1)821 83IZV476 83IZV2765 83CZ271 83CZ274

GEORGII G. FURIN

[Refs.

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Refs.]

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

83ZN769 84CZ205 84IZVS113 84JFC(26)77 84ZN(B)1442 84ZOR1964 85CZ185 85IZV144 85JCS(P1)2643 85JFC327 85JFC333 85JHC1325 85M6

85UK1997 86CB2127 86IZV123 86DAN1133 87AC168 87AGF921 87CBP825 87GERP3632291 87GEP3713744 87JFC(35)87 87JFC(36)93 87JOC1113 87POL2169 87T3123 87ZOB1910 88CL819 88CZ109 88EUP295117 88JCS(P1)1837 88JFC(40)51 88JMC144

375

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376 88SL107 88ZN(D)196 89CB1465 89H985 89IZV1213 89JFC(43)393 89JMC2507 89M4 89T1409 89TL2049 89S215 90AF1349 90CZ249 90EurP353187 90IZV561 90IZV640

90IZV2048

90IZV2057

90IZV2063

90IZV2183 90IZV2338 90JAP(K)02129171 90JFC(48)99 90JFC(48)123 90JFC(50)229 90JFC(50)359 90JOC2872 90JOC2964 90ZOR1877 91CGS502 91CRV1237 91CZ77 91DOK619

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Refs.] 91EUP418845 91IZV239 91IZV890 91IZV2088 91IZV2611

91ZVKO447

91JBCS118 91JFC(52)159 91JFC(53)339 91JFC(54)77 91JFC(56)297 91JFC(56)325 91S483 91TL643 91USP4303439 91ZVKO447

92IZV2186 92JCS(CC)348 92JCS(CC)349 92JFC(56)141 92JFC(58)134 92JFC(58)300 92JFC(58)345 92JFC(58)375 92JFC(58)380 92JMC337

92JOC5630 92JOC6351 92JPC311

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378 92JPP04,316576 92JPP04,316577 92POL1137 92SL195 92UK1422 92UK1457 92ZOR1380 92ZOR1463

93M2

93PCTWO11112 93JFC(64)73 93IZV2134 93JOC972 93JFC(65)37 93IZV362 93IZV858 93IC5079 93TL7933 93IZV1773

93TL5075 93JHC49 93JHC1159 93JHC389 93TL7737 93ZOR2416

94AHC2 94HAC561

GEORGII G. FURIN

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Refs.] 94IC415 94IZV279 94IZV282 94IZV299

94JFC(66)69 94JFC(67)87 94JFC(67)143 94JFC(69)25 94JFC(69)119 94JCS(P1)2161 94JOC7688 94TL613 94ZOR1225 95BCJ2085 95CEN39 95H521 95IJPAP431 95IZV762 95IZV1599 95IZV1809

95IZV2289 95JHC731 95JHC735 95JHC543 95JHC735 95JHC739 95JFC(70)121 95JPR34 95S1491 95T2639

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380 95ZOR266 96BCZ93 96IZV1306 96IZV1493 96IZV3026 96IZV2278 96IZV2795 96JHC1 96JHC1223 96JFC(79)45 96M7 96MC15 96RusP2054416 96TL2845 96TL9155 96ZOR320 96ZOR1386 97JCS(P1)1581 97JHC509 97JFC(81)123 97JFC(84)107 97JFC(84)145 97JFC(86)127 97MC109 97PTC15559

97RusP2100345 97S1321 97SL679 97T5847

GEORGII G. FURIN

[Refs.

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Refs.] 97UK1985 97UK1997 97ZOR299 97ZOR442 97ZOR1418 97ZOR1556 98IZV673 98JHC451 98JFC(87)49 98JFC(92)23 98JFC(92)101 98JOC2550 98KGS634 98KGS847 98MC83 98MC131 98T2819 98ZOR371 98ZOR405 98ZOR411 98ZOR436

98ZOB1727 98ROB1804 99IZV361 99IZV546 99IZV562 99IZV1279

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382 99IZV1410 99IZV2135 99IZV2195 99IZV2234 99JHC45 99JHC837 99JFC(94)91 99JFC(96)87 99JFC(97)115 99JFC(99)177

99KGS395 99MC231

99MC671 99UK203 99ZOR100 99ZOR106 99UK483 99ZOR1447 99ZOR1729

00H1411 00IZV1090 00IZV1234

00IZV1432

00JFC(103)17 00JFC(103)139 00JFC(104)155

GEORGII G. FURIN

[Refs.

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Refs.] 00PCJ19

00PCTWO6382

00SC677 00S1738

00T7267 00ZOR700 00ZOR887

00ZOR1180 01CGS1232 01CJC183 01IZV643 01IZV689 01JFC(107)107 01JFC(108)1 01JFC(108)51 01JFC(108)187 01MC76 01ZOR604

01ZOR915 02IZV332

02JFC(115)175 02JFC(117)185 03JFC(120)41

SYNTHESIS OF PERFLUOROALKYL HETEROCYCLES

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Contents

CONTRIBUTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

vii

PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ix

The Literature of Heterocyclic Chemistry, Part VIII, 1999–2001 L.I. BELEN’KII and V.N. GRAMENITSKAYA I. II. III. IV. V. VI. VII. VIII.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . General Sources and Topics . . . . . . . . . . . . . . Three-Membered Rings . . . . . . . . . . . . . . . . . Four-Membered Rings . . . . . . . . . . . . . . . . . . Five-Membered Rings . . . . . . . . . . . . . . . . . . Six-Membered Rings . . . . . . . . . . . . . . . . . . . Rings with More Than Six Members . . . . . . . . Heterocycles Containing Unusual Heteroatoms. References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Purines Fused with Five-Membered Heterocycles . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85 86 134

Annulated Heterocyclo-Purines I. Fused Five-Membered Heterocyclo-Purinediones, -Purinones, and -Purineimines ALFONZ RYBA´R

Pyrazol-3-ones. Part II: Reactions of the Ring Atoms GEORGE VARVOUNIS, YIANNIS FIAMEGOS, and GEORGE PILIDIS I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Silylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitrosation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diazonium Salt Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Condensation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleophilic Addition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleophilic Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

142 143 143 154 155 161 168 170 171 179

180 209 228 240

vi

CONTENTS

XV. XVI. XVII. XVIII.

Reduction . . . . . . . . . . . Cycloaddition . . . . . . . . Photolysis . . . . . . . . . . . Miscellaneous Reactions . References . . . . . . . . . . .

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249 253 257 260 266

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . From Hexaﬂuoroacetone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . From Perﬂuoroalkyl-Containing -Diketones . . . . . . . . . . . . . . . . . . . . . From Other Carbonyl-Containing Compounds with Perﬂuoroalkyl Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Synthesis of Oxygen-Containing Heterocycles by Intramolecular Cyclizations in Antimony Pentaﬂuoride . . . . . . . . . . . . . . . . . . . . . . . . . New Strategy of Heterocyclic Design . . . . . . . . . . . . . . . . . . . . . . . . . . . Intramolecular Nucleophilic Cyclizations with Annulated Fluorinated Heterocyclic Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Innovations in the Use of Rearrangements in Heterocyclic Syntheses . . . . Polyﬂuoro-2,3-Epoxyalkanes in the Synthesis of Heterocyclic Compounds Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . .

273 275 288

.

316

. .

334 342

. . . . .

344 361 364 372 372

INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

385

Fluorine-Containing Heterocycles. Part II. Synthesis of Perﬂuoroalkyl Heterocycles from Carbonyl Compounds GEORGII G. FURIN I. II. III. IV. V. VI. VII. VIII. IX. X.

Contributors

Numbers in parantheses indicate the pages on which the author’s contributions begin.

L.I. Belen’kii (1), N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia Yiannis Fiamegos (141), University of Ioannina, Department of Chemistry, GR-451 10 Ioannina, Greece Georgii G. Furin (273), Novosibirsk Institute of Organic Chemistry, Siberian Division of the Russian Academy of Sciences, 630090 Novosibirsk, Russia V.N. Gramenitskaya (1), N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia George Pilidis (141), University of Ioannina, Department of Chemistry, GR-451 10 Ioannina, Greece Alfonz Ryba´r (85), Institute of Chemistry, Slovak Academy of Science, Bratislava 84538, Slovak Republic George Varvounis (141), University of Ioannina, Department of Chemistry, GR-451 10 Ioannina, Greece

vii

Preface

Volume 87 consists of four chapters. L. I. Belen’kii and V. N. Gramenitskaya (Moscow, Russia) have provided Part VIII of our series on the literature of heterocyclic chemistry, which covers reviews dealing with the subject, appearing during the period 1999 through 2001. A. Rybar (Bratislava, Slovakia) has contributed the ﬁrst of a two-part series dealing with annulated heterocyclo-purines. The present chapter deals with fused ﬁve-membered heterocyclo-purinediones, -purinones and -purineimines, many of which are of signiﬁcant biological interest. The third chapter is the Part II of the survey by Varvounis, Fiamegos, and Pilidis (Ioannina, Greece) on the pyrazol-3-ones. This second part is concerned with reactions taking place at the ring atoms of these important compounds. Finally, G.G. Furin (Novosibirsk, Russia) deals with the synthesis of perﬂuoroalkyl heterocycles from carbonyl compounds. This is the second part of Professor Furin’s survey of ﬂourine-containing heterocycles. Alan R. Katritzky Department of Chemistry University of Florida Gainesville, Florida

ix

Index

2-Acetyl-5-amino-4-(20 ,20 -dicyanoethylene)pyrazol-3-one, 217 5-Acetyl –6,7-bis-(acetoxy)-1-(4-acetoxybutyl)5,6,7,9-tetrahydro-1H-imidazo[1,2-a]purin-9one, 119 5-Acetyl-6,7-bis-(acetoxy)-5,6,7,8-tetrahydro3H-imidazo[1,2-a]purin-9-one, formation, 112 4-Acetyl-2-ﬂuoro-6-methyl-5-methoxycarbonyl-3triﬂuoromethylpyran, formation, 320 2-Acetyloxiranes, condensation with ethyl perﬂuoroalkanoates, 287 1-Acetylpyrazol-3-ones, formation, 155 5-Acetyl-5,6,7,9-tetrahydro-9-oxo-3Himidazo[1,2-a]purine-6,7-diol, formation, 108 2-Acetyl-4,4,5-trimethylpyrazol-3-one, formation, 159 Acyclovir, alkylation of sodium salt, 107 6-[(Acylalkyl)thio]-purines, formation of and use in formation of thiazolopurines, 105 9-(Acylalkylthio)purinediones, 99 1-Acyl-3-aminopyrazol-3-one, reaction with ethyl ethoxymethylene-cyanoacetate, 217 7-(Acylmethyl)-8-mercaptopurines, formation, 100 1-Acylpyrazol-3-ones, reaction with arylaldehydes, 183 2(4)-Adamantylpyrazol-3-one, 146 4-(Alk-1-enyl)pyrazol-3-ones, 215 2-Alkoxycarbonyl-3,3-bis(triﬂuoromethyl)-2azabicyclo[2.2.1]hept-5-ene, 287 6-Alkyl(aryl)-2[3-alkyl(aryl)-5-triﬂuoromethyl-5hydroxy-4,5-dihydro-1H-pyrazol-1-yl]-4-triﬂuoromethylpyrimidine, formation, 328 6-Alkyl(aryl)-2[3-alkyl(aryl)-5-triﬂuoromethyl1H-pyrazol-1-yl]-4-triﬂuoromethylpyrimidine, formation, 329 4-[(Alkylamino)methyl]-5-pyridin-3-ylpyrazol-3one, 151 2-Alkylamino(anilino)-2-pentaﬂuorobenzoylacrylic acids, formation and cyclisation, 304 7-Alkyl-6-aryl-thiazolo[2,3-f ]purine-2,4(1H,3H)diones, 99 3-Alkyl-3,4-dihydro-4,6-dimethyl-9Himidazo[1,2-a]purin-9-ones, formation, 108 3-Alkyl-7,8-dihydropyrrolo[2,1-f ]purin-4(6H)ones, 89 385

1-Alkyl-4-formamido-5-tetrazol-5-ylimidazole, reaction with dimethoxymethylacetate, 132 O-Alkyl-5-hydroxypyrazole-4-carbothioates, formation, 159 3-Alkylidene-2(3H)-pyrrolidone, 343 9-Alkyl-3-methylguanines, reaction with bromoacetone, 108 7-Alkyl purine-2,4-(1H,3H)-diones, 101 2-Alkylpyrazol-3-ones, formation, 145 6-Alkyl-thiazolo[2,3-f ]purine-2,4(1H,3H)-diones, 99 7-Alkyl-thiazolo[2,3-f ]purine-2,4(1H,3H)-diones, formation, 99 6-Alkylthiazolo[2,3-f ]purine-4(3H)-one, 100 2-Alkyl-4-triﬂuoromethyl-5-ﬂuoro-1,3-oxazole, synthesis, 279 4-Allyl-1,5-dimethyl-2-phenyl-1,2dihydropyrazol-3-one, formation, 154 5-Amino-6-acylaminothiazolo[3,2-a]pyrimidin-7one, formation, 98 4-Amino-5-acylamino-triazolo[2,3-e]pyrimidine, alkaline cyclization, 128 4-Amino-6-aroyl-hydrazido-5-nitropyrimidine, cyclisation in PPA, 129 4-Amino-2-aryl-thiazolo[2,3-b]purines, 98 3-Amino-1-aryl-4,4,4-triﬂuoro-2-buten-1-ones, reaction with 2-aminoethanol, 314 5-Amino-6-azidocarbonyltetrazolo[1,5-a] pyrimidine, formation, 133 (6-Amino-5-benzylamino)-3-alkylpyrimidine, acylation, 119 (E/Z)-4(2-Aminobenzylidene)pyrazol-3-ones, formation, 186 4-(2-Aminobenzyl)pyrazol-3-ones, 220 6-Amino-5-(4-chlorobutyryl)-amino-1,3-dipropyl1H,3H-pyrimidine-2,4-dione, 88 6-Amino-5-(cyclopentane-carboxamido)-3propargyluracil, cyclisation, 94 4-Amino-7,8-dihydro-6H-pyrrolo[2,1-f ]purine, synthesis, 90 4-Amino-7,8-dihydro-thiazolo[2,3-b]purine, 97 2-Amino-2-R-2,3-dihydro-5H-thiazolo[3,2-a] pyrimidine-5-ones, formation, 95 4-Amino-1,5-dimethyl-2-phenylpyrazol-3-one, diazotisation, 173 reaction with cyclohexadiones, 196 reaction with hydrazinopyrimidines, 199

386

INDEX

2-Amino-3-ethoxycarbonyl-5,6-dihydro-7Hpyrrolo[1,2-a]imidazole, 89 (E/Z)-4-(1-Aminoethylidene)pyrazol-3-one, formation, 237 5-Amino-5-ﬂuoroalkyl-2-isoxazoline, 313 2-Amino-5-ﬂuoro-5-heptaﬂuoropropyl-4hydroxy-4-triﬂuoromethyl-1,3-thiazoline, formation, 367 2-Amino-5-ﬂuoro-4-hydroxy-4,5-bis(polyﬂuoroalkyl)-1,3-thiazolines, formation, 367 2-Amino-5-ﬂuoro-4-hydroxy-4,5-bis(triﬂuoromethyl)-1,3-thiazoline, formation, 367 4-Amino-2-hydrazinopyrimidine-5carbohydrazide, treatment with nitrous acid, 133 4-Amino-1H-imidazole-5-carbonitrile, reaction with 2-methylmercapto-imidazoline, 109 5-Amino-imidazole-4-carbonitrile, reaction with dihydropyrroles, 86 5-Amino-imidazole-5-carbonitrile, in preparation of triazolopurines, 129 5-Amino-4-(imidazol-2-yl)-1-R-imidazole, cyclisation, 120 2-Amino-4-iminoperﬂuoropent-2-ene, reaction with anhydrides, 297 reaction with ethylenediamine, 297 3-Amino-2-iminothiazolidines, formation, 369 2-Amino-3-methoxypyrazole, formation, 149 7-[N,N-(R00 ,R000 )Aminomethyl]-6,7-dihydrothiazolo[2,3-f ]purine-2,4(1H,3H)-diones, 101 (E/Z)-4-Aminomethylenepyrazol-3-ones, 202 4-Amino-1-methyl-2-phenylpyrazol-3-one, oxidative ring opening, 248 2-Amino-1-methylpyrazol-3-one, formation, 149 5-Amino-6-nitroso-thiazolo[3,2-a]pyrimidin-7one, formation, 98 (E/Z)-4-[1-(4{[(E/Z)-1-(4Aminophenyl)ethylidene]amino} phenyl) ethylidene]pyrazol-3-ones, 192 3-Amino-1-phenyl-4,4,4-triﬂuorobut-2-en-1-ones, reaction with diaminopropanes, 313 2-Amino-4-phenyl-1,1,1-triﬂuoromethylbut-2-en4-one, reaction with acetophenone, 310 2-Aminopyrazoles, methylation with diazomethane, 149 2-Aminopyrazol-3-ones, methylation with diazomethane, 149 formation, 235

4-Aminopyrazol-3-ones, by reduction of corresponding oximes, 251 photolysis, 257

5-Amino-1-( -D-ribofuranosyl)-imidazole-4carboxamide, 97 4-{(E/Z)-2-[(E/Z)Amino(substituted)methylidene]hydrazono}-5-oxopyrazoles, 206 2-Amino-1,3,4-thiadiazines, formation, 369 4-Amino-2-X-7-R-7-R0 -thiazolo-[3,2-e]purines, formation, 104 2-Aminothiophenol, reaction with ﬂuorinecontaining -diketones, 295 6-Amino-2-thiouracil, in formation of thiazolopurines, 95 4-Amino-1,2,4-triazoles, reaction with polyﬂuoro acylcycloalkanones, 328 -Aminovinylketones, reaction with hydroxylamines, 313 -Aminovinylthiones, reaction with Lawessons reagent, 311 2-Anilino-2-pentaﬂuorobenzoylacrylic acids, formation and cyclisation, 304 6-Aroylhydrazidopurines, cyclodehydration, 128 2-(Aroylmethylthio)-7-alkyl-hypoxanthines, formation, 98 6-[(Aroylmethyl)thio]-purines, formation of and use in formation of thiazolopurines, 105 7-Aryl-1-alkyl-thiazolo-[3,2-a]purin-9(1H )-ones, formation, 98 4-Arylaminocyanomethylenepyrazol-3-ones, preparation, 206 4-Arylazo-2-(4-chlorophenyl)-5-methylpyrazol-3one, synthesis, 173 (E/Z)-4-[1-Arylethylidene]pyrazol-3-ones, 192 4-Arylhydrazonopyrazol-3-ones, formation, 177 2-(Arylidenehydrazino)-purines, in formation of triazolopurines, 129 (E/Z)-4-Arylidenepyrazol-3-ones, glycosylated derivatives, 182 preparation, 183 formation, 185 reaction with reactive methylene compounds, 222

4-Arylidenepyrazol-3-ones, reaction with indole, 224 reaction with Grignard reagents, 227 reaction with secondary amines, 227 cycloaddition reactions, 253 Diels-Alder reactions, 254 reaction with 1,2-phenylenediamine, 260 4-(Arylimino)-pyrazol-3-ones, reaction with hydrazones, 205 4-(Arylmethylidene)pyrazol-3-ones, conformations, 180 chemical and electrochemical reduction, 249

INDEX (E/Z)-4-Arylmethylidenepyrazol-3-ones, formation, 188, 235 1-Arylpyrazol-3-ones, methylation, 150 4-(Arylsulfonyl)methylpyrazol-3-ones, synthesis, 152 2-Aryl-4,5,6,7-tetraﬂuorobenzoxazole, formation, 346 6-Aryl-thiazolo[2,3-f ]purine-2,4(1H,3H)-diones, 99 2-Aryl-thiazolo[2,3-b]purin-4(3H)-ones, formation, 98 4-Arylthiopyrazoles, formation, 179 4-Arylthiopyrazol-3-ones, formation, 179 3-Aryltriazin-5(2H)-ones, reaction with dihydropyrazolones, 210 3-Aryl(alkyl)-5-triﬂuoromethyl-1H-pyrazoles, production, 332 Aspartame, synthesis, 277 4-(Azepin-2-ylidene)pyrazol-3-one, formation, 238 2-Azidoadenine, tautomerism, 131 5-Azido-4-cyanoimidazole, reaction with malononitrile, 130 2-Azidohypoxanthine, tautomerism, 131 2-Azidopurine, tautomerism, 131 3-Azolylamino-2-polyﬂuorobenzoylacrylates, formation, 355 Benzimidazolin-2-thione, reaction with ﬂuoroepoxides, 371 Benzimidazo[1,2-a]pyrazolo[1,5-c]quinazoline, formation, 354 4-(2-Benzofuran-1-yl)-1,2-dihydropyrazol-3-ones, formation, 217 2-(Benzo-2-nitrile)pyrazol-3-one, formation, 230 2-(2-Benzothiazolyl)-5-methylpyrazol-3-one, 230 2-(Benzothiazol-2-yl)pyrazol-3-one, reaction with aryl aldehydes, 188 3-(2,2,3-2H-Benzothiazolyl)-2-(triﬂuoromethyl) tetrahydrofuran-2-ol, 327 3-(2,2,3-2H-Benzothiazolyl)-2-(triﬂuoromethyl) tetrahydro-2H-pyran-2-ol, 327 (2Z)-2-(Benzoylamino)-3-(dimethylamino)acrylate, reaction with pyrazolones, 215 4-Benzoyl-2,5-diphenylpyrazol-3-one, formation, 157 7-[(X-Benzoyl)methyl]-8-bromopurine-diones, 100 7-[(X-Benzoyl)methyl]-8-mercaptopurines, formation, 100 1-Benzoylpyrazol-3-one, formation, 155 1-Benzoyl-4,4,5-trimethylpyrazol-3-one, reduction, 251

387 1-Benzyl-4,9-dihydro-4,6-dimethyl-7(hydroxymethyl)-1H-imidazo[1,2-a]purin-9one, 114 1-Benzyl-4,9-dihydro-4,6-dimethyl-1Himidazo[1,2-a]purin-9-one, formation, 106 reactions, 112

1-Benzyl-4,9-dihydro-4,7-dimethyl-6-(3-methyl-1butenyl)-1H-imidazo[1,2-a]purin-9-one, 115 1-Benzyl-4,9-dihydro-4,6-dimethyl-7-(3-methyl-1butenyl)-1H-imidazo[1,2-a]purin-9-one, preparation, 114 1-Benzyl-4,9-dihydro-4,6-dimethyl-7-substituted1H-imidazo[1,2-a]purin-9-one, rearrangements, 113 O6-Benzylguanosine, reaction with bromoacetaldehyde, 119 2-Benzyl-4,5,6,7,8,9-hexaﬂuoronaphtho[2,1-b] furan, formation, 362 4,40 -Benzylidenebipyrazol-3-ones, oxidation, 243 (Z)-5-Benzylidene-1-(2,6-dimethylphenyl)-2phenyl-4,4-bis(triﬂuoromethyl)-2imidazoline, synthesis and structure, 284 2-Benzylideneindan-1,3-dione, reaction with pyrazolones, 211 7-Benzyl-3-methylguanine, in preparation of imidazopurines, 106 2-Benzyl-3-methylpyrazol-3-one, reaction with aldehydes, 185 1-Benzyl-5-phenylpyrazol-3-one, formation, 145 4-Benzylpyrazol-3-ones, formation, 253 1-Benzylsulfonyl-hexaﬂuoropentan-2-one, reaction with phthalimidosulfenyl chloride, 295 2-Benzyl-4,5,6,7-tetraﬂuorobenzo[b]furan, formation, 349 4,40 -Bipyrazol-3,30 -dione, reaction with phosphoryl oxychloride, 163 reaction with bromine, 164 formation, 229, 242 8[2-Bis(chloroethyl)amino]purine, alkaline hydrolysis, 126 Bis(ﬂuorosulfato)perﬂuoroalkanes, heating with antimony pentaﬂuoride, 340 Bis(5-hydroxy-2-isoxazolines), dehydration, 310 4,6-Bis(hydroxyl)-4,6-bis(triﬂuoromethyl)hexahydropyrimidine-2-one, 301 4,6-Bis(hydroxyl)-4,6-bis(triﬂuoromethyl)hexahydropyrimidine-2-thione, 301 4,40 -Bis(5-hydroxy-1H-pyrazol-4-yl)pyrazol-3one, 235 Bis(3-oxopyrazol-4-yl)(isocyano)acetonitriles, 217

388

INDEX

2,6-Bis(perﬂuoroalkyl)-1,5-diazaanthracene, formation, 318 4,4-Bis(triﬂuoromethyl)-N-acylimines, reaction with trimethylphosphite, 280 3,3-Bis(triﬂuoromethyl)-1,5-diaryl-1,2,4oxadiazol-4-in, formation, 280 5,5-Bis(triﬂuoromethyl)-2,3-diaryl-1,2,4oxadiazol-3-in, formation, 280 4,4-Bis(triﬂuoromethyl)-1,3-diazabuta-1,3-diene, reaction with isonitriles, 281 reaction with cyanamide, 283 reaction with cyclic 1,3-diketones, 289

2,3-Bis(triﬂuoromethyl)-5,6-dihydro-1,4-oxazin-2ol, formation, 367 4,4-Bis(triﬂuoromethyl)-1,4-dihydropyrimidines, formation, 283, 289 2,2-Bis(triﬂuoromethyl)-4-methylene-1,3dioxolane, formation, 281 4,4-Bis(triﬂuoromethyl)-1-oxabuta-1,3-dienes, formation, 277 4,4-Bis(triﬂuoromethyl)-4H-oxazine, formation, 289 5,5-Bis(triﬂuoromethyl)-1H-3-pyrazolines, formation and thermolysis, 285 1,9-Bis(triﬂuoromethyl)-3,4,6,7-tetrahydro-2Hpyrazino-[1,2-a]pyrazine, formation and structure, 297 2,3-Bis(triﬂuoromethyl)-1,5,6-trihydro-1,4-diazin2-ol, formation, 367 5,8-Bis(vinylthio)-6,7-diﬂuoro-2,3-dihydro-1,4benzoxazine, formation, 346, 350 3,6-Bis(vinylthio)-1,2,4,5-tetraﬂuorobenzene, reaction with aminoethanol, 346 3-Bornyloxycarbonyl-5-ﬂuoroalkylpyrazoles, formation, 304 Bornyl polyﬂuoroacylpyruvate, reaction with hydrazine hydrate, 304 8-Bromo-7-(acylalkyl)purinedione, intramolecular cyclisation, 91 8-Bromo-7-(acylmethyl)purine-2,6-dione, reduction, 92 8-Bromoadenine, heating with tritylglycidol, 94 4-Bromo-4-[bromo(2-aryl)methyl]-pyrazol-3-ones, formation, 164 7-Bromo-2-chloro-1-benzyl-4,9-dihydro-4,6dimethyl-1H-imidazo[1,2-a]purin-9-one, formation, 113 8-Bromo-7-(2-chloroethyl)purine-2,4-dione, 101 4-Bromo-1,5-dimethyl-2-phenylpyrazol-3-one, formation, 167 (S)-8-Bromo-9-[2-hydroxy-3-(trityloxy)propyl] adenine, formation and cyclisation, 94

3-Bromo-2-methyl-5-phenyl-7-triﬂuoromethylpyrazolo[1,5-a]pyrimidines, structure, 293 4-Bromo-5-methylpyrazol-3-one, oxidative cleavage, 249 8-(3-Bromopropyl)-1,3-dimethyl-3,7-dihydro-1Hpurine-2,6-diones, reaction with benzhydrylpiperazine, 87 8-Bromopurinedione, alkylation, 122 8-Bromopurine-2,6-diones, formation of thiazolo purinediones, 100 4-Bromopyrazol-3-ones, preparation, 164, 165 reaction with anion of pyrazolothiones, 229 reaction with pyrazolones, 229 reaction with acetylacetone, 240 3-Bromo-1,1,1-triﬂuoroacetone, reaction with ethyl triﬂuoroacetoacetate, 308 2-(t-Butyl)-5,5-dimethyl-4-(4-methylphenyl)-2,5dihydrofuran-2-ol, reaction with pyrazolones, 231 3-[(t-Butyldimethylsilyloxyethoxy)methyl]-3,9dihydro-6-methyl-5H-imidazo[1,2-a]purin-9ones, tritylation, 112 5-(Butylimino)-1-(2,6-dimethylphenyl)-2-phenyl4,4-bis(triﬂuoromethyl)-2-imidazoline, synthesis, 281 6-t-Butyl-3- -D-ribofuranosyl-5H-imidazo[1,2-a] purine-9-ones, benzylation, 112 Camphor 50 -ﬂuoro-40 -hydroxy-40 ,50 -di(perﬂuoro alkyl)-10 ,30 -thiazolinyl-20 -hydrazones, isomers formation and structures, 370 8-[(1-Carboxy-1-alkyl)thio]-thiopurine-2,4-diones, 102 4-Carboxy-2-triﬂuoromethyl-2-carbethoxymethylthiazolidine, formation, 308 8-Chloro-7-(acylalkyl)purinedione, intramolecular cyclisation, 91 2-Chlorobenzo[1,3]thiazole, reaction with 1,2-dihydropyrazol-3-ones, 230 4-(Chlorobenzyl)-6,7-dihydro-3H-imidazo[1,2-a] purine-9(4H )-ones, anti-allergic activity, 109 3-(Chlorodiﬂuoromethyl)-benzoxazolin-2(1H)one, formation, 367 3-(Chlorodiﬂuoromethyl)-1,4-naphtho[1,8a,8-e,f ] diazepin-2(1H )-one, formation, 367 3-(Chlorodiﬂuoromethyl)-quinazolin-2(1H )-one, formation, 367 6-Chloro-1,3-dimethyluracil, 87 6-Chloro-3,7-di-n-propyl-purinone, reaction with sodium azide, 132 5-[3-(2-Chloroethyl)-1-thioureido]-1-( -Dribofuranosyl)-imidazole-4-carboxamide, 97 3-Chloro-1-methoxypyridinium perchlorate, reaction with pyrazolones, 210

INDEX 7-Chloromethyl-6,7-dihydro-oxazolo[2,3-f ] purinedione, ring cleavage, 93 3-Chloro-5-methylpyrazole, formation, 163 3-Chloropentaﬂuoro-2,3-epoxypropane, reaction with bifunctional nucleophiles, 367 -Chloro- -perﬂuorovinylaldehydes, reaction with sodium sulﬁde, 317 2-(2-Chlorophenyl)-5-methylpyrazol-3-ones, reaction with furan-2-carbaldehydes, 188 2-(4-Chlorophenyl)-5-methylpyrazol-3-one, reaction with diazonium salts, 173 4-[(4-Chlorophenyl)methyl]-4,6,7,9-tetrahydro1H-imidazo[1,2-a]purin-9-imine, formation, 118 4-[(4-Chlorophenyl)methyl]-4,6,7,9-tetrahydro1H-imidazo[1,2-a]purin-9-one, reaction with phosphorus sulﬁde, 118 1-Chloropropane-1,2-dione 1-(N-phenylhydrazone), reaction with pyrazolones, 230 6-Chloropurine, reaction with sodium azide, 132 4-Chloropyrazoles, formation, 163 4-Chloropyrazol-3-ones, formation, 163, 249 4-(5-Chloropyrazol-4-yl)-pyrazol-3-one, formation, 163 N-Chlorosulfenylphthalimide, Diels-Alder reactions with pyrazol-3-ones, 256 8-Chlorotheophylline, reaction with aryl glycidyl ethers, 92 Copper chelate of ethyl pentaﬂuorobenzoylpyruvate, reaction with o-aminophenol, 293 3-Cyano-2,6-dimethyl-4-triﬂuoromethylpyridine, formation, 295 Cyanoformamidines, reaction with hexaﬂuoro acetone, 276 1-Cyanomethyl-2-(cyanimino)pyrrolidine, formation, 90 3-Cyano-2-pyridones, formation, 295 Cyclic 4-methyl-tetrazolo[1,5-a]purin-9-one, formation and structure, 133 4-(Cyclopent-1-enyl)pyrazol-3-ones, 215 2-Cyclopentyl-6-methyl-oxazolo[3,2-a]purin9(1H)-one, formation, 95 8-Cyclopentyl-1-propargyl-3,7-dihydro-1Hpurine-2,6-dione, 95 4-Cyclopentylpyrazol-3-ones, formation, 191 1,3-Dialkyl-7-aryloxazolo[2,3-f ]purine2,4(1H,3H)-diones, reaction with sodium sulﬁde, 101 1,3-Dialkyl-7-aryl-thiazolo[2,3-f ]purine2,4(1H,3H)-diones, formation, 101 spectra, 104

389 1,3-Dialkyl-6,7-dihydrothiazolo[2,3-f ]purine-2,4(1H,3H)-diones, formation, 101 1,8-Dialkyl-7-phenyl-imidazo[2,1-f ]purines, mass spectral fragmentation, 125 6,7-Dialkyl-thiazolo[2,3-f ]purine-2,4(1H,3H)diones, 99 2,6-Diamino-4-{[(aminocarbonyl)oxy]methyl}3a,4,5,6,8,9-hexahydro-1H,10H-pyrrolo [1,2-c]purine-10,10-diol, isolation and local anaesthetic activity, 90 2,6-Diamino-4-{[(aminocarbonyl)oxy]methyl}3a,4,5,6,8,9-hexahydro-1H,10H-pyrrolo [1,2-c]purine-9,10,10-triol, isolation and local anaesthetic activity, 90 2,6-Diamino-4-{[(aminocarbonyl)oxy]methyl}3a,4,8,9-tetrahydro-1H,10H-pyrrolo [1,2-c]purine-10,10-diol, isolation and local anaesthetic activity, 90 7,8-Diamino-2,3-dihydro-5H-thiazolo[3,2-c] pyrimidine, 105 6,7-Diamino-2,3-dihydro-2-R-5H-thiazolo[3,2-a]pyrimidine-5-one, 95 5,6-Diamino-1,3-dipropyluracil, 88 1,2-Diamino-7,8-disubstituted purine-6,8-diones, reaction with carboxylic anhydrides, 130 2,2-Diaminohexaﬂuoropropane, reaction with glyoxal, 333 6,7-Diamino-pyrazolo[1,5-a]purines, formation, 126 5,6-Diamino-4-thiouracil-sodium salt, in preparation of thiazolopyrimidines, 105 4,5-Diaminouracil, reaction with oxazolethiones, 131 Diaryl diazomethanes, in preparation of 1,3,4oxadiazoles, 277 4-Diaryl(or arylalkyl)methylpyrazol-3-ones, formation, 227 1,5-Diazabicyclo[3.3.0]octa-2,6-dienes, 285 1,5-Diazabicyclo[3.3.0]octenes, 285 4,4-Diazapyrazol-3-ones, 240 4-Diazo-2-methylpyrazol-3-ones, 171 4-Diazo-5-phenylpyrazol-3-one, methylation, 144 4-Diazopyrazol-3-ones, 171 photolysis, 259 (E/Z)-Dibenzo[c,h]xanthen-7-ylideneethylidenepyrazol-3-one, 189 4,4-Dibromobut-2-ene oxide, reaction with hexaﬂuoroacetone, 275 7-(2,3-Dibromopropyl)-8-hydroxyxanthines, in formation of oxazolopurines, 92 4,4-Dibromopyrazol-3-ones, reduction, 165 formation, 167 reaction with sodium azide, 240

390

INDEX

1,4-Dibromotetraﬂuorobenzene, reaction with glycol ethers, 346 4,4-Dichloropyrazol-3-ones, reduction to monochloro derivatives, 163 reduction, 249 4-(Dicyanomethylene)pyrazol-3-one, condensation with amines and phenols, 208 reaction with malononitrile, 222 reaction with indoles, 224 N,N-Diethylaminomethylene-1,1,1,5,5,5hexaﬂuoro-acetylacetone, 328 4-(4-Diethylaminophenylimino)-pyrazol-3-one, 201 Diethyl (4-iminocyclohexa-2,5-dienylidene)ammonium salts, reaction with pyrazol-3-ones, 201 4,4-Diethyl-5-methoxypyrazol-3-one, trimethylsilylation, 154 6,6-Diﬂuoro-1,5-bis(triﬂuoromethyl)[1,3,5]triazine-2,4-dione, formation, 341 2-Diﬂuoromethyl-4-phenyl-3H-benzo[b]-1,4diazepines, formation, 293 4,4-Diﬂuoro-5-methyl-2-phenyl-2,4-dihydro-3Hpyrazol-3-one, formation, 163 2-Diﬂuoromethyl-4-phenyl-3H-naphtho[2,3-b]1,4-diazepines, formation, 293 2R-9,10-Diﬂuoro-7-oxo-7H-1,3,4thiadiazino[6.5.4-i,j]quinoline-6-carboxylic esters, formation, 355 4,4-Diﬂuoro-3-triﬂuoromethylbut-3-en-1-one, formation and reduction, 277 1,5-Difuran-2-yl-penta-1,4-dien-3-one, reaction with pyrazolones, 227 6,7-Dihydro-7-aryl-oxazolo[2,3-f ]purinediones, formation, 92 Dihydroazirinoquinoxalinones, formation, 320 1,2-Dihydro-4-benzoyl-5-benzoylaminopyrazol-3one, formation and structure, 157 2,3-Dihydro-5,7-bis(triﬂuoromethyl)-1,4diazepine, 290 2,3-Dihydro-1H-1,4-diazepines, formation, 313 monohydroperchlorates, 290 4,9-Dihydro-4,6-dimethyl-1H-imidazo[1,2-a] purine-9-one, from yeast, 109 1,2-Dihydro-1,5-dimethyl-4-isopropyl-2-(20 thienyl)pyrazol-3-one, formation, 143 4,9-Dihydro-4,6-dimethyl-9-oxo-1H-imidazo[1,2-a] purine-7-carbonyl chloride, formation, 113 4,9-Dihydro- 4,6-dimethyl-9-oxo-3-[2,3,5-tris-O(tert-butyldimethylsilyl)- -D-ribofuranosyl]3H-imidazo[1,2-a]purin-7-carbaldehyde, in synthesis of wybutine, 115

4,9-Dihydro-4,6-dimethyl-3- -D-ribofuranosyl3H-imidazo[1,2-a]purine-9-one, from yeast, 109 4,9-Dihydro-4,6-dimethyl-1-(20 ,30 ,50 ,-tri-O-acetyl -D-ribofuranosyl)-1H-imidazo[1,2-a]purin9-one, formation, 113 2,4-Dihydro-2,5-disubstituted pyrazol-3-ones, benzoylation, 156 2,3-Dihydro-7-ﬂuoroalkyl-1H-1,4-diazepines, formation, 293 2,3-Dihydro-7-ﬂuoroalkyl-1H-1,4-diazepine monohydroperchlorates, formation and basiﬁcation, 293 2,3-Dihydro-6-ﬂuoro-5,7-bis(triﬂuoromethyl)-1H1,4-diazepine, formation, 297 3,9-Dihydro-3-[(2-hydroxyethoxy)methyl]-3,9dihydro-6-methyl-5H-imidazo[1,2-a]purin-9ones, tritylation, 112 5,9-Dihydro-3-[(2-hydroxyethoxy)methyl]-6methyl-3H-imidazo[1,2-a]purin-9-one, 107 2,3-Dihydro-3-hydroxy-6-perﬂuoroalkyl-4Hpyran-4-ones, formation and dehydration, 287 6,7-Dihydroimidazo[1,2-a]purine-9-ones, formation, 108 1,2-Dihydro-4-isopropyl-5-methyl-4-nitro-2-(2,4dinitrophenyl)-3H-pyrazol-3-one, 170 1,2-Dihydro-4-isopropyl-5-methyl-2-phenyl-3Hpyrazol-3-one, nitration, 170 2,4-Dihydro-4-isopropyl-5-methyl-2-(20 thienyl)pyrazol-3-one, methylation, 143 1-R-2-R0 -6,7-Dihydro-7-methylthiazolo[3,2-a] purin-5(1H)-one, formation, 96 1-R-2-R0 -7-R00 -6,7-Dihydro-7-methylthiazolo [3,2-a]purin-5(1H)-one, formation, 96 4-Dihydronaphthalenehydrazonopyrazol-3-ones, 178 3,4-Dihydro-2H-pyranes, formation, 333 1,2-Dihydropyrazol-3-one, acylation, 155 2,4-Dihydropyrazol-3-ones, monochlorination, 163 reaction with aryl aldehydes, 180 reaction with trichloroacetaldimines, 209 oxidation, 246 6,7-Dihydro-5H-pyrrolo[1,2-a]purine-9-amine, synthesis and phytohormone eﬀect, 86 7,8-Dihydro-3H-pyrrolo[2,1-f ]purin-4(6H)-one, 89 1,4-Dihydro-1,2,4,5-tetrazines, formation, 286 7,8-Dihydrothiazolo[2,3-i]purine-2,5(1H,3H)dione, 105 6,7-Dihydrothiazolo[2,3-f ]purine-4(1H)-one, 101 7,8-Dihydrothiazolo[3,2-e]purine-4(1H)-one, 101 1,4-Dihydro-1,3,5-triazines, synthesis, 283

INDEX 1,2-Dihydro-2-(4-triﬂuoromethylphenyl)-5methylpyrazol-3-one, triﬂuoroacetylation, 158 1,2-Dihydro-2-(4-triﬂuoromethylphenyl)-4triﬂuoracetyl-5-methylpyrazol-3-one, 158 7-(2,3-Dihydroxypropyl)-8-hydrazinopurinediones, formation, 93 2,2-Dimethoxy-3-oxo-N-phenylbutanamide, formation by photolysis of pyrazolones, 257 (E/Z)-4-(4-Dimethylamino)benzylidenepyrazol-3-one, formation, 181 N,N0 -Dimethylaminomethylacetylene, cycloaddition reactions with pyrazolones, 253 4-(4-Dimethylaminophenylimino)pyrazol-3-one, reaction with chloroacetyl chloride, 219 2-(2,5-Dimethylbenzyl)-4,5,6,7,8,9-hexaﬂuoronaphtho[2,1-b]furan, formation, 362 5,50 -Dimethyl-2,20 -diphenyl-4,40 -bipyrazole-3,30 (2H,20 H)-dione, reaction with diazomethane, 149 Dimethyl hexaﬂuoronaphtho[b]thiophenedicarboxylic esters, 348 1,5-Dimethyl-3H-5-iodo-2-phenylpyrazol-3-one, Grignard reagent derived from, 154 2,5-Dimethyl-3-methoxypyrazole, formation, 147 2-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1Hpyrazol-4-ylmethyl)acrylic acid ethyl ester, 154 Dimethyl 4,5,6,8,9-pentaﬂuorothieno[2,3-g] isoquinoline-1,2-dicarboxylic ester, 348 Dimethyl 4,5,6,8,9-pentaﬂuorothieno[3,2-f ] isoquinoline-1,2-dicarboxylic ester, 348 1,5-Dimethyl-2-phenyl-4-dimethylaminopyrazol3-ones, photolysis, 257 1,3-Dimethyl-7-phenyl-oxazolo[2,3-f ]purine-2,4dione, bromination, 92 1,5-Dimethyl-2-phenylpyrazol-3-one, formation, 148 bromination, 167 1,3-Dimethyl-6-phenylthiazolo[2,3-f ]purine2,4(1H,3H)-dione, reaction with electrophiles, 102 1,2-Dimethylpyrazol-3-one, formation, 149 4,4-Dimethylpyrazol-3-one, chemical and electrochemical reduction, 249 1,5-Dimethyl-2-(2-thienyl)-4-nitrosopyrazol-3one, formation, 169 1,5-Dimethyl-2-(2-thienyl)pyrazol-3-one, formation, 147 nitrosation, 169 N,N0 -Diphenyldiaza-18-crown-6, reaction with pyrazolones, 224

391 (E/Z)-Diphenyldiaza-18-crown-6bispyrazolideneacetonitrile, 226 4,5-Diphenylimidazolin-2-thione, reaction with ﬂuoroepoxides, 371 4-(Diphenylmethylene)pyrazol-3-ones, 192 1,5-Diphenyl-penta-1,4-dien-3-one, reaction with pyrazolones, 227 1,5-Diphenyl-2-phenyl-4-iodopyrazol-3-one, formation, 168 2,5-Diphenylpyrazol-3-one, methylation, 153 2,4-Diphenylpyrazol-3-ones, Diels-Alder reactions, 256 2,3-Diphenyl-4,5,6,7-tetraﬂuorobenzofuran, formation, 346 4-(2,6-Diphenylthiopyran-4-ylidene)pyrazol-3one, formation, 204 2,4-Diphenyl-6-(triﬂuoromethyl)-pyridine, formation, 310 Dispiroundeca-3,9-diene-1,7-dione, formation and rapid isomerisation, 206 2,6-Disubstituted-4,9-dihydro-4-methyl-1Himidazo[1,2-a]purines, formation, 109 5,50 -Dithioxo-4,40 ,40 ,400 -terpyrazol-30 -one, 229 2,5-Di(trimethylsilyloxy)-4,4-dimethylpyrazol-3one, formation, 154 Dodecaﬂuoro-2,3-epoxyhexane, reaction with thiosemicarbazide, 369 3-(Ethoxycarbonyl)-2-(N,N-dimethylaminomethyl enamino)-5,6-dihydro-7H-pyrrolo[1,2-a] imidazole, preparation, 89 1-(Ethoxycarbonylmethyl)-2-cyanoiminopyrrolidine, 89 3-Ethoxycarbonyl-5,6,7,8-tetraﬂuorochromone, formation, 309 5-Ethoxy-3,4-dihydro-2H-pyrrole, 86 -Ethoxy-substituted enones, as heterodynes, 333 4-Ethoxy-1,1,1-triﬂuoro-3-buten-2-one, formation, 322 reaction with phenylhydrazine, 323

Ethyl 4-aminoimidazole-5-carboxylate, in synthesis of pyrrolopurines, 86 Ethyl 7-aminopyrazolo[1,5-a]pyrimidine-6carboxylates, in synthesis of pyrazolo[5,1-b] purin-2-ones, 126 Ethyl 2-amino-4-triﬂuoromethyl-thiazolecarboxylic ester, formation, 310 Ethyl 3-(benzazol-2-yl)hydrazine-2-polyﬂuorobenzoylacrylic esters, formation, 354 Ethyl 2,4-bis(triﬂuoromethyl)-4-hydroxydihydro3-furanate, 308 Ethyl-2-diazoﬂuoroacetoacetate, formation and reaction with nitriles, 302

392

INDEX

N,N0 -Ethylenebis(aminovinylketones), formation, 290 Ethyl 5-ethoxy-3,4-dihydro-2H-pyrrole-2carboxylate, in synthesis of pyrrolopurines, 86 Ethyl 2-ethoxymethylidene-pentaﬂuorobenzoylacetate, cyclisation, 309 O6-Ethylguanosine, reaction with bromoacetaldehyde, 119 Ethyl 1-(5-hydroxy-4-ethoxycarbonyl-1,2,3triazol-1-yl)-4-oxo-6,7,8-triﬂuoro-1,4-dihydroquinoline-3-carboxylic ester, formation, 356 Ethyl 5-hydroxypyrazole-4-carboxylates, formation, 157 2-Ethyl-5-methyl-4-nitrosopyrazol-3-one, tautomerism, 169 (E/Z)-Ethyl 3-(5-oxopyrazol-4ylidene)butanoates, formation, 200 Ethyl 4-oxo-1-(pyrazol-3-yl)-5,6,7,8-tetraﬂuoro1,4-dihydroquinoline-3-carboxylic ester, formation, 355 Ethyl 2-pentaﬂuorobenzoyl-3-(pyrazol-3-yl)aminoacrylate, cyclisation, 355 Ethyl pentaﬂuorobenzoylpyruvate, in formation of ﬂuoroquinolones, 306 Ethyl pyrazol-5-ylcarbonates, formation, 157 Ethyl 4-(pyrrol-1-yl)imidazole-5-carboxylate, reaction with hydrazine, 86 Ethyl 3- -D-ribofuranosylpyrazolo[3,2-i]purine-6carboxylate, formation, 126 Ethyl 4,4,4-triﬂuoroacetoacetate, reaction with bromotriﬂuoroacetones, 308 Fluorinated benzo[b]thiophenes, 347 Fluorinated 1,3-dioxolanes, preparation, 275 Fluorinated uracils, formation, 315 Fluorine-containing 2-oximino-1,3-oxo ethers, reaction with o-phenylenediamines, 298 Fluoroalkylated 1,3-diketones, reaction with ethylenediamine monohydroperchlorate, 293 3-Fluoroalkyl-2-aziridinylketones, syntheses, 333 4-Fluoroalkyl-4-hydroxy-2-oxo(thioxo)-6-phenylhexahydropyrimidine-5-carboxylates, formation and dehydration, 301 6-Fluoroalkyl-2-oxo(thioxo)-4-phenyl-1,2,3,4tetrahydropyrimidine-5-carboxylates, formation, 301 5-Fluoroalkyl-substituted 1,3-oxazoles, formation, 302 2-Fluorobenzonitrile, reaction with pyrazolone, 229 2-Fluoro-1,3-diketones, reaction with phenylhydrazines, 298 1-Fluoro-2,4-dinitrobenzene, reaction with pyrazolones, 230

5-Fluoro-3-ethoxycarbonylalkylpyrazoles, formation, 303 3-Fluoromethyl-4(p-methoxyphenyl)hydrazonepyrazolin-5-one, 299 2-Fluoromethyl-4,5,6,7-tetraﬂuorobenz[b]furan, 362 4-Fluoropyrazol-3-one, formation, 161 Fluoroquinolones, formation, 357 -Fluorosulfatoperﬂuoroketone, formation, 340 2-Fluoro-2-(triﬂuoromethyl)-2,3-dihydro-1,4benzothiazin-3-one, formation, 365 2-Fluoro-3-triﬂuoromethylfuran, formation, 277 2-Fluoro-3-triﬂuoromethylthiophene, formation, 277 4-[(2-Furfuryl)methylidene]pyrazol-3-ones, reduction, 251 3-(2-Furyl)acrolein, condensation with pyrazolones, 190 (4E)-4-[(2E/Z)-3-(2-Furyl)prop-2enylidene]pyrazol-3-one, formation, 190 Gonyautoxin, see 2,6-diamino-4-{[(aminocarbonyl)oxy]methyl}-3a,4,5,6,8,9-hexahydro1H,10H-pyrrolo[1,2-c]purine-9,10,10-triol 8-Halogeno-7-(halogenoalkyl)-purinedione, in synthesis of tricyclics, 123 8-Halogenopurines, used in formation of oxazolopurines, 91 8-Halogeno-7-(thiiranylmethyl)-purinediones, reaction with secondary amines, 101 Heptaﬂuoronapthylsulfur diimide, cyclisation, 352 6-[(Heteroaroyl)methylthio]-purines, formation of and use in formation of thiazolopurines, 105 (E/Z)-2-Heteroarylpyrazol-3-ones, formation, 189 Hexaﬂuoroacetones, in synthesis of ﬂuoroheterocycles, 275 Hexaﬂuoroacetone N-acylimines, reaction with trivalent phosphorus compounds, 280 Hexaﬂuoroacetone alkoxycarbonylimine, reaction with diethyl cyanamide, 287 as dienophiles, 287

Hexaﬂuoroacetone azine, reactions with oleﬁns, 285 4,5,6,7,8,9-Hexaﬂuorobenz[e]indole, formation, 363 Hexaﬂuoro-2,3-epoxypropane, reaction with benzimidazolin-2-thione, 371 4,5,6,7,8,9-Hexaﬂuoro-2-ﬂuoromethylnaphtho[2,1-b]thiophene, 362 1,3,4,5,7,8-Hexaﬂuoro-6-isoquinolinethiol, 348 4,5,6,7,8,9-Hexaﬂuoronaphtho[1,2-c] [1,2,5]thiadiazole, formation and structure, 352

INDEX 4,5,6,7,8,9-Hexaﬂuoronaphtho[2,3-c] [1,2,5]thiadiazole, formation and structure, 352 2,3,4,5,7,8-Hexaﬂuoro-4-quinolinethiol, 348 1,4,4a,5,6,7-Hexahydro-1,4,4a-trimethyl-9Hpyrrolo-[1,2-a]purin-9-one, preparation and vasodilation activity, 86 8-Hydrazinocaﬀeine, in formation of tetrazolopurines, 133 2-Hydrazino-3-methyl-8-R-purines, reaction with nitrous acid, 133 8-Hydrazino-7-methylpurine-2,4-dione, thermal cyclisation, 130 2-Hydrazinopurine, reaction with diethoxymethyl acetate, 130 6-Hydrazinopurine, in formation of triazolopurines, 127 reaction with nitrous acid, 132

2-Hydrazinothiazolines, reaction with thiosemicarbazide, 369 6-Hydro-4,4-bis(triﬂuoromethyl)-1,4,5,6-tetrahydropyrimidine derivatives, 288 5-Hydroxy-3-alkoxycarbonyl-5-polyﬂuoroalkylpyrazolines, formation, 304 7-(2-Hydroxy-3-aryloxypropyl)-8hydrazinopurinediones, formation, 93 4-(Hydroxybutylamino)-5-nitrosouracil, 87 7-(4-Hydroxybutyl)guanine, formation, 119 7-Hydroxy-7,8-dihydrothiazolo[2,3-i]purines, formation, 105 8-Hydroxy-8,9-dihydro-7H-thiazolo[2,3-i]purine, formation, 105 2-Hydroxy-6-R-6,7-dihydro-thiazolo-[3,2-a]purin9(1H)-one, 95 2-Hydroxy-N1,2-dimethyl-N3-phenylmalonamide, by photolysis of pyrazolones, 257 3-[(Hydroxyethoxy)methyl]-5,6-imidazo[1,2-a] purin-9(5H)-one, reaction with N-bromosuccinimide, 118 2-(2-Hydroxyethylamino)-3-methyl-7H-purin6(3H)-one, formation, 109 4-(2-Hydroxyethyl)pyrazol-3-ones, cyclisation to spiropyrazolones, 234 1-(2-Hydroxyethyl)-5,6,7,8-tetraﬂuoro-4quinolone-2-carboxylic acid, formation, 306 7-R-8-R0 -1-(2-Hydroxyethyl)-1H,3H-2thioxopurin-6-one, formation, 96 3-Hydroxy-5-ﬂuoroalkyl-2-isoxazoline, 313 3-Hydroxy-5(3)-ﬂuoroalkylpyrazoles, formation, 307 2-Hydroxy-3-hydroximino-4-phenyl-2-triﬂuoromethyl-2,3-dihydro-1H-1,5-benzodiazepine, formation, 298

393 3-Hydroxy-2-hydroximino-4,4,4-triﬂuorobutanoyl hydrazide, 298 3-Hydroxy-4-hydroximino-3-triﬂuoromethylpyrazolidin-5-one, 299 5-Hydroxy-2-isoxazolines, formation, 295 7-(2-Hydroxy-3-methoxypropyl)-8-hydrazino purinediones, formation, 93 7-Hydroxymethyl-7,8-dihydrothiazolo[2,3-i] purine, formation, 105 4-Hydroxy-4-(2-oxocyclopentyl)pyrazol-3-one, 191 5-Hydroxy-1-pentaﬂuorophenyl-5-triﬂuoromethyl-4,5-dihydropyrazole, formation and structure determination, 323 4-(Hydroxyphenylmethyl)pyrazol-3-ones, 209 5-Hydroxy-5-polyﬂuoroalkyl-2-pyrazolines, formation, 292 8-(3-Hydroxypropyl)-1,3-dipropyl-7H-purine2,4(1H,3H)-dione, 88 3-Hydroxy-2-(thio)-carbamoyl-3-polyﬂuoroalkyl3,3a,4,5,6,7-hexahydro-2H-indazoles, 292 5-Hydroxy-5-triﬂuoromethyl-2-pyrazoline, formation, 311 4-Hydroxy-2,4,5-triphenylpyrazol-3-one, formation, 246 Imidazopurinediones, formation, 93 Imidazo[2,1-f ]purinediones, reactions with electrophiles, 124 1(3)H-Imidazo[2,1-f ]purine-2,4-dione, formation, 122 4-[Imino(phenyl)methyl]pyrazol-3-one, formation, 235 Indoles, reaction with pyrazolones, 224 1-(3-Indolyl)-1-(pyrazol-4-yl)methanes, formation, 224 7-Iodo-1-benzyl-4,9-dihydro-4,6-dimethyl-1Himidazo[1,2-a]purin-9-one, Heck reaction, 116 7-Iodo-1-benzyl-4,9-dihydro-4,6-dimethyl-3- -Dribofuranosyl-1H-imidazo[1,2-a]purin-9-one, in synthesis of wybutosine, 116 Isothiocyanatodialkylphosphites, reaction with hexaﬂuoroacetone, 278 1-R-2-R0 -4-Isothiocyanato-imidazole-5carboxylate, 95 Ketenylidenetriphenylphosphorane, react with pyrazol-3-ones, 160 Ketoﬂuorosulfatoperﬂuoroalkanes, eﬀect of heating with antimony pentaﬂuoride, 340 4,40 -Linked bipyrazol-3-ones, formation, 261 Lithium 1,3,4,5,6,7,8-heptaﬂuoro-2-naphthalene thiolate, reaction with diethyl acetylenedicarboxylate, 348 Lithium salts of ﬂuorinated -diketones, in synthesis of ﬂuorinated heterocycles, 293

394

INDEX

Malononitrile, reaction with substituted pyrazolones, 222 2-Mercaptobenzimidazole, reaction with ﬂuorinated benzoyl chlorides, 357 2-Mercapto-6-R-6,7-dihydro-thiazolo-[3,2-a] purin-9(1H )-one, 95 2-Mercaptohypoxanthine, alkylation, 98 2-Mercapto-4-methyl-5(2,2,2-triﬂuoro-1-triﬂuoromethylethyl)-1,3-thiazoles, formation, 320 6-Mercaptopurine, in formation of thiazolopurines, 105 8-Mercaptopurine-2,4-diones, reaction with 2-halogenoalkanoic acids, 102 4-Mesitylmethylidenepyrazol-3-ones, 187 8-Methanesulfonyl-4-(2-hydroxypropyl)xanthines, in formation of oxazolopurines, 92 1-(4-Methoxybenzyl)pyrazol-3-one, formation, 145 (R)-2-[(Methoxycarbonyl)amino]-3triphenylphosphonio propanoate, in formation of wybutine derivatives, 116 5-Methoxy-4,4-dimethyl-2-trimethylsilyloxypyrazol-3-one, formation, 154 6-(4-Methoxyphenyl)-3,9-dihydro-3-[(1,3dihydroxy-2-propoxy)-methyl-5Himidazo[1,2-a]purin-9-ones, as antiviral agents, 108 8-Methoxy-7-(3-phthalimido-2-hydroxypropyl)purinedione, formation, 93 5-Methoxypyrazoles, formation, 150 Methyl 1-R-2-R0 -4-[1-(3-alkenyl)thioureido]imidazole-5-carboxylate, 96 Methyl 4-amino-imidazol-5-carboxylate, in formation of thiazolopyrimidines, 95 2-(Methylamino)propanoyl-(phenyl)-carbamic acid, formation by photolysis of pyrazolones, 257 3-Methyl-2-aryl-thiazolo[2,3-b]purin-4(3H)-ones, formation, 98 5-Methyl-3,3-bis(triﬂuoromethyl)-3H-pyrazole, 319 Methyl 2-bromo-2,3-butadienoate, formation by ring opening of pyrazolones, 248 (E/Z)-4-{2-[3-Methyl(but-2enyl)oxy]benzylidine}-pyrazol-3-ones, 183 (E/Z)-4-{[1-(3-Methylbut-2-enyl)-1H-pyrrol-2yl]methylene}-pyrazol-3-ones, 182 2-Methyl-4-diazo-5-phenylpyrazol-3-one, formation, 144 Methyl 4,9-dihydro-4,6-dimethyl-9-oxo-3-[2,3,5tris-O-(tert-butyldimethylsilyl)- -Dribofuranosyl)-3H-imidazo[1,2-a]purin-7-yl(-methoxycarbonylamino)-butenoate, cis-hydroxylation, 118

1-Methyl-2,5-diphenylpyrazol-3-one, formation, 153 (E/Z)-4-Methylenepyrazol-3-ones, formation, 224 4-(1-Methylethylidene)pyrazol-3-ones, formation, 191 reaction with acetone, 223 Methyl hexaﬂuoronaphtho[b]thiophenecarboxylates, 348 Methyl 1-R-2-R0 -4-[1-(3-hydroxyethyl)thioureido]imidazole-5-carboxylate, 95 Methyl (4S,5S)-4-hydroxypyrazol-4-carboxylate, formation and structure, 265 2-Methylmercapto-imidazoline, reaction with imidazolcarbonitriles, 109 Methyl-2-methylthio-7H-purin-6(3H)-one, reaction with aminoalcohols, 109 (E/Z)-4-{2-[(4-Methylpent-3enyl)oxy]benzylidene}pyrazol-3-ones, 182 7-Methyl-6-phenyl-3,9-dihydro-3-[(1,3-dihydroxy2-propoxy)-methyl-5H-imidazo[1,2-a]purin9-ones, as antiviral agents, 108 5-Methyl-2-phenylpyrazol-3-one, methylation with dimethyl carbonate, 148 5-Methyl-2-phenylpyrazol-3-thione, reaction with bromopyrazoles, 229 1-Methylpyrazol-3-one, formation, 147 5-Methylpyrazol-3-one, alkylation, 145 formation, 150 heating with adamantyl bromide, 146 reaction with nitrosobenzenes, 198

5-Methyl-4-substituted pyrazol-3-ones, reaction with phenyliodonium diacetates, 262 6-Methyl-thiazolo[2,3-f ]purine-2,4-(1H,3H)dione, 100 5-Methyl-2-(2-thienyl)pyrazol-3-one, methylation, 147 5-Methyl-4-unsubstituted pyrazol-3-ones, reaction with phenyliodonium diacetates, 262 4-[Morpholin-4-yl-(4-nitrophenyl)methyl]pyrazol3-one, formation, 154 Neosaxitoxin, see 2,6-diamino-4-{[(aminocarbonyl)oxy]methyl}-3a,4,5,6,8,9-hexahydro1H,10H-pyrrolo[1,2-c]purine-10,10-diol (E/Z)-4(2-Nitrobenzylidene)pyrazol-3-ones, formation, 186 8-Nitro-4-(2-hydroxypropyl)-xanthines, in formation of oxazolopurines, 92 2-(4-Nitrophenyl)-4-dimethylaminoformylidene5-methylpyrazol-3-one, formation, 160

INDEX 4-[(2-Nitrophenyl)methylidene]pyrazol-3-ones, reduction with sodium borohydride, 220 reduction, 251

4-Nitropyrazol-3-ones, 171 3-Nonaﬂuorobutyl-4(p-methoxyphenyl)hydrazonepyrazolin-5-one, 299 Octaﬂuorodibenzoxazepine, formation, 351 5,6-Oligomethylenepyrimidines, formation, 292 1-Oxa-5,6-diazaspiro[2,4]hept-6-ene-4-ones, formation, 246 11-Oxa-2,4-diazaspiro-[4.0.4]undec-3-en-1-ones, formation, 191 1,3,4-Oxadiazoles, formation, 277 [1,3,4]-Oxazole-2-thione, reaction with 4,5-diaminouracil, 131 Oxazolo[2,3-f ]purine-2,4-diones, formation, 91 (E/Z)-4-(3-Oxo-1,3-diphenylpropylidene)-5triﬂuoromethylpyrazol-3-one, formation, 193 2-(2-Oxoindol-3-ylidene)malononitrile, reaction with pyrazolones, 212 1-Oxo-3-pentaﬂuorophenyl-1H-pyrano[4,3-b] 6,7,8,9-tetraﬂuorochromone, formation, 309 2-Oxo-1-polyﬂuoroalkyl-1,1a,2,3-tetrahydroazirino[1,2-a]-quinoxalines, formation, 320 3-Oxopyrazole-4-diazonium chloride, coupling with enamines, 173 4-[(3-Oxopyrazol-4-yl)(aryl)methyl]pyrazol-3ones, 185 (E/Z)-3-(5-Oxopyrazol-4-yl)-N,N0 diphenylpent-2-enediamide, 194 (E/Z)-[(5-Oxopyrazol-4-ylidene) butylidene]pyrazol-3-one, formation, 193 (3E/Z)-3-(5-Oxopyrazol-4-ylidene)indol-2-one, 194 2-(3-Oxopyrazol-4-ylidene)malononitriles, formation, 200 3-(5-Oxopyrazol-4-ylidene)propionaldehyde, 234 4-[(3-Oxopyrazol-4-yl)methyl]pyrazol-3-ones, formation, 151 4-[(5-Oxopyrazol-4-yl)(2-nitrophenyl)methyl] pyrazol-3-ones, 186 4-[1-(3-Oxopyrazol-4-yl)-3-phenylprop-2-enyl]pyrazol-3-one, formation, 215 2-(3-Oxopyrazol-4-yl)-2-(pyrazol-4-yl)malononitrile, 213, 219 4-Oxo-7,8,9,10-tetraﬂuoro-1,2,4,5-tetrahydro[1,4]oxazino[4,3-a]-4-quinolone, formation, 305 Pentaﬂuorobenzaldehyde, reaction with substituted anilines, 346 3-Pentaﬂuorobenzoylmethylene-morpholin-2-one, formation and further cyclisation, 305

395 3-Pentaﬂuorobenzoylmethylidene-2H-1,4benzooxazin-2-one, formation, 306 3-Pentaﬂuorobenzoylmethylidene-2H-1,4benzothiazin-4-one, formation, 306 (Pentaﬂuorobenzyl)benzylketone, reaction with sodium hydride, 349 4,5,6,7,8-Pentaﬂuorocyclohepta[b]furan-2-one, formation, 362 2-(Pentaﬂuoroethyl)-4H-3,1-benzoxazin-4-one, formation, 365 2-(Pentaﬂuoroethyl)benzoxazole, formation, 365 5-Pentaﬂuorophenyl-isoxazole-3-carboxylic acid, formation, 304 2-(Pentaﬂuorophenyl)methylthio-1Hbenzimidazole, formation, 357 2,3,4,5,6-Pentaﬂuorophenylprop-2-enyl sulﬁde, cyclisation, 362 Pentaﬂuorophenylpropionate, pyrolysis, 362 1-Pentaﬂuorophenyl-3-trimethyl-1,3-diaza-2thiaallene, heating, 351 1-Pentaﬂuorophenyl-4-trimethylsilyl-2,4-diaza1,3-dithia-2,3-butadiene, 352 Pentaﬂuorothiophenol, reaction with diethyl acetylenedicarboxylate, 347 Perﬂuoro-2-acyloxolane, formation, 338 2-Perﬂuoroalkylbenzothiazoles, formation, 295 2-Perﬂuoroalkyl-3,5-diarylthiophenes, 317 Perﬂuoroalkylthiopyrans, formation, 291 Perﬂuoro-2-azapropene, electrophilic trimerisation, 341 Perﬂuoro-2,4-dimethyl-2,5-dihydrofuran, 339 Perﬂuoro-2,7-dimethyl-3,6-dioxacycloheptanone, formation and irradiation, 289 Perﬂuoro-2,3-dimethyl-1,4-dioxane, formation, 289 Perﬂuoro-2,7-dimethyl-3,6-dioxasuberic diﬂuoride, reaction in presence of metal carbonates, 289 Perﬂuoro-4,6-dimethylhept-4-en-3-one, heating with antimony pentaﬂuoride, 339 Perﬂuoro-2,2-dimethyloxolane, formation, 340 Perﬂuoro-2,4-dimethyloxolane, 339 Perﬂuoro-2,4-dimethyltetrahydrofuran, formation, 336 Perﬂuoroethylisopropylketone, 339 Perﬂuoro-2-ethyl-3,5,5-trimethyl-4,5dihydrofuran, formation, 339 Perﬂuoro-3-isopropyl-2,4-dimethyl-2,5dihydrofuran, formation, 338 Perﬂuoro-3-isopropyl-4-methylbut-3-en-2-one, cyclisation on heating, 338 Perﬂuoro-2-methyloxan-3-one, isomerisation, 338 Perﬂuoro-2-methyloxolane, 337 Perﬂuoro-4-methylpentan-2-one, heating with antimony pentaﬂuoride, 336

396

INDEX

Perﬂuoro-4-methylpent-3-en-2-one, cyclisation, 339 Perﬂuoro-2-methylpent-3-ene oxide, eﬀect of heating, 339 Perﬂuoro-2,2,4-trimethyl-5-ethyl-2,5dihydrofuran, formation, 339 -Phenoxy-substituted enones, as heterodynes, 333 (E/Z)-4-Phenylaminomethylenepyrazol-3-ones, 205 (E/Z)-2-Phenyl-4-arylidenepyrazol-3-ones, formation, 186 2-Phenyl-3-chloro-4-formyl-5-methylpyrazole, 160 4-Phenyldiazopyrazol-5-ols, formation, 177 6-Phenyl-3,9-dihydro-3-[(1,3-dihydroxy-2propoxy)-methyl-5H-imidazo[1,2-a]purin-9ones, as antiviral agents, 108 7-[(4-X-Phenyl)hydrazone]-thiazolo[2,3-f ]purine2,4,6,7(1H,3H)-tetrones, formation, 102 2-Phenyl-4-(2-mercaptobenzyl)-5-methylpyrazol3-one, oxidative cyclisation, 249 5-Phenyl-3-methoxy-2-phenylpyrazole, formation, 148 7-[(4-X-Phenyl)methylene]-thiazolo[2,3-f ]purine2,4,6(1H,3H,6H)-triones, formation, 102 (E/Z)-4-Phenylmethylidenepyrazol-3-ones, formation, 187 reaction with anilines, 251 2-Phenyl-5-methylpyrazol-3-one, reaction with phthaloyl chloride, 157 nitrosation, 168 reaction with pyridinium salts, 210 reaction with tetracyanoethylene, 213

2-Phenylpyrazol-3-one, reaction with aldehydes, 183 (E/Z)-4-[Phenyl(pyridine-4-yl) methylene]pyrazol-3-ones, 192 6-X-Phenyl-3- -D-ribofuranosyl-5H-imidazo [1,2-a]purine-9-ones, benzylation, 112 4-(Phenylsulfonyl)methylpyrazol-3-ones, synthesis, 152 4-Phenylthiopyrazol-3-one, formation, 179, 238 2-Phenyl-5-triﬂuoromethylpyrazol-3-one, reaction with diones, 193 2-Phthalazin-1-ylpyrazol-3-one, benzoylation, 155 8-Phthalimido-7-(2-hydroxy-3-chloropropyl) purinedione, formation, 93 2-Polyﬂuoroacylcycloalkanone, reaction with aminotriazoles, 328 2-Polyﬂuoroacylcyclohexanones, reaction with phenylhydrazines, 291

Polyﬂuoroacylpyruvic acid, reaction with hydrazine hydrate, 304 Polyﬂuoroalkylated 3-iodoalkyliden-2-(3H)dihydrofuranone, formation, 343 2-Polyﬂuoroalkylbenzimidazoles, formation, 327 Polyﬂuoroalkylidenepyrazol-3-ones, reaction with butadienes, 256 (7-Polyﬂuoroalkyl)pyrazolo[1,5-a]pyrimidines, 293 Polyﬂuoro-2,3-epoxyalkanes, reaction with ﬂuoride ions, 364 reaction with bifunctional nucleophiles, 367 Polyﬂuoro-2,3-epoxypropane, reaction with o-phenylenediamine, 365 Potassium 8-(substituted-amino)purinedione, alkylation, 122 Purin-8-ylthiocarbaldehyde acetals, 99 Pyrazol-3,5-diones, tautomerism, 149 Pyrazol-4,5-dione-4-N-(pyrazol-4-yl)hydrazones, 171 oxidation, 246 1H-3-Pyrazoline, 285 Pyrazol-3-one, reaction with 4-methoxybenzyl chloride, 145 Pyrazol-3-one 4-oximes, formation, 168 Pyrazol-3-one phosphonium salts, formation, 160 Pyrazol-3-one-4-spiro-3-isoxazolidines, formation, 253 Pyrazolo[5,1-b]purin-2-ones, synthesis, 126 Pyrazolo[3,4-b]quinolines, formation, 253 Pyrazolo-sulfonium ylides, formation, 179 (Pyrazol-4-yl)(indolyl)malononitriles, formation, 224 4-[(Pyrazol-4-yl)methylene]pyrazol-3-one, formation, 205 structure, 206 Pyrazol-4-ylmethylenepyrazol-3-one, 234 4-[(Pyrazol-5-yl)methylene]pyrazol-3-one, formation and structure, 149 [(Pyrazol-4yl)(5-oxopyrazol-4-ylidene) methyl]benzoic acid, formation, 157 (E/Z)-4-[3-(Pyrazol-4-yl)prop-2-enylidenepyrazol3-one, formation, 234 4-(Pyrazol-4-yl)pyrazol-3-one, formation, 197 Pyrazolylpyrazol-3-one/bis(pyrazolyl)methane perchlorates, 219 5-Pyridin-3-ylpyrazol-3-one, Mannich reactions, 151 1-H-Pyrrolo[2,1-b]purin-4(5H)-one, synthesis, 86

INDEX 3-( -D-Ribofuranosyl)-6,7-dihydrothiazolo[3,2-a] purin-9(1H)-one, 97 Saxitoxin, see 2,6-diamino-4-{[(aminocarbonyl) oxy]methyl}-3a,4,8,9-tetrahydro-1H,10Hpyrrolo[1,2,-c]purine-10,10-diol Sodium salt of 4-acylpyrazol-3-ones, reaction with epichlorohydrin, 145 Spiroindolepyrazol-3-ones, 220 Spiro{pyrano[2,3-c]pyrazole-4,40 -pyrazo}-30 -one, structure, 213 Spiropyrazol-3-ones, synthesis, 234 ring opening with methoxide, 265

Spiro(pyrazolopyrazopyrazolo)indolone, 194 8-(Substituted-amino)-7-acylmethyl-purinedione, cyclisation, 122 8-Substituted amino-7-(3-substituted amino-2hydroxypropyl)-purinedione, formation, 93 4-[(Substituted)benzyl]-6,7-dihydro-2-substituted3-imidazo[1,2-a]purin-9(4H)-ones, methylation, 111 5-Substituted 3,3-bis(triﬂuoromethyl)-2,2dihydro-1,4,2-oxazaphospharol-4-ene, as intermediate in oxazole synthesis, 280 3-Substituted-4,9-dihydro-4,6-dimethyl-1Himidazo[1,2-a]purin-9-ones, reaction with phosphorus oxychloride, 113 4-(Substituted methylene)pyrazol-3-ones, oxidation, 246 7-Substituted methyl-hexahydro-oxazolo[2,3-f ] purinediones, formation, 91 5-Substituted 2-perﬂuoroalkyl-4H-pyran-4-ones, formation, 287 Substituted perﬂuorooxolan-3-ones, formation, 337 5-Substituted pyrazol-3-ones, reaction with phenyliodonium diacetates, 262 N-Substituted 4-quinolone-2-carboxylic acids, 302 2-Substituted 4-triﬂuoromethyl-5-ﬂuoro-1,3oxazole-2,4-dienes, formation, 280 7-Substituted 1,3,9-trimethylxanthinium tosylates, in formation of ylides, 88 cis-2,4,6,8-Tetraazabicyclo[3.3.0]octane, formation, 333 Tetracyanoethylene, reaction with pyrazolones, 213, 226 1,2,3,4-Tetraﬂuoroacridines, formation, 346 Tetraﬂuorobenzimidazobenzothiazine, formation, 357 1,2,3,4-Tetraﬂuoro-12H-benzimidazo[2,1-b] [1,3]benzothiazin-1,2-dione, formation, 357 5,6,7,8-Tetraﬂuoro-1,3,2,4-benzodithiadiazole, 352

397 2,2,3,3-Tetraﬂuorobutyleneglycol triethylsilyl ether, reactions, 346 5,6,7,8-Tetraﬂuorochromane, formation, 361 1,2,3,4-Tetraﬂuorodibenz[b, f ][1,4]-oxazepine, formation, 350 1,2,3,4-Tetraﬂuoro-10,11-dihydrobenz[b, f ][1,4]oxazepine, formation, 351 1,2,3,4-Tetraﬂuoro-7,8-dihydro-5H-1,4-dihydroquinolino[1,2-a]quinoxaline-5,7-dione, formation, 295 6,7,8,9-Tetraﬂuoro-2,3-dihydro-5H-imidazo[2,1-b] [1,3]benzothiazin-5-one, formation, 357 4,5,6,7-Tetraﬂuoro-2,3-dihydro-2-methyl-1benzothiophene, formation, 362 4,5,6,7-Tetraﬂuoro-2-ﬂuoromethylbenzo[b]thiophene, 362 6,7,8,9-Tetraﬂuoro-5H-imidazo[2,1-b] [1,3]benzothiazin-5-one, formation, 357 4,5,6,7-Tetraﬂuoroindole, formation, 363 1,2,3,4-Tetraﬂuorophenoxazine, formation, 360 7-Tetraﬂuorophenyl-6-ethoxycarbonylpyrazolo[1,5-a]pyrimidine, formation, 355 7-Tetraﬂuorophenyl-6-ethoxycarbonyltriazolo[1,5-a]pyrimidine, formation, 355 4,5,6,7-Tetraﬂuoro-2,1,3-thiadiazole, formation, 351 5,6,7,8-Tetraﬂuorothiochromane, formation, 362 3,6,7,9-Tetrahydro-9-iminothiazolo[3,2-a]purine, 97 4,6,7,9-Tetrahydro-4-methyl-1H-imidazo[1,2-a] purin-9-ones, formation, 109 5,6,7,9-Tetrahydro-9-oxo-3H-imidazo[1,2-a] purine-6,7-diol, formation, 108 3,6,7,8-Tetrahydro-4-oxo-4H-pyrrolo[1,2-e] purine-8-carboxylic acid, synthesis, 86 1,6,7,8-Tetrahydro-4-thioxo-4H-pyrrolo[1,2-e] purine-8-carboxylic acid, 87 2,3,7,8-Tetrahydro-2-thioxothiazolo[2,3-i]purine5(1H)-one, 105 6,7-Tetramethylene-thiazolo[2,3-f ]purine2,4(1H,3H)-diones, 100 Tetrazolo[5,1-a]purin-7-ones, formation, 133 10-Thia-8-azabenzo[a]azulene, reaction with pyrazolones, 238 Thiazolo[2,3-f ]purinediones, formation, 93 Thiazolo[2,3-f ]purine-2,4,6-(1H,3H,6H)-triones, formation, 102 4-[3H-Thiazol-2-ylidene)hydrazono]pyrazol-3one, formation, 244 2(2-Thienoylmethyl)-2-triﬂuoromethyloxazolidine, formation, 314 5-(1-Thiosemicarbazido)-2-pyrazoline-1-thiocarboxamide, formation, 332 9H-Thioxanthen-9-ol, reaction with pyrazolones, 231

398

INDEX

5-Thioxo-4,40 -bipyrazol-30 -one, formation, 229 50 -Thioxo-4,40 -bipyrazolyliden-3-one, formation, 243 50 -Thioxo-4,40 -bipyrazolyl-3-one, oxidation, 243 3,5-2-Thioxo-1,3,2-oxaphosphorine, formation, 311 3,5-2-Thioxo-1,3,2-thiazaphosphorine, formation, 311 4-Toluenesulfonylazide, reaction with pyrazol-3ones, 171 1-[4-p-Tolylthiazol-2-ylaminomethyl]pyrazol-3one, formation, 150 20 ,30 ,50 -Tri-O-acetyl-7-formylwyosine, formation, 113 3-(Tri-O-acetyl- -D-ribofuranosyl)-5,9-dihydro4,6-dimethyl-3H-imidazo[1,2-a]purin-9-one, 107 9-(Tri-O-acetyl- -D-ribofuranosyl)-5,9-dihydro4,6-dimethyl-3H-imidazo[1,2-a]purin-9-one, 107 Triazabicyclo[5.3.0]dec-4-ene, formation, 314 2-(Triazin-3-yl)pyrazol-3-one, reaction with salts of heterocyclic bases, 200 3-(1,2,3-Triazol-1-yl)-aminoacrylate, formation, 356 2-(Triazol-3-yl)-1,1-diaminoethylene, formation, 129 [1,2,4]Triazolo-[3,4-a]purines, preparation, 129 Triazolo[5,1-i]purines, antagonism of adenosine A2 receptors, 129 [1,2,3]Triazolo[5,1-b]purine-3-carbonitrile, formation, 130 [1,2,4]Triazolo[4,3-e]purinedione, formation, 130 [1,3,4]Triazolo[3,4-f ]purine-5,7-dione, formation, 131 [1,2,4]Triazolo-[4,3-a]purin-9-ones, preparation, 129 Triﬂuoroacetaldehyde azine, formation of tetrazines, 286 2-Triﬂuoroacetyl-4H-1,4-benzothiazine, formation and structure, 325 3-Triﬂuoroacetyl-2,3-dihydrofuran, in synthesis of ﬂuorinated heterocycles, 323 3-Triﬂuoroacetyl-3,4-dihydro-2H-pyran, in synthesis of ﬂuorinated heterocycles, 323 4-Triﬂuoroacetylpyrazoles, formation, 324 2-Triﬂuoroacetyl-4H-1,4-thiazine, 325 1,1,1-Triﬂuoro-4-ethoxy-3-butene-2-one, in synthesis of ﬂuorinated heterocycles, 323 6,7,8-Triﬂuoro-5-hydroxy-2-methylchromone, synthesis, 357

5,6,8-Triﬂuoro-7-hydroxy-1-R-4-quinolone-2carboxylic acids, formation, 305 2-Triﬂuoromethylacetylperﬂuorooxolane, formation, 337 6-Triﬂuoromethyl-2-amino-4-hydroxypyrimidine, 327 3-(Triﬂuoromethyl)-2H-1,4-benzoxazin-2-one, 365 2-Triﬂuoromethyl-2-carbethoxymethylperhydrooxazine, formation, 308 Triﬂuoromethyl isocyanate, reaction with hexaﬂuoroacetone, 278 1-Triﬂuoromethyl-2-phenyl-1,1adihydroazirino[1,2-a]quinoxaline, formation, 321, 322 (7-Triﬂuoromethyl)-5-phenyl-1,4,8triazabicyclo[5.3.0]dec-4-ene, formation, 311 3-Triﬂuoromethylpyrazoles, 285 5-Triﬂuoromethylpyrazoles, formation, 316 3-Triﬂuoromethyl quinoxalin-2-one, formation, 298, 365 5-Triﬂuoromethyl-1,2,4-thiazole, formation, 281 3-Triﬂuoromethyl-1,2,4-triazoles, synthesis, 284 (Triﬂuoromethyl)-trimethylsilane, reaction with diacetyl ﬂuorides, 289 4,5,6-Triﬂuoro-3H-pyrido[3,2,1-k]phenoxazin-3one, 353 5,5,5-Triﬂuoro-4-triﬂuoromethylpent-3-en-2-one, reaction with hydrazines, 318 1,1,1-Triﬂuoro-2-(triﬂuoromethyl)-4-(p-toluenesulfonylhydrazone)pent-2-ene, formation, structure and cyclisation, 319 1,1,1-Triﬂuoro-2-(triﬂuoromethyl)-4-(20 ,40 ,60 -tri isopropylbenzenesulfonylhydrazone)pent-2ene, formation, structure and cyclisation, 319 6,7-Trimethylene-thiazolo[2,3-f ]purine2,4(1H,3H)-diones, 100 1,2,5-Trimethyl-4-formylpyrazol-3-one, formation, 161 1,2,5-Trimethylpyrazol-3-one, Vilsmeier reaction, 161 4,4,5-Trimethylpyrazol-3-one, reaction with acetic anhydride, 159 5,7,9-Trimethyltetrazolo[1,5-e]purine-6,8-dione, formation, 133 2,4,6-Tris(perﬂuoroalkyl)-5-ﬂuoropyrimidines, formation, 297 (S)-7-[(Trityloxy)methyl]-7,8-dihydrooxazolo[3,2-e]purin-4-amine, formation, 94 9H-Xanthen-9-ol, reaction with pyrazolones, 231 Xanthinium-(N7) ylides, formation, 88