Synthesis of aromatic heterocycles Thomas L. Gilchrist Chemistry Department, The University of Liverpool, Liverpool, UK L697ZD E-mail(@liv. ac uk Received (in Cambridge, Uk)7th June 1999 Covering: March 1997 to February 1999 corresponding bis(trimethylsilyl)furan for the synthesis of other Previous review: J. Chem. Soc., Perkin Trans. 1, 1998, 615 3, 4-disubstituted furans has also been reviewed. An improved version of Marshalls synthesis of furans from B-alkynyl 1 Introduction allylic alcohols, making use of silver nitrate on silica gel as the 2 Furans and benzofurans catalyst, has been described. 3 Thiophenes and benzothiophenes As in earlier reviews. several of the useful new routes to 4 Pyrroles furans involve cyclisation reactions in which oxygen nucleo- 5 Indoles indolizines and carbazoles philes undergo addition to alkynes. The intramolecular add 6 Oxazoles thiazoles and benzothiazoles ition of enolate anions to activated alkynes provides a simple 7 Isoxazoles, isothiazoles and fused analogues and versatile route to several furans. An example is shown 8 Imidazoles and benzimidazoles n Scheme 1; other terminal activating groups on the alkyne, 9 Pyrazoles and indazoles including benzenesulfonyl and vinyl groups, are also effective 10 Oxadiazoles and thiadiazoles promoting the cyclisation. Full details of the scope and limit 11 Triazoles. benzotriazoles and tetrazoles ations of the similar base catalysed cyclisation of l-aryl-and I 12 Pyrones, coumarins and chromones vinylpent-4-ynones to furans have also appeared. Two othe related cyclisations of alkynes are shown in Scheme 2 Methyl 14 Quinolines and isoquinolines uran-2-acetates are formed by the palladium catalysed cyclis 15 Pyrimidines and quinazolines ation and carbonylation of 5-hydroxyenynes 1 and a related 16 Other diazines, triazines and tetrazines clisation, using potassium tetraiodopalladate as a catalyst 17 References has been used in a new synthesis of rosefuran. The ba induced cyclisation of acetylenic ketones such as 2 provides a 1 Introduction route to 2-alkenylfurans; the authors suggest that cumulenes such as 3 are intermediates This review, as with previous ones in the series, has the aim of covering reports of new and improved methods of construc tion of aromatic heterocycles from acyclic precursors or by Moc ring interconversion. The coverage cannot be comprehensive because of pressure of space. Many useful applications of exist- ing methods are not included; in particular, several of those that make use of solid phase and polymer bound reagents, COMe the literature on these is now extensively covered elsewhere(for Scheme 1 example, in Perkin I Abstracts and in other reviews). As with the earlier literature surveys in this series the ring systems overed are mainly restricted to the more common monocyclic Co(100 atm), Me and bicyclic heterocycles. COmE lew synthetic methods that make use of transition metals 5582% as catalysts or metal complexes(e.g, carbene complexes)as reagents continue to appear; cyclisation reactions that are atalysed by palladium(o) species have been extended to the NaHMDS.-78°C ynthesis of many of the common ring systems. Some interest ng new cycloaddition reactions have also been reported in this 66% period. For example, Sauer's group has made extensive use of Iverse electron demand Diels-Alder reactions of triazines and tetrazines for the synthesis of new pyridines and pyridazines and Wong and co-workers have made impressive use of cycloaddition reactions of trialkylsilyl- and trialkylstannyl acetylenes to provide routes to 3, 4-disubstituted furans, thio- phenes and pyrroles. Rees and co-workers have continued to find new applications of trithiazyl chloride for the preparation of five-membered heterocycles containing sulfur and nitrogen. Scheme 2 2 Furans and benzofurans Two furan syntheses involving metal carbene complexes ar exemplified in Schemes 3 and 4. The aldehyde 4 reacts with the Methods for the synthesis of substituted furans, involving both carbene complex(CO)s CrC(Me)OMe to give the bicyclic furan construction of the ring and substitution reactions, have been 5 in which the carbon atoms from the carbene complex are reviewed. The use of 3, 4-bis( trialkylstannylfurans and the located in a side chain; an analogous cyclisation occurs with the Chem Soc. perkin Trans. 1999. 2849-2866 2849 This journal is o The Royal Society of Chemistry 1999REVIEW J. Chem. Soc., Perkin Trans. 1, 1999, 2849–2866 2849 This journal is © The Royal Society of Chemistry 1999 Synthesis of aromatic heterocycles Thomas L. Gilchrist Chemistry Department, The University of Liverpool, Liverpool, UK L69 7ZD. E-mail tlg57@liv.ac.uk Received (in Cambridge, UK) 7th June 1999 Covering: March 1997 to February 1999 Previous review: J. Chem. Soc., Perkin Trans. 1, 1998, 615 1 Introduction 2 Furans and benzofurans 3 Thiophenes and benzothiophenes 4 Pyrroles 5 Indoles, indolizines and carbazoles 6 Oxazoles, thiazoles and benzothiazoles 7 Isoxazoles, isothiazoles and fused analogues 8 Imidazoles and benzimidazoles 9 Pyrazoles and indazoles 10 Oxadiazoles and thiadiazoles 11 Triazoles, benzotriazoles and tetrazoles 12 Pyrones, coumarins and chromones 13 Pyridines 14 Quinolines and isoquinolines 15 Pyrimidines and quinazolines 16 Other diazines, triazines and tetrazines 17 References 1 Introduction This review, as with previous ones in the series, has the aim of covering reports of new and improved methods of construc￾tion of aromatic heterocycles from acyclic precursors or by ring interconversion. The coverage cannot be comprehensive because of pressure of space. Many useful applications of exist￾ing methods are not included; in particular, several of those that make use of solid phase and polymer bound reagents, since the literature on these is now extensively covered elsewhere (for example, in Perkin 1 Abstracts and in other reviews 1 ). As with the earlier literature surveys in this series the ring systems covered are mainly restricted to the more common monocyclic and bicyclic heterocycles. New synthetic methods that make use of transition metals as catalysts or metal complexes (e.g., carbene complexes) as reagents continue to appear; cyclisation reactions that are catalysed by palladium(0) species have been extended to the synthesis of many of the common ring systems. Some interest￾ing new cycloaddition reactions have also been reported in this period. For example, Sauer’s group has made extensive use of inverse electron demand Diels–Alder reactions of triazines and tetrazines for the synthesis of new pyridines and pyridazines and Wong and co-workers have made impressive use of cycloaddition reactions of trialkylsilyl- and trialkylstannyl￾acetylenes to provide routes to 3,4-disubstituted furans, thio￾phenes and pyrroles. Rees and co-workers have continued to find new applications of trithiazyl chloride for the preparation of five-membered heterocycles containing sulfur and nitrogen. 2 Furans and benzofurans Methods for the synthesis of substituted furans, involving both construction of the ring and substitution reactions, have been reviewed.2 The use of 3,4-bis(trialkylstannyl)furans and the corresponding bis(trimethylsilyl)furan for the synthesis of other 3,4-disubstituted furans has also been reviewed.3 An improved version of Marshall’s synthesis of furans from β-alkynyl allylic alcohols, making use of silver nitrate on silica gel as the catalyst, has been described.4 As in earlier reviews, several of the useful new routes to furans involve cyclisation reactions in which oxygen nucleo￾philes undergo addition to alkynes. The intramolecular add￾ition of enolate anions to activated alkynes provides a simple and versatile route to several furans. An example is shown in Scheme 1; other terminal activating groups on the alkyne, including benzenesulfonyl and vinyl groups, are also effective in promoting the cyclisation.5 Full details of the scope and limit￾ations of the similar base catalysed cyclisation of 1-aryl- and 1- vinylpent-4-ynones to furans have also appeared.6 Two other related cyclisations of alkynes are shown in Scheme 2. Methyl furan-2-acetates are formed by the palladium catalysed cyclis￾ation and carbonylation of 5-hydroxyenynes 1 7 and a related cyclisation, using potassium tetraiodopalladate as a catalyst, has been used in a new synthesis of rosefuran.8 The base induced cyclisation of acetylenic ketones such as 2 provides a route to 2-alkenylfurans; the authors suggest that cumulenes such as 3 are intermediates.9 Two furan syntheses involving metal carbene complexes are exemplified in Schemes 3 and 4. The aldehyde 4 reacts with the carbene complex (CO)5CrC(Me)OMe to give the bicyclic furan 5 in which the carbon atoms from the carbene complex are located in a side chain; an analogous cyclisation occurs with the Scheme 1 Scheme 2