《杂环合成》（英文版）Synthesis of aromatic heterocycles

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 1999

REVIEW 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

Cr(Co) MeO Me Scheme 3 OMe (OC)5W (OC)5W Scheme 5 MeO,C CBH13 (i)MeOH Meo. STol R2 methyl ketone corresponding to 4. In an extension of a STol method reported earlier Iwasawa and co-workers have des- Scheme 6 cribed a synthesis of substituted methyl furan-3-carboxylates uch as 6 from tungsten carbene complexes, lithium acetylide and aldehydes. Tetrasubstituted furan-3-carboxylates have synthesis of 2-substituted furan-4-methanols involves the also been synthesised in moderate yield from 3-hydroxy- intermediacy of enones 14, which are prepared by a Horner- 1, 2-dioxane-4-carboxylates (cyclic peroxides) by reaction Wadsworth-Emmons reaction then cyclised by reaction wit HCLI9 The dimerisation of terminal allenic ketones 15 le ads to 2, 4-disubstituted furans 16 in preparatively useful yields when The palladium catalysed annelation of iodo compounds with pdCL(MeCN), is used as the catalyst in acetonitrile. A poten- internal alkynes, previously used by Larock's group to syn hesse a variety of heterocycles, has now been applied to furan tially general route to 2, 4-disubstituted furans has been used by Furstner and his co-workers in a synthesis of the terpene synthesis. For example, the tetrahydrobenzofuran 8 was pro- ircinin-4, the structure of which incorporates a 2, 4-dialkylfurar duced (69%) from the vinyl iodide 7 and 4, 4-dimethylpent subunit. This makes use of essentially the same methodology 2-yne. The mercury(m) catalysed cyclisation of the allenic as was invented for 2, 4-disubstituted pyrroles in Furstner's alcohols 10, generated in situ from 3-methoxy-l-phenyl te to roseophilin and which is outli ee furans I1 ise 9 and aldehydes, leads to the 2, 3-disubstituted Scheme 26 13 14 9 11 15 An unusual route to c-fused furans is illustrated in Scheme 5 Several furans have been prepared in moderate to good yield Intramolecular cycloaddition of conjugated ynones to triple by the reaction of a-bromomethyl ketones with enol ethers bonds leads to the formation of furans such as 12 which, the the presence of the catalyst [ReCI(N)(PMe, Ph)]. It is pro- authors suggest, are formed by way of strained bicyclic allenes posed that this generates acylmethyl radicals as the reactive and carbenes 6 Two existing routes to 3. 4-disubstituted furans have been mproved. The Garst-Spencer furan annelation from 3- (butylthio )enones was modified by replacing the butyl group ith a 4-tolyl group and by using iodine as the aromatising agent (Scheme 6). The oxidation of 2-substituted and 2, 3- disubstituted but-2-ene-1, 4-diols 13 in a two phase system led to a variety of 3-substituted and 3, 4-disubstituted furans in Scheme 7 good yield; for example, 3, 4-dibromofuran was prepared ( 83%) in this way. Cyclisation reactions involving palladium catalysis are pre- There are relatively few good methods for the synthesis of ominant among recently described methods for preparing dor furans with specific substituents at the 2 and 4 positions benzofurans. Details have been published of the sequential and some useful new methods have been described. A simple palladium catalysed coupling of 2-iodophenols with alk-l-yne 2850 J. Chem. Soc. Perkin Trans. 1. 1999. 2849-2866

2850 J. Chem. Soc., Perkin Trans. 1, 1999, 2849–2866 methyl ketone corresponding to 4. 10 In an extension of a method reported earlier 11 Iwasawa and co-workers have des￾cribed a synthesis of substituted methyl furan-3-carboxylates such as 6 from tungsten carbene complexes, lithium acetylides and aldehydes.12 Tetrasubstituted furan-3-carboxylates have also been synthesised in moderate yield from 3-hydroxy- 1,2-dioxane-4-carboxylates (cyclic peroxides) by reaction with acids.13 The palladium catalysed annelation of iodo compounds with internal alkynes, previously used by Larock’s group to syn￾thesise a variety of heterocycles, has now been applied to furan synthesis. For example, the tetrahydrobenzofuran 8 was pro￾duced (69%) from the vinyl iodide 7 and 4,4-dimethylpent- 2-yne.14 The mercury() catalysed cyclisation of the allenic alcohols 10, generated in situ from 3-methoxy-1-phenyl￾thioprop-1-yne 9 and aldehydes, leads to the 2,3-disubstituted furans 11. 15 An unusual route to c-fused furans is illustrated in Scheme 5. Intramolecular cycloaddition of conjugated ynones to triple bonds leads to the formation of furans such as 12 which, the authors suggest, are formed by way of strained bicyclic allenes and carbenes.16 Two existing routes to 3,4-disubstituted furans have been improved. The Garst–Spencer furan annelation from 3- (butylthio)enones was modified by replacing the butyl group with a 4-tolyl group and by using iodine as the aromatising agent (Scheme 6).17 The oxidation of 2-substituted and 2,3- disubstituted but-2-ene-1,4-diols 13 in a two phase system led to a variety of 3-substituted and 3,4-disubstituted furans in good yield; for example, 3,4-dibromofuran was prepared (83%) in this way.18 There are relatively few good methods for the synthesis of furans with specific substituents at the 2 and 4 positions and some useful new methods have been described. A simple Scheme 3 Scheme 4 synthesis of 2-substituted furan-4-methanols involves the intermediacy of enones 14, which are prepared by a Horner– Wadsworth–Emmons reaction then cyclised by reaction with HCl.19 The dimerisation of terminal allenic ketones 15 leads to 2,4-disubstituted furans 16 in preparatively useful yields when PdCl2(MeCN)2 is used as the catalyst in acetonitrile.20 A poten￾tially general route to 2,4-disubstituted furans has been used by Fürstner and his co-workers in a synthesis of the terpene ircinin-4, the structure of which incorporates a 2,4-dialkylfuran subunit.21 This makes use of essentially the same methodology as was invented for 2,4-disubstituted pyrroles in Fürstner’s route to roseophilin and which is outlined in Section 4 (see Scheme 26). Several furans have been prepared in moderate to good yield by the reaction of α-bromomethyl ketones with enol ethers in the presence of the catalyst [ReCl(N2)(PMe2Ph)4]. It is pro￾posed that this generates acylmethyl radicals as the reactive intermediates (Scheme 7).22 Cyclisation reactions involving palladium catalysis are pre￾dominant among recently described methods for preparing benzofurans. Details have been published of the sequential palladium catalysed coupling of 2-iodophenols with alk-1-ynes Scheme 5 Scheme 6 Scheme 7

and endo cyclisation to 2-substituted benzofurans. With silyl protected alkynols the method provides a route to benzofuran 3-methanol (Scheme 8)and to other alkan-3-ols. A variant which leads to 2, 3-disubstituted benzofurans is to carry out the reaction with allyl 2-alkynylphenyl ethers; for example, the ether 17 gave 3-allyl-2-methylbenzofuran 18(76%)on pal adium(o)catalysed cyclisation. A T-allylpalladium complex is reaction probably involves the generation and cyclisation of a suggested as an intermediate.3-Allenylbenzofurans have als phenoxy radical. been prepared by a similar method. a different approach to Two base-induced cyclisation reactions that lead to benzo- 3-allylbenzofurans has been described that is based on salicyl- furans are illustrated in Scheme 1033and in Scheme 11. The aldehyde derivatives; the aldehyde function is converted into an base induced fragmentation of 1, 2, 3-thiadiazoles is a prece- allyl vinyl ether (such as 19) by Wittig olefination and this is dented reaction and results in the generation of the anions 26 then subjected to Claisen rearrangement. The aldehydes(such intermediates in the route to 2-alkylthiobenzofurans as 20)so formed are then converted into 3-allylbenzofurans by acid catalysed cyclisation and dehydration NaH. DMF 80% TBDMS Scheme 10 OTBDMS 80 Scheme 8 9197% Schen 3 Thiophenes and benzothiophenes Several 2-alkylaminothiophenes have been prepared from terminal alkynes and alkyl or aryl isothiocyanates by the rout shown in Scheme 12.Similar syntheses of 2-alkylaminothio OMOM phenes bearing dialkylamino substituents at C-56 and hetero atom substituents at C-3 have also been described Palladium catalysed cyclisation reactions involving allene have provided another route to 3-substituted benzofurans. The B2NCS allene 21 gave 3-azidomethylbenzofuran 22(71%)with sodium azide and a palladium(o) catalyst. 2 Other nucleophiles can be O Bu'OK, DMSO used to capture the intermediate organopalladium species; thus, n)Ho with sodium benzenesulfinate, 3-(phenylsulfonylmethy l)benzo- NHR uran was isolated. Phenyl allyl ethers such as 23 have been 4387% cyclised to benzofurans by heating with caesium carbonate and Scheme 12 a palladium catalyst(Scheme 9).It is suggested that the reac- tion is promoted by the formation of phenolate anions, which The tertiary amide 27 gave the 2-aminot re more reactive than free phenols in the cyclisation step. on reaction with Lawesson's reagent 3 When secondary amides Intramolecular Heck reactions of allyl 2-iodophenyl ethers were used mixtures of aminothiophene and pyrroles were mides知 yield from reactions of ketene N, S-acetals such as 29 with 1, 3- dicarbonyl compounds and mercury(un)acetate, an hown in Scheme 13 CS (CO)3. Pd(O) 27 a standard route to benzofurans is the acid catal cyclodehydration of phenoxymethyl ketones 24. A versatile Ph NAMe route to these ketones based on the reaction of anions of Hg(OAc)2 I-phenoxymethylbenzotriazoles with aldehydes, has been des- s NAMe cribed; the complete sequence leading to the benzofurans can Me 91 PhS be carried out in one pot. Benzofuran has been isolated in 60% yield from the flash pyrolysis of the cinnamyl ester 25: the Scheme 13 Chem Soc. perkin Trans 1999. 2849-2866 2851

J. Chem. Soc., Perkin Trans. 1, 1999, 2849–2866 2851 and endo cyclisation to 2-substituted benzofurans.23 With silyl protected alkynols the method provides a route to benzofuran- 3-methanol (Scheme 8) and to other alkan-3-ols.24 A variant which leads to 2,3-disubstituted benzofurans is to carry out the reaction with allyl 2-alkynylphenyl ethers; for example, the ether 17 gave 3-allyl-2-methylbenzofuran 18 (76%) on pal￾ladium(0) catalysed cyclisation. A π-allylpalladium complex is suggested as an intermediate.25 3-Allenylbenzofurans have also been prepared by a similar method.26 A different approach to 3-allylbenzofurans has been described that is based on salicyl￾aldehyde derivatives; the aldehyde function is converted into an allyl vinyl ether (such as 19) by Wittig olefination and this is then subjected to Claisen rearrangement. The aldehydes (such as 20) so formed are then converted into 3-allylbenzofurans by acid catalysed cyclisation and dehydration.27 Palladium catalysed cyclisation reactions involving allenes have provided another route to 3-substituted benzofurans. The allene 21 gave 3-azidomethylbenzofuran 22 (71%) with sodium azide and a palladium(0) catalyst.28 Other nucleophiles can be used to capture the intermediate organopalladium species; thus, with sodium benzenesulfinate, 3-(phenylsulfonylmethyl)benzo￾furan was isolated. Phenyl allyl ethers such as 23 have been cyclised to benzofurans by heating with caesium carbonate and a palladium catalyst (Scheme 9).29 It is suggested that the reac￾tion is promoted by the formation of phenolate anions, which are more reactive than free phenols in the cyclisation step. Intramolecular Heck reactions of allyl 2-iodophenyl ethers have been applied to a solid phase synthesis of benzofuran-3- ylacetamides.30 A standard route to benzofurans is the acid catalysed cyclodehydration of phenoxymethyl ketones 24. A versatile route to these ketones, based on the reaction of anions of 1-phenoxymethylbenzotriazoles with aldehydes, has been des￾cribed; the complete sequence leading to the benzofurans can be carried out in one pot.31 Benzofuran has been isolated in 60% yield from the flash pyrolysis of the cinnamyl ester 25; the Scheme 8 Scheme 9 reaction probably involves the generation and cyclisation of a phenoxy radical.32 Two base-induced cyclisation reactions that lead to benzo￾furans are illustrated in Scheme 10 33 and in Scheme 11.34 The base induced fragmentation of 1,2,3-thiadiazoles is a prece￾dented reaction and results in the generation of the anions 26 as intermediates in the route to 2-alkylthiobenzofurans. 3 Thiophenes and benzothiophenes Several 2-alkylaminothiophenes have been prepared from terminal alkynes and alkyl or aryl isothiocyanates by the route shown in Scheme 12.35 Similar syntheses of 2-alkylaminothio￾phenes bearing dialkylamino substituents at C-5 36 and hetero￾atom substituents at C-3 37 have also been described. The tertiary amide 27 gave the 2-aminothiophene 28 (57%) on reaction with Lawesson’s reagent.38 When secondary amides were used mixtures of aminothiophenes and pyrroles were produced. 3-Alkylaminothiophenes were obtained in high yield from reactions of ketene N,S-acetals such as 29 with 1,3- dicarbonyl compounds and mercury() acetate; an example is shown in Scheme 13.39 Scheme 10 Scheme 11 Scheme 12 Scheme 13

Details have been published of the remarkably efficient syn- In a continuation of their work on benzo[c]thiophenes, Cava thesis of 3, 4-bis(trimethylsilyl)thiophene by the high temper- and his group have described a synthesis of the bis(2-thienyl)- ature Diels-Alder addition of bis(trimethylsilyl)acetylene benzo[c]thiophene 36 from the phthalide 37. They have also 4-phenylthiazole. The thiophene can be prepared in batches described a much improved synthesis of naphtho[2, 3-c]thio- of up to 8g by this method, which has also been extended phene 38 which makes use of a base catalysed Pummerer to some other 3, 4-disubstituted thiophenes. " A 1, 3-dipolar reaction. cycloaddition approach was also investigated (Scheme 14) but was less efficient. Experimental details have als provided for the preparation of 3, 4-disubstituted thiophenes from the diketones 30 by reductive cyclisation using titanium reagents. Thiophenes bearing bulky substituents(tert-butyl 1-adamantyl, etc. ) have been prepared by this route. TMSS TMS HMPA100°C TMS--MS DDQ 15 Scheme 14 A review of routes to arylpyrroles covers both classical and Two new thiophene syntheses have been described that make recent methods, with particular emphasis on the Trofimov use of the methodology previously developed for the prepar- synthesis from aryl ketoximes and acetylenes. Several useful ation of other heterocycles. Marson and Campbell have applied variants of classical methods have been reported. The optimum a synthesis of furans, based on the ring expansion of function- conditions for the preparation of l-benzylpyrroles from ed epoxides, to analogous episulfides; for example, the benzylamines and 2, 5-dimethoxytetrahydrofuran require the episulfide 31 gave the thiophene-2-methanol 32(80%) when use of a mixture of pyridine and acetic acid as solvent. This treated with a catalytic amount of mercury(u) oxide in dilute ynthetic method has also been adapted to provide a route to sulfuric acid at room temperature. a-Fluoroalkylcarbonyl 3, 4-dialkoxypyrroles 0 5-Trifluoromethylpyrroles have been compounds 33, which have previously been used in the syn- prepared by a modified Hantzsch synthesis(Scheme 17)in thesis of fluoroalkyl substituted pyrazoles and pyrimidines, which the use of preformed enamines avoids the side reaction gave 2(a-fluoroalkyl)thiophenes on reaction with methyl that leads to furans. I The use of organotin enamines, which are mercaptoacetate and sodium methoxide( Scheme 15). table enough to be isolated and stored, also leads to pyrroles in high yields. The products of Knorr-type reductive con sensation of 1, 3-diketones with oximinocyanoacetate esters r aque solvent(Scheme 18).>Glyoxal monophenylhydrazone has been used in Knorr-type condensations with B-keto esters to give 1, 2,3,4-tetrasubstituted pyrroles. Atmospheric nitrogen has been used for the first time in place of the usual ammonia in the synthesis of pyrroles from 1, 4-dicarbonyl compounds: the reaction involves the reduction of nitrogen by a mixture of titanium(Iv) chloride, chlorotrimethylsilane and lithium R, HS CO2Me 54-76% Meo2c metal.5 33(X=F or Br Relatively few new routes to benzothiophenes have been 0-71%F2C described in the period under review. The route to benzofurans described by Katritzky and co-workers has also been used as a Scheme 17 one pot synthesis of benzothiophenes, the thioethers analogous to 24 being intermediates.36-Hydroxybenzothiophenes have been synthesised by a procedure in which the benzene ring is annelated to a 2-substituted thiophene by acid catalysed cyclis- ation."4-Chloro-1, 2, 3-dithiazole-5-thione, which is readily prepared from 4, 5-dichlorodithiazolium chloride(Appel's salt) Scheme 18 Some cyclisation reactions that were previously used to syn- lesise furans have been successfully adapted to the preparation of pyrroles. Thus, the imines 39, which are formed from the cyclise to pyrroles(Scheme 19). Some related palladium 2852 J. Chem. Soc. Perkin Trans. 11999. 2849-2866

2852 J. Chem. Soc., Perkin Trans. 1, 1999, 2849–2866 Details have been published of the remarkably efficient syn￾thesis of 3,4-bis(trimethylsilyl)thiophene by the high temper￾ature Diels–Alder addition of bis(trimethylsilyl)acetylene to 4-phenylthiazole. The thiophene can be prepared in batches of up to 8 g by this method, which has also been extended to some other 3,4-disubstituted thiophenes.40 A 1,3-dipolar cycloaddition approach was also investigated (Scheme 14) but was less efficient. Experimental details have also been provided for the preparation of 3,4-disubstituted thiophenes from the diketones 30 by reductive cyclisation using titanium reagents.41 Thiophenes bearing bulky substituents (tert-butyl, 1-adamantyl, etc.) have been prepared by this route. Two new thiophene syntheses have been described that make use of the methodology previously developed for the prepar￾ation of other heterocycles. Marson and Campbell have applied a synthesis of furans, based on the ring expansion of function￾alised epoxides, to analogous episulfides; for example, the episulfide 31 gave the thiophene-2-methanol 32 (80%) when treated with a catalytic amount of mercury() oxide in dilute sulfuric acid at room temperature.42 α-Fluoroalkylcarbonyl compounds 33, which have previously been used in the syn￾thesis of fluoroalkyl substituted pyrazoles and pyrimidines, gave 2-(α-fluoroalkyl)thiophenes on reaction with methyl mercaptoacetate and sodium methoxide (Scheme 15).43 Relatively few new routes to benzothiophenes have been described in the period under review. The route to benzofurans described by Katritzky and co-workers has also been used as a one pot synthesis of benzothiophenes, the thioethers analogous to 24 being intermediates.31 6-Hydroxybenzothiophenes have been synthesised by a procedure in which the benzene ring is annelated to a 2-substituted thiophene by acid catalysed cyclis￾ation.44 4-Chloro-1,2,3-dithiazole-5-thione, which is readily prepared from 4,5-dichlorodithiazolium chloride (Appel’s salt) and hydrogen sulfide, reacts with diphenyldiazomethane to give the benzothiophene 35 by way of the isolable intermediate 34 (Scheme 16).45 Scheme 14 Scheme 15 Scheme 16 In a continuation of their work on benzo[c]thiophenes, Cava and his group have described a synthesis of the bis(2-thienyl)- benzo[c]thiophene 36 from the phthalide 37. 46 They have also described a much improved synthesis of naphtho[2,3-c]thio￾phene 38 which makes use of a base catalysed Pummerer reaction.47 4 Pyrroles A review of routes to arylpyrroles covers both classical and recent methods, with particular emphasis on the Trofimov synthesis from aryl ketoximes and acetylenes.48 Several useful variants of classical methods have been reported. The optimum conditions for the preparation of 1-benzylpyrroles from benzylamines and 2,5-dimethoxytetrahydrofuran require the use of a mixture of pyridine and acetic acid as solvent.49 This synthetic method has also been adapted to provide a route to 3,4-dialkoxypyrroles.50 5-Trifluoromethylpyrroles have been prepared by a modified Hantzsch synthesis (Scheme 17) in which the use of preformed enamines avoids the side reaction that leads to furans.51 The use of organotin enamines, which are stable enough to be isolated and stored, also leads to pyrroles in high yields.52 The products of Knorr-type reductive con￾densation of 1,3-diketones with oximinocyanoacetate esters depend on whether dry or aqueous acetic acid is used as the solvent (Scheme 18).53 Glyoxal monophenylhydrazone has been used in Knorr-type condensations with β-keto esters to give 1,2,3,4-tetrasubstituted pyrroles.54 Atmospheric nitrogen has been used for the first time in place of the usual ammonia in the synthesis of pyrroles from 1,4-dicarbonyl compounds: the reaction involves the reduction of nitrogen by a mixture of titanium() chloride, chlorotrimethylsilane and lithium metal.55 Some cyclisation reactions that were previously used to syn￾thesise furans have been successfully adapted to the preparation of pyrroles. Thus, the imines 39, which are formed from the corresponding ketones and primary amines, spontaneously cyclise to pyrroles (Scheme 19).6 Some related palladium Scheme 17 Scheme 18

NOTS 5097% Scheme 23 catalysed cyclisations of none p-tolylsulfonylhydrazones to Ar 1-(p-tolylsulfonylamino)aminopyrroles have been described. 6 Knight and co-workers have adapted their iodocyclisation reactions to provide routes 2, 5-disubstituted pyrroles with or ithout an iodo substituent at C-357-58 The methodology is illustrated in Scheme 20. The synthesis of methyl 2-aryl- pyrrole-3-carboxylates from methyl buta-2, 3-dienoate which is exemplified in Scheme 21 is conceptually quite different but probably involves the same kind of endo-cyclisation and induced dehydrohalogenation. s Other cyclisation reactions hat have been used for specifically substituted pyrroles include he reaction of the diene 44 with arylamines to give l-aryl l2, K CO3 2, 3, 4, 5-tetrakis( trifluoromethyl)pyrroles, the cyclisation of Meo 5-chloropent-3-en-2-one with homochiral NHTS 1-substituted 2-methylpyrroles6 and the reaction of the dienones 45 with various amines to give 1, 2, 5-trisubstituted DS ONE MO.C- Two three-component pyrrole syntheses are illustrated in cheme 2467 and in Scheme 25.6 The samarium(n) iodide catalysed condensation of alkylamines, aldehydes and nitro- alkanes gave 1, 2, 3, 4-tetrasubstituted pyrroles in moderate to methodology to construct intermediates from which 1, 2, 3- triarylpyrroles were obtained by acid catalysed cyclisation. CO Me CO Me R'NH + R2 CO,Me Scheme 24 Scheme 21 Other new cyclisation reactions in which the N-C2 bonds of pyrroles are formed are illustrated in Scheme 22and Scheme 23. I Trimethylsilyldiazomethyllithium is used to generate a vinylidene carbene 40 from which the five-membered ring is generated by intramolecular N-Hinsertion The oxime tosylate 41 probably cyclises by N-o insertion of the palladium catalyst ICO, H followed by an intramolecular Heck reaction. 2-Substituted-3- 66-74%Ph itropyrroles were isolated in good yield from the reaction of aminoacetaldehyde dimethyl acetal with B(methylthio)nitro- (Bt= benzotriazolyl alkenes 62 Scheme 25 TMSC(L)N2 C NHBn Furstner's remarkably short synthesis of the macrotricyclic core of roseophilin, a pyrrolic antitumour agent, incorporates a new and potentially more general method of synthesis of 2, 4-disubstituted pyrroles; the key steps are outlined in Scheme 26.,/ It includes the formation and reaction of tw Tt-allylpalladium intermediates A simple route to 2-(alkylthio)pyrroles is the base catalysed yclisation of allyl isothiocyanate followed by s-alkylation (Scheme 27). The use of isothiocyanate anions has been extended to the synthesis of more highly substituted 2-(alkyl Scheme 2? thio)pyrroles. A similarly mild synthesis of 2-arylpyrro is the opening of cyclopropane-1, 2-diammonium salts 47 with The aza-Wittig reaction of azido ketones 42 has been previ- aromatic aldehydes. The reactions go in buffered methanol at ously reported as a route to pyrrolines 43. These pyrrolines have room temperature and bis(alkylam n)salts can be used i now been efficiently converted into 2-aryl-3-halopyrroles by the same way bis-halogenation at C-3 with NCS or NBS followed by base B-Enaminocarbonyl compounds have been used to construct Chem Soc. perkin Trans. 1999. 2849-2866 2853

J. Chem. Soc., Perkin Trans. 1, 1999, 2849–2866 2853 catalysed cyclisations of ynone p-tolylsulfonylhydrazones to 1-(p-tolylsulfonylamino)aminopyrroles have been described.56 Knight and co-workers have adapted their iodocyclisation reactions to provide routes 2,5-disubstituted pyrroles with or without an iodo substituent at C-3.57,58 The methodology is illustrated in Scheme 20.58 The synthesis of methyl 2-aryl￾pyrrole-3-carboxylates from methyl buta-2,3-dienoate which is exemplified in Scheme 21 is conceptually quite different but probably involves the same kind of endo-cyclisation and aromatisation steps.59 Other new cyclisation reactions in which the N–C2 bonds of pyrroles are formed are illustrated in Scheme 22 60 and Scheme 23.61 Trimethylsilyldiazomethyllithium is used to generate a vinylidene carbene 40 from which the five-membered ring is generated by intramolecular N–H insertion. The oxime tosylate 41 probably cyclises by N–O insertion of the palladium catalyst followed by an intramolecular Heck reaction. 2-Substituted-3- nitropyrroles were isolated in good yield from the reaction of aminoacetaldehyde dimethyl acetal with β-(methylthio)nitro￾alkenes.62 The aza-Wittig reaction of azido ketones 42 has been previ￾ously reported as a route to pyrrolines 43. These pyrrolines have now been efficiently converted into 2-aryl-3-halopyrroles by bis-halogenation at C-3 with NCS or NBS followed by base Scheme 19 Scheme 20 Scheme 21 Scheme 22 induced dehydrohalogenation.63 Other cyclisation reactions that have been used for specifically substituted pyrroles include the reaction of the diene 44 with arylamines to give 1-aryl- 2,3,4,5-tetrakis(trifluoromethyl)pyrroles,64 the cyclisation of 5-chloropent-3-en-2-one with homochiral amines to give chiral 1-substituted 2-methylpyrroles 65 and the reaction of the dienones 45 with various amines to give 1,2,5-trisubstituted pyrroles 46. 66 Two three-component pyrrole syntheses are illustrated in Scheme 24 67 and in Scheme 25.68 The samarium() iodide catalysed condensation of alkylamines, aldehydes and nitro￾alkanes gave 1,2,3,4-tetrasubstituted pyrroles in moderate to good yield. Katritzky and co-workers used benzotriazole methodology to construct intermediates from which 1,2,3- triarylpyrroles were obtained by acid catalysed cyclisation.68 Fürstner’s remarkably short synthesis of the macrotricyclic core of roseophilin, a pyrrolic antitumour agent, incorporates a new and potentially more general method of synthesis of 2,4-disubstituted pyrroles; the key steps are outlined in Scheme 26.69,70 It includes the formation and reaction of two π-allylpalladium intermediates. A simple route to 2-(alkylthio)pyrroles is the base catalysed cyclisation of allyl isothiocyanate followed by S-alkylation (Scheme 27).71,72 The use of isothiocyanate anions has been extended to the synthesis of more highly substituted 2-(alkyl￾thio)pyrroles.73 A similarly mild synthesis of 2-arylpyrroles is the opening of cyclopropane-1,2-diammonium salts 47 with aromatic aldehydes.74 The reactions go in buffered methanol at room temperature and bis(alkylammonium) salts can be used in the same way. β-Enaminocarbonyl compounds have been used to construct Scheme 23 Scheme 24 Scheme 25

TBDMSO TBDMSO RCHO TBDMSO PhO?s COpl PhO2S atalyst but it was subsequently found that simple protic and PhOs PhO2s Lewis acids could also be used to bring about cyclisations The dimerisation of propargylamines to under the influence of a example is shown in Scheme 30 PhOs 2 Scheme 30 EtO, C Isocyanides continue to be key intermediates in the synthesi of novel pyrroles. The Barton-Zard reaction(the base catalysed E addition of alkyl isocyanoacetates to nitroalkenes) has be used to prepare a variety of new pyrroles; in particular, Lashs COH group has made extensive use of the reaction as a route to pyrrolic intermediates for porphyrin synthesis starting fror 49 polycyclic aromatic nitro compounds. -s The fused pyrroles 52-54 are examples of compounds that have been obtained in a variety of new pyrroles. The little-used Zav yalov pyrrole s preparatively useful yields by this method. In an analogue of thesis, the cyclisation of enamino acl acids 48 to N-acetylpyrroles the Barton-Zard reaction, addition of the anions of alkyl iso- 49 with acetic anhydride and a base, has been reinvestigate cyanoacetates to a, B-unsaturated sulfones led to the formation and applied to the synthesis of some novel [cl-fused pyrroles. of a variety of unusually substituted pyrroles, including the Several new trifiuoromethylpyrroles have been prepared by a bicyclic pyrrole 56(60%)from the sulfone 55.86 Tosylmethy related base catalysed cyclisation of trifluoroacetylenamines. isocyanide(Tos MIC) has been used to make new [cJannelated involves the intermediacy of vinylogous amidinium salts. 7 pyrroles 87 and 3-arylpyrroles. By prior reaction with base and 3-Aminopyrrole-24-dicarboxylates 51 have been prepared by direct route to 2-trimethylstannylpyrroles 9 This provides the he acid catalysed cyclisation of enaminones 50"and an effi- basis for the preparation of other 2-substituted pyrroles. In a ient solid phase pyrrole synthesis is based on the condensation similar way, 3, 4-bis(trimeth hylsilyl)pyrrole can be used as a pre of resin bound enaminoamides with nitroalkenes 7y cursor of other B-substituted pyrroles; this has been prepared efficiently by 1, 3-dipolar cycloaddition of the azomethine ylide (i)POCla, CH2 Cla derived from the aziridine 57 to bis( trimethylsilyl)acetylene. 0 间BncH2CO2Et Pyrroledicarboxylic esters have been prepared by similar 1, 3- dipolar addition of benzotriazolylaziridines 58 to acetylenic 5 Indoles, indolizines and carbazoles Several useful new modifications of classical methods of indole CO2Et ROc. tion of indoles bearing oxygen substituents at NMe? avoid"abnormal"cyclisation on to the substituted carbon. A temporary tether was used in the cyclisation of the hydrazone 59: the tether was subsequently removed by reaction with sodium ethoxide to provide a route to the 7-hydroxy-4-nitro- An interesting new pyrrole synthesis was developed as part of indole. 2 A sulfonyloxy group in hydrazones 60 also directs a route to the antibiotic streptorubin B. An enyne metathesis cyclisation to give mainly 7-substituted indoles. The N-H reaction( Scheme 29)was used as the key step in constructing insertion reaction of rhodium carbenoids has been used by the pyrrolic core. Initially platinum(n) chloride was used as the Moody and Swann to construct a-arylamino ketone inter 2854 J Chem. Soc.. Perkin Trans. I.1999. 2849-2866

2854 J. Chem. Soc., Perkin Trans. 1, 1999, 2849–2866 a variety of new pyrroles. The little-used Zav’yalov pyrrole syn￾thesis, the cyclisation of enamino acids 48 to N-acetylpyrroles 49 with acetic anhydride and a base, has been reinvestigated and applied to the synthesis of some novel [c]-fused pyrroles.75 Several new trifluoromethylpyrroles have been prepared by a related base catalysed cyclisation of trifluoroacetylenamines.76 A synthesis of ethyl 3-arylpyrrole-2-carboxylates (Scheme 28) involves the intermediacy of vinylogous amidinium salts.77 3-Aminopyrrole-2,4-dicarboxylates 51 have been prepared by the acid catalysed cyclisation of enaminones 50 78 and an effi- cient solid phase pyrrole synthesis is based on the condensation of resin bound enaminoamides with nitroalkenes.79 An interesting new pyrrole synthesis was developed as part of a route to the antibiotic streptorubin B.80 An enyne metathesis reaction (Scheme 29) was used as the key step in constructing the pyrrolic core. Initially platinum() chloride was used as the Scheme 26 Scheme 27 Scheme 28 catalyst but it was subsequently found that simple protic and Lewis acids could also be used to bring about such cyclisations. The dimerisation of propargylamines to pyrroles proceeds under the influence of a lanthanide catalyst; an example is shown in Scheme 30.81 Isocyanides continue to be key intermediates in the synthesis of novel pyrroles. The Barton–Zard reaction (the base catalysed addition of alkyl isocyanoacetates to nitroalkenes) has been used to prepare a variety of new pyrroles; 82 in particular, Lash’s group has made extensive use of the reaction as a route to pyrrolic intermediates for porphyrin synthesis starting from polycyclic aromatic nitro compounds.83–85 The fused pyrroles 52–54 are examples of compounds that have been obtained in preparatively useful yields by this method. In an analogue of the Barton–Zard reaction, addition of the anions of alkyl iso￾cyanoacetates to α,β-unsaturated sulfones led to the formation of a variety of unusually substituted pyrroles, including the bicyclic pyrrole 56 (60%) from the sulfone 55. 86 Tosylmethyl isocyanide (TosMIC) has been used to make new [c]annelated pyrroles 87 and 3-arylpyrroles.88 By prior reaction with base and chlorotrimethylstannane, its addition to enones provided a direct route to 2-trimethylstannylpyrroles.89 This provides the basis for the preparation of other 2-substituted pyrroles. In a similar way, 3,4-bis(trimethylsilyl)pyrrole can be used as a pre￾cursor of other β-substituted pyrroles; this has been prepared efficiently by 1,3-dipolar cycloaddition of the azomethine ylide derived from the aziridine 57 to bis(trimethylsilyl)acetylene.90 Pyrroledicarboxylic esters have been prepared by similar 1,3- dipolar addition of benzotriazolylaziridines 58 to acetylenic esters.91 5 Indoles, indolizines and carbazoles Several useful new modifications of classical methods of indole synthesis have been described. Two variants of the Fischer indole cyclisation enable the method to be used for the prepar￾ation of indoles bearing oxygen substituents at C-7 and thus avoid “abnormal” cyclisation on to the substituted carbon. A temporary tether was used in the cyclisation of the hydrazone 59; the tether was subsequently removed by reaction with sodium ethoxide to provide a route to the 7-hydroxy-4-nitro￾indole.92 A sulfonyloxy group in hydrazones 60 also directs cyclisation to give mainly 7-substituted indoles.93 The N–H insertion reaction of rhodium carbenoids has been used by Moody and Swann to construct α-arylamino ketone inter￾Scheme 29 Scheme 30

The reductive palladium catalysed endo cyclisation of 2-nitro- styrenes has previously been shown to provide a route to indoles; new, milder conditions for the reaction, involving heating the precursor and catalyst at 70C under 4 atm carbon monoxide have now been described. The indoles are isolated COEt CO2Et in moderate to excellent yield; for example. 4-methoxy-2-nitro- styrene 61 gave 6-methoxyindole 62 in 89% yield 103A base induced endo cyclisation of the difluoroalkene 63 led to the formation of 3-butyl-2-fluoro-1-(p-tolylsulfonyl)indole in higl ield; a similar methodology was used to produce the corre- sponding benzofuran and benzothiophene. SOpH TMS NO2 MeO Although limited in scope, the radical cyclisatic shown in Scheme 33 represents an unusual method fo SOO struction of the n-c2 bond of indoles 04 Another which is represented as a new method of constructing thi (intramolecular nucleophilic addition to an allyl cation) is the cyclisation of the enaminone 64 to the benzindole 65 with mediates similar to those in the Bischler indole synthesis; methanesulfonyl chloride 0S these were then cyclised under acidic conditions to produce a variety of indole-2-carboxylic acid esters A route to 2- SPh substituted 5-hydroxyindoles that provides an alternative to the Nenitzescu synthesis makes use of cyclohexane-1, 4-dione as the 6-membered ring component; an example is shown in Scheme he Sundberg indole synthesis has been used to pro he first preparation of 2-nitroindole: 2-azido-B-nitrostyrene Scheme 33 was heated in xylene to give the indole in 54% yield. NHBn NBCc HBOc A route to substituted tryptamines from iodo Scheme 31 use of a Heck vinylation reaction followed by a ation to construct an intermediate aldehyde fror versatile synthesis of indoles and several new variants of the formed from the iodoaniline by a Heck reaction, was converted eaction have been reported. 3-Arylindoles are obtained by into the substituted tryptamine 67( Scheme 34) the palladium catalysed endo cyclisation of 2-ethynyltrifluor acetanilide and trapping of the intermediate palladium species with aryl iodides (Scheme 32). 2-Substituted 3-allylindoles N(BOC)2 have also been prepared by a palladium catalysed cyclisation [Rhl, H2, CO and capture of the intermediates by allylic esters. Similar syn theses of 23.6-trisubstituted indoles have been carried out in the solid phase. Such cyclisations can also be brought about by bases and this methodology has been applied to the synthesis N(Boc) of 4, 5, 7-trimethoxyindole and other indoles. Molybdenum catalysed cyclisations of this type have also been reported; indole itself has been prepared in good yiel 62% from 2-ethynylaniline with the aid of a molybdenum catalyst 01 yclisations of 2-alkynylanilines to 2-substituted indoles so be catalysed by TBAF, and in this mild procedure other eactive functional groups are unaffected. Scheme 34 A new route to indoles, outlined in Scheme 35, makes use Pd aba3, K,CO3 of the reaction of the air stable complex Cp2TiCl2 with ar Grignard reagents to generate a titanocene-benzyne complex NHCOCF3 56-85% which undergoes insertion reactions with alkenes. The indole ring is constructed by bromination followed by palladium J. Chem. Soc. Perkin Trans I. 1999. 2849-2866 2855

J. Chem. Soc., Perkin Trans. 1, 1999, 2849–2866 2855 mediates similar to those in the Bischler indole synthesis; these were then cyclised under acidic conditions to produce a variety of indole-2-carboxylic acid esters.94 A route to 2- substituted 5-hydroxyindoles that provides an alternative to the Nenitzescu synthesis makes use of cyclohexane-1,4-dione as the 6-membered ring component; an example is shown in Scheme 31.95 The Sundberg indole synthesis has been used to provide the first preparation of 2-nitroindole: 2-azido-β-nitrostyrene was heated in xylene to give the indole in 54% yield.96 The cyclisation of 2-alkynylaniline derivatives provides a versatile synthesis of indoles and several new variants of the reaction have been reported. 3-Arylindoles are obtained by the palladium catalysed endo cyclisation of 2-ethynyltrifluoro￾acetanilide and trapping of the intermediate palladium species with aryl iodides (Scheme 32).97 2-Substituted 3-allylindoles have also been prepared by a palladium catalysed cyclisation and capture of the intermediates by allylic esters.98 Similar syn￾theses of 2,3,6-trisubstituted indoles have been carried out in the solid phase.99 Such cyclisations can also be brought about by bases and this methodology has been applied to the synthesis of 4,5,7-trimethoxyindole and other oxygen substituted indoles.100 Molybdenum catalysed cyclisations of this type have also been reported; indole itself has been prepared in good yield from 2-ethynylaniline with the aid of a molybdenum catalyst.101 Cyclisations of 2-alkynylanilines to 2-substituted indoles can also be catalysed by TBAF, and in this mild procedure other reactive functional groups are unaffected.102 Scheme 31 Scheme 32 The reductive palladium catalysed endo cyclisation of 2-nitro￾styrenes has previously been shown to provide a route to indoles; new, milder conditions for the reaction, involving heating the precursor and catalyst at 70
C under 4 atm carbon monoxide, have now been described. The indoles are isolated in moderate to excellent yield; for example, 4-methoxy-2-nitro￾styrene 61 gave 6-methoxyindole 62 in 89% yield.103 A base induced endo cyclisation of the difluoroalkene 63 led to the formation of 3-butyl-2-fluoro-1-(p-tolylsulfonyl)indole in high yield; a similar methodology was used to produce the corre￾sponding benzofuran and benzothiophene.33 Although limited in scope, the radical cyclisation process shown in Scheme 33 represents an unusual method for the con￾struction of the N–C2 bond of indoles.104 Another reaction which is represented as a new method of constructing this bond (intramolecular nucleophilic addition to an allyl cation) is the cyclisation of the enaminone 64 to the benzindole 65 with methanesulfonyl chloride.105 A route to substituted tryptamines from iodoanilines makes use of a Heck vinylation reaction followed by a hydroformyl￾ation to construct an intermediate aldehyde from which the N–C2 bond is formed. For example, the intermediate aniline 66, formed from the iodoaniline by a Heck reaction, was converted into the substituted tryptamine 67 (Scheme 34).106 A new route to indoles, outlined in Scheme 35, makes use of the reaction of the air stable complex Cp2TiCl2 with aryl Grignard reagents to generate a titanocene–benzyne complex, which undergoes insertion reactions with alkenes. The indole ring is constructed by bromination followed by palladium catalysed amination of the resulting aryl bromide.107 Scheme 33 Scheme 34

ates 74 were generated from the corresponding diazonium tetrafluoroborates with sodium iodide in acetone and cyclised to the indoles 75. 6 The cyclisation onto a vinyl bromide allow a wider variety of indoles to be constructed than the analogous radical cyclisation onto a triple bond. Vinyl bromides are als substituted indoles shown in Scheme 37. 7 This reaction is rationalised as involving BnNH2 an aryne intermediate; after cyclisation the aryllithium species 18-54% is intercepted by electrophiles such as benzaldehyde and ethyl hloroformate. Kuehm-Caubere and co-workers have also described an efficient synthesis of 2-substituted indoles by Scheme 35 arynic cyclisation. The aryl imines 76 derived from methyl ketones gave the indoles 77 in the presence of the complex base An electrochemical method, involving the use of a redox flow derived from sodamide and sodium tert-butoxide. cell, has provided an efficient synthesis of l-alkylaminoindoles from the nitroamines 68. 3-Cyano-1-hydroxyindoles have been prepared od yield by base catalysed cyclisation of the aromatic nitro compounds 69. In concentrated hydrochloric tion requires the 2-methyl substituent and occurs only in the presence of concentrated acids, indicating that a tertiary carbo cation intermediate is involved 10 The known"lateral lithi- ation"of the methyl group of Boc-protected o-toluidines has Bu' Li(3. 3 mol been applied to the synthesis of ethyl indole-2-carboxylates by quenching the anion with diethyl oxalate; the reaction allows the preparation of indole esters bearing a range of substituents In t the six-membered ring 1 New examples of base catalysed reactions which lead to formation of the indole C2-C3 bond include the cyclisation of the succinimide 72 to the indole 7312 and the intramolecular addition of benzyl sulfones to imines and carbodiimides NHR CO2 Me 3-Methylindoles can be prepared from propargylanilines prop-2-ynylanilines) by the. new and conceptually simple method illustrated in Scheme 38.19 There are several con- straints on the method which were established experimentally Palladium catalysed cyclisation reactions are increasingly the trialkylsilyl group and the nitrogen protecting group were mportant methods for the formation of the C3-C3a bond of chosen in order to be stable to methanesulfonic acid, the cyclis- indoles. The methodology illustrated in Scheme 9 for the con- ing agent, and the position at which the cation cyclises must struction of hydroxybenzofurans has also been applied to be sufficiently activated by ring substituents. Another acid indole synthesis as has the solid phase intramolecular Heck catalysed cyclisation procedure which leads to indoles unsubsti reaction. A simple condensation-cyclisation procedure, tuted in the five-membered ring, is the reaction of anilines with shown in Scheme 36, is the palladium catalysed reaction of triethanolamine in the presence of tin() chloride and 2-iodoanilines with ketones. Related cyclisations of pre- ruthenium catalyst formed enamines to 2-trifluoromethylindole-3-carboxylic acid esters have been described. 115 A new indole synthesis makes use of radical cyclisation for OMe TIPS the construction of the c3--c3a bond. The radical intermedi Meo NH R The indoloquinone 79 has been synthesised by a route in which the key step is intramolecular 1, 3-dipolar addition of the azomethine ylide 78. The 1, 3-dipole was generated from an N-methyloxazolium salt by ring opening with cyanide. A novel 2856 J Chem. Soc. Perkin Trans.1999. 2849-2866

2856 J. Chem. Soc., Perkin Trans. 1, 1999, 2849–2866 An electrochemical method, involving the use of a redox flow cell, has provided an efficient synthesis of 1-alkylaminoindoles from the nitroamines 68. 108 3-Cyano-1-hydroxyindoles have been prepared in good yield by base catalysed cyclisation of the aromatic nitro compounds 69. 109 In concentrated hydrochloric acid 4-amino-2-methylbenzofurans 70 are converted in high yield into the isomeric 4-hydroxy-2-methylindoles 71. The reac￾tion requires the 2-methyl substituent and occurs only in the presence of concentrated acids, indicating that a tertiary carbo￾cation intermediate is involved.110 The known “lateral lithi￾ation” of the methyl group of Boc-protected o-toluidines has been applied to the synthesis of ethyl indole-2-carboxylates by quenching the anion with diethyl oxalate; the reaction allows the preparation of indole esters bearing a range of substituents in the six-membered ring.111 New examples of base catalysed reactions which lead to formation of the indole C2–C3 bond include the cyclisation of the succinimide 72 to the indole 73 112 and the intramolecular addition of benzyl sulfones to imines and carbodiimides.113 Palladium catalysed cyclisation reactions are increasingly important methods for the formation of the C3–C3a bond of indoles. The methodology illustrated in Scheme 9 for the con￾struction of hydroxybenzofurans has also been applied to indole synthesis 29 as has the solid phase intramolecular Heck reaction.30 A simple condensation–cyclisation procedure, shown in Scheme 36, is the palladium catalysed reaction of 2-iodoanilines with ketones.114 Related cyclisations of pre￾formed enamines to 2-trifluoromethylindole-3-carboxylic acid esters have been described.115 A new indole synthesis makes use of radical cyclisation for the construction of the C3–C3a bond. The radical intermedi￾Scheme 35 Scheme 36 ates 74 were generated from the corresponding diazonium tetrafluoroborates with sodium iodide in acetone and cyclised to the indoles 75. 116 The cyclisation onto a vinyl bromide allows a wider variety of indoles to be constructed than the analogous radical cyclisation onto a triple bond. Vinyl bromides are also used as precursors in the synthesis of 3,4-disubstituted indoles shown in Scheme 37.117 This reaction is rationalised as involving an aryne intermediate; after cyclisation the aryllithium species is intercepted by electrophiles such as benzaldehyde and ethyl chloroformate. Kuehm-Caubère and co-workers have also described an efficient synthesis of 2-substituted indoles by arynic cyclisation. The aryl imines 76 derived from methyl ketones gave the indoles 77 in the presence of the complex base derived from sodamide and sodium tert-butoxide.118 3-Methylindoles can be prepared from propargylanilines (prop-2-ynylanilines) by the new and conceptually simple method illustrated in Scheme 38.119 There are several con￾straints on the method which were established experimentally: the trialkylsilyl group and the nitrogen protecting group were chosen in order to be stable to methanesulfonic acid, the cyclis￾ing agent, and the position at which the cation cyclises must be sufficiently activated by ring substituents. Another acid catalysed cyclisation procedure which leads to indoles unsubsti￾tuted in the five-membered ring, is the reaction of anilines with triethanolamine in the presence of tin() chloride and a ruthenium catalyst.120 The indoloquinone 79 has been synthesised by a route in which the key step is intramolecular 1,3-dipolar addition of the azomethine ylide 78. 121 The 1,3-dipole was generated from an N-methyloxazolium salt by ring opening with cyanide. A novel Scheme 37 Scheme 38

NC NC OTS H Scheme 39 synthesis of 3-nitroindoles is based on the construction of the x-membered ring from a 3-nitropyrrole intermediate Scheme 40 One of the standard synthetic methods for indolizines is the seaction of activated alkenes or alkynes with pyridinium ylides. acylisoxazoles are used instead, they give thiazoles in an analo- his method has been used to prepare some new I-trifluoro- gous manner. 5-Arylisoxazole-4-carbaldehydes have been methylindolizines from 2-bromo-3,3, 3-trifluoropropene 123 isolated in moderate yield from the reaction of aryl 2-azido- Methods of synthesis that start from pyrroles are much less methyl ketones with the Vilsmeier reagent at 80-90.C. 136 common.A method involving(stepwise) cycloaddition of rad A full paper has appeared on the insertion of rhodium ical cations such as 80 to B-acceptor substituted enamines has carbenoids derived from diazocarbonyl compounds into the been described. The cations were generated by electrochemical H-H bonds of amides. 7 This leads to dihydrooxazoles, which oxidation of the corresponding pyrroles and the final products were oxidised by the use of triphenylphosphine, iodine and tri- were indolizines such as 81(X=CN, CO, Me, etc ).12 thylamine, a method first described by Wipf. A comparative tudy of methods for the oxidation of 4, 5-dihydrooxazoles to oxazoles has also been published. 38 A solid phase adaptation of the Hantzsch synthesis of 2-aminothiazoles has been achieved s The solution synthesis CO, Me CO, Me of N-substituted 2-aminothiazoles from a-haloketones, potas ium thiocyanate and a primary amine has been simplified to an CO Me efficient one pot procedure. 40 Several N-substituted 2-aminc thiazoles have also been prepared from N-thiocarbamoyl- imidates and activated haloalkanes. 141 2-Cyanobenzothiazoles are formed by the sequence shown in Scheme 41. The second reaction step can be carried out 人人 onventional heating, or, more efficiently, by microwave irradi The thermal ring closure of N-arylketenimines 82 to benzo- ate. 125, 126 Cyclisations of this type can also lead to the formation cr3-w b]carbazoles 83 is proposed to involve a diradical intermedi- of quinolines, depending on the nature of the substituents Section 14). Examples of the formation of carbazoles by oxid ative cyclisation of diphenylamines 27 and from pentacarbo es and fused analogues hromium carbene complexes have also been reported 3-Substituted 5-aminoisoxazoles have been produced from oximes of a-haloketones and isocyanides(Scheme 42):trans- 6 Oxazoles thiazoles and benzothiazoles ient vinylnitroso compounds are probably intermediates. A A synthesis of 5-amino-4-cyanooxazoles with a functionalised synthesis of trisubstituted isoxazoles from aromatic aldehydes side chain at C-2 has been described; the procedure is simple and nitroethane or nitropr (Scheme 43) requires the and uses aminomalononitrile toluene-p-sulfonate, a carboxylic incorporation of two moles of the nitroalkane in the product acid and dCC in pyridine(Scheme 39). 2-Substituted 5-ary oxazoles are produced in good yield by the oxidation of yl methyl ketones and trifluoromethanesulfonic acid in an base RNI hatic nitrile( Scheme 40). Both thallium(u) acetate 0 and iodosylbenzene diacetate 31 have been used as oxidants. The o40-9 mechanism probably involves formation and cyclisation of a nitrilium salt. In a simple synthesis of 2-substituted 4-phenyl Scheme 4 oxazoles, phenacyl carboxylates were heated with acetamide and boron trifluoride-diethyl ether at about 140C. The N-acetylimines 84 are formed as intermediates. 132 N-Acyl- isoxazolones 85 lose carbon dioxide on flash pyrolysis or on photolysis to give trisubstituted oxazoles 86. 53.When N-thio- Scheme 43 A simple route to 3, 5-disubstituted isoxazole-4-carb aldehydes, and also to the corresponding pyrazoles, depend upon the clean reduction of ketene dithioacetals with zinc and acetic acid. For example, the dithioacetal 87 was reduced to the diketone 88 from which J. Chem. Soc. Perkin Trans I. 1999. 2849-2866 2857

J. Chem. Soc., Perkin Trans. 1, 1999, 2849–2866 2857 synthesis of 3-nitroindoles is based on the construction of the six-membered ring from a 3-nitropyrrole intermediate.122 One of the standard synthetic methods for indolizines is the reaction of activated alkenes or alkynes with pyridinium ylides. This method has been used to prepare some new 1-trifluoro￾methylindolizines from 2-bromo-3,3,3-trifluoropropene.123 Methods of synthesis that start from pyrroles are much less common. A method involving (stepwise) cycloaddition of rad￾ical cations such as 80 to β-acceptor substituted enamines has been described. The cations were generated by electrochemical oxidation of the corresponding pyrroles and the final products were indolizines such as 81 (X = CN, CO2Me, etc.).124 The thermal ring closure of N-arylketenimines 82 to benzo- [b]carbazoles 83 is proposed to involve a diradical intermedi￾ate.125,126 Cyclisations of this type can also lead to the formation of quinolines, depending on the nature of the substituents (Section 14). Examples of the formation of carbazoles by oxid￾ative cyclisation of diphenylamines 127 and from pentacarbonyl￾chromium carbene complexes 128 have also been reported. 6 Oxazoles, thiazoles and benzothiazoles A synthesis of 5-amino-4-cyanooxazoles with a functionalised side chain at C-2 has been described; the procedure is simple and uses aminomalononitrile toluene-p-sulfonate, a carboxylic acid and DCC in pyridine (Scheme 39).129 2-Substituted 5-aryl￾oxazoles are produced in good yield by the oxidation of aryl methyl ketones and trifluoromethanesulfonic acid in an aliphatic nitrile (Scheme 40). Both thallium() acetate 130 and iodosylbenzene diacetate 131 have been used as oxidants. The mechanism probably involves formation and cyclisation of a nitrilium salt. In a simple synthesis of 2-substituted 4-phenyl￾oxazoles, phenacyl carboxylates were heated with acetamide and boron trifluoride–diethyl ether at about 140
C. The N-acetylimines 84 are formed as intermediates.132 N-Acyl￾isoxazolones 85 lose carbon dioxide on flash pyrolysis or on photolysis to give trisubstituted oxazoles 86. 133,134 When N-thio￾acylisoxazoles are used instead, they give thiazoles in an analo￾gous manner.135 5-Arylisoxazole-4-carbaldehydes have been isolated in moderate yield from the reaction of aryl 2-azido￾methyl ketones with the Vilsmeier reagent at 80–90
C.136 A full paper has appeared on the insertion of rhodium carbenoids derived from diazocarbonyl compounds into the N–H bonds of amides.137 This leads to dihydrooxazoles, which were oxidised by the use of triphenylphosphine, iodine and tri￾ethylamine, a method first described by Wipf. A comparative study of methods for the oxidation of 4,5-dihydrooxazoles to oxazoles has also been published.138 A solid phase adaptation of the Hantzsch synthesis of 2-aminothiazoles has been achieved.139 The solution synthesis of N-substituted 2-aminothiazoles from α-haloketones, potas￾sium thiocyanate and a primary amine has been simplified to an efficient one pot procedure.140 Several N-substituted 2-amino￾thiazoles have also been prepared from N-thiocarbamoyl￾imidates and activated haloalkanes.141 2-Cyanobenzothiazoles are formed by the sequence shown in Scheme 41. The second reaction step can be carried out by conventional heating, or, more efficiently, by microwave irradi￾ation.142 7 Isoxazoles, isothiazoles and fused analogues 3-Substituted 5-aminoisoxazoles have been produced from oximes of α-haloketones and isocyanides (Scheme 42); trans￾ient vinylnitroso compounds are probably intermediates.143 A synthesis of trisubstituted isoxazoles from aromatic aldehydes and nitroethane or nitropropane (Scheme 43) requires the incorporation of two moles of the nitroalkane in the product.144 A simple route to 3,5-disubstituted isoxazole-4-carb￾aldehydes, and also to the corresponding pyrazoles, depends upon the clean reduction of ketene dithioacetals with zinc and acetic acid. For example, the dithioacetal 87 was reduced to the diketone 88, from which 3,5-dimethylisoxazole-4-carbaldehyde Scheme 39 Scheme 40 Scheme 41 Scheme 42 Scheme 43

NR 2(R=H)(Route 1) was formed by conventional with hydroxylamine and deprotection.'A route to metrically 3, 5-disubsti- tuted isoxazoles, outlined in Sc of regiocontrol inherent in reactions of 1, 3-diketones with HR2 Scheme 45 Anthranils can be prepared by dehydration of 2-nitrobenzyl erivatives and this method has been used as a route to the sulfones 90 from the readily available nitro compounds 89 MNR2 CH2l2 Zn-Cu 3-Alkylaminoanthranils have been obtained by cyclisation of the nitrobenzylphosphonates 91.48 SMe MesH NHR Scheme 46 SOpH P(O)OEth2 isocyanide(TosMiC) to N-tosyl- or N-(dimethylsulfamoyl)- aldimines 97. 5 The N-substituent is easily removed from the imidazoles, either spontaneously or by reaction with aqueous HBr. Tetrasubstituted imidazoles 99 have been prepared by NR2 heating the amides 98 with ammonium trifluoroacetate. The reaction of methyl isothiocyanate with LDA can take different courses that are dependent on the reaction conditions(Scheme 47). The thiazole 100 is isolated after methylation of the reac- tion mixture with dimethyl sulfate, but the imidazole 101 is 93 obtained if the reaction mixture is quenched with water before methylation. 57 Further experimental and mechanistic details have appeared of the unusual conversion of 2, 5-diarylfurans into 3, 5-disubsti tuted isothiazoles which was described in the report. 49, 150 The dithiazole 92, which is easily prepared from Appels salt and malononitrile, has been converted in high yield into the isothiazole 93 by heating with benzyltriethyl- ammonium chloride.s3-Dialkylamino-1, 2-benzisothiazoles 95 are formed in excellent yields from the disulfide 94 by nucleo- philic addition of the amide r,NMg Br to the nitrile followed by oxidative cyclisation with copper()chloride. 5I 2MeN·=s 8 midazoles and benzimidazoles MeHN SMe A compilation of methods of synthesis of imidazoles and benz- nidazoles is available. 52 Several new routes to tri-and tetrasubstituted imidazoles are based on the cyclisation of amino( thiocarbonyl)amidines and related species. Two of these routes are outlined in Scheme 45. 3 Oxidative cyclisation followed by treatment with base 5% es N (Route I)resulted in the extrusion of sulfur, probably by way of the thiadiazine shown. alternatively the imidazole could be formed by S-methylation followed by the elimination of methanethiol ( Route 2). This second route is related mech Scheme 47 nistically to a different synthesis of imidazoles of this type which is shown in Scheme 46. In this synthesis the carbenoid attacks the nitrogen and the reaction then follows the same described that is a refinement of a method first published 80 course as in Route 2 above years ago by Pellizzari. Arylhydrazines were converted by suc- In a new application of their isocyanide methodology, van cessive cyanation and acylation into the hydrazides 102 monosubstituted imidazoles by the addition of tosylmethyl ether at 190C. This method was earlier shown to go by 2858 Chem. Soc. Perkin Trans. I.1999. 2849-2866

2858 J. Chem. Soc., Perkin Trans. 1, 1999, 2849–2866 was formed by conventional reaction with hydroxylamine and deprotection.145 A route to unsymmetrically 3,5-disubsti￾tuted isoxazoles, outlined in Scheme 44, avoids the problems of regiocontrol inherent in reactions of 1,3-diketones with hydroxylamine.146 Anthranils can be prepared by dehydration of 2-nitrobenzyl derivatives and this method has been used as a route to the sulfones 90 from the readily available nitro compounds 89. 147 3-Alkylaminoanthranils have been obtained by cyclisation of the nitrobenzylphosphonates 91. 148 Further experimental and mechanistic details have appeared of the unusual conversion of 2,5-diarylfurans into 3,5-disubsti￾tuted isothiazoles which was described in the previous report.149,150 The dithiazole 92, which is easily prepared from Appel’s salt and malononitrile, has been converted in high yield into the isothiazole 93 by heating with benzyltriethyl￾ammonium chloride.45 3-Dialkylamino-1,2-benzisothiazoles 95 are formed in excellent yields from the disulfide 94 by nucleo￾philic addition of the amide R2NMgBr to the nitrile followed by oxidative cyclisation with copper() chloride.151 8 Imidazoles and benzimidazoles A compilation of methods of synthesis of imidazoles and benz￾imidazoles is available.152 Several new routes to tri- and tetrasubstituted imidazoles are based on the cyclisation of amino(thiocarbonyl)amidines 96 and related species. Two of these routes are outlined in Scheme 45.153 Oxidative cyclisation followed by treatment with base (Route 1) resulted in the extrusion of sulfur, probably by way of the thiadiazine shown. Alternatively the imidazole could be formed by S-methylation followed by the elimination of methanethiol (Route 2). This second route is related mech￾anistically to a different synthesis of imidazoles of this type which is shown in Scheme 46.154 In this synthesis the carbenoid attacks the nitrogen and the reaction then follows the same course as in Route 2 above. In a new application of their isocyanide methodology, van Leusen and his co-workers have prepared a series of 4(5)- monosubstituted imidazoles by the addition of tosylmethyl Scheme 44 isocyanide (TosMIC) to N-tosyl- or N-(dimethylsulfamoyl)- aldimines 97. 155 The N-substituent is easily removed from the imidazoles, either spontaneously or by reaction with aqueous HBr. Tetrasubstituted imidazoles 99 have been prepared by heating the amides 98 with ammonium trifluoroacetate.156 The reaction of methyl isothiocyanate with LDA can take different courses that are dependent on the reaction conditions (Scheme 47). The thiazole 100 is isolated after methylation of the reac￾tion mixture with dimethyl sulfate, but the imidazole 101 is obtained if the reaction mixture is quenched with water before methylation.157 A new synthesis of 2-acylaminobenzimidazoles has been described that is a refinement of a method first published 80 years ago by Pellizzari. Arylhydrazines were converted by suc￾cessive cyanation and acylation into the hydrazides 102. These rearranged cleanly to benzimidazoles when heated in diphenyl ether at 190
C.158 This method was earlier shown to go by way Scheme 45 Scheme 46 Scheme 47