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 construction of aromatic heterocycles from acyclic precursors or by ring interconversion. The coverage cannot be comprehensive because of pressure of space. Many useful applications of existing 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 interesting 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 trialkylstannylacetylenes to provide routes to 3,4-disubstituted furans, thiophenes 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 nucleophiles undergo addition to alkynes. The intramolecular addition 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 limitations 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 cyclisation 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 described 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 synthesise a variety of heterocycles, has now been applied to furan synthesis. For example, the tetrahydrobenzofuran 8 was produced (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-phenylthioprop-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 potentially 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 proposed that this generates acylmethyl radicals as the reactive intermediates (Scheme 7).22 Cyclisation reactions involving palladium catalysis are predominant 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 palladium(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 salicylaldehyde 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)benzofuran 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 reaction 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 described; 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 benzofurans are illustrated in Scheme 10 33 and in Scheme 11.34 The base induced fragmentation of 1,2,3-thiadiazoles is a precedented 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-alkylaminothiophenes bearing dialkylamino substituents at C-5 36 and heteroatom 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 synthesis of 3,4-bis(trimethylsilyl)thiophene by the high temperature 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 preparation of other heterocycles. Marson and Campbell have applied a synthesis of furans, based on the ring expansion of functionalised 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 synthesis 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 cyclisation.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]thiophene 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 condensation 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 synthesise 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-arylpyrrole-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)nitroalkenes.62 The aza-Wittig reaction of azido ketones 42 has been previously 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 nitroalkanes 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-(alkylthio)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