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 2855J. 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