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 synthesis, 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 isocyanoacetates 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 precursor 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 preparation 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-nitroindole.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 interScheme 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-ethynyltrifluoroacetanilide 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 syntheses 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-nitrostyrenes 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-nitrostyrene 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 corresponding benzofuran and benzothiophene.33 Although limited in scope, the radical cyclisation process shown in Scheme 33 represents an unusual method for the construction 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 hydroformylation 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