Reductive cyclization Leimgruber-Batcho indole synthesis

A procedure for obtaining indole-3-carboxylate ester from the f-pyrrolidino-o-nitrostyrene intermediates in the Leimgruber-Batcho indole synthesis was demonstrated. Although ethyl chloroformate is evidently not reactive enough, phosgene followed by methanolysis effects f) -carbomethoxylation. Reductive cyclization then gives the indole esters. <95SC95>... 

Garcia et al. has extended the Batcho-Leimgruber procedure to the synthesis of 2-substituted indoles. Treatment of 36 with o-fluorobenzoyl chloride 37, followed by in situ hydrolysis and deformylation gave ketone 38. Reduction of nitroarylketone 38 with sodium hydrosulfite then furnished indole 39. Similarly, bromoacetylation of 36 gave an acylenamine which was converted into the phthalimido derivative 40. Hydrolysis and deformylation gave phthalimidoketone 41 which underwent reductive cyclization to furnish indole 42. 

The widely employed Leimgruber-Batcho protocol for indole synthesis comprises two consecutive steps—the formation of enamines followed by a reductive cyclization. The formation of enamines (such as 14, Scheme 7) presumably required an initial deprotonation of the methyl ortho to the aromatic nitro-group by methoxide generated from DMF-DMA under elevated temperatures (overnight heating in DMF) [27]. The use of microwave irradiation at 180 °C allowed the reduction of the time of formation of enamines such as 14 from 22 h (at 110°C) to 4.5 h (and even to 40 min in several... 

A few type la reductive cycUzations leading to indoles have been reported. A palladium (II) trifluoroacetate catalyst was effective in the reductive cyclization of orfho-nitrostyrenes to 2-substituted indoles <05T6425>. The Batcho-Leimgruber indole synthesis, the reductive cyclization of p-amino-2-nitrostyrenes, was utilized in a synthesis of 5-formylindole <05JHC137>. A partial reduction of a nitroarene provided a route to iV-hydroxyindoles <05AG(E)3736>. Treatment of nitro ketoester 90 with tin chloride in the presence of a primary alcohol nucleophile provided Al-hydroxyindole 93 via hydroxylamine intermediate 91. 

The indole nucleus is present in various bioactive molecules and many selective protocols for its construction have been developed. Classical methods for the indole synthesis include the Fischer indole synthesis, the Batcho-Leimgruber synthesis from o-nitrotoluenes and dimethylformamide acetals, the Gassman synthesis from N-haloanilines, the reductive cyclization of o-nitrobenzyl ketones, and the Madelung cyclization of A/ -acyl-o-toluidines [42,43]. 

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