A Convenient Reductive Cyclisation of 2-Nitro-b-nitrostyrenes to Indoles

Abstract

A simple synthesis of a variety of 2.3-unsubstituted indoles containing akoxy and acetoxy groups has been developed. This method involves the reductive cyclisation of 2,pduutrostyrenes with ammonium formate in the presence of a catalytic amount of PdIC in refluxing methanol, and affords indoles in good to excellent yields.There is ongoing interest in the development of new and improved methods for the synthesis of the indole nucleus due to the biochemical and pharmacological importance of many of its derivatives.' One convenient method is the reductive cycliisation of 2,witrostyrenes using irodacetic acid or catalytic hydrogenation.2 (The 2,Pdinitrostyrenes are easily obtained in high yields from readily available o-nitrobenzaldehydes. These reductive cyclisations, however, are neither clean nor high yielding. Conventional catalytic hydrogenation has resulted in poor yields and has only sparsely been used. 3'4 The earliest method developed and the one most widely used is irodacetic acid reduction, but the procedures have given poor yields (15 -55%)2 and involved cumbersome workups. Recently, an improved hodacetic acid reduction protocol using silica gel has been reported, but this does not improve the yields greatly, and only moderately simplifies the workup. For this reason, we have proceeded to develop a better cyclisation technique, as exemplif~d for the conversion of 2,Pdinitrostyrenes (1 -8) to indoles (9 -16). The Pdinitrostyrenes were obtained by the facile condensation of substituted o-nitrobenzaldehydes with nitromethane in refluxing ammonium acetate~methanol.~ We found that a variety of indoles (9 -16) were produced in high yields (58-82%) when 2,!3d1nitrostyrenes were reacted with ammonium formate and formic acid in refluxing methanol in the presence of PcUC (5% by weight). Ammonium formate -PcUC is reported as being a very versatile, selective and rapid method for catalyic hydrogenolysis? In our reaction the products were easily purified and isolated by simple chromatography through silica gel. The results are summarized in Table I. In the case of the benzyloxy substituted nitrostyrene (7), h e expected &benzylation8 occurs and thus the product was acetylated before isolation. Table 1 Ammonium Formate Reductive Cyclisation of 2,P-Dinitrostyrenes to Indoles Ammonium Formate -R3