Novel chemistry of nitroindoles and synthetic studies towards pyrrolo[3,4-b]indoles, iheyamines and indolylarylmaleimides

Both 2- and 3-nitroindoles are important building blocks in the synthesis of novel indole-containing heterocycles. Although 3-nitroindoles can be easily prepared by the nitration of N-protected indoles, the synthesis of 2-nitroindoles is difficult. A convenient synthesis of 2-nitroindoles from 2-iodo- or 2-bromoindoles using silver nitrite as the nitrating agent is developed. Direct reduction of 3- and 2-nitroindoles to the corresponding aminoindoles or their derivatives was unknown. A successful reductive acylation strategy was developed in which the 3- and 2-nitroindole can be easily reduced to their corresponding acylaminoindoles by indium and acetic acid in the presence of the appropriate anhydride. An improved high-yielding version of this reductive acylation, without using acetic acid, is also developed by one-pot hydrogenation followed by protection of amines. A new synthesis of 3-pyrroloindoles is realized using this strategy.;Nucleophilic amination of 2-iodo-3-nitroindoles was also investigated. The reaction of 2-iodo-3-nitro-1-(phenylsulfonyl)indole with amines affords the corresponding 2-amino-3-nitroindoles in excellent yields via a nucleophilic aromatic substitution.;The normal electron-rich behavior of the indole is reversed by the incorporation of electron-withdrawing nitro groups at the indole C2 and C3 positions. The 1,3-dipolar cycloaddition of unstabilized azomethine ylides with 2- and 3-nitroindoles furnishes the expected hexahydropyrrolo[3,4-b]indole cycloadducts in good to excellent yields. The cycloadduct can be denitrated and subsequently oxidized to a pyrrolo[3,4-b]indole.;Several attempts to the novel anti-tumor bisindole alkaloid iheyamine are made. A new route for the synthesis of indolopyrrolocarbazole is realized starting from 2,2'-biindole which might be optimized further for higher yields. Along this line, a convenient method for the synthesis of indolylarylmaleimides is also reported.