AgI-Catalyzed Cascade Strategy: Regioselective Access to Diversely Substituted Fused Benzimidazo[2,1-a]isoquinolines, Naphthyridines, Thienopyridines, and Quinoxalines in Water

An environmentally benign and operationally simple one-pot approach to the regioselective tandem synthesis of diversely substituted fused benzimidazo[2,1-a]isoquinolines, naphthyridines, thienopyridines, and quinoxalines from o-alkynylaldehydes and arylamines with tethered nucleophiles using AgI as catalyst in water is described. The reaction showed selective NC bond formation on the more electrophilic alkynyl carbon, resulting in the regioselective 6-endo-dig cyclized products in good to excellent yields. The proposed mechanistic pathway for the synthesis of fused heterocycles proceeding through formation of ring A prior to ring B, which formed through a second intramolecular attack of the nitrogen onto the alkynyl carbon, was supported by mechanistic experiments and X-ray crystallographic studies of isolated intermediate U and cyclized product 5a. Comparative experiments showed the viability of intramolecular nucleophilic attack over intermolecular attack of an external nucleophile. This catalytic, green protocol has been efficiently applied for the bis-tandem cyclization in water.