Synthesis of 3-formyl-6-azaindoles via Vilsmeier-Haack formylation of 3-amino-4-methyl pyridines

An efficient method for the preparation of 6-azaindoles bearing 3-formyl functionality from commercially available substrates with (ortho-methyl)aminopyridine moiety is described. This transformation features a distinct, though broad, substrate scope, and simple experimental procedure and can easily be scaled up to 40 g of the target formyl derivative. The structural characteristics of pyridine substrates that allow them to be successfully used in the reaction were investigated and discussed. Collected observations were mechanistically rationalized and the proposed mechanism was additionally confirmed by spectroscopic studies. Mechanistic studies clearly reveal the crucial role of the methyl group activation by in situ protonation of in-ring nitrogen atom. Functional group interconversions employing synthesized 3-formyl-6-azaindoles additionally prove this building block utility for MedChem investigations.