Synthesis of 6-azaindoles via electrophilic [4+1]-cyclization of 3-amino-4-methyl pyridines: scope and limitations

A scalable and efficient synthesis of the 2-trifluoromethyl-3-trifluoroacetyl-6-azaindoles from 3-amino-4-methylpyridines under treatment with TFAA was disclosed. The reaction scope and limitation towards the pyridine and electrophilic components were investigated. Examining the pyridine components using trifluoroacetic anhydride (TFAA) as a model electrophile allowed us to divide them into three groups with different impacts on the reaction outcome. Among electrophilic components difluoroacetic anhydride (DFAA), trichloroacetic anhydride (TCAA) and Vilsmeier-Haack reagent (VHR) were inspected. The results superposition led to a cyclization mechanism rationalizing our observations.