Synthesis of 6-azaindoles via formal electrophilic [4 + 1]-cyclization of 3-amino-4-methyl pyridines: new frontiers of diversity†
Abstract
A scalable and efficient synthesis of 2-trifluoromethyl-3-trifluoroacetyl-6-azaindoles from 3-amino-4-methylpyridines under treatment with TFAA is disclosed. The reaction scope and limitations of pyridine and electrophilic components were investigated. Activation of the methyl group in aminomethylpyridines under mildly acidic conditions appeared promising for significantly expanding the scope of principally novel substrates. 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 the electrophilic components, difluoroacetic anhydride (DFAA), trichloroacetic anhydride (TCAA) and Vilsmeier–Haack reagent (VHR) were inspected. Combining the results led to a cyclization mechanism rationalizing our observations.