Titanium(IV) chloride promoted syntheses of new imidazo[1,2-a]pyridine derivatives under microwave conditions

A new method is described for the synthesis of imidazo[1,2-a]pyridine derivatives from the reaction of 2-aminopyridines with alpha-haloketones. The critical reagent is titanium(IV) chloride, which appears to serve as a strong dehydrating agent to promote formation of putative Schiff base intermediates, which cyclize subsequently to form the products. The reactions were performed rapidly under microwave conditions. Multiple reaction conditions were evaluated, including reaction temperature, solvent and other Lewis acids. Various combinations of substitution patterns in both the alpha-haloketone and 2-aminopyridine substrates were examined to evaluate the scope of the reaction. The reaction is quite sensitive to substituents in both substrates, especially those with basicity or coordination ability.