An Efficient and Regioselective Difluoromethylation of 3-Iodoindazole with Chlorodifluoromethane

A regioselective and efficient procedure for the N-alkylation of 3-iodoindazole with chlorodifluoromethane is described. The reaction was extensively optimized with regard to combinations of base, solvent, addition order as well as stoichiometry. A key reaction parameter was the generation of a 2-M stock solution of the gaseous reagent chlorodifluoromethane in acetonitrile. This allowed control of the quantity of carbene generated in the reaction mixture, providing good N1-regioselectivity between the two reactive indazole nitrogens. Upon optimization of this protocol 1-difluoromethyl-3-iodoindazole was synthesized on a preparative scale providing 14.2 grams of product in 59% yield.