1. An Efficient and Regioselective Difluoromethylation of 3-Iodoindazole with Chlorodifluoromethane
- Author
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Matthew James Pelc, John I. Trujillo, Wei Huang, Atli Thorarensen, John Baldus, Pete Kleine, Shengtian Yang, and Steve R. Turner
- Subjects
chemistry.chemical_compound ,Indazole ,Chemistry ,Reagent ,Yield (chemistry) ,Organic Chemistry ,Chlorodifluoromethane ,Regioselectivity ,Organic chemistry ,Acetonitrile ,Combinatorial chemistry ,Stock solution ,Stoichiometry - Abstract
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.
- Published
- 2009