An efficient method for the direct C(sp)–H difluoromethylation of terminal alkynes and their further use in the preparation of difluoromethylated heterocycles is disclosed. The copper-catalyzed transformation provides access to a wide range of CF<sub>2</sub>H-alkynes in very good yields, utilizing a (difluoromethyl)zinc reagent. The synthetic utility of these alkynes is further demonstrated by preparing an array of difluoromethyl-containing pyrazoles and triazoles via [3+2] cycloaddition reactions. Similarly, the tandem difluoromethylation/intramolecular cyclization of substituted 2-ethynylanilines provides selective access to 2-CF<sub>2</sub>H indoles. Further demonstration of the method’s applicability is achieved by the total synthesis of a difluoromethyl analogue of the NSAID Indomethacin.

Copper-catalyzed synthesis of (difluoromethyl)alkynes and their applications in intramolecular cyclization and [3+2] cycloaddition reactions for the preparation of CF2H-Heterocycles

ACS Spring 2022

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