Continuous-Flow Difluoromethylation with Chlorodifluoromethane under Biphasic Conditions

Herein, we present the development of a continuous-flow process for a difluoromethylation with difluorocarbene as the reactive reagent. The difluoromethylated product is a key intermediate during the synthesis of eflornithine, a pharmaceutical that is on the World Health Organization's Model List of Essential Medicines. The developed procedure uses inexpensive and commercially available chlorodifluoromethane (CHF2Cl, Freon 22) as difluorocarbene source. Deprotonation of CHF2Cl with NaOH in a biphasic mixture of organic solvent-water generates the carbene. A fast subsequent reaction of the difluorocarbene with the substrate generates the desired product with excellent selectivity.