Ex-situ generation and synthetic utilization of bare trifluoromethyl anion in flow via rapid biphasic mixing

Fluoroform (CF(3)H) is the simplest reagent for nucleophilic trifluoromethylation intermediated by trifluoromethyl anion (CF(3)(–)). However, it has been well-known that CF(3)(–) should be generated in presence of a stabilizer or reaction partner (in-situ method) due to its short lifetime, which results in the fundamental limitation on its synthetic utilization. We herein report a bare CF(3)(–) can be ex-situ generated and directly used for the synthesis of diverse trifluoromethylated compounds in a devised flow dissolver for rapid biphasic mixing of gaseous CF(3)H and liquid reagents that was designed and structurally optimized by computational fluid dynamics (CFD). In flow, various substrates including multi-functional compounds were chemoselectively reacted with CF(3)(–), extending to the multi-gram-scale synthesis of valuable compounds by 1-hour operation of the integrated flow system.