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

Fluoroform (CF₃H) is the simplest reagent for nucleophilic trifluoromethylation intermediated by trifluoromethyl anion (CF₃^-). However, it has been well-known that CF₃^- 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 CF₃^- 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 CF₃H 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 CF₃^-, extending to the multi-gram-scale synthesis of valuable compounds by 1-hour operation of the integrated flow system.