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

Abstract

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.

Flow Chemistry of Metal Carbenoid Species towards Selective Organic Synthesis

“…In 2023, Kim et al reported the reaction of 1 equivalent of CF 3 H with a Schlosser-Lochmann base generated from PhLi and KO t Bu in a flow system (Scheme 18). 26 The originally developed built-in devices for mixing the gaseous and liquid phases has been employed to improve the mixing efficiency, and 1 equivalent of CF 3 H was successfully reacted.…”

Current State of Microflow Trifluoromethylation Reactions

“…The microflow trifluoromethylation of carbonyls using HFC‐23 via the ex‐situ generation of the trifluoromethyl anion in a devised flow dissolver was developed by Kim et al in 2023 (Figure 32). [47] Initially, they found that using a simple tubing flow reactor or a tube‐in‐tube microfluidic reactor was inappropriate for rapid gas‐liquid biphasic mixing and controlling the CF 3 anion. Therefore, a gas‐liquid flow device (GLD) was developed for rapid biphasic mixing and handling of the unstable trifluoromethyl anion.…”