Continuous-Flow Synthesis of Perfluoroalkyl Ketones via Perfluoroalkylation of Esters Using HFC-23 and HFC-125 under a KHMDS–Triglyme System

Abstract

Hydrofluorocarbons (HFCs) are widely used as cooling agents in refrigerators and air conditioners and as solvents in industrial processes. However, their application has been restricted by their high global warming potential. Thus, strategies for HFC decomposition and effective utilization are urgently required. Herein, we describe a method for the chemical transformation of two HFCs, viz. HFC-23 and HFC-125, based on the continuous-flow perfluoroalkylation of esters to synthesize the pharmaceutically and agrochemically vital trifluoromethyl and pentafluoroethyl ketones. The combination of a potassium base and a glyme solvent system is found to be the most effective. The proposed method is attractive for industrial use because it allows the consumption of a large volume of HFCs, promotes the synthesis of high-value medicinal compounds, and serves as an ideal alternative to the current HFC decomposition processes like thermal plasma treatment.

Current State of Microflow Trifluoromethylation Reactions

“…reported the synthesis of pentafluoroethyl ketones by the microflow pentafluoroethylation of methyl esters with HFC‐125 using the same flow system as in the case of microflow trifluoromethylation with HFC‐23 (Figure 40). [46] The optimal microflow reaction conditions for HFC‐23 afforded low yields of pentafluoroethylated products; however, the reaction temperature was found to have a significant effect on the transformation, and yields were considerably improved under low‐temperature conditions. The choice of solvent is another critical factor, with a combination of THF and triglyme being ideal for this reaction.…”

“…In 2022, the same group reported the continuous synthesis of trifluoromethyl ketones via the microflow trifluoromethylation of methyl esters using HCF 3 with the same flow devices (Figure 31). [46] Triglyme solutions of the substrates and KHMDS, along with gaseous HFC‐23, were mixed under optimized flow reaction conditions at room temperature, and the corresponding trifluoromethyl ketones were obtained in good yields. Substrates with aromatic groups containing electron‐withdrawing groups or halogens produced mixtures of hydrated form, which was separated by column chromatography.…”

“…Most pentafluoroethylation reactions were developed by adapting batch trifluoromethylation procedures using pentafluoroethyl halides (C 2 F 5 X), [54] R 3 Si−C 2 F 5 , [55] M−C 2 F 5 , [56] and HC 2 F 5 [57] . Conversely, relatively few flow pentafluoroethylation reactions are known [46,57b,58–59] …”

Reactions Using Freons and Halothane as Halofluoroalkyl/Halofluoroalkenyl Building Blocks

“…The KHMDS–triglyme system described by Shibata et al. is noteworthy in terms of its applicability to both flow chemistry and industry [104] …”

“…The KHMDS-triglyme system described by Shibata et al is noteworthy in terms of its applicability to both flow chemistry and industry. [104] Vugts et al prepared the [ 18 F]-CF 3 H reagent 55 from difluoroiodomethane for use in positron emission tomography and added the [ 18 F]-CF 3 group to aldehydes and ketones (Scheme 12). [105] The reaction gave 99 % radiochemical conversion, and is expected to use practically in medical treatments.…”