The functionalization of compounds with fluorine atoms can be useful for tuning their physicochemical properties, in particular, in medicinal chemistry. Therefore, low-cost, environmentally friendly trifluoromethyl sources, for example, are interesting research targets. Trifluoroacetic acid (TFA) could be useful in this context because is inexpensive, readily available, and produces nontoxic byproducts. However, TFA has a high oxidation potential that can make it challenging to use as a trifluoromethylation reagent.
Yanwei Lum, Jie Wu, National University of Singapore, and colleagues have developed a method for an electrophotochemical, catalyst- and oxidant-free trifluoromethylation of arenes, using TFA as the CF3 source. The team reacted a range of (hetero)arenes with TFA in an undivided electrochemical cell with a graphite anode and a Pt cathode under LED light, using CH3CN as the solvent and n-Bu4NBF4 as the electrolyte. The reactions were performed at room temperature under an argon atmosphere.
The desired trifluoromethylated products were obtained in moderate to good yields. The method could be used for the late-stage functionalization of drug-like molecules. It can also be employed to introduce other perfluoroalkyl groups or difluoromethyl groups, using polyfluoric acids or difluoroacetic acid as reagents, respectively. Overall, the combination of electrochemistry and light allows the use of TFA as a CF3 source in otherwise challenging reactions.
- Electrophotochemical Synthesis Facilitated Trifluoromethylation of Arenes Using Trifluoroacetic Acid,
Jing Qi, Jinhui Xu, Hwee Ting Ang, Bingbing Wang, Nipun Kumar Gupta, Srinivas Reddy Dubbaka, Patrick O’Neill, Xianwen Mao, Yanwei Lum, Jie Wu,
J. Am. Chem. Soc. 2023.