The continuous flow synthesis of 2,4,5-trifluorobenzoic acid via sequential Grignard exchange and carboxylation reactions using microreactors

Abstract

2,4,5-Trifluorobenzoic acid is a valuable synthetic intermediate with important application in pharmaceutical industry and material science. In this paper, we report a facile continuous microflow process for the synthesis of 2,4,5-trifluorobenzoic acid via the generation of an unstable aryl-Grignard reagent followed by its reaction with gaseous CO2. The microflow system is easily assembled by a simple T-micromixer, a commercial available falling film microreactor, tube microreactor and several pumps. The use of a composed T-micromixer and tube microreactor facilitates the Grignard exchange reaction of 2,4,5-trifluorobromobenzene with ethylmagnesium bromide producing 2,4,5-trifluorophenylmagnesium bromide almost in quantitative yield, and the use of the falling film microreactor enables a highly efficient gas–liquid reaction of the resultant Grignard reagent with CO2 under an atmosphere pressure, which ultimately gave the product 2,4,5-trifluorobenzoic acid in high yield with high purity after a simple and extractive workup. The influence of reaction parameters on the two steps in microreactors was discussed.