Organocatalyzed Decarboxylative Trifluoromethylation of β-Ketoacids

Abstract

A new protocol has been developed for the synthesis of α-trifluoromethyl ketones via organocatalyzed decarboxylative trifluoromethylation of β-ketoacids with Togni’s reagent. Among various simple amine catalysts, primary amines and secondary amines were identified to be more effective than tertiary amines, with piperazine being the most effective. Mechanistic investigations suggested that the primary or secondary amine-catalyzed reactions proceed mainly through trifluoromethylation of an enamine intermediate, which is more effective than the tertiary amine-catalyzed pathway that involves an enol intermediate. By using piperazine as the optimal organocatalyst, various β-ketoacids, including the sterically hindered α,α-disubstituted ones, were converted into the corresponding α-trifluoromethyl ketones in good yields. This research not only provides a useful strategy for the efficient synthesis of a wide range of α-trifluoromethyl ketones under mild conditions, but also constitutes one of the few studies on decarboxylative alkylation of β-ketoacids, which can intrigue further exploitation on organocatalyzed asymmetric decarboxylative alkylation reactions.