Efficient N-Trifluoromethylation of Amines with Carbon Disulfide and Silver Fluoride as Reagents

Abstract

The installation of a trifluoromethyl group onto a nitrogen atom can effectively modulate the basicity of amines owing to the strong electron-withdrawing effect of fluorine. Nevertheless, efficient and operationally simple methods for N-trifluoromethylation of amines are yet to be developed. This protocol involves the use of readily available secondary amines as starting materials, along with CS₂ and AgF as the N-trifluoromethylation reagents, enabling the target molecules to be synthesized in a single step. The versatility of our method was demonstrated by successfully synthesizing N,N-dialkyl and N-(hetero)aromatic N-CF₃-containing compounds with various substituents. Moreover, this methodology has been successfully applied to the late-stage modification of complex bioactive molecules, facilitating the synthesis of N-CF₃ drug bioisosteres and N-CF₃-tailored amino acids, which would broadly stimulate the drug discovery of N-CF₃ containing molecules.