Study on the mild, rapid and selective difluorocarbene-mediated triclassification of iododifluoroacetophenone with secondary amines and tree model for product classification

Difluorocarbene is a very active and widely used intermediate in organic synthesis. In this work, a room temperature difluorocarbene-mediated triclassification reaction of iododifluoroacetophenone (2) and secondary amines with mild condition, short reaction time (only 10 min) and high selectivity had been studied, which produced one of the following three substances: N-CF2H derivatives (up to 87% yield), formamides (82–89% yield) or the recycled starting secondary amines. This phenomenon was related to the structural stability of the corresponding products. If unstable, it would be hydrolyzed to formamides first, and then further hydrolyzed to starting amines. Based on the geometric structure of the raw materials, the corresponding prediction tree model was established, which provided guidance for the further application of difluoromethylation of Vemurafenib (1ee) and AZD9291 (1ff). [Display omitted] •A mild, rapid and selective difluorocarbene-mediated triclassification of iododifluoroacetophenone was developed.•The corresponding prediction tree model was based on the geometry structure of raw materials.•This triclassification reaction and tree model were used to implement the late stage modification of medicinal drugs.