In silico reaction screening with difluorocarbene for N-difluoroalkylative dearomatization of pyridines

Abstract

Quantum chemical calculations are mainly regarded as a method for mechanistic studies in organic chemistry, whereas their use for the simulation of unknown reactions could greatly assist in reaction development. Here we report a strategy for developing multicomponent reactions on the basis of the results of computational reaction simulations. In silico screening of multicomponent reactions with difluorocarbene using the artificial force induced reaction method suggested that cycloadditions between an azomethine ylide and a variety of coupling partners would proceed to generate the corresponding α,α-difluorinated N-heterocyclic compounds. The predicted reaction was successfully realized experimentally, leading to a multicomponent N-difluoroalkylative dearomatization of pyridines involving a pyridinium ylide-mediated 1,3-dipolar cycloaddition with a diverse range of electrophiles such as aldehydes, ketones, imines, alkenes and alkynes. Moreover, the performance of the cycloaddition could be explained by comparing the energy barrier of the desired pathway with that of the competitive undesired pathway, which was also identified by the artificial force induced reaction search.