New synthetic approaches for the construction of difluoromethylated architectures

Fluorinated compounds play a vital role in the fields of agrochemicals, pharmaceuticals, and materials science because of their unique lipophilicity, permeability, and metabolic stability. Among all such appealing fluorine-containing functional groups, the difluoromethyl group has attracted considerable attention owing to its outstanding chemical and physical properties. It has been used as a lipophilic hydrogen bond donor and a bioisostere of thiol, hydroxy, or amino groups. The excellent properties of the CF₂H group have motivated many chemists to develop effective strategies for the selective incorporation of the CF₂H group into target molecules. Over the past decades, a variety of efficient, atom-economical, and facile methods have been discovered for the difluoromethylation of organic substrates. This review summarizes the developments in different types of difluoromethylations, which could be classified into the following categories: radical difluoromethylation, transition metal-catalyzed difluoromethylation, and nucleophilic and electrophilic difluoromethylation.