Nickel‐Catalyzed Umpolung Difluoroalkylation of Imines Enables General Access to β‐Difluoroalkylated Amines

Abstract Fluoroalkylated amines play a pivotal role in medicinal chemistry, yet the general and efficient synthesis of β‐difluoroalkylated amines remains elusive. Here, we developed a nickel‐catalyzed umpolung strategy that enables the difluoroalkylation of 2‐azaallyl anions generated from aliphatic and aromatic imines, effectively overcoming the previous limitations. By inverting the polarity of imines, this strategy allows for the coupling of a variety of readily accessible difluoroalkyl bromides and iodides. This approach is characterized by its high efficiency, broad substrate scope, high functional group tolerance, and ease of synthesis. The rapid modification of bioactive molecules by the efficient synthesis of difluorinated analogs of key amine moieties present in bioactive molecules, including amphetamine, using the current approach shows the promising potential of this protocol in advancing drug discovery and development.