Nickel-Catalyzed Three-Component Difluoroalkylation-Amination for the Direct Access to Anti-Inflammatory β-Difluoroalkyl Amines.

Fluoroalkyl amines represent a promising structural motif in pharmaceutical sciences, but the development of an efficient and practical synthetic method is in urgent need, especially for β-difluoroalkyl amines, in which the concurrent introduction of fluoroalkyl and aminyl groups remains challenging. Here, we report a nickel-catalyzed three-component reductive difluoroalkylation-amination strategy of enamides for the direct access to the α-amidyl-β-difluoroalkyl amines. This strategy utilizes carboamination of alkene with nitrogen electrophiles and fluoroalkyl chlorides to simultaneously forge C─C and C(sp3)-N bond, being compatible with various chlorodifluoroacetamides and nitrogen electrophiles, including amino acid-derived or drug-derived substrates. The synthetic method features with broad substrate scope, mild conditions, high functional group tolerance, and easy handling. Control experiments and DFT calculations are performed to elucidate the mechanism of the reaction, and an SH2 pathway regarding C─N bond-forming step is proposed. More remarkably, the products α-amidyl-β-difluoroalkyl amines exhibit prominent anti-inflammatory activity both in vitro and in vivo, indicating promising applications of this strategy in medicinal chemistry and drug development.