Copper-Mediated −CF(OCF3)(CF2H) Transfer to Organic Electrophiles

The integration of fluorine into medicinal compounds has become a widely used strategy to improve the biochemical and therapeutic properties of drugs. Inclusion of −CF2H and −OCF3 fluoroalkyl groups has garnered attention due to their bioisosteric properties, enhanced lipophilicity, and potential hydrogen-bonding capability in bioactive substances. In this study, we prepared a series of stable Cu[CF(OCF3)(CF2H)]Ln complexes by insertion of commercially available perfluoro(methyl vinyl ether), CF2═CF(OCF3), into Cu-H bonds derived from Stryker’s reagent, [CuH(PPh3)]6, using ancillary ligands L. Notably, certain of these complexes effectively transfer the fluoroalkyl group to aroyl chlorides. Through reaction optimization and computational analysis, we identified dimethylsulfoxide as a pivotal coligand, playing a distinctive role in enabling the fluoroalkylation of a range of aroyl chlorides and aryl iodides. The latter also benefits from addition of CuBr to abstract PPh3, generating solvent-stabilized Cu[CF(OCF3)(CF2H)]. These methodologies allow for the introduction of geminal −OCF3 and −CF2H groups in a single transformation.