Nickel-Catalyzed Difluoroalkylation of β,γ-Unsaturated α-Amino Nitrile Derived Lithium Reagents

Organolithium reagents, known for their low cost, ready availability, and high reactivity, allow fast cross-coupling under ambient conditions. However, their direct cross-coupling with fluoroalkyl electrophiles remains a formidable challenge due to the easy formation of thermo-unstable fluoroalkyl lithium species during the reaction, which are prone to decomposition via rapid α/β-fluoride elimination. Here, we exploit heteroatom-stabilized allylic anions to harness the exceptional reactivity of organolithium reagents, enabling the compatibility of difluoroalkyl halides and facilitating versatile and precise fluorine functionality introduction under mild conditions. In this process, a nickel-catalyzed difluoroalkylation of β,γ-unsaturated α-amino nitrile derived lithium reagents (N-stabilized allyl lithium reagents) with various difluoroalkyl bromides has been developed, opening a new avenue to access fluorinated compounds through catalytic cross-coupling of organolithium reagents with fluoroalkyl electrophiles. This approach allows for the efficient and precise construction of secondary C(sp³)-CF₂R bonds, previously challenging in transition-metal-catalyzed fluoroalkylation reactions due to β-hydride elimination. The rapid fluorine-editing of drugs demonstrates the synthetic versatility and utility of this protocol, showing the perspective in modern drug discovery.