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

• Published in: Angewandte Chemie 2025-01, Vol.137 (5), p.n/a
• Main Authors: Tong, Fei‐Fei, Luo, Yun‐Cheng, Zhao, Hai‐Yang, Fu, Xia‐Ping, Zhang, Xingang
• Format: Article
• Language: English
• Subjects: Anions; Bromides; Chemical bonds; Chemical reactions; Cross coupling; Decomposition reactions; difluoroalkylation; Drug discovery; Fluorine; Halides; Lithium; Nickel; nickel catalysis; organolithium reagents; Reagents; β,γ-unsaturated α-amino nitriles
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202417858

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. A nickel‐catalyzed difluoroalkylation of β,γ‐unsaturated α‐amino nitrile derived lithium reagents with various difluoroalkyl bromides has been developed. The rapid fluorine‐editing of drugs demonstrates the synthetic versatility and utility of this protocol, showing the perspective in modern drug discovery.