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.

中文翻译：

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镍催化的 β，γ-不饱和 α-氨基腈衍生锂试剂的二氟烷基化反应


有机锂试剂以其低成本、易用性和高反应性而闻名，可在环境条件下实现快速交叉偶联。然而，由于在反应过程中容易形成热不稳定的氟烷基锂种类，它们与氟烷基亲电试剂的直接交叉偶联仍然是一个艰巨的挑战，这些物质很容易通过快速α/β 氟化物消除而分解。在这里，我们利用杂原子稳定的烯丙基阴离子来利用有机锂试剂的特殊反应性，实现二氟烷基卤化物的相容性，并促进在温和条件下引入多功能和精确的氟功能。在该工艺中，已经开发了 β，γ-不饱和 α-氨基腈衍生锂试剂（N-稳定烯丙基锂试剂）与各种二氟烷基溴化物的镍催化二氟烷基化反应，为通过有机锂试剂与氟烷基亲电试剂的催化交叉偶联获得氟化化合物开辟了一条新途径。这种方法允许高效、精确地构建次级 C（sp3）-CF2R 键，这在以前由于β氢消除而在过渡金属催化的氟烷基化反应中具有挑战性。药物的快速氟编辑证明了该方案的合成多功能性和实用性，展示了现代药物发现的前景。