Wan Yanjun, Shao Ronghui, Norton Jack R
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China.
Department of Chemistry, Columbia University, 3000 Broadway, New York, NY, 10027, USA.
Adv Sci (Weinh). 2025 Jul;12(26):e2501799. doi: 10.1002/advs.202501799. Epub 2025 Apr 25.
The introduction of F-containing groups into organic molecules can significantly alter their physical and chemical properties. Particularly, gem-difluoroalkenes serve as versatile precursors for a broad variety of organofluorine compounds, commonly used in agrochemicals, pharmaceuticals, and materials science. Based on the kinetics of H• transfer to acrylamide (k = 2.28 × 10 M s at 300 K in toluene), the study describes a nickel-hydride-(or Li[BEtH]) initiated hydrocyclization/defluorination of CF-substituted acrylamides, offering alternative access to 4-fluorovinyl-substituted 2-pyrrolidones (Seletracetam derivatives that are antiepileptic drug candidates). This process proceeds with high yields and remarkable chemo- and regioselectivity. The hydrocyclization/defluorination can be initiated by either H• or H transfer, followed by a 5-exo-trig cyclization and subsequent fluorine elimination. The strategy has been applied in the late-stage functionalization of drug molecules, providing a valuable tool in the synthesis of pharmaceutical compounds.
将含氟基团引入有机分子可显著改变其物理和化学性质。特别是偕二氟烯烃，作为多种有机氟化合物的通用前体，常用于农用化学品、药物和材料科学领域。基于氢原子转移至丙烯酰胺的动力学（在300 K的甲苯中k = 2.28 × 10 M s），该研究描述了一种由氢化镍 - （或Li[BEtH]）引发的CF - 取代丙烯酰胺的氢环化/脱氟反应，为获得4 - 氟乙烯基取代的2 - 吡咯烷酮（作为抗癫痫药物候选物的司来西坦衍生物）提供了另一种途径。该过程以高产率以及显著的化学和区域选择性进行。氢环化/脱氟反应可由氢原子或氢转移引发，随后进行5 - 外向 - 三角环化和随后的氟消除。该策略已应用于药物分子的后期官能团化，为药物化合物的合成提供了一种有价值的工具。
