Ghaffari Behnaz, L T N Porto Luana, Johnson Nicole, Ovens Jeffrey S, Ehm Christian, Baker R Tom
Department of Chemistry and Biomolecular Sciences and Centre for Catalysis Research and Innovation, University of Ottawa, 30 Marie Curie, Ottawa, Ontario K1N 6N5, Canada.
Faculty of Science, University of Ottawa, 150 Louis Pasteur Pvt., Ottawa, Ontario K1N 6N5, Canada.
ACS Org Inorg Au. 2024 Sep 20;4(6):628-639. doi: 10.1021/acsorginorgau.4c00038. eCollection 2024 Dec 4.
The integration of fluorine into medicinal compounds has become a widely used strategy to improve the biochemical and therapeutic properties of drugs. Inclusion of -CFH and -OCF 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(OCF)(CFH)]L complexes by insertion of commercially available perfluoro(methyl vinyl ether), CF=CF(OCF), into Cu-H bonds derived from Stryker's reagent, [CuH(PPh)], 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 PPh, generating solvent-stabilized Cu[CF(OCF)(CFH)]. These methodologies allow for the introduction of geminal -OCF and -CFH groups in a single transformation.
将氟引入药用化合物已成为一种广泛应用的策略，用于改善药物的生化和治疗特性。由于其生物电子等排体性质、增强的亲脂性以及在生物活性物质中的潜在氢键能力，包含 -CFH 和 -OCF 氟烷基基团受到了关注。在本研究中，我们通过将市售的全氟（甲基乙烯基醚）CF₂=CF(OCF₃) 插入源自斯特雷克试剂 [CuH(PPh₃)₃] 的 Cu-H 键中，并使用辅助配体 L，制备了一系列稳定的 Cu[CF₂(OCF₃)(CFH)]L 配合物。值得注意的是，其中某些配合物能有效地将氟烷基转移至芳酰氯。通过反应优化和计算分析，我们确定二甲基亚砜是一种关键的共配体，在实现一系列芳酰氯和芳基碘的氟烷基化过程中发挥着独特作用。后者还受益于添加 CuBr 以夺取 PPh₃，生成溶剂稳定的 Cu[CF₂(OCF₃)(CFH)]。这些方法允许在单一转化中引入偕二 -OCF₃ 和 -CFH 基团。
