Catalytic Appel fluorination of alcohols with potassium fluoride

• 成果类型: Article
• 署名作者: Mondal, Anirban; Struijs, Job J. C.; Doyle, Caleb J. N.; Chen, Zijun; Wang, Zian; Tangamornchaipattana, Worawit; Allais, Christophe; Richardson, Paul F.; Piper, Jared; Paton, Robert S.; Aldridge, Simon; Gouverneur, Veronique
• 署名单位: University of Oxford; Colorado State University System; Colorado State University Fort Collins
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aec6298
• 发表日期: 2026-07-30
• 页码: 514-521
• 关键词: density functionals; TRANS INFLUENCE; deoxyfluorination; secondary; TRANSFORMATION; substitution; alkylation; energies; reagents; TIN(IV)

摘要

Appel halogenation reactions are widely used to convert alcohols to alkyl halides but are not suitable to prepare alkyl fluorides because fluoride is sequestered as a difluorophosphorane. In this work, we introduce bench-stable neopentoxyphosphonium salts to solve this enduring challenge. With these reagents, various alcohols undergo fluorination with potassium fluoride under hydrogen bonding phase-transfer catalysis, a manifold offering a pathway to enantioselective fluorination of alcohols. Mechanistically, a neopentoxyfluorophosphorane is formed, which undergoes reversible exchange with the alcohol substrate in preference to difluorophosphorane formation. The catalyst assists with potassium fluoride solubilization and with phosphorus-fluorine bond dissociation, leading to the alkoxyphosphonium fluoride ion pair undergoing stereoinvertive fluorination. Turnover results from stronger binding of the catalyst to fluoride than phosphine oxide, the by-product of the reaction, which is recyclable as starting material for the synthesis of the phosphonium reagents.