康 · 学术 | Reaction of the Day No. 1737

Catalytic Appel Fluorination of Alcohols with Potassium Fluoride

Anirban Mondal1?, Job J. C. Struijs1?, Caleb J. N. Doyle1?,Zijun Chen1, Zian Wang1, Worawit Tangamornchaipattana1, Christophe Allais2, Paul F. Richardson3, Jared Piper2, Robert S. Paton4, Simon Aldridge1*, Véronique Gouverneur1

1 Chemistry Research Laboratory, University of Oxford, Oxford, UK. 2 Pfizer, Chemical Research and Development, Eastern Point Road, Groton, CT, USA. 3 Pfizer, Medicine Design, 10770 Science Center Drive, San Diego, CA, USA. 4 Department of Chemistry, Colorado State University, Fort Collins, CO, USA

—Science. 2026, 6810, 514-521

Recommended by Songlei Li _MC4

KEY WORDS: Appel fluorination,phase-transfer catalysis (反应类型), Csp3-F (成键类型), Alcohols, Potassium fluoride (原料), alkyl fluorides (产物), [Ph3P(OCH2tBu)][BF4] (P1·BF4), N-alkylated 1,1'-binaphthyl-2,2'-diamine(BINAM)–derived bis-urea (其他)

ABSTRACT: In this work, bench-stable neopentoxyphosphonium salts are introduced for the fluorination of 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.

Optimization of reaction conditions

Selected Substrate scope of primary, secondary, and tertiary alcohols

Applications with biorelevant alcohols and asymmetric catalysis (selected examples)

Scale-up and sustainability of the Appel fluorination

Mechanistic studies

Summary and Comments

VéroniqueGouverneur et al. have developed [PPh3(OCH2tBu)][BF4] as a reagent to convert alcohols into alkyl fluorides with KF under hydrogen bonding phase-transfer catalysis. This phosphonium salt undergoes monofluorination, leading to PPh3F(OCH2tBu), an intermediate undergoing alcohol exchange in preference to overfluorination to PPh3F2. Alkoxyfluorophosphoranes ionize under hydrogen bonding catalysis into the reactive phosphonium hydrogen-bonded fluoride ion pairs. Fluorination liberates alkyl fluorides and regenerates the catalyst. The choice of catalyst is critical to allow for preferential binding to fluoride over OPPh3 sequestration. The by-product OPPh3 is recyclable for P1·BF4 synthesis. The procedure is applicable to a broad class of alcohols with a good degree of functional group and heterocycle tolerance. Furthermore, racemic alcohols are converted into enantioenriched alkyl fluorides with a BINAM-derived bis-urea catalyst.