Electrochemical Halogenation and Etherification of Alcohols Enabled by a Halide-Coupled Phosphine Oxidation

Phosphine-mediated nucleophilic substitution reactions of alcohol substrates, such as the Appel and Mitsunobu reactions, have found widespread applications in chemical synthesis. However, their reliance on stoichiometric chemical oxidants (e.g., carbon tetrachloride and azodicarboxylate reagents) often results in limited functional group tolerance, environmentally hazardous wastes, and unsatisfactory reaction economy. Herein, we describe a user-friendly electrochemical Appel reaction employing readily available tetrabutylammonium halide salts ( ^<i>n</i> Bu₄N⁺X^-, X = Cl, Br, and I) as the halogen source. A survey of alcohol substrates revealed broad functional group tolerance, including complex pharmaceutical and bioactive scaffolds. Electroanalytical voltammetry and control experiments support a halide-coupled phosphine oxidation pathway under mild anodic potentials, affording key alkoxyphosphonium intermediates prior to nucleophilic substitution. Notably, the electrochemical halogenation conditions can also facilitate intramolecular alcohol etherification with oxidation-sensitive phenols and weakly acidic alcohol nucleophiles.