Hexafluoroisopropanol (HFIP)-Promoted Metal-Free Chemoselective <i>O</i> -Alkylation of 2-Pyridones with α-Halo Hydroxamates at Room Temperature

A mild, efficient, and metal-free protocol has been developed for the chemoselective O-alkylation of 2-pyridones (over N-alkylation), employing α-halohydroxamates as electrophilic partners. The reaction proceeds smoothly at room temperature in hexafluoroisopropanol (HFIP) in the presence of Na2CO3, delivering the corresponding O-alkylated products in good to excellent yields. The transformation leverages the electrophilic aza-oxyallyl intermediate and the inherent nucleophilicity of the pyridone oxygen. This method was found to be suitable for the O-alkylation of 3-hydroxypyridine under optimized conditions. Furthermore, the synthetic utility of the products was demonstrated through late-stage functionalization of the O-alkylated hydroxypyridines via Suzuki–Miyaura and Heck cross-coupling reactions, as well as C–N bond functionalization reactions. Overall, this operationally simple strategy enables rapid access to structurally diverse heterocyclic scaffolds that are of significant relevance to medicinal chemistry and drug discovery.