Photocatalytic phosphorylation of alcohols via oxidative activation of 1,4-dihydropyridine-N-phosphoramide

Phosphotriesters play a crucial role in pharmaceutical development, acting as key intermediates and prodrug components that enhance membrane permeability and enzymatic stability. Here, we develop two oxidative phosphorylation methods utilizing 1,4-dihydropyridine- N -phosphoramides as phosphoryl donors. The first method employs a photoredox catalyst and a stoichiometric weak oxidant, achieving efficient phosphotriester synthesis under mild conditions. The second method uses a hybrid catalytic system that incorporates a photoredox catalyst, a hydrogen atom transfer (HAT) catalyst, and a cobaloxime catalyst, allowing for dehydrogenative phosphorylation without the need for external oxidants or bases. This ternary catalytic approach improves reaction efficiency, and might offer a potential alternative to existing methodologies. Mechanistic investigations, including control experiments and DFT calculations, confirm the role of oxidative activation in facilitating nucleophilic substitution. This study presents a novel approach to the mild and selective synthesis of phosphotriesters, with potential applications in drug discovery and organic synthesis.