Electrochemical PINOylation of Methylarenes: Improving the Scope and Utility of Benzylic Oxidation through Mediated Electrolysis

A mediated electrosynthetic method has been developed for selective benzylic oxidation of methylarenes. Phthalimide-N-oxyl (PINO) radical generated by proton-coupled electrochemical oxidation of N-hydroxypthalimide serves as a hydrogen atom-transfer (HAT) mediator and as a radical trap for the benzylic radicals generated in situ. This mediated electrolysis method operates at much lower anode potentials relative to direct electrolysis methods for benzylic oxidation initiated by single-electron transfer (SET). A direct comparison of SET and mediated-HAT electrolysis methods with a common set of substrates shows that the HAT reaction exhibits a significantly improved substrate scope and functional group compatibility. The PINOylated products are readily converted into the corresponding benzylic alcohol or benzaldehyde derivative under photochemical conditions, and the synthetic utility of this method is highlighted by the late-stage functionalization of the non-steroidal anti-inflammatory drug celecoxib.