Aerobic Oxidation of 4‑Alkyl‑N,N‑dimethylbenzylamines Catalyzed by N‑Hydroxyphthalimide: Protonation-Driven Control over Regioselectivity

A change in regioselectivity has been observed in the hydrogen atom transfer (HAT) reactions from 4-alkyl-N,N-dimethylbenzylamines (alkyl = ethyl, isopropyl, and benzyl) to the phthalimide N-oxyl radical (PINO) by effect of protonation. This result can be rationalized on the basis of an acid-induced deactivation of the C–H bonds α to nitrogen toward HAT to PINO as evidenced by the 10⁴–10⁷-fold decrease in the HAT rate constants in acetonitrile following addition of 0.1 M HClO₄. This acid-induced change in regioselectivity has been successfully applied for selective functionalization of the less activated benzylic C–H bonds para to the CH₂N­(CH₃)₂ group in the aerobic oxidation of 4-alkyl-N,N-dimethylbenzylamines catalyzed by N-hydroxyphthalimide in acetic acid.