Mechanisms of Metal-Free Aerobic Oxidation To Prepare Benzoxazole Catalyzed by Cyanide: A Direct Cyclization or Stepwise Oxidative Dehydrogenation and Cyclization?

The detailed mechanism of the cyanide-catalyzed synthesis of benzoxazole from 2-aminophenol and benzaldehyde was investigated in depth using density functional theory (DFT). The metal-free aerobic oxidative process as well as the dehydrogenation detail were examined and described. Cyanide anion was proved to assist the oxygen atoms to undergo an aerobic dehydrogenation rather than direct cyclization which was predicted according to Baldwin's 5-exotet rule. The dehydrogenation pathway was thermodynamically favored over cyclization with an activation energy difference of 24.2 kcal/mol. Another point noteworthy was the observation that a trace amount of water could reduce the activation energy effectively during the condensation step (ΔΔG⧧ = 22.3 kcal/mol).