Efficient Construction of 5H-1,4-Benzodiazepine Derivatives by a Catalyst-Free Direct Aerobic Oxidative Annulation Strategy.

A catalyst-free direct aerobic oxidative annulation reaction of 2-aminobenzylic amines and α-hydroxy ketones efficiently afforded versatile 5H-1,4-benzodiazepine derivatives by employing air as economic and green oxidant under mild conditions. Interestingly, solvent was found to be crucial to the reaction, so that by using acetic acid as the best solvent an efficient and practical method could be achieved, requiring no catalysts or additives at all. This method tolerates a wide range of 2-aminobenzylic amines and α-hydroxy ketones and could be scaled up to multigram synthesis and directly applied in one-step synthesis of the pharmaceutically active N-desmethylmedazepam derivatives, revealing the potential of this new method in the synthesis of 5H-1,4-benzodiazepine skeleton-based pharmaceuticals and chemicals.