Synthesis of 1,4-Benzodiazepines via Intramolecular C-N Bond Coupling and Ring Opening of Azetidines

A facile and efficient synthesis of functionalized 1,4-benzodiazepine derivatives under mild conditions was developed. The CuI/N,N-dimethylglycine-catalyzed intramolecular cross-coupling reaction of 1-(2-bromobenzyl)azetidine-2-carboxamides proceeded smoothly under mild conditions to provide 1,4,9,10a-tetrahydroazeto[1,2-a]benzo[e][1,4]diazepin-10(2H)-ones. The resulting azetidine-fused 1,4-benzodiazepine compounds underwent consecutive N-methylation with methyl triflate and the opening of the four-membered heterocyclic ring by NaN3, KCN and PhSNa to produce diverse 1,4-benzodiazepine derivatives in good to excellent yields. Upon treatment with methyl chloroformate, on the other hand, the 1,4,9,10a-tetrahydroazeto[1,2-a]benzo[e][1,4]diazepin-10(2H)-ones were straightforwardly converted into 2-chloroethyl-substituted 1,4-benzodiazepine derivatives.