Direct Access to Quinone-Fused 5-Substituted-1,4-Benzodiazepine Scaffolds from Azidoquinones with/without...

Seven-membered nitrogen heterocycles have a strong influence in drug discovery due to their inherent 3D character, which allows the ability to explore a vast conformational space with a biological target. Notably, the privileged 1,4-benzodiazepine scaffold is dominant in treating the central nervous system due to its binding affinity with the GABA_A receptor. Herein, we report a protocol for the transformation of azidoquinones to p-quinone fused 5-substituted-1,4-benzodiazepines (p-QBZDs) from InCl₃-catalyzed intermolecular tandem cycloannulation of azidoquinones with amines and aldehydes. Detailed mechanistic studies reveal that the EDA complex between azidoquinones and InCl₃ is crucial in determining the reaction pathway. In the absence of EDA complex formation, the reaction proceeds via the intermediacy of 2,3-bridged-2H-azirine followed by regiospecific addition of an amine to C═N/ring opening/cyclization to deliver p-QBZD with 1,2-azide-nitrogen migration. In the case of EDA complex formation, the reaction proceeds through regioselective aza-Michael addition/nitrene insertion with aldehyde and subsequent cyclization to deliver p-QBZD and p-quinone fused imidazole as a secondary product without 1,2-azide-nitrogen migration. This protocol provides straightforward access to redox-active quinone embedded 5-substituted-1,4-benzodiazepines from azidoquinones with diverse substrate scopes that would find potential applications in medicinal chemistry and drug discovery.