Water Promoted Regiospecific Synthesis of p-Quino-Coumarin Fused 1,4-Benzodiazepine Scaffolds from Azido-p-Quino-coumarin: Mechanistic Insights

Herein, we report an efficient and straightforward threecomponent synthesis of a novel pentacyclic scaffold comprising the privileged coumarin, p-quinone, and benzodiazepine moieties in good yields with a wide substrate scope. The synthetic strategy involves a three-component cascade reaction of azido quino-coumarin with amines and aldehydes in acetonitrile, using either water or InCl3 as a catalyst at 100 °C. A detailed mechanistic study reveals that, in the presence of water as a promoter and catalyst, this transformation provides the quino-coumarin fused benzodiazepine (QCBZD) scaffold with 1,2-azide nitrogen migration through a single reaction pathway, via the intermediacy of 2,3-bridged-2H-azirine, in a regiospecific fashion.On the other hand, the InCl 3 -catalyzed transformation provides a regioisomeric mixture of QCBZD scaffolds, with and without 1,2-azide nitrogen migration, via a dual reaction pathway involving the intermediacy of 2,3-bridged-2H-azirine and an aza-Michael adduct. This metal-catalyst-free, water-assisted transformation of azido quinocoumarin to the QCBZD scaffold provides excellent regioselectivity, mild conditions, broad functional-group compatibility, and operational simplicity, making it a potentially valuable method in medicinal chemistry and drug discovery research.