A highly efficient Buchwald-Hartwig-type intramolecular C-N bond cyclization strategy was developed, enabling the facile annulation of 3-chloro-benzofuran-2-carbaldehyde with various substituted phenylenediamines to form a novel series of benzofuro-fused-azeto[1,2-a]benzoimidazoles. The Pd2(dba)3/XPhos/Cs2CO3 catalytic system efficiently delivered desired tetracyclic derivatives in excellent yield of up to 87%. The protocol demonstrates high synthetic efficiency, broad functional group tolerance, and wide substrate scope, highlighting its practical scalability. Synthesized derivatives were evaluated for their in vitro antimycobacterial activity against the Mycobacterium tuberculosis H37Rv strain. Among them, analogs functionalized with unsubstituted benzimidazole, fluoro, benzophenone, and pyridyl groups demonstrated potent activity with MIC values of 3.12 mu g/mL, respectively. Structure-activity relationship studies further reveal how specific functional group variations modulate the antimycobacterial potency of the compounds, highlighting their potential as powerful inhibitors of M. tuberculosis H37Rv.
