Selective [3 + 2]\nC–H/C–H Alkyne Annulation\nvia Dual (Distal) C<sub>(β, δ)</sub>–H Bond\nActivation Relay: A Novel Therapeutic Quinazolone-Tethered Benzofulvenes\nfor Oral Cancer

In contrast to proximal C–H bond activations,\ndistal C–H\nbond activation is fundamentally more challenging and requires distinctly\nspecialized directing partners or techniques. In this context, we\nreport an unprecedented dual (distal) β-C(benzylic)–H\nand δ-C(aryl)–H bond activation relay protocol for the\nchemo-, regio-, and stereoselective construction of heterocycle-tethered\nbenzofulvenes via [3 + 2] CH/CH-alkyne annulation under palladium\ncatalysis. The protocol overrides the more favorable [4 + 2] CH/NH\nannulation and does not follow the vinylic C–H bond activation\npathway. Mechanistic studies provide insight into the favored cyclopalladation\nof key intermediates (resulting from β-C(benzylic)–H\nbond cleavage) through relay δ-C(aryl)–H cleavage (vs\nN–H cleavage) prior to reductive elimination, which is the\nkey to desired annulation. The synthesized new chemical entities (NCEs)\nconstitute a novel scaffold with favorable anticancer activity against\noral squamous cell carcinoma (OSCC). Detailed biomolecular studies,\nincluding RNA-sequencing and analysis, indicate that these compounds\n(<b>4e</b> and <b>4w</b>) arrest the cell cycle at the\nS-phase and target multiple cancer hallmarks, such as the activation\nof apoptotic pathways and impairment of mitochondrial activity simultaneously,\nsuggesting their chemotherapeutic potential for oral cancer by addressing\nthe complexity and adaptability of cancer cells in chorus.