Halogen Bond-Driven Oxa-Pictet–Spengler Cyclization Using CBr₄: A Metal-Free and Regioselective Approach for the Synthesis of Tetracyclic Dihydrochromenoindole Scaffolds

Abstract Halogenated organic compounds have long served as valuable reagents in synthetic chemistry due to their distinctive reactivity and catalytic profiles. Among them, carbon tetrabromide (CBr₄) has recently gained attention as an efficient, metal-free catalyst capable of promoting selective bond activation under mild conditions. In this study, we exploit the catalytic utility of CBr₄ to develop an operationally simple and regioselective synthesis of dihydrochromenoindole-fused heterocyclic frameworks; the scaffolds known for their diverse biological activities, including anti-inflammatory, anticancer, and antimicrobial properties. Compared to existing protocols that often require transition-metal catalysts, pre-functionalized substrates, or harsh conditions, the present method offers a sustainable alternative with high yields and broad substrate compatibility. All synthesized compounds were fully characterized using 1H NMR, 13C NMR, DEPT-35, and mass spectrometry. Furthermore, a successful scale-up synthesis underscores the practicality and robustness of this protocol. This methodology not only improves access to bioactive dihydrochromenoindoles but also highlights the potential of CBr₄ as a green and cost-effective catalyst in heterocyclic synthesis.