Synthesis, crystal structure and docking studies of tetracyclic 10‐iodo‐1,2‐dihydroisoquinolino[2,1‐ b ][1,2,4]benzothiadiazine 12,12‐dioxide and its precursors

The title compound, 10‐iodo‐1,2‐dihydroisoquinolino[2,1‐ b ][1,2,4]benzothiadiazine 12,12‐dioxide, C 15 H 11 IN 2 O 2 S ( 8 ), was synthesized via the metal‐free intramolecular N ‐iodosuccinimide (NIS)‐mediated radical oxidative sp 3 ‐C—H aminative cyclization of 2‐(2′‐aminobenzenesulfonyl)‐1,3,4‐trihydroisoquinoline, C 15 H 16 N 2 O 2 S ( 7 ). The amino adduct 7 was prepared via a two‐step reaction, starting from the condensation of 2‐nitrobenzenesulfonyl chloride ( 4 ) with 1,2,3,4‐tetrahydroisoquinoline ( 5 ), to afford 2‐(2′‐nitrobenzenesulfonyl)‐1,3,4‐trihydroisoquinoline, C 15 H 14 N 2 O 4 S ( 6 ), in 82% yield. The catalytic hydrogenation of 6 with hydrogen gas, in the presence of 10% palladium‐on‐charcoal catalyst, furnished 7 . Products 6 – 8 were characterized by their melting points, IR and NMR ( 1 H and 13 C) spectroscopy, and single‐crystal X‐ray diffraction. The three compounds crystallized in the monoclinic space group, with 7 exhibiting classical intramolecular hydrogen bonds of 2.16 and 2.26 Å. All three crystal structures exhibit centrosymmetric pairs of intermolecular C—H…π(ring) and/or π–π stacking interactions. The docking studies of molecules 6 , 7 and 8 with deoxyribonucleic acid (PDB id: 1ZEW) revealed minor‐groove binding behaviours without intercalation, with 7 presenting the most favourable global energy of the three molecules. Nonetheless, molecule 8 interacted strongly with the DNA macromolecule, with an attractive van der Waals energy of −15.53 kcal mol −1 .