Atropisomeric and Conformational Properties of 6N-benzoyl- and 6N-p-tosyl-1,6-benzodiazocines: Comparison with Those of 1,5-Benzodiazepines

Hideaki Natsugari, Hidetsugu Tabata, Hideyo Takahashi, Kazuya Murai, Kaoru Funaki, Chihiro Takemae, Tomohiko Tasaka, Tetsuta Oshitari
2019 Heterocycles  
The atropisomeric and conformational properties of the eight-membered 1,6-benzodiazocines (2) with 6N-benzoyl (A) and 6N-p-tosyl (B) groups were examined by comparing them with those of the seven-membered 1,5-benzodiazepine congeners (1) (A, B). The conformation (orientation) of the benzene ring in the benzoyl and tosyl groups differed depending on the ring size (7/8) and N-substituent (-CO-/-SO2-). The activation free-energy barrier to rotation of the axes in N-p-tosyl derivatives (B) was
more » ... to be much higher than those of the benzoyl derivatives (A). INTRODUCTION Benzo-fused seven-membered-ring nitrogen-heterocycles are found as the scaffolds of many biologically active molecules 1 Since these heterocycles possess relatively flexible rings, the ring often changes its conformation so as to exert biological activity. It should be noted that, although often overlooked, atropisomerisms 2 are latent in these heterocycles. Thus far, we have investigated the conformations of several seven-membered-ring nitrogen-heterocycles and their relationships with their biological activities. 3 5N-Benzoyl derivatives of 1,5-benzodiazepine (1A), 3d which form the core structure of the vaptan class of arginine-vasopressin (VP) receptor ligands, were our first target. 3d,i,k The (aR)-and (aS)-atropisomers 4 caused by the Ar-N(CO) (sp 2 -sp 2 ) axis are present in 1A, and, although the NH4Cl, and dried over MgSO4. The filtrate was concentrated to give 8B as a white solid (45 mg, 59%): mp 247-250 °C: 1 H NMR (600 MHz, CDCl3) 1.73-1.78 (m, 1H), 1.98 (ddd, J = 0.9, 12.4, 12.5 Hz, 1H), 2.04-2.11 (m, 1H), 2.13 (s, 3H), 2.32 (dd, J = 8.0, 12.4 Hz, 1H), 2.43 (s, 3H), 2.91 (ddd, J = 3.8, 12.7, 15.0 Hz, 1H), 4.39 (ddd, J = 1.1, 4.3, 15.0 Hz, 1H), 6.82 (br, 1H), 6.99 (dd, J = 0.6, 7.9 Hz, 1H), 7.18 (dd, J = 0.6, 7.9 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H); 13 C NMR (150 MHz, cm -1 ; HRMS (ESI) m/z calcd for C18H20N2O3S 345.1267 (M+H) + , found 345.1270. Benzoyl-1,7-dimethyl-3,4,5,6-tetrahydro-1,6-benzodiazocin-2-one (2A) . To a solution of 8A (76 mg, 0.26 mmol) in DMF (2.0 mL) was added sodium hydride (60% in oil) (21 mg, 0.52 mmol) at 0 °C under argon. The mixture was stirred for 30 min at 25 °C, cooled to 0 °C, and treated with MeI (48 L, 0.77 6-
doi:10.3987/com-18-s(f)55 fatcat:kbea3pe45rc2papydyq6m7ilra