All reagents were procured from Sigma Aldrich India and were of synthetic grade. The progression of the reaction was monitored by TLC on pre-coated plates (silica gel 60F-254, 0.25 mm thick) from Merck, India, visualized in a UV Chamber and later with iodine vapors. A Shimadzu FT-IR spectrometer was used to record the IR spectra in KBr pellets. An Avance 300 MHz spectrometer was used to produce the 1H-NMR spectra in DMSO-d6, employing TMS as an internal standard. An EI-Shimadzu-GC-MS mass spectrometer was used to record the mass spectra of the synthesized compounds. A Carlo Erba 106 Perkin-Elmer model 240 analyzer was employed for elemental analysis.
The General Method Used for the Synthesis of 2,4-(Substituted-aryl)-2,3-dihydro-1,5-benzothiazepines
The derivatives of 1,5-benzothiazepine were synthesized as follows. Equimolar quantities of 2-Amino-4-methylbenzenethiol (1 mmol) and substituted 2′-hydroxy chalcone (1 mmol) were placed in a flat-bottomed flask, and a catalytic quantity of bleaching earth (10 wt.%, pH 12.5) in PEG-400 (20 mL) was added and stirred at 60–65 °C for 55 min (
Figure 9). Product formation was confirmed by TLC (solvents: ethyl acetate and petroleum ether at 3:7). Later, the mixture was filtered in order to isolate the catalyst, the filtrate was poured into a beaker of ice-cold water (100 mL) while continuously stirring, and the resultant solid was vacuum filtered. The solid product was extracted, washed, and recrystallized with water (2 × 20 mL) and ethanol to produce the 1,5-benzothiazepine derivatives. Compound formation was confirmed using the Wilson test; none of the synthetic reactions showed the positive response signified by the red coloration of concentrated sulphuric acid [
35,
36,
37].
2-(2-(4-(dimethylamino)phenyl)-7-methyl-2,3-dihydrobenzo[b][1,4]thiazepin-4-yl)-4,6-diiodophenol (2a): Yellow solid, Percentage yield: 88, m.p. 230–232 °C. IR (KBr):3169 (OH), 3042 (C-H arom), 1570 (C=N), 638 (C-Br); 1H NMR (300 MHz, DMSO- δ6):δ 10.42 (s, 1H, OH), δ 6.81–7.93 (m, 10H, ArH), 5.42 (dd, Hx, Jax = 10.81 Hz, Jbx = 2.12 Hz, 1H), 3.53 (dd, Hb, Jbx = 2.1 Hz, Jab = 14.1 Hz, 1H), 3.12 (dd, Ha, Jax = 10.82 Hz, Jab = 14.0 Hz, 1H), δ 2.1 (s, 3H, CH3), δ 2.79 (s, 6H, (CH3)2 13C NMR (125 MHz, CDCl3, ppm) δ: 162.6, 159.1, 155.5, 149.5, 147.6, 136.6, 136.1, 133.0, 130.4, 128.6, 128.6, 128.0, 124.0, 122.0, 119.2, 112.9, 112.9, 88.6, 83.8, 50.1, 41.3, 41.3, 40.4,21.3; MS: m/z (%) 639 (M+1), Anal. Calcd. for C24H22I2N2OS: C,45.02; H, 3.47; N, 4.37; Found: C, 45.01; H, 3.43; N, 4.35%.
2-(2-(4-(dimethylamino)phenyl)-7-methyl-2,3-dihydrobenzo[b][1,4]thiazepin-4-yl)-6-iodo-4-methylphenol (2b): White solid, Percentage yield: 89, m.p. 218–220 °C. IR (KBr):3176(OH), 3052(C-H arom), 1582 (C=N); 1H NMR (300 MHz, DMSO- δ6):δ 10.39 (s, 1H, OH), δ 6.81–7.90 (m, 10H, ArH), 5.43 (dd, Hx, Jax = 10.79 Hz, Jbx = 2.10 Hz, 1H), 3.52 (dd, Hb, Jbx = 2.12 Hz, Jab = 14.1 Hz, 1H), 3.10 (dd, Ha, Jax = 10.81 Hz, Jab = 14.1 Hz, 1H), δ 2.72(s, 6H, (CH3)2, δ 2.39 (s, 3H, CH3), δ 2.18 (s, 3H, CH3), 13C NMR (125 MHz, CDCl3, ppm) δ: 162.6, 157.2, 155.5, 149.5, 143.6, 136.1, 133.0, 132.7, 130.4, 129.7, 128.6, 128.6, 128.0, 124.0, 120.3, 119.2, 112.9, 112.9, 87.5, 50.1,41.3, 41.3, 40.4, 21.3,20.4 ; MS: m/z (%) 528 (M+1), Anal. Calcd for C25H25IN2OS: C,56.82; H, 4.77; N, 5.30; Found: C, 56.79; H, 4.75; N, 5.29%.
2,4-dichloro-6-(2-(4-(dimethylamino)phenyl)-7-methyl-2,3-dihydrobenzo[b][1,4]thiazepin-4-yl)phenol (2c): Yellow solid, Percentage yield: 92, m.p. 222–224 °C. IR (KBr):3187(OH), 3068(C-H arom), 1570(C=N), 732(C-Cl); 1H NMR (300 MHz, DMSO- δ6):δ 10.40 (s, 1H, OH), δ 6.81–7.93 (m, 10H, ArH), 5.39 (dd, Hx, Jax = 10.80 Hz, Jbx = 2.11 Hz, 1H), 3.50 (dd, Hb, Jbx = 2.14 Hz, Jab = 14.2 Hz, 1H), 3.14 (dd, Ha, Jax = 10.81 Hz, Jab = 14.2 Hz, 1H), δ 2.19 (s, 3H, CH3), δ 2.70(s, 6H, (CH3)2 13C NMR (125 MHz, CDCl3, ppm) δ: 162.6, 157.9, 155.5, 149.5, 136.1, 134.1, 133.0, 130.4, 128.7, 128.6, 128.6, 128.4, 128, 126.9, 124.0, 121.6, 119.2, 112.9, 112.9, 50.1, 41.3, 41.3, 40.4, 21.3; MS: m/z (%) 456 (M+1), Anal. Calcd for C24H22Cl2N2OS: C,63.02; H, 4.85; N, 6.12; Found: C, 63.00; H, 4.82; N, 6.09%.
4-chloro-2-(2-(4-(dimethylamino)phenyl)-7-methyl-2,3-dihydrobenzo[b][1,4]thiazepine-4-yl)-6-iodophenol (2d): Creamy white solid, Percentage yield: 94, m.p. 244–246 °C. IR (KBr):3310(OH), 3056(C-H arom), 1587(C=N), 732(C-Cl); 1H NMR (300 MHz, DMSO- δ6):δ 10.48 (s, 1H, OH), δ 6.81–7.93 (m, 10H, ArH), 5.41 (dd, Hx, Jax = 10.81 Hz, Jbx = 2.11 Hz, 1H), 3.53 (dd, Hb, Jbx = 2.12 Hz, Jab = 14.2 Hz, 1H), 3.15 (dd, Ha, Jax = 10.81 Hz, Jab = 14.4 Hz, 1H), δ 2.14 (s, 3H, CH3), δ 2.72(s, 6H, (CH3)2 13C NMR (125 MHz, CDCl3, ppm) δ: 162.6, 158.3, 155.5, 149.5, 141.5, 136.1, 133.0, 130.4, 129.5, 128.6, 128.6, 128.6, 128.0, 124.0, 121.8, 119.2, 112.9, 112, 89.0, 50.1, 41.3, 41.3, 40.4, 21.3; MS: m/z (%) 548 (M+1), Anal. Calcd for C24H22ClIN2OS: C,52.52; H, 4.05; N, 6.09; Found: C, 52.49; H, 4.02; N, 5.09%.
2-bromo-6-(2-(4-(dimethylamino)phenyl)-7-methyl-2,3-dihydrobenzo[b][1,4]thiazepine-4-yl)-4-methylphenol (2e): brown solid, Percentage yield: 86, m.p. 244–246 °C. IR (KBr):3174(OH), 3042(C-H arom), 1575(C=N), 629(C-Br); 1H NMR (300 MHz, DMSO- δ6):δ 10.43 (s, 1H, OH), δ 6.80–7.93 (m, 10H, ArH), 5.43 (dd, Hx, Jax = 10.82 Hz, Jbx = 2.1 Hz, 1H), 3.52 (dd, Hb, Jbx = 2.1 Hz, Jab = 14.2 Hz, 1H), 3.12 (dd, Ha, Jax = 10.82 Hz, Jab = 14.0 Hz, 1H), δ 2.72 (s, 6H, (CH3)2, δ 2.36 (s, 3H, CH3), δ 2.1 (s, 3H, CH3), 13C NMR (125 MHz, CDCl3, ppm) δ: 162.6, 158.2, 155.5, 149.5, 137.5, 136.1, 133.3, 133.0, 130.4, 129.8, 128.6, 128.6, 128.0, 124.0, 120.9, 119.2, 115.1, 112.9, 112.9, 50.1, 41.3,41.3,40.4,21.3,20.6; MS: m/z(%) 480 (M+1), Anal. Calcd for C25H25BrN2OS: C,62.37; H, 5.23; N, 5.82; Found: C, 62.33; H, 5.20; N, 5.79%.
2-bromo-4-chloro-6-(2-(4-(dimethylamino)phenyl)-7-methyl-2,3-dihydrobenzo [b][1,4]thiaz epin-4-yl)phenol (2f): Yellow solid, Percentage yield: 87, m.p. 244–246 °C. IR (KBr):3171(OH), 3039(C-H arom), 1572(C=N), 632(C-Br); 1H NMR (300 MHz, DMSO- δ6):δ 10.45 (s, 1H, OH), δ 6.81–7.93 (m, 10H, ArH), 5.45 (dd, Hx, Jax = 10.82 Hz, Jbx = 2.1 Hz, 1H), 3.54 (dd, Hb, Jbx = 2.1 Hz, Jab = 14.2 Hz, 1H), 3.10 (dd, Ha, Jax = 10.82 Hz, Jab = 14.0 Hz, 1H), δ 2.2 (s, 3H, CH3), δ 2.70 (s, 6H, (CH3)2 13C NMR (125 MHz, CDCl3, ppm) δ: 162.6, 159.3, 155, 149, 136.2, 136.1, 133.0, 130, 129.6, 129, 128.6, 128.6,128.0, 124,122.4, 119.2, 115.3, 112.9, 112.9, 50.1, 41.3,41, 40.4, 21.3; MS: m/z (%) 500 (M+1), Anal. Calcd for C24H22BrClN2OS: C,57.44; H, 4.42; N, 5.58; Found: C, 57.43; H, 4.40; N, 5.56%.
2,4-dibromo-6-(2-(4-(dimethylamino)phenyl)-7-methyl-2,3-dihydrobenzo[b][1,4]hiazepine-4-yl)phenol (2g): Light brown solid, Percentage yield: 89, m.p. 244–246 °C. IR (KBr):3179(OH), 3056(C-H arom), 1579(C=N), 645(C-Br); 1H NMR (300 MHz, DMSO- δ6):δ 10.39 (s, 1H, OH), δ 6.80–7.92 (m, 10H, ArH), 5.39 (dd, Hx, Jax = 10.80 Hz, Jbx = 2.12 Hz, 1H), 3.45 (dd, Hb, Jbx = 2.2 Hz, Jab = 14.2 Hz, 1H), 3.09 (dd, Ha, Jax = 10.82 Hz, Jab = 14.1 Hz, 1H), δ 2.1 (s, 3H, CH3), δ 2.69 (s, 6H, (CH3)2 13C NMR (125 MHz, CDCl3, ppm) δ: 162.6, 160.2, 155.5, 149.5, 138.4, 136.1, 133.1, 133.0, 130.4,128.6,128.6,128.0,124.0 123.2, 119.2, 116.1, 113.5, 112.9, 112.9, 50.1, 41.3, 41.3, 40.4, 21.3; MS: m/z (%) 545 (M+1), Anal. Calcd for C24H22Br2N2OS: C,52.76; H, 4.06; N, 5.13; Found: C, 52.72; H, 4.05; N, 5.10%.
4-bromo-2-(2-(4-(dimethylamino)phenyl)-7-methyl-2,3-dihydrobenzo[b][1,4]thiazepin-4-yl)-6-iodophenol (2h): brown solid, Percentage yield: 85, m.p. 244–246 °C. IR (KBr):3197(OH), 3084(C-H arom), 1569(C=N), 652(C-Br); 1H NMR (300 MHz, DMSO- δ6):δ 10.42 (s, 1H, OH), δ 6.81–7.93 (m, 10H, ArH), 5.38 (dd, Hx, Jax = 10.81 Hz, Jbx = 2.11 Hz, 1H), 3.43 (dd, Hb, Jbx = 2.1 Hz, Jab = 14.2 Hz, 1H), 3.12 (dd, Ha, Jax = 10.82 Hz, Jab = 14.2 Hz, 1H), δ 2.2 (s, 3H, CH3), δ 2.70 (s, 6H, (CH3)2 13C NMR (125 MHz, CDCl3, ppm) δ: 162.6, 159.2, 155.5, 149.5, 144.4, 136.1, 133.0, 133.0, 130.4, 128.6, 128.6, 128.0,124.0,122.6, 119.2, 117.4, 112.9, 112.9, 89.8, 50.1, 41.3, 41.3, 40.4, 21.3; MS: m/z (%) 591 (M+1), Anal. Calcd for C24H22BrIN2OS: C,48.58; H, 3.74; N, 4.72; Found: C, 48.55; H, 3.72; N, 4.69%.