P. Zhang et al. / European Journal of Medicinal Chemistry 61 (2013) 95e103
101
4.1.3.4. 2,3-Dihydro-2-(2-thienyl)-5-cyclohexthylmethyl-1,5-
4.1.3.12. 2,3-Dihydro-2-phenyl-5-(2-nitrobenzyl)-1,5-benzothiazepin-
benzothiazepin-4(5H)-one (6d). Yield: 15%; mp 142.5e143.2 ꢁC; 1H
4(5H)-one (6l). Yield: 75%; mp 186.7e189.5 ꢁC; 1H NMR (400 MHz,
NMR (400 MHz, CDCl3)
1H), 5.08e4.70 (m, 2H), 3.10e2.60 (m, 2H), 1.98e1.08 (m, 11H). 13C
NMR (100 MHz, CDCl3) 170.6, 158.8, 146.1, 143.9, 136.5, 130.1,
d
7.84e6.52 (m, 7H), 5.23 (d, J ¼ 15.0 Hz,
CDCl3)
d
8.24e6.88 (m, 13H), 5.54 (d, J ¼ 25.7 Hz, 2H), 5.06e4.73 (m,
1H), 3.15e2.74 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
171.0, 148.1,
d
145.8, 143.6, 136.8, 133.7, 132.7, 130.7, 129.6, 128.8, 128.0, 127.8, 127.4,
127.1,126.1,125.0,123.4, 52.9, 50.9, 49.5, 42.1, 29.7; ESI-MS (positive):
390.9 (M þ 1)þ.
129.4, 129.1, 128.7, 127.6, 127.5, 127.1, 126.1, 124.2, 55.2, 52.9, 51.1,
50.8, 42.1, 29.7; ESI-MS (positive): 358.1 (M þ 1)þ.
4.1.3.5. 2,3-Dihydro-2-(2-thienyl)-5-benzoyl-1,5-benzothiazepin-
4.1.3.13. 2,3-Dihydro-2-phenyl-5-(2-cyanobenzyl)-1,5-benzothiazepin-
4(5H)-one (6e). Yield: 89%; mp 234.8e235.6 ꢁC; 1H NMR (400 MHz,
4(5H)-one (6m). Yield: 88%; mp 148.6e149.8; 1H NMR (400 MHz,
CDCl3)
d
8.26e6.58 (m, 12H), 5.12 (dd, J ¼ 11.1, 6.1 Hz,1H), 3.01 (ddd,
CDCl3)
J ¼ 16.0 Hz, 1H), 4.87 (dd, J ¼ 12.6, 5.6 Hz, 1H), 2.90 (dd, J ¼ 15.9,
9.1 Hz, 2H); 13C NMR (100 MHz, CDCl3)
170.7, 145.4, 143.6, 138.3,
136.8, 132.6, 131.6, 131.1, 130.5, 129.2, 128.8, 127.8, 127.6, 126.0, 123.9,
118.7, 112.4, 52.8, 51.1, 41.8, 31.9, 29.7; ESI-MS (positive): 370.8
(M þ 1)þ.
d
8.02e6.96 (m, 13H), 5.69 (d, J ¼ 16.0 Hz, 1H), 5.12 (d,
J ¼ 23.5, 12.3, 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 172.3, 170.3,
143.2, 137.6, 134.3, 133.1, 130.9, 129.6, 128.6, 128.5, 126.9, 126.6,
d
125.0, 124.2, 47.4, 43.5; ESI-MS (positive): 366.1 (M þ 1)þ.
4.1.3.6. 2,3-Dihydro-2-(2-thienyl)-5-benzyl-1,5-benzothiazepin-
4(5H)-one (6f). Yield: 86%; mp 143.7e145.1 ꢁC; 1H NMR (400 MHz,
CDCl3)
1H), 5.19 (d, J ¼ 14.9 Hz, 1H), 5.14 (m, 1H), 5.01 (d, J ¼ 14.9 Hz, 1H),
3.00 (m, 1H), 2.85e2.79 (m, 1H); 13C NMR (100 MHz, CDCl3)
170.1,
147.7, 146.1, 137.1, 137.0, 133.4, 130.8, 130.5, 129.3, 128.4, 128.0, 127.3,
127.1, 126.7, 126.5, 124.6, 123.9, 123.6, 58.5, 51.8, 48.5, 42.9; ESI-MS
(positive): 352.1 (M þ 1)þ.
d
7.58e7.15 (m, 10H), 6.90e6.88 (m, 1H), 5.99 (d, J ¼ 3.5 Hz,
4.1.3.14. 2,3-Dihydro-2-phenyl-5-(2-flurobenzyl)-1,5-benzothiazepin-
4(5H)-one (6n). Yield: 87%; mp 143.2e146.4 ꢁC; 1H NMR (400 MHz,
d
CDCl3)
d
7.96e6.57 (m, 13H), 5.50e4.95 (m, 2H), 4.85 (dd, J ¼ 12.6,
5.5 Hz, 1H), 3.12e2.62 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
170.8,
145.9, 143.9, 136.5, 130.3, 130.31, 130.27, 129.00, 128.92, 128.76,
127.69, 127.30, 127.24, 126.08, 124.13, 124.09, 123.95, 123.91, 123.76,
115.13, 114.91, 52.82, 44.90, 44.86, 42.01. ESI-MS (positive): 364.1
(M þ 1)þ.
4.1.3.7. 2,3-Dihydro-2-(2-furyl)-5-benzyl-1,5-benzothiazepin-4(5H)-
one (6g). Yield: 75%; mp 104.9e105.7 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.47e7.14 (m, 10H), 6.26 (s, 1H), 5.99 (d, J ¼ 2.4 Hz, 1H), 5.17 (d,
J ¼ 15.3 Hz,1H), 5.01 (d, J ¼ 15.3 Hz,1H), 4.89 (dd, J ¼ 5.9,12.6 Hz,1H),
2.92e2.81 (m, 2H); 13C NMR (100 MHz, CDCl3)
170.4, 154.9, 146.1,
4.1.3.15. 2,3-Dihydro-2-phenyl-5-(2-chlorobenzyl)-1,5-benzothiazepin-
4(5H)-one (6o). Yield: 100%; mp 169.3e172.5 ꢁC; 1H NMR (400 MHz,
d
CDCl3)
d
7.99e6.66 (m, 13H), 5.26 (s, 2H), 4.89 (dd, J ¼ 12.8, 5.2 Hz,
142.2,137.0,136.0,130.3,128.4,128.0,127.3,127.0,126.7,123.8,110.3,
1H), 3.18e2.74 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
170.9, 146.0,
105.3, 58.5, 51.8, 45.9, 38.8; ESI-MS (positive): 336.1 (M þ 1)þ.
143.8, 136.6, 134.3, 132.8, 130.4, 129.3, 129.0, 128.8, 128.4, 127.8, 127.3,
127.1, 126.1, 124.5, 123.6, 52.9, 50.9, 49.3, 42.1, 29.7; ESI-MS (positive):
380.0 (M þ 1)þ.
4.1.3.8. 2,3-Dihydro-5-benzyl-1,5-benzothiazepin-4(5H)-one
(6h).
Yield: 78.7%; mp 104.7e105.8 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.57e
7.55 (d, J ¼ 1.6 Hz, 1H), 7.35e7.19 (m, 7H), 7.16e7.13 (m, 1H), 5.18e
4.1.3.16. 2,3-Dihydro-2-phenyl-5-(2-bromobenzyl)-1,5-benzothiazepin-
4.98 (m, 2H), 3.5e3.3 (m, 2H), 2.7e2.5 (m, 2H); 13C NMR (100 MHz,
4(5H)-one (6p). Yield: 71%; mp 168.6e170.4 ꢁC; 1H NMR (400 MHz,
CDCl3)
d
172.0, 146.4, 137.2, 135.9, 129.9, 128.3, 128.2, 127.9, 127.2,
CDCl3)
d
7.91e6.66 (m, 13H), 5.24 (d, J ¼ 4.6 Hz, 2H), 4.91 (s, 1H), 2.93
124.1, 51.8, 34.5, 34.2; ESI-MS (positive): 270.1 (M þ 1)þ.
(dd, J ¼ 26.2, 8.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 170.8, 146.1,
143.8, 136.6, 135.9, 132.6, 130.4, 129.0, 128.8, 128.7, 127.8, 127.6, 127.2,
127.1, 126.1, 123.6, 122.8, 52.9, 51.9, 42.1, 31.4, 29.7; ESI-MS (positive):
424.0, 426.4 (M þ 1)þ.
4.1.3.9. 2,3-Dihydro-2-methyl-5-benzyl-1,5-benzothiazepin-4(5H)-
one (6i). Yield: 79.5%; mp 115.6e117.9 ꢁC; 1H NMR (400 MHz,
CDCl3)
d
7.6e7.48 (d, J ¼ 7.4 Hz,1H), 7.41e7.18 (m, 7H), 7.18e7.07 (m,
1H), 5.16e5.06 (d, J ¼ 15.3 Hz, 1H), 5.06e4.88 (d, J ¼ 15.3 Hz, 1H),
4.1.3.17. 2,3-Dihydro-2-phenyl-5-(2-methylbenzyl)-1,5-benzothiazepin-
3.90e3.55 (m, 1H), 2.70e2.55 (m, 1H), 2.36e2.17 (m, 1H), 1.32e1.26
4(5H)-one (6q). Yield: 85%; mp 133.2e134.6 ꢁC; 1H NMR (400 MHz,
(d, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
171.4, 146.3, 137.2,
CDCl3)
d
7.85e6.71 (m, 13H), 5.10 (dd, J ¼ 63.2, 15.9 Hz, 2H), 4.87 (dd,
136.8, 135.4, 130.4, 129.8, 128.3, 128.0, 127.6, 127.2, 126.8, 123.8, 51.7,
J ¼ 12.7, 5.1 Hz, 1H), 3.10e2.74 (m, 2H), 2.33 (s, 3H); 13C NMR
45.1, 42.5, 24.3; ESI-MS (positive): 284.2 (M þ 1)þ.
(100 MHz, CDCl3) d 170.6, 146.4, 144.0, 136.5, 135.7, 134.8, 130.3, 130.1,
128.8, 127.7, 127.3, 127.2, 127.1, 126.1, 126.0, 123.9, 58.5, 52.9, 49.7, 42.2,
4.1.3.10. 2,3-Dihydro-2-(3-pyridyl)-5-benzyl-1,5-benzothiazepin-
19.3, 18.4; ESI-MS (positive): 360.1 (M þ 1)þ.
4(5H)-one (6j). Yield: 60%; mp 178.9e180.2 ꢁC; 1H NMR (400 MHz,
CDCl3)
d
8.52 (d, J ¼ 4.7 Hz, 1H), 8.43 (s, 1H), 7.57 (dd, J ¼ 2.0 Hz,
4.1.3.18. 2,3-Dihydro-2-phenyl-5-(4-methoxylbenzyl)-1,5-benzothiazepin
7.8 Hz, 1H), 7.35e7.00 (m, 10H), 5.32 (d, J ¼ 16.0 Hz, 1H), 5.16 (d,
J ¼ 16.0 Hz, 1H), 3.71 (dd, J ¼ 5.1, 9.8 Hz, 1H), 3.36 (dd, J ¼ 5.1,
14.1 Hz, 1H), 2.86 (dd, J ¼ 9.8, 14.5 Hz, 1H); 13C NMR (100 MHz,
-4(5H)-one (6r). Yield: 60%; mp 110.8e113.1 ꢁC; 1H NMR (400 MHz,
CDCl3)
J ¼ 13.7, 7.8 Hz,1H), 3.75 (s, 3H), 3.31 (dd, J ¼ 13.7, 5.8 Hz,1H), 3.07e2.46
(m, 2H); 13C NMR (100 MHz, CDCl3)
170.0, 147.9, 146.6, 137.2, 130.5,
d
8.07e6.50 (m, 7H), 5.12 (dd, J ¼ 12.6, 5.4 Hz, 1H), 4.23 (dd,
CDCl3)
d
166.5, 150.4, 148.2, 139.2, 137.1, 136.6, 132.9, 129.1, 128.8,
d
127.5, 127.3, 126.2, 124.0, 123.4, 121.2, 117.9, 48.9, 44.8, 32.0; ESI-MS
127.0, 126.7, 126.6, 126.5, 124.5, 123.9, 123.5, 54.6, 50.9, 48.9, 48.5, 43.1,
(positive): 347.2 (M þ 1)þ.
37.0, 31.2; ESI-MS (positive): 376.1 (M þ 1)þ.
4.1.3.11. 2,3-Dihydro-2-phenyl-5-benzyl-1,5-benzothiazepin-4(5H)-
4.1.3.19. 2,3-Dihydro-2-phenyl-5-(3-carboxylbenzyl)-1,5-benzothiazepin
-4(5H)-one (6s). A solution of 6m (0.2 g, 0.54 mmol) in conc. HCl (5 ml)
was reflux in a sealed tube at 100 ꢁC for 7 h, and then cooled to room
temperature. The pale-yellow precipitate was collected by filtration and
washed with methanol, yield: 70%, mp 186.4e188.7 ꢁC; 1H NMR
one (6k). Yield: 89%; mp 146.7e150.6 ꢁC; 1H NMR (400 MHz,
CDCl3)
d
7.58e7.14 (m, 14H), 5.23 (d, J ¼ 15.2 Hz), 1H, 5.01 (d,
J ¼ 15.2 Hz, 1H), 4.88e4.83 (m, 1H), 2.94e2.82 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d 170.7, 146.2, 144.0, 137.1, 136.6, 130.2, 128.8,
128.4, 128.0, 127.7, 127.3, 127.2, 126.1, 124.1, 52.9, 51.8, 42.1; ESI-MS
(400 MHz, DMSO-d6)
7.62e7.16 (m,11H), 5.44 (d, J¼ 15.6 Hz,1H), 4.94 (d, J¼ 15.6 Hz,1H), 4.98
d
12.89 (s, 1H), 7.88 (s, 1H), 7.74 (d, J ¼ 7.6 Hz, 1H),
(positive): 346.1 (M þ 1)þ.