Huang et al.
(1H, m), 1.77 (1H, m), 1.83–1.90 (2H, m), 2.39 (1H, m), 2.58–2.59
(2H, m), 2.96–3.00 (1H, m), 3.01–3.07 (2H, m), 3.95–3.99 (2H, m),
4.60 (1H, s), 5.39 (1H, s), 7.22 (1H, m), 7.28–7.31 (4H, m). 13C NMR
(150 MHz, CDCl3): 22.3, 23.0, 24.5, 25.8, 28.0, 34.1, 50.3, 51.8,
68.2, 123.2, 126.8, 128.7, 128.8, 129.9, 134.0, 137.6, 139.7, 163.5,
163.6, 168.9.
s), 5.35 (1H, d, J = 14.4 Hz), 6.58 (1H, s), 6.72 (2H, s), 7.32 (1H, d,
J = 7.8 Hz), 7.45 (1H, d, J = 8.4 Hz). 13C NMR (150 MHz, CDCl3):
17.1, 20.8, 22.2, 22.9, 24.6, 26.1, 52.3, 67.0, 121.8, 128.9, 129.4,
129.6, 129.7, 130.5, 134.6, 134.7, 135.3, 137.4, 162.7, 163.5, 167.7.
3,4,6,7,8,9-Hexahydro-3-(N-benzyl)-carboxamide-4-(4-
chlorobenzyl)-1H-benzo thieno-[2,3-e]-1,4-diazepine-
2,5-dione (5a-7): The product was isolated by silica gel chroma-
tography (petroleum ether ⁄ ethyl acetate, 2:1) as yellowish solids
(20 mg, yield: 16% over three steps). HPLC ⁄ MS: tR = 11.04 min,
m ⁄ z = 494.0 [M+H]+ HRMS: 493.122043 (found); C26H24ClN3O3S,
493.12269 (calcd.). 1H NMR (600 MHz, CDCl3): 1.60 (1H, m), 1.77
(1H, m), 1.87 (2H, m), 2.29 (1H, m), 2.59 (1H, m), 2.65 (1H, m), 3.01
(1H, m), 3.94 (1H, m), 4.07 (1H, m), 4.29 (1H, d, J = 14.4 Hz), 4.63
(1H, s), 5.22 (1H, d, J = 14.4 Hz), 5.47 (1H, s), 6.86 (2H, m), 7.20–
7.21 (2H, m), 7.26–7.29 (3H, m), 7.34–7.36 (2H, m). 13C NMR
(150 MHz, CDCl3): 22.2, 22.9, 24.6, 25.7, 44.1, 51.9, 66.6, 122.1,
127.9, 128.7, 129.5, 130.2, 134.6, 135.0, 136.6, 139.8, 163.3, 163.9,
167.6.
3,4,6,7,8,9-Hexahydro-3-(N-tert-butyl)-carboxamide-4-
(4-chlorobenzyl)-1H-benzo thieno-[2,3-e]-1,4-diazepine-
2,5-dione (5a-3): The product was isolated by silica gel chroma-
tography (petroleum ether ⁄ ethyl acetate, 2:1) as yellowish solids
(32 mg, yield: 28% over three steps). HPLC ⁄ MS: tR = 11.32 min,
m ⁄ z = 460.0 [M+H]+ HRMS: 459.136130 (found); C23H26ClN3O3S,
459.13834 (calcd.). 1H NMR (600 MHz, CDCl3): 0.92 (9H, s), 1.61
(1H, m), 1.78 (1H, m), 1.86 (1H, m), 1.93 (1H, m), 2.40 (1H, m),
2.58–2.60 (2H, m), 3.09 (1H, s), 4.19 (1H, d, J = 14.4 Hz), 4.58 (1H,
s), 4.86 (1H, s), 5.37 (1H, d, J = 13.2 Hz), 7.38 (1H, d, J = 7.8 Hz),
7.49 (1H, d, J = 8.4 Hz). 13C NMR (150 MHz, CDCl3): 22.3, 22.9,
24.5, 26.0, 27.9, 51.6, 51.9, 67.3, 122.3, 129.6, 129.9, 130.5, 134.1,
134.6, 135.4, 140.3, 163.2, 163.3, 168.4.
3,4,6,7,8,9-Hexahydro-3-(N-3,4-dichlorobenzyl)-carbo-
xamide-4-(4-chlorobenzyl)-1H-benzothieno-[2,3-e]-1,4-
diazepine-2,5-dione (5a-8): The product was isolated by
silica gel chromatography (petroleum ether ⁄ ethyl acetate, 1:1) as
yellowish solids (18 mg, yield: 16% over three steps). HPLC ⁄ MS:
tR = 11.72 min; m ⁄ z = 561.9 [M+H]+ HRMS: 561.044289 (found);
C26H22Cl3N3O3S, 561.04475 (calcd.). 1H NMR (600 MHz, CD3OD):
1.35–1.36 (1H, m), 1.66–1.77 (3H, m), 2.12–2.15 (1H, m), 2.51–2.54
(2H, m), 2.87 (1H, m), 4.00 (1H, d, J = 14.4 Hz), 4.27 (1H, d,
J = 14.4 Hz), 4.34 (1H, d, J = 15.0 Hz), 7.43 (1H, d, J = 15.0 Hz),
6.98 (1H, m), 7.31–7.33 (5H, m), 7.37 (1H, m). 13C NMR (150 MHz,
CD3OD): 21.8, 22.6, 23.8, 25.0, 40.1, 42.0, 51.8, 121.5, 127.8, 128.4,
128.6, 129.6, 130.1, 130.2, 130.7, 131.6, 133.3, 133.9, 135.4, 139.4,
164.1, 165.8, 167.8.
3,4,6,7,8,9-Hexahydro-3-(N-cyclopropylmethyl)-carbox-
amide-4-(4-chlorophenyl)-1H-benzothieno-[2,3-e]-1,4-
diazepine-2,5-dione (5a-4): The product was isolated by
silica gel chromatography (petroleum ether ⁄ ethyl acetate, 3:1) as
yellowish solids (18 mg, yield: 16% over three steps). HPLC ⁄ MS:
tR = 11.10 min, m ⁄ z = 446.0 [M+H]+ HRMS: 445.121614 (found);
1
C22H24ClN3O3S, 445.12269 (calcd.). H NMR (600 MHz, CDCl3): 1.16
(9H, s), 1.61 (1H, m), 1.78 (1H, m), 1.86–1.88 (2H, m), 2.47 (1H, m),
2.61 (2H, m), 3.00 (1H, m), 4.88 (1H, s), 5.01 (1H, s), 7.33 (2H, d,
J = 7.2 Hz), 7.39 (2H, d, J = 6.6 Hz).13C NMR (150 MHz, CDCl3):
22.3, 23.0, 24.6, 25.9, 28.2, 29.7, 52.3, 70.3, 123.4, 127.7, 129.7,
130.2, 133.3, 135.0, 141.3, 162.7, 168.4, 170.7.
3,4,6,7,8,9-Hexahydro-3-(N-cyclopropylmethyl)-carbo-
xamide-4-benzyl-1H-benzo thieno-[2,3-e]-1,4-diazepi-
ne-2,5-dione (5a-5): The product was isolated by silica gel
chromatography (petroleum ether ⁄ ethyl acetate, 2:1) as yellowish
solids (27 mg, yield: 26% over three steps). HPLC ⁄ MS:
tR = 10.34 min, m ⁄ z = 424.3 [M+H]+ HRMS: 423.161189 (found);
Method B for the synthesis of 5b
Ethyl 2-[({2-[(tert-butoxycarbonyl)amino]thien-3-yl}car-
bonyl)(phenethyl)amino]-3-(tert-butyl-amino)-3-oxo-
propanoate (4b-1): The mixture of 3b (74.3 mg, 0.25 mmol),
2-phenylethylamine (0.25 mmol, 31.4 lL), ethyl glyoxylate
(0.25 mmol, 49.6 lL), tert-butyl isocyanide (0.25 mmol, 28.3 lL) in
0.5 mL of methanol was stirred under RT for 2 days. 4b-1 was iso-
lated by silica gel chromatography (petroleum ether ⁄ ethyl acetate,
5:1) as yellowish solids (74 mg, yield: 56%). HPLC ⁄ MS:
tR = 12.57 min; m ⁄ z = 532.2 [M+H]+ HRMS: 531.238491 (found);
C27H37N3O6S, 531.24031 (calcd.). 1H NMR (600 MHz, CDCl3): 1.30
(3H, t, J = 7.2 Hz), 1.41 (9H, s), 1.50 (9H, s), 3.00 (2H, m), 3.81 (2H,
m), 4.25–4.31 (2H, m), 4.49 (1H, s), 6.75 (1H, d, J = 5.4 Hz), 6.87
(1H, d, J = 6.0 Hz), 7.14–7.15 (2H, m), 7.20–7.23 (1H, m), 7.26–7.29
(2H, m), 7.84 (1H, br.s), 9.40 (1H, br.s). 13C NMR (150 MHz, CDCl3):
14.0, 28.2, 28.5, 35.4, 51.7, 62.3, 64.7, 73.0, 81.6, 114.1, 115.4,
122.7, 126.7, 128.6, 128.7, 137.8, 146.6, 152.3, 164.3, 168.4, 168.7.
1
C23H25N3O3S, 423.16166 (calcd.). H NMR (600 MHz, CDCl3): )0.10
(2H, m), 0.32 (2H, m), 0.43 (1H, m), 1.76 (1H, m), 1.83 (1H, m), 1.89
(1H, m), 2.45 (1H, m), 2.51 (1H, m), 2.58–2.59 (2H, m), 2.77 (1H, m),
3.07 (1H, m), 4.22 (1H, d, J = 14.4 Hz), 4.63 (1H, s), 5.28 (1H, s),
5.45 (1H, d, J = 14.4 Hz), 7.35 (1H, m), 7.39–7.41 (2H, m), 7.53–7.54
(2H, m). 13C NMR (150 MHz, CDCl3): 3.29, 3.33, 10.1, 22.3, 23.0,
24.5, 25.9, 44.5, 52.4, 66.4, 122.1, 128.68, 128.74, 129.0, 129.49,
129.52, 134.3, 136.8, 140.5, 163.3, 164.2, 168.2.
3,4,6,7,8,9-Hexahydro-3-(N-mesityl)-carboxamide-4-
(4-chlorobenzyl)-1H-benzo thieno-[2,3-e]-1,4-diazepi-
ne-2,5-dione (5a-6): The product was isolated by silica gel
chromatography (petroleum ether ⁄ ethyl acetate, 2:1) as yellowish
solids (15 mg, yield: 12% over three steps). HPLC ⁄ MS:
tR = 11.63 min, m ⁄ z = 522.2 [M+H]+ HRMS: 521.153301 (found);
3,4-Dihydro-3-(N-tert-butyl)-carboxamide-4-phenethyl-1
H-thieno[2,3-e]-1,4-diazepine-2,5-dione (5b-1): The mix-
ture of 4b-1 and 0.5 mL of DCM (10% TFA) was stirred under RT
overnight. To the reaction was added 10 mL of DCM, then neutra-
1
C28H28ClN3O3S, 521.15399 (calcd.). H NMR (600 MHz, CDCl3): 1.26
(1H, m), 1.58 (6H, s), 1.77 (1H, m), 1.87–1.89 (2H, m), 2.17 (3H, m),
2.50–2.61 (3H, m), 3.08 (1H, m), 4.27 (1H, d, J = 14.4 Hz), 4.83 (1H,
Chem Biol Drug Des 2010; 76: 116–129
119