Z. Guo, Z. Zhang, Y. Zhang et al.
European Journal of Medicinal Chemistry 218 (2021) 113383
2.8 g, 60%, colorless oil; 1H NMR (400 MHz, DMSO‑d6)
d
1.43e1.56
85.1e86.3 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d 1.48e1.62 (m, 4H),
(m, 2H), 1.62e1.75 (m, 2H), 2.66e2.76 (m, 2H), 2.87e2.98 (m, 2H),
3.70 (s, 3H), 5.13 (t, J ¼ 3.7 Hz, 1H), 6.39 (dd, J ¼ 8.1, 1.1 Hz, 1H), 6.43
(dd, J ¼ 7.9, 1.1 Hz, 1H), 6.87 (t, J ¼ 8.0 Hz, 1H).
2.20 (s, 3H), 2.73e2.84 (m, 4H), 3.84 (s, 3H), 4.37 (s, 2H), 6.60e6.67
(m, 1H), 6.78 (d, J ¼ 1.6 Hz, 1H), 6.98 (d, J ¼ 7.5 Hz, 1H), 7.56 (d,
J ¼ 8.2 Hz, 2H), 7.90e7.97 (m, 2H); LC-MS (ESI) m/z: 310.20 (Mþ).
4-((8-Fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)
methyl)-N-hydroxybenzamide (14): 630 mg, 63%, colorless oil; 1H
7-Methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine
(34d):
3.0 g, 65%, brown oil; 1H NMR (400 MHz, DMSO‑d6)
d 1.45e1.56 (m,
2H), 1.64 (td, J ¼ 7.7, 6.6, 3.9 Hz, 2H), 2.56e2.64 (m, 2H), 2.77e2.85
(m, 2H), 3.65 (s, 3H), 6.54 (dd, J ¼ 8.4, 2.9 Hz, 1H), 6.64 (d, J ¼ 2.9 Hz,
1H), 6.74 (d, J ¼ 8.4 Hz, 1H).
NMR (400 MHz, DMSO‑d6) d 1.50e1.65 (m, 4H), 2.74e2.83 (m, 2H),
2.86e2.96 (m, 2H), 4.35 (s, 2H), 6.54e6.62 (m,1H), 6.71 (dd, J ¼ 11.9,
2.6 Hz, 1H), 7.10 (dd, J ¼ 8.3, 7.1 Hz, 1H), 7.46 (d, J ¼ 8.1 Hz, 2H),
7.68e7.75 (m, 2H), 9.05 (s, 1H), 11.20 (s, 1H); 13C NMR (101 MHz,
8-Methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine
(34e):
2.4 g, 52%, yellow solid; 1H NMR (400 MHz, DMSO‑d6)
d
1.44e1.55
DMSO‑d6)
d
25.22, 29.33, 33.53, 53.85, 57.13, 104.64 (d, J ¼ 23 Hz),
(m, 2H), 1.59e1.70 (m, 2H), 2.53e2.61 (m, 2H), 2.82e2.94 (m, 2H),
3.65 (s, 3H), 5.17 (t, J ¼ 3.5 Hz, 1H), 6.24 (dd, J ¼ 8.2, 2.6 Hz, 1H), 6.40
(d, J ¼ 2.6 Hz, 1H), 6.89 (d, J ¼ 8.2 Hz, 1H).
106.64 (d, J ¼ 21 Hz), 126.93, 127.77, 130.76 (d, J ¼ 9 Hz), 130.86 (d,
J ¼ 2 Hz), 131.47, 142.46, 153.14 (d, J ¼ 9 Hz), 159.85, 162.24, 164.05;
LC-MS (ESI) m/z: 315.22 (Mþ); HRMS (ESI-TOF) m/z [M þ H]þ calcd
7,8-Dimethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine (34f):
for
(220 nm).
4-((8-Bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)
methyl)-N-hydroxybenzamide (15): 440 mg, 44%, white solid; mp
127.7e130.1 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
1.45e1.66 (m, 4H),
C18H20N2O2F 315.1509, found 315.1509; Purity: 93.89%
1.6 g, 38%, white solid; 1H NMR (400 MHz, DMSO‑d6)
d 1.48 (p,
J ¼ 5.7 Hz, 2H), 1.60e1.67 (m, 2H), 2.53e2.58 (m, 2H), 2.81e2.86 (m,
2H), 3.64 (s, 3H), 3.66 (s, 3H), 4.87 (t, J ¼ 3.4 Hz, 1H), 6.50 (s, 1H),
6.65 (s, 1H).
d
8-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (34g): 2.5 g,
2.67e2.83 (m, 2H), 2.88 (t, J ¼ 4.9 Hz, 2H), 4.36 (s, 2H), 6.97 (dd,
J ¼ 7.9, 1.9 Hz, 1H), 7.04 (d, J ¼ 2.0 Hz, 1H), 7.05 (d, J ¼ 8.0 Hz, 1H),
7.45 (d, J ¼ 8.2 Hz, 2H), 7.72 (d, J ¼ 8.2 Hz, 2H), 9.10 (s, 1H), 11.20 (s,
54%, grey solid; 1H NMR (400 MHz, DMSO‑d6)
d 1.44e1.56 (m, 2H),
1.60e1.70 (m, 2H), 2.16 (s, 3H), 2.54e2.63 (m, 2H), 2.82e2.97 (m,
2H), 5.07 (t, J ¼ 3.5 Hz, 1H), 6.48 (dd, J ¼ 7.5, 1.7 Hz, 1H), 6.60 (d,
J ¼ 1.6 Hz, 1H), 6.88 (d, J ¼ 7.5 Hz, 1H).
1H); 13C NMR (101 MHz, DMSO‑d6)
d 24.92, 29.18, 33.68, 53.69,
57.09, 119.06, 120.28, 123.35, 126.93, 127.78, 131.52, 134.34, 142.36,
153.19, 163.97; LC-MS (ESI) m/z: 375.00 (Mþ); HRMS (ESI-TOF) m/z
[M þ H]þ calcd for C18H20N2O2Br 375.0708, found 375.0709; Purity:
97.93% (220 nm).
Methyl 4-((8-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-
1-yl)methyl)benzoate (35a): 3.1 g, 65%, colorless oil; 1H NMR
(400 MHz, DMSO‑d6)
d 1.49e1.67 (m, 4H), 2.75e2.85 (m, 2H),
2.87e2.95 (m, 2H), 3.84 (s, 3H), 4.40 (s, 2H), 6.60 (td, J ¼ 8.3, 2.6 Hz,
1H), 6.71 (dd, J ¼ 11.9, 2.6 Hz, 1H), 7.11 (dd, J ¼ 8.3, 7.1 Hz, 1H), 7.54
(d, J ¼ 8.2 Hz, 2H), 7.92e7.97 (m, 2H); LC-MS (ESI) m/z: 358.28 (Mþ).
Methyl 4-((8-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-
1-yl)methyl)benzoate (35b): 6.0 g, 80%, light yellow solid; mp
N-Hydroxy-4-((6-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]
azepin-1-yl)methyl)benzamide (16): 590 mg, 59%, white solid; mp
138.4e140.5 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d 1.42e1.54 (m, 2H),
1.54e1.70 (m, 2H), 2.87 (t, J ¼ 5.3 Hz, 4H), 3.73 (s, 3H), 4.34 (s, 2H),
6.57 (dd, J ¼ 10.7, 8.2 Hz, 2H), 6.99 (t, J ¼ 8.1 Hz, 1H), 7.45 (d,
96.5e98.1 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d
1.46e1.65 (m, 4H),
J ¼ 7.9 Hz, 2H), 7.71 (d, J ¼ 8.0 Hz, 2H), 9.20 (s, 1H), 10.98 (s, 1H); 13
C
2.68e2.83 (m, 2H), 2.89 (t, J ¼ 5.1 Hz, 2H), 3.84 (s, 3H), 4.41 (s, 2H),
6.97 (dd, J ¼ 7.9, 2.0 Hz, 1H), 7.03 (d, J ¼ 2.0 Hz, 1H), 7.06 (d,
J ¼ 7.9 Hz, 1H), 7.48e7.56 (m, 2H), 7.89e7.97 (m, 2H); LC-MS (ESI)
m/z: 374.00 (Mþ).
NMR (101 MHz, DMSO‑d6) d 23.76, 24.23, 29.17, 53.83, 55.51, 57.41,
104.40, 110.54, 122.60, 126.29, 126.84, 127.77, 131.37, 143.01, 152.69,
156.82, 164.07; LC-MS (ESI) m/z: 327.10 (Mþ); HRMS (ESI-TOF) m/z
[M þ H]þ calcd for C19H23N2O3 327.1709, found 327.1714; Purity:
99.48% (220 nm).
Methyl 4-((6-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]aze-
pin-1-yl)methyl)benzoate (35c): 3.3 g, 72%, white solid; mp
N-Hydroxy-4-((7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]
azepin-1-yl)methyl)benzamide (17): 620 mg, 62%, white solid; mp
98.1e99.4 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d 1.43e1.53 (m, 2H),
1.53e1.63 (m, 2H), 2.83e2.91 (m, 4H), 3.73 (s, 3H), 3.83 (s, 3H), 4.38
(s, 2H), 6.57 (dd, J ¼ 8.1, 6.1 Hz, 2H), 6.99 (t, J ¼ 8.2 Hz,1H), 7.49e7.56
(m, 2H), 7.88e7.95 (m, 2H); LC-MS (ESI) m/z: 326.19 (Mþ).
131.2e132.7 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d 1.48e1.61 (m, 4H),
2.77 (dt, J ¼ 15.5, 5.5 Hz, 4H), 3.67 (s, 3H), 4.28 (s, 2H), 6.63 (dd,
J ¼ 8.7, 3.0 Hz, 1H), 6.73 (d, J ¼ 3.0 Hz, 1H), 6.89 (d, J ¼ 8.7 Hz, 1H),
7.47 (d, J ¼ 8.1 Hz, 2H), 7.66e7.73 (m, 2H), 9.06 (s, 1H), 11.16 (s, 1H);
Methyl 4-((7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]aze-
pin-1-yl)methyl)benzoate (35d): 3.7 g, 75%, white solid; mp
13C NMR (101 MHz, DMSO‑d6)
d 25.53, 29.98, 34.35, 54.32, 54.97,
84.0e84.7 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d
1.48e1.63 (m, 4H),
57.72, 110.79, 115.48, 118.66, 126.81, 127.90, 131.33, 137.68, 143.20,
145.02, 153.94, 164.08; LC-MS (ESI) m/z: 327.14 (Mþ); HRMS (ESI-
TOF) m/z [M þ H]þ calcd for C19H23N2O3 327.1709, found 327.1714;
Purity: 99.13% (220 nm).
2.77 (dt, J ¼ 16.2, 5.6 Hz, 4H), 3.67 (s, 3H), 3.83 (s, 3H), 4.32 (s, 2H),
6.63 (dd, J ¼ 8.7, 3.0 Hz, 1H), 6.73 (d, J ¼ 3.0 Hz, 1H), 6.89 (d,
J ¼ 8.7 Hz, 1H), 7.51e7.58 (m, 2H), 7.88e7.95 (m, 2H); LC-MS (ESI)
m/z: 326.17 (Mþ).
N-Hydroxy-4-((8-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]
azepin-1-yl)methyl)benzamide (18): 640 mg, 64%, white solid; mp
Methyl 4-((8-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]aze-
pin-1-yl)methyl)benzoate (35e): 2.1 g, 64%, white solid; mp
103.8e105.4 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d 1.45e1.63 (m, 4H),
65.0e66.3 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d
1.40e1.66 (m, 4H),
2.70e2.78 (m, 2H), 2.81e2.93 (m, 2H), 3.65 (s, 3H), 4.34 (s, 2H), 6.38
(dd, J ¼ 8.2, 2.4 Hz, 1H), 6.47 (d, J ¼ 2.5 Hz, 1H), 6.99 (d, J ¼ 8.2 Hz,
1H), 7.46 (d, J ¼ 8.0 Hz, 2H), 7.60e7.77 (m, 2H), 9.09 (s, 1H), 11.14 (s,
2.66e2.79 (m, 2H), 2.86 (t, J ¼ 5.1 Hz, 2H), 3.65 (s, 3H), 3.83 (s, 3H),
4.38 (s, 2H), 6.38 (dd, J ¼ 8.2, 2.4 Hz, 1H), 6.46 (d, J ¼ 2.5 Hz, 1H),
6.99 (d, J ¼ 8.1 Hz, 1H), 7.55 (d, J ¼ 7.8 Hz, 2H), 7.87e7.95 (m, 2H);
LC-MS (ESI) m/z: 326.20 (Mþ).
1H); 13C NMR (101 MHz, DMSO‑d6)
d 25.81, 29.79, 33.61, 54.11,
54.78, 57.25, 104.40, 105.23, 126.86, 127.61, 127.80, 130.23, 131.41,
142.92, 152.54, 158.03, 164.04; LC-MS (ESI) m/z: 327.10 (Mþ); HRMS
(ESI-TOF) m/z [M þ H]þ calcd for C19H23N2O3 327.1709, found
327.1708; Purity: 98.50% (220 nm).
Methyl
azepin-1-yl)methyl)benzoate (35f): 1.7 g, 71%, white solid; mp
113.7e114.9 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
4-((7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[b]
d
1.50 (d, J ¼ 7.3 Hz,
2H), 1.58 (s, 2H), 2.71e2.83 (m, 4H), 3.66 (s, 3H), 3.67 (s, 3H), 3.83 (s,
3H), 4.37 (s, 2H), 6.60 (s, 1H), 6.74 (s, 1H), 7.53e7.60 (m, 2H),
7.89e7.94 (m, 2H); LC-MS (ESI) m/z: 356.21 (Mþ).
4-((7,8-Dimethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-
yl)methyl)-N-hydroxybenzamide (19): 450 mg, 45%, white solid;
mp 141.2e143.3 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d 1.39e1.65 (m,
Methyl 4-((8-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-
1-yl)methyl)benzoate (35g): 2.6 g, 78%, white solid; mp
4H), 2.63e2.89 (m, 4H), 3.67 (d, J ¼ 2.0 Hz, 6H), 4.32 (s, 2H), 6.61 (s,
1H), 6.74 (s, 1H), 7.48 (d, J ¼ 8.0 Hz, 2H), 7.63e7.76 (m, 2H), 9.06 (s,
11