2796 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 12
Tan et al.
with ether. The reaction was washed with water and brine, dried
over MgSO4, and concentrated under reduced pressure. The
crude product was dissolved in toluene (20 mL) and refluxed
for 1 h. After cooling to ambient temperature, the crude
mixture was concentrated in vacuo. The crude product was
dissolved in dioxane (5 mL), concentrated HCl (3 mL), and water
(3 mL) and then refluxed for 1 h. After cooling to ambient
temperature, the crude mixture was diluted with ether, washed with
water and brine, dried over MgSO4, and concentrated under reduced
pressure.
(t, J ) 6.8 Hz, 2H), 2.93 (t, J ) 7.8 Hz, 2H), 1.69 (m, 4H), 1.46
(m, 2H). HRMS (EI+) m/ z for C18H22N2O2 [M + H]+: calcd,
299.1760; found, 299.1767.
N,N-Dimethyl-2-(4-phenoxybenzamido)ethylamine Hydro-
chloride (11). Refer to general procedure for N,N-dimethylation
fo amine hydrochloride salt described above: 0.09 g, 98% yield.
1H NMR (400 MHz, methanol-d4) δ 7.87 (d, J ) 8.8 Hz, 2H),
7.42(t, J ) 7.8 Hz, 2H), 7.21 (t, J ) 7.6 Hz, 1H), 7.05 (d, J ) 8.8
Hz, 2H), 7.02 (d, J ) 9.2 Hz, 2H), 3.74 (t, J ) 5.8 Hz, 2H), 3.37
(t, J ) 5.8 Hz, 2H), 2.98 (s, 6H). HRMS (EI+) m/z for C17H20N2O2
[M + H]+: calcd, 285.1603; found, 285.1609.
3-[(4-Phenoxyphenyl)oxy]propylamine Hydrochloride (3).
Refer to general procedure for t-Boc deprotection described
N,N-Dimethyl-3-(4-phenoxybenzamido)propylamine Hydro-
chloride (12). Refer to general procedure for N,N-dimethylation
fo amine hydrochloride salt described above: 0.12 g, 76%
1
above: 0.12 g, 53% yield). H NMR (400 MHz, methanol-d4) δ
7.29 (t, J ) 8.0 Hz, 2H), 7.04 (t, J ) 7.4 Hz, 1H), 6.96 (s, 4H),
6.89 (d, J ) 7.6 Hz, 2H), 4.11 (t, J ) 5.8 Hz, 2H), 3.16 (t, J ) 7.2
Hz, 2H), 2.14 (m, 2H). HRMS (EI+) m/z for C15H17NO2 [M +
H]+: calcd, 244.1338; found, 244.1343.
1
yield. H NMR (400 MHz, methanol-d4) δ 7.86 (d, J ) 8.8 Hz,
2H), 7.41 (t, J ) 8.1 Hz, 2H), 7.20 (t, J ) 7.6 Hz, 1H), 7.05
(d, J ) 7.8 Hz, 2H), 7.01 (d, J ) 8.8 Hz, 2H), 3.48 (t, J ) 6.6 Hz,
2H), 3.19 (t, J ) 7.6 Hz, 2H), 2.91 (s, 6H), 2.03 (m, 2H). HRMS
(EI+) m/z for C18H22N2O2 [M + H]+: calcd, 299.1760; found,
299.1757.
N,N-Dimethyl-3-[(4-phenoxyphenyl)oxy]propylamine Hydro-
chloride (4). Refer to general procedure for N,N-dimethylation to
1
amine hydrochloride salt described above; 0.17 g, 76% yield. H
NMR (400 MHz, methanol-d4) δ 7.30 (t, J ) 8.0 Hz, 2H), 7.04 (t,
J ) 7.4 Hz, 1H), 6.96 (s, 4H), 6.89 (d, J ) 8.0 Hz, 2H), 4.10 (d,
J ) 5.8 Hz, 2H), 3.32 (m, 2H), 2.92 (s, 6H), 2.21 (m, 2H). HRMS
(EI+) m/z for C17H21NO2 [M + H]+: calcd, 272.1651; found,
272.1641.
N,N-Dimethyl-4-(4-phenoxybenzamido)butylamine Hydro-
chloride (13). Refer to general procedure for N,N-dimethylation
to amine hydrochloride salt: 0.16 g, 11% yield. 1H NMR
(400 MHz, methanol-d4) δ 7.82 (d, J ) 8.8 Hz, 2H), 7.41 (t, J )
7.8 Hz, 2H), 7.20 (t, J ) 7.4 Hz, 1H), 7.06 (d, J ) 7.6 Hz, 2H),
7.00 (d, J ) 8.8 Hz, 2H), 3.43 (t, J ) 6.8 Hz, 2H), 3.19
(t, J ) 8.0 Hz, 2H), 2.89 (s, 6H), 1.77 (m, 2H), 1.69 (m, 2H).
HRMS (EI+) m/z for C19H24N2O2 [M + H]+: calcd, 313.1916;
found, 313.1925.
3-[(3-Phenoxyphenyl)oxy]propylamine Hydrochloride (5).
Refer to general procedure for t-Boc deprotection described
1
above: 0.76 g, 75% yield. H NMR (400 MHz, methanol-d4) δ
7.35 (t, J ) 8.2 Hz, 2H), 7.24 (t, J ) 8.4 Hz, 1H), 7.12 (t, J ) 7.4
Hz, 1H), 6.98 (d, J ) 7.6 Hz, 2H), 6.70 (app d, J ) 7.6 Hz, 1H),
6.57 (app s, 1H), 6.56 (app s, 1H), 4.08 (t, J ) 5.8 Hz, 2H), 3.13
(t, J ) 7.2 Hz, 2H), 2.12 (m, 2H). HRMS (EI+) m/z for C15H17-
NO2 [M + H]+: calcd, 244.1338; found, 244.1339.
N,N-Dimethyl-5-(4-phenoxybenzamido)pentylamine Hydro-
chloride (14). Refer to general procedure for N,N-dimethylation
1
fo amine hydrochloride salts: 0.09 g, 31% yield. H NMR (400
MHz, methanol-d4) δ 7.82 (d, J ) 8.8 Hz, 2H), 7.41 (t, J ) 8.0
Hz, 2H), 7.20 (t, J ) 7.6 Hz, 1H), 7.04 (d, J ) 8.4 Hz, 2H), 7.00
(d, J ) 8.8 Hz, 2H), 3.40 (t, J ) 6.0 Hz, 2H), 3.13 (t, J ) 7.8 Hz,
2H), 2.88 (s, 6H), 1.78 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H). HRMS
(EI+) m/z for C20H26N2O2 [M + H]+: calcd, 327.2073; found,
327.2087.
2-(4-Phenoxyphenyl)-2-phenylethylamine Hydrochloride (15).
Refer to general procedure for the reduction of nitrile to amine
hydrochloride described above: 0.24 g, 47% yield. 1H NMR (400
MHz, methanol-d4) δ 7.22-7.35 (m, 9H), 7.04 (t, J ) 7.6 Hz, 1H),
6.89-6.92 (m, 4H), 4.22 (t, J ) 8.0 Hz, 1H), 3.56 (d, J ) 8.0 Hz,
1H). HRMS (EI+) m/z for C20H19NO [M + H]+: calcd, 290.1545;
found, 290.1559.
2-(3-Phenoxyphenyl)-2-phenylethylamine Hydrochloride (16).
Refer to general procedure for the reduction of nitrile to amine
hydrochloride described above: 2.79 g, 26% yield. 1H NMR (400
MHz, methanol-d4) δ 7.34 (m, 10H), 7.12 (app t, J ) 7.3 Hz, 1H),
6.98 (m, 1H), 6.86 (dd, J ) 8.1, 2.7 Hz, 1H), 4.26 (t, J ) 8.1 Hz,
1H), 3.62 (d, J ) 8.3 Hz, 2H). HRMS (EI+) m/z for C20H19NO [M
+ H]+: calcd, 290.1545; found, 290.1548.
N-Methyl-3-[(4-phenoxyphenyl)oxy]propylamine Hydrochlo-
ride (6). Refer to general procedure for t-Boc deprotection
described above: 0.94 g, 90% yield. 1H NMR (400 MHz,
methanol-d4) δ 7.29 (t, J ) 8.0 Hz, 2H), 7.04 (t, J ) 7.4 Hz, 1H),
6.96 (s, 4H), 6.90 (app t, J ) 7.4 Hz, 2H), 4.11 (t, J ) 5.8 Hz,
2H), 3.23 (t, J ) 7.2 Hz, 2H), 2.74 (s, 3H), 2.17 (m, 2H). HRMS
(EI+) m/z for C16H18NO2 [M + H]+: calcd, 258.1494; found,
258.1503.
2-(4-Phenoxybenzamido)ethylamine Hydrochloride (7). Refer
to general procedure for t-Boc deprotection described above: 0.25
g, ∼100% yield. 1H NMR (400 MHz, methanol-d4) δ 7.88 (d, J )
8.8 Hz, 2H), 7.41(t, J ) 7.8 Hz, 2H), 7.20 (t, J ) 7.4 Hz, 1H),
7.05 (d, J ) 8.0 Hz, 2H), 7.01 (d, J ) 8.8 Hz, 2H), 3.66 (t, J ) 5.8
Hz, 2H), 3.17 (t, J ) 6.0 Hz, 2H); 13C NMR (400 MHz, methanol-
d4) δ 170.5, 162.5, 157.2, 131.2, 130.6, 129.1, 125.6, 121.0, 118.4,
41.4, 38.8. HRMS (EI+) m/z for C15H16N2O2 [M + H]+: calcd,
257.1290; found, 257.1293.
3-(4-Phenoxybenzamido)propylamine Hydrochloride (8). Re-
fer to general procedure for t-Boc deprotection described above:
0.23 g, 96% yield. 1H NMR (400 MHz, methanol-d4) δ 7.84 (d, J
) 8.8 Hz, 2H), 7.41 (t, J ) 8.1 Hz, 2H), 7.20 (t, J ) 7.3 Hz, 1H),
7.06 (d, J ) 7.8 Hz, 2H), 7.01 (d, J ) 8.8 Hz, 2H), 3.49 (t, J ) 6.6
Hz, 2H), 2.98 (t, J ) 7.3 Hz, 2H), 1.94 (quintet, J ) 7.0 Hz, 2H).
HRMS (EI+) m/z for C16H18N2O2 [M + H]+: calcd, 271.1447;
found, 271.1447.
8-Phenoxy-1-phenyl-2,3,4,5-tetrahydro-3-benzazepine Hy-
drochloride (17). Refer to general procedure for t-Boc depro-
1
tection described above: 0.50 g, 90% yield. H NMR (400 MHz,
methanol-d4) δ 7.40 (t, J ) 7.6 Hz, 2H), 7.32 (app t, J ) 7.4 Hz,
2H), 7.27 (m, 2H), 7.19 (d, J ) 7.6 Hz, 2H), 7.07 (t, J ) 7.4 Hz,
1H), 6.87 (d, J ) 7.6 Hz, 2H), 6.81 (dd, J ) 8.4, 2.4 Hz, 1H), 6.40
(d, J ) 1.6 Hz, 1H), 4.61 (d, J ) 8.4 Hz, 1H), 3.72 (m, 2H), 3.48
(dd, J ) 11.8, 7.6 Hz, 2H), 3.18 (m, 2H). HRMS (EI+) m/z for
C22H21NO [M + H]+: calcd, 316.1701; found, 316.1713.
4-(4-Phenoxybenzamido)butylamine Hydrochloride (9).
Refer to general procedure for t-Boc deprotection described
1
above: 0.21 g, 97% yield. H NMR (400 MHz, methanol-d4) δ
7.82 (d, J ) 9.3 Hz, 2H), 7.41 (t, J ) 8.1 Hz, 2H), 7.20 (t, J ) 7.3
Hz, 1H), 7.05 (d, J ) 8.8 Hz, 2H), 7.00 (d, J ) 8.8 Hz, 2H), 3.42
(t, J ) 6.6 Hz, 2H), 2.98 (t, J ) 7.1 Hz, 2H), 1.71 (m, 4H). HRMS
(EI+) m/z for C17H20N2O2 [M + H]+: calcd, 285.1603; found,
285.1603.
7-Phenoxy-1-phenyl-2,3,4,5-tetrahydro-3-benzazepine Hy-
drochloride (18). Refer to general procedure for t-Boc depro-
1
tection described above: 0.10 g, 85% yield. H NMR (400 MHz,
methanol-d4) δ 7.44 (t, J ) 7.6 Hz, 3H), 7.35 (app t, J ) 8.1 Hz,
3H), 7.23 (d, J ) 8.1, 2H), 7.12 (t, J ) 7.3 Hz, 1H), 7.00 (dd, J )
8.8, 1.0 Hz, 1H), 6.90 (s, 1H), 6.77 (s, 2H), 4.60 (dd, J ) 8.6, 1.7
Hz, 1H), 3.66-3.84 (m, 2H), 3.22 (m, 2H), 3.09 (m, 2H). HRMS
(EI+) m/z for C22H21NO [M + H]+: calcd, 316.1701; found,
316.1702.
5-(4-Phenoxybenzamido)pentylamine Hydrochloride (10).
Refer to general procedure for t-Boc deprotection described
1
above: 0.13 g, 98% yield. H NMR (400 MHz, methanol-d4) δ
7.81 (d, J ) 8.8 Hz, 2H), 7.41 (t, J ) 8.1 Hz, 2H), 7.20 (t, J ) 7.6
Hz, 1H), 7.05 (d, J ) 8.8 Hz, 2H), 7.00 (d, J ) 9.3 Hz, 2H), 3.39