A. Bali et al. / European Journal of Medicinal Chemistry 74 (2014) 477e490
487
1498, 1369, 1326, 1129,833, 747 and 691. 1H NMR (400 MHz; CDCl3,
, J): 12.5 (broad s, 1H); 7.43 (dd, 1H, J ¼ 7.96 Hz, 1.56 Hz); 7.31 (td,
(14.9) [M þ 2], 204 (51.3) [M þ H], 166 (4.6) [[m/z 204 e HCl] e 2H],
142 (33.9) [ClC6H4N]CH2], 140 (100) [ClC6H4N]CH2] e 2H, 130
(12.4) [m/z 204 e 2HCl], 127 (8.2) [ClC6H4NH], 113 (33.8) [ClC6H6].
d
1H, J ¼ 7.00 Hz, 1.92 Hz); 7.22 (td, 2H, J ¼ 7.00 Hz, 1.92 Hz); 7.04 (dd,
2H, J ¼ 7.96 Hz, 1.56 Hz); 7.00 (broad s, 1H); 6.98 (dd, 1H, J ¼ 8.00,
2.00 Hz); 6.94 (td, 1H, J ¼ 7.00 Hz, 1.90 Hz); 6.88 (m, 1H); 2.32 (s,
3H). MS [ESI, m/z (relative intensity)]: 227 (83.5) [M þ H], 209 (17.5)
[m/z 227 e H2O], 199 (20.4) [m/z 227 e CO], 184 (20.0) [m/z 199 e
CH3], 136 (40.7) [OH(C6H4)e(C)(NH)CH3], 133 (100.0) [C6H5(NH)e
N](C)CH3].
4.1.4. Preparation of N-(3-chloropropyl)-X0-methoxyphenylamines
(7e8)
A mixture of 4- or 2-anisidine (5.0 g, 0.04 M), 1-bromo-3-chloro
propane (4.0 ml, 0.04 M) and anhydrous potassium carbonate
(5.52 g, 0.04 M) in 70 ml of ethyl methyl ketone was heated under
reflux for 8 h. After removal of insoluble solid by filtration, the
solvent was evaporated under vacuum yielding the corresponding
N-(3-chloropropyl)-X-methoxyphenylamine products.
4.1.2. Preparation of X-(1H-indol-2-yl)phenols (3e4)
4- or 2-hydroxy acetophenone phenylhydrazone (10.0 g,
0.044 M) was heated with 60 g of polyphosphoric acid on an oil
bath for 1 h and with continuous stirring maintaining the tem-
perature at 100e120 ꢀC. The mixture was finally poured over
crushed ice and stirred well. The precipitates obtained were filtered
at the pump and washed well with water affording the corre-
sponding X-(1H-indol-2-yl)phenols.
4.1.4.1. N-(3-chloropropyl)-4-methoxyphenylamine (7). Yield 66.9%,
b.p. 242e244 ꢀC. FTIR (KBr, cmꢂ1): 3358, 3049, 2980, 1600, 1498,
1436, 1330, 1246, 1170, 1137, 1065, 744 and 690; 1H NMR (400 MHz;
CDCl3,
d
, J): 8.17 (broad s, 1H); 7.02 (d, 2H, J ¼ 7.2 Hz); 6.72 (d, 2H,
J ¼ 7.2 Hz); 3.58 (s, 3H); 3.41 (t, 2H, J ¼ 6.2 Hz); 3.27 (t, 2H,
J ¼ 6.2 Hz); 1.83 (q, 2H, J ¼ 6.2 Hz). MS [ESI, m/z (relative intensity)]:
202 (22.9) [M þ 2], 200 (63.9) [M þ H],199 (100.0) [M],164 (9.2) [m/
z 200 e HCl], 150 (5.2) [m/z 200 e CH3Cl], 136 (55.2) [CH3OC6H4N]
CH2], 123 (38.6) [CH3OC6H4]NH], 108 (19.3) [CH3OC6H5].
4.1.2.1. 4-(1H-indol-2-yl)phenol (3). Yield 84.6%, m.p.193e197 ꢀC,
FTIR (KBr, cmꢂ1):, 3425, 3212, 3046, 1601, 1498, 1246, 1177, 830 and
749; 1H NMR (400 MHz; CDCl3,
d, J): 9.09 (broad s, 1H); 7.76 (broad
s, 1H); 7.58 (d, 2H, J ¼ 7.2 Hz); 7.41 (d, 1H, J ¼ 7.7 Hz); 7.33 (d, 1H,
J ¼ 7.9 Hz); 6.91 (m, 1H); 6.82 (d, 2H, J ¼ 7.2 Hz); 6.53 (s, 1H). MS [EI,
m/z (relative intensity)]: 211 (17.5) [M þ 2], 210 (100.0) [M þ H], 192
(3.3) [m/z 210 e H2O], 182 (5.3) [m/z 210 e CO], 133 (12.3) [m/z 210
e C6H4], 116 (8.5) [m/z 210 eC6H4eOH].
4.1.4.2. N-(3-chloropropyl)-2-methoxyphenylamine (8). Yield 69.3%,
b.p. 247e248 ꢀC. FTIR (KBr, cmꢂ1): 3412, 3060, 2937, 1605, 1507,
1457, 1260, 1172, 1118, 1021, 751 and 650; 1H NMR (400 MHz; CDCl3,
d, J): 7.19 (dd, 1H, J ¼ 8.0 Hz, 1.4 Hz); 7.10 (td, 1H, J ¼ 7.8 Hz, 1.4 Hz)
7.00 (td, 1H, J ¼ 7.8 Hz, 1.4 Hz); 6.70 (dd, 1H, J ¼ 8.0 Hz, 1.4 Hz); 4.06
(broad s, 1H); 3.81 (s, 3H); 3.58 (t, 2H, J ¼ 6.6 Hz); 3.30 (t, 2H,
J ¼ 6.6 Hz); 2.39 (q, 2H, J ¼ 6.6 Hz). MS [ESI, m/z (relative intensity)]:
202 (20.1) [Mþ2], 200 (59.4) [M þ H],199 (14.0) [M],164 (76.6) [m/z
200 e HCl], 150 (4.7) [m/z 200 e CH3Cl], 136 (100.0) [CH3OC6H4N]
CH2], 123 (34.0) [CH3OC6H4]NH], 108 (14.3) [CH3OC6H5].
Melting point: 247e248 ꢀC. Yield 69.3%.
4.1.2.2. 2-(1H-indol-2-yl)phenol (4). Yield 92.4%, m.p.187e189 ꢀC.
FTIR (KBr, cmꢂ1): 3445, 3349, 3144, 3055, 1590, 1495, 1508,
1370,1324, 1130, 830 and 749; 1H NMR (400 MHz; CDCl3,
d, J): 10.08
(broad s, 1H); 7.90 (broad s, 1H); 7.76 (dd, 1H, J ¼ 7.76 Hz, 1.16 Hz);
7.53 (dd, 1H, J ¼ 7.76 Hz, 1.16 Hz); 7.43 (dd, 1H, J ¼ 7.76 Hz, 1.16 Hz);
7.28 (td, 1H, J ¼ 8.00 Hz, 2.00 Hz); 7.08 (m, 2H); 7.00 (m, 1H); 6.83
(m, 2H). MS [ESI, m/z (relative intensity)]: 210 (100.0) [M þ H], 192
(5.3) [m/z 210 e H2O], 182 (3.7) [m/z 210 e CO], 116 (8.5) [m/z 210 e
C6H4eOH].
4.1.5. Preparation of N-[3-{X-(1H-indol-2-yl)phenoxy}propyl]-X0-
chlorophenyl amines (9e12)
A mixture of X-(1H-indol-2-yl)phenol (3e4) (5.0 g, 0.024 M)
with X0-chloro-N-(3-chloropropyl)phenylamines (5e6) (4.9 g,
0.024 M) and anhydrous potassium carbonate (6.62 g, 0.048 M) in
100 ml of acetone was heated under reflux for 24 h. After removal of
insoluble solid by filtration, the solvent was evaporated under
vacuum affording the crude N-[3-{X-(1H-indol-2-yl)phenoxy}pro-
pyl]-X0-chlorophenyl amines.
4.1.3. Preparation of X0-chloro-N-(3-chloropropyl)phenylamines
(5e6)
A mixture of 4- or 2-chloroaniline (5.0 g, 0.04 M), 1-bromo-3-
chloro propane (4.0 ml, 0.04 M) and anhydrous potassium car-
bonate (5.52 g, 0.04 M) in 70 ml of ethyl methyl ketone was heated
under reflux for 8 h. After removal of insoluble solid by filtration,
the solvent was evaporated under vacuum yielding X-chloro-N-(3-
chloropropyl)phenyl amine as a liquid. Yield 5.07 g (62.52%), b.p.
180e183 ꢀC.
4.1.5.1. N-[3-{2-(1H-indol-2-yl)phenoxy}propyl]-4-chlorophenylamine
(9). Yield 65.83%, m.p. 116e118 ꢀC. UV (lmax (MeOH) 224.6 (
3
max
353.22). FTIR (KBr, cmꢂ1): 3349, 2896, 1600, 1450, 1305, 1224, 1090,
4.1.3.1. 4-Chloro-N-(3-chloropropyl)phenylamines (5). Yield 62.52%,
b.p. 180e183 ꢀC. FTIR (KBr, cmꢂ1): 3348, 2921, 1599, 1494, 1302,
1065,1040 and 745; 1H NMR (400 MHz; CDCl3,
d, J): 9.5 (broad s,1H);
7.8 (dd, 1H, J ¼ 7.9 Hz, 1.85 Hz); 7.63 (dd, 1H, J ¼ 7.9 Hz, 1.85 Hz)
7.38(dd,1H, J ¼ 7.9 Hz,1.85 Hz); 7.30 (td,1H, J ¼ 7.20 Hz,1.70 Hz); 7.25
(s, 1H); 7.18 (td, 1H, J ¼ 7.20 Hz, 1.70 Hz); 7.05 (m, 2H); 6.85 (m, 1H);
6.6 (d, 2H, J ¼ 8.8 Hz); 6.5 (d, 2H, J ¼ 8.8 Hz); 4.4 (t, 2H, J ¼ 6.1 Hz);
4.32 (broad s, 1H); 3.75 (t, 2H, J ¼ 6.1 Hz); 2.35 (q, 2H, J ¼ 6.1 Hz). MS
[ESI, m/z (relative intensity)]: 379 (13.99) [M þ 2], 377 (42.92) [M],
266 (4.88) [C6H4CH(C)NHeC6H5O(CH2)3NH2], 248 (21.95)
[C6H4CH(C)NHC6H4 OCH2 CH]CH2 e [H], 222 (7.31) [C6H4CH(C)NH
e C6H5O]CH2], 210 (100) [C6H4CH(C)NH C6H4 OH], 192 (1.95)
[C6H4CH(C)NHC6H4], 168 (21.95) [ClC6H4NHCH2CH]CH2], 152 (9.75)
1150, 1093, 817, 745 and 675; 1H NMR (400 MHz; CDCl3,
d, J): 7.20
(d, 2H, J ¼ 9.6 Hz); 6.82 (d, 2H, J ¼ 9.6 Hz); 5.75 (broad s,1H); 3.70 (t,
2H, J ¼ 6.1 Hz); 3.58 (t, 2H, J ¼ 6.1 Hz); 2.25 (q, 2H, J ¼ 6.1 Hz). MS
[ESI, m/z (relative intensity)]: 208 (14.2) [M þ 4], 206 (69) [M þ 2],
204 (100.0) [M þ H],168 (17.3) [m/z 204 e HCl],154 (5.7) [m/z 204 e
CHCl3], 142 (8.8) [ClC6H4N]CH2], 140 (25.1) [ClC6H4N]CH2e2H],
130 (17.2) [m/z 204 e 2HCl], 127 (30.4) [ClC6H4NH].
4.1.3.2. 2-Chloro-N-(3-chloropropyl)phenylamines (6). Yield 77.60%,
b.p. 210e212 ꢀC. FTIR (KBr, cmꢂ1): 3342, 2963, 1613, 1491, 1444,
_
[ClC6H4NHCH]CH2] [2H], 140 (4.87) [ClC6H4N]CH2], 127 (2.44)
1307, 1152, 1089, 745 and 662; 1H NMR (400 MHz; CDCl3,
d, J): 7.24
[ClC6H4NH]. Anal. Calcd. for C23H21N2ClO: C, 73.30; H, 5.62; N, 7.43.
Found: C, 73.24; H, 5.59; N, 7.35.
(dd, 1H, J ¼ 7.9 Hz, 2.0 Hz); 7.04 (td, 1H, J ¼ 7.3 Hz, 1.8 Hz); 6.75 (dd,
1H, J ¼ 7.9 Hz, 2.0 Hz) 6.68 (td, 1H, J ¼ 7.3 Hz, 1.8 Hz); 3.90 (broad s,
1H); 3.70 (t, 2H, J ¼ 6.1 Hz); 3.53 (t, 2H, J ¼ 6.1 Hz); 2.26 (q, 2H,
J ¼ 6.1 Hz). MS [ESI, m/z (relative intensity)]: 208 (6.4) [M þ 4], 206
4.1.5.2. N-[3-{2-(1H-indol-2-yl)phenoxy}propyl]-2-chlorophenylamine
(10). Yield 59.55%, m.p. 176e178 ꢀC. UV (lmax (MeOH) 206.2