S. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 670e675
673
dried. The product was recrystallized from methanol to give col-
ourless to cream colored crystals.
4.1.3.3. N-[(2-chloro-8-methylquinolin-3-yl)-methyl]-4-fluoroaniline
4c. IR (KBr) cmꢀ1; 3410 (NeH), 1629 (C]C), 1590 (C]N), 1023
Yield: 82%; m.p.: 167e168 ꢃC; IR (KBr) cmꢀ1; 3617 (OH), 1623
(CeN), 765 (CeCl).1H NMR (300 MHz, CDCl3)
d; 2.74 (s, 3H, CH3),
(C]C), 1599 (C]N), 758 (CeCl). 1H NMR (300 MHz, DMSO-d6)
d;
4.36 (s,1H, NH), 4.55 (s, 2H, CH2), 6.54e6.57 (d, 2H, H-20 and 60,
J ¼ 8.0 Hz), 7.13e7.16 (d, 2H, H-30 and 50, J ¼ 7.7 Hz), 7.38e7.4 (t, 1H,
H-6, J ¼ 7.2 Hz), 7.54e7.61 (m, 2H, H-5 and 7), 8.09 (s,1H, H-4). 13C
2.74 (s, 3H, CH3), 4.68 (s, 2H, CH2), 5.66 (s, 1H, OH, D2O-exchan-
geble), 7.46e7.51 (t, 1H, H-6, J ¼ 7.5 Hz), 7.60e7.62 (d, 1H, H-7,
J ¼ 7.1 Hz), 7.84e7.86 (d, 1H, H-5, J ¼ 7.8 Hz), 8.37 (s, 1H, H-4). 13C
NMR (CDCl3, 75 MHz) d; 17.63 (CH3), 46.39 (CH2), 113.93, 121.82,
NMR (75 MHz, DMSO-d6)
d; 17.39 (CH3), 59.88 (CH2), 125.71, 126.91,
125.96, 127.42, 129.17, 130.98, 133.98, 136.08, 141.51, 146.96, 149.87,
153.47. FAB-MS; m/z 301 (Mþ), 303 (Mþ2), 190 (C11H9ClNþ). Anal.
Calcd. for C17H14ClFN2 : C, 67.89; H, 4.69; N, 9.31. Found: C, 67.70;
H, 4.65; N, 9.35%.
127.19, 130.01, 133.60, 135.22, 136.15, 145.10, 147.45. FAB-MS; m/z
208 (Mþ), 210 (Mþ2). Anal. Calcd. for C11H10ClNO: C, 63.62; H, 4.85;
N, 6.75. Found: C, 63.52; H, 4.83; N, 6.78%.
4.1.2. Synthesis of 2-chloro-3-(chloromethyl)-8-methylquinoline 3
To a solution of compound 2 (2.07 g, 0.01 mol) in dry benzene
(30 ml), SOCl2 (1.54 g, 0.013 mol) was added and the mixture was
refluxed for 4e6 h. Solvent was evaporated under reduced pressure
and the residue was dissolved in ether, washed with 10% NaHCO3
and twice with water. It was then dried over Na2SO4 and concen-
trated in vacuo to give a residue which was crystallized from
methanol as brown to light brown crystals.
4.1.3.4. 3-Chloro-N-[(2-chloro-8-methylquinolin-3-yl)methyl]-4-flu-
oroaniline 4d. IR (KBr) cmꢀ1; 3428 (NeH), 1636 (C]C), 1597
(C]N), 1036 (CeN), 749 (CeCl). 1H NMR (300 MHz, CDCl3)
d; 2.75
(s, 3H, CH3), 4.37 (s,1H, NH), 4.57 (s, 2H, CH2), 6.55e6.57 (d, 1H,
H-60, J ¼ 7.7 Hz), 6.71 (s, 1H, H-20), 7.19e7.21 (d, 1H, H-50, J ¼ 7.7 Hz),
7.40e7.44 (t, 1H, H-6, J ¼ 7.5 Hz), 7.52e7.60 (m, 2H, H-5 and 7), 8.10
(s,1H, H-4). FAB-MS; m/z 335 (Mþ), 337 (Mþ2), 190 (C11H9ClNþ).
Anal. Calcd. for C17H13Cl2FN2 : C, 60.91; H, 3.91; N, 8.36. Found:
C, 61.11; H, 3.92; N, 8.38%.
Yield: 89%; m.p.: 80e81 ꢃC; IR (KBr) cmꢀ1; 1624 (C]C), 1599
(C]N), 763 (CeCl). 1H NMR (300 MHz, CDCl3)
d; 2.74 (s, 3H, CH3),
4.85 (s, 2H, CH2), 7.47e7.53 (t, 1H, H-6, J ¼ 7.4 Hz), 7.61e7.63
4.1.3.5. 3,4-Dichloro-N-[(2-chloro-8-methylquinolin-3-yl)methyl]an-
(d, 1H, H-7, J ¼ 7.2 Hz), 7.84e7.87 (d, 1H, H-5, J ¼ 7.7 Hz), 8.24
iline 4e. IR (KBr) cmꢀ1; 3420 (NeH), 1643 (C]C), 1602 (C]N), 1021
(s,1H, H-4). 13C NMR (CDCl3, 75 MHz)
d; 17.64 (CH3), 43.11 (CH2),
(CeN), 758 (CeCl). 1H NMR (300 MHz, CDCl3)
d; 2.77 (s, 3H, CH3),
125.29, 127.04, 128.47, 130.85, 136.34, 138.72, 146.33, 148.37. FAB-
MS; m/z 226 (Mþ), 228 (Mþ2), 190 (C11H9ClNþ). Anal. Calcd. for
C11H9Cl2N : C, 58.43; H, 4.01; N, 6.19. Found: C, 58.63; H, 4.03; N,
6.23%.
4.39 (s,1H, NH), 4.54 (s, 2H, CH2), 6.55e6.57 (d, 1H, H-60, J ¼ 7.8 Hz),
6.72 (s, 1H, H-20), 7.18e7.20 (d, 1H, H-50, J ¼ 7.8 Hz), 7.40e7.44 (t, 1H,
H-6, J ¼ 7.5 Hz), 7.53e7.60 (m, 2H, H-5 and 7), 8.07 (s,1H, H-4). Anal.
Calcd. for C17H13Cl3N2 : C, 58.06; H, 3.73; N, 7.97. Found: C, 58.26; H,
3.71; N, 7.99%.
4.1.3. General procedure for the synthesis of compounds 4aep
Compound 3 (1.13 g, 0.005 mol) was dissolved in 20 ml of
absolute ethanol and to this solution equimolar amount of
substituted aniline/butyl/cyclohexyl/benzylamine (0.005 mol)
along with 1 ml of triethylamine was added and the mixture was
refluxed for 12e16 h. After completion of the reaction (moni-
tored by TLC), the contents of the flask were reduced to one
third of its volume and left overnight. The solid mass obtained
was filtered, washed with water, dried and recrystallized from
ethanol. The physical data of compounds 4aep is presented in
the Table 1
4.1.3.6. N-[(2-chloro-8-methylquinolin-3-yl)methyl]-4-methylaniline
4f. IR (KBr) cmꢀ1; 3396 (NeH), 1629 (C]C), 1598 (C]N), 1042
(CeN), 762 (CeCl). 1H NMR (300 MHz, CDCl3)
d; 2.52 (s, 3H,
Ph-CH3), 2.75 (s, 3H, CH3), 4.17 (bs,1H, NH), 4.52 (s, 2H, CH2),
6.50e6.53 (d, 2H, H-20 and 60, J ¼ 7.5 Hz), 6.79e6.81 (d, 2H, H-30 and
50, J ¼ 7.0 Hz), 7.37e7.42 (t, 1H, H-6, J ¼ 7.3 Hz), 7.53e7.60 (m, 2H,
H-5 and 7), 8.11 (s, 1H, H-4). Anal. Calcd. for C18H17ClN2 : C, 72.84;
H, 5.77; N, 9.44. Found: C, 72.97; H, 5.80; N, 9.48%.
4.1.3.7. N-[(2-chloro-8-methylquinolin-3-yl)methyl]-4-methoxyanili-
ne 4g. IR (KBr) cmꢀ1; 3430 (NeH), 1637 (C]C), 1605 (C]N), 1046
4.1.3.1. N-[(2-chloro-8-methylquinolin-3-yl)methyl]aniline 4a. IR (KBr)
cmꢀ1; 3418 (N-H), 1632 (C]C), 1591 (C]N), 1025 (CeN), 746 (CeCl).
(CeN), 758 (CeCl). 1H NMR (300 MHz, CDCl3)
d; 2.76 (s, 3H, CH3),
3.72 (s, 3H, OCH3), 4.09 (s,1H, NH), 4.51 (s, 2H, CH2), 6.57e6.60
(d, 2H, H-20 and 60, J ¼ 7.7 Hz), 6.75e6.77 (d, 2H, H-30 and 50,
J ¼ 6.5 Hz), 7.37e7.42 (t, 1H, H-6, J ¼ 7.3 Hz), 7.53e7.59 (m, 2H, H-5
and 7), 8.10 (s,1H, H-4). Anal. Calcd. for C18H17ClN2O : C, 69.12; H,
5.48; N, 8.96. Found: C, 69.30; H, 5.50; N, 8.98%.
1H NMR (300 MHz, CDCl3)
d; 2.77 (s, 3H, CH3), 4.33 (s,1H, NH), 4.56 (s,
2H, CH2), 6.61e6.64 (d, 2H, H-20 and 6’, J ¼ 7.5 Hz), 6.71e6.76 (t, 1H, H-
40 J ¼ 6.9 Hz), 7.14e7.19 (t, 2H, H-30 and 50, J ¼ 7.0 Hz), 7.37e7.42 (t, 1H,
H-6, J ¼ 7.3 Hz), 7.51e7.58 (m, 2H, H-5 and 7), 8.10 (s,1H, H-4). 13C
NMR (CDCl3, 75 MHz) d; 17.64 (CH3), 45.92 (CH2), 112.86, 116.36,
126.13, 127.24, 129.10, 131.64, 135.98, 140.07, 145.79 148.05, 149.87.
FAB-MS; m/z 283 (Mþ), 285 (Mþ2), 190 (C11H9ClNþ). Anal. Calcd. for
C17H15ClN2 : C, 72.21; H, 5.35; N, 9.91. Found: C, 72.39; H, 5.34; N,
9.95%.
4.1.3.8. 4-Bromo-N-[(2-chloro-8-methylquinolin-3-yl)methyl]aniline
4h. IR (KBr) cmꢀ1; 3428 (NeH), 1632 (C]C), 1588 (C]N), 1027
(CeN), 743 (CeCl). 1H NMR (300 MHz, CDCl3)
d; 2.77 (s, 3H, CH3),
4.39 (s,1H, NH), 4.54 (s, 2H, CH2), 6.49e6.52 (d, 2H, H-20 and 60,
J ¼ 7.5 Hz), 7.23e7.26 (d, 2H, H-30 and 50, J ¼ 7.4 Hz), 7.39e7.44
(t, 1H, H-6, J ¼ 7.2 Hz), 7.52e7.59 (m, 2H, H-5 and 7), 8.04 (s,1H, H-
4). Anal. Calcd. for C17H14BrClN2 : C, 56.46; H, 3.90; N, 7.75. Found:
C, 56.33; H, 3.92; N, 7.78%.
4.1.3.2. 4-Chloro-N-[(2-chloro-8-methylquinolin-3-yl)methyl]aniline
4b. IR (KBr) cmꢀ1; 3392 (NeH), 1622 (C]C), 1581 (C]N), 1032
(CeN), 752 (CeCl). 1H NMR (300 MHz, CDCl3)
d; 2.77 (s, 3H, CH3),
4.37 (s,1H, NH), 4.54 (s, 2H, CH2), 6.53e6.56 (d, 2H, H-20 and 60,
J ¼ 8.0 Hz), 7.09e7.12 (d, 2H, H-30 and 50, J ¼ 7.7 Hz), 7.39e7.43
(t, 1H, H-6, J ¼ 7.2 Hz), 7.52e7.59 (m, 2H, H-5 and 7), 8.05 (s,1H,
4.1.3.9. 3-Chloro-N-[(2-chloro-8-methylquinolin-3-yl)methyl]aniline
4i. IR (KBr) cmꢀ1; 3417 (NeH), 1623 (C]C), 1593 (C]N), 1029
H-4). 13C NMR (CDCl3, 75 MHz)
d; 18.21 (CH3), 46.18 (CH2), 114.58,
(CeN), 768 (CeCl). 1H NMR (300 MHz, CDCl3)
d; 2.79 (s, 3H, CH3),
123.87, 125.91, 126.76, 129.10, 131.64, 135.98, 140.07, 145.79 148.05,
149.87. FAB-MS; m/z 317 (Mþ), 319 (Mþ2), 190 (C11H9ClNþ). Anal.
Calcd. for C17H14Cl2N2 : C,. 64.37; H, 4.45; N, 8.83. Found: C, 64.24;
H, 4.46; N, 8.87%.
4.46 (bs,1H, NH), 4.58 (s, 2H, CH2), 6.49e6.52 (d, 1H, H-60,
J ¼ 8.0 Hz), 6.63 (s, 1H, H-20), 6.71e6.73 (d, 1H, H-40, J ¼ 7.6),
7.06e7.11 (t, 1H, H-50, J ¼ 7.9 Hz), 7.41e7.46 (t, 1H, H-6, J ¼ 7.5 Hz),
7.56e7.63 (m, 2H, H-5 and 7), 8.08 (s,1H, H-4). Anal. Calcd. for