2-(4-Alkylpiperazin-1-yl)quinolines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 309
concentrated sulfuric acid (95-97%, 80 mL, 0 °C), and the
mixture was stirred at 20 °C for 1.5 h. The resulting mixture
was poured into a mixture of water and ice (500 mL), and after
stirring for 1 h, the product was isolated by filtration. The solid
was dried by coevaporation with EtOH/MeCN/PhMe and then
recrystallized from boiling MeCN (800 mL) to give 5.50 g (51%)
of a mixture of 7-chloro-2-quinolone and 5-chloro-2-quinolone
(67:33; 1H NMR). Recrystallization of this mixture from boiling
AcOH (200 mL) yielded 2.94 g (27%) of the title compound as
needles: 1H NMR (DMSO-d6) δ 6.52 (d, J ) 10 Hz, 1H), 7.21
(m, 1H), 7.32 (m, 1H), 7.69 (d, J ) 9 Hz, 1H), 7.91 (d, J ) 10
Hz, 1H), 11.84 (br s, 1H).
2-Chloro-6-cyclohexylquinoline: yield 56%; 1H NMR
(DMSO-d6) δ 1.27 (m, 1H), 1.35-1.55 (m, 4H), 1.73 (m, 1H),
1.85 (m, 4H), 2.71 (m, 1H), 7.55 (d, J ) 9 Hz, 1H), 7.73 (dd, J
) 2 Hz, 9 Hz, 1H), 7.84 (br s, 1H), 7.88 (d, J ) 9 Hz, 1H), 8.38
(d, J ) 9 Hz, 1H).
2-Chloro-6-pyrazol-1-ylquinoline: yield 81%; 1H NMR
(DMSO-d6) δ 6.64 (t, J ) 2 Hz, 1H), 7.66 (d, J ) 9 Hz, 1H),
7.85 (d, J ) 2 Hz, 1H), 8.08 (d, J ) 9 Hz, 1H), 8.38 (dd, J ) 2
Hz, 9 Hz, 1H), 8.51 (m, 2H), 8.69 (d, J ) 2 Hz, 1H).
General Procedure for the Preparation of 2-(4-Alky-
lpiperazin-1-yl)quinolines. 2-(4-Cyclopropylpiperazin-1-
yl)-6-pyrazol-1-ylquinoline Dihydrochloride (2o). A mix-
ture of 1-cyclopropylpiperazine (0.25 g, 1.98 mmol), 2-chloro-
6-pyrazol-1-ylquinoline (0.23 g, 1.00 mmol), and propionitrile
(1.0 mL) was stirred at 95 °C for 20 h. More 1-cyclopropylpip-
erazine (0.25 g) was added and heating was continued for 24
h. Saturated aqueous NaHCO3 (50 mL) was added and the
product was extracted with AcOEt. The combined extracts
were washed twice with water and then extracted with 0.1 M
HCl (25 mL). The acidic aqueous extract was concentrated
under reduced pressure, and the residue was coevaporated
once with EtOH and then recrystallized from EtOH to give
225 mg (57%) of the title compound as a yellow solid: mp 315-
329 °C; 1H NMR (DMSO-d6) δ 0.83 (m, 2H), 1.22 (m, 2H), 2.88
(m, 1H), 3.30-3.80 (m, 6H), 4.79 (m, 2H), 6.61 (m, 1H), 7.59
(d, J ) 6 Hz, 1H), 7.81 (s, 1H), 8.10-8.30 (m, 2H), 8.34 (s,
1H), 8.41 (d, J ) 6 Hz, 1H), 8.59 (s, 1H), 11.47 (br s, 1H);
HPLC-MS m/z 320 (MH+). Anal. (C19H21N5·2HCl·0.25H2O) C,
H, N.
5,7-Dichloro-2-quinolone: yield 71%; 1H NMR (DMSO-
d6) δ 6.66 (d, J ) 10 Hz, 1H), 7.32 (d, J ) 2 Hz, 1H), 7.47 (d,
J ) 2 Hz, 1H), 8.04 (d, J ) 10 Hz, 1H), 12.05 (br s, 1H).
6-Trifluoromethyl-2-quinolone: yield 44%; 1H NMR (DM-
SO-d6) δ 6.63 (d, J ) 10 Hz, 1H), 7.46 (d, J ) 8 Hz, 1H), 7.81
(d, J ) 8 Hz, 1H), 8.03 (d, J ) 10 Hz, 1H), 8.13 (br s, 1H),
12.10 (br s, 1H).
1
6-Cyclohexyl-2-quinolone: yield 90%; H NMR (DMSO-
d6) δ 1.15-1.50 (m, 5H), 1.65-1.89 (m, 6H), 6.46 (d, J ) 10
Hz, 1H), 7.23 (d, J ) 8 Hz, 1H), 7.38 (dd, J ) 2 Hz, 8 Hz, 1H),
7.48 (d, J ) 2 Hz, 1H), 7.86 (d, J ) 10 Hz, 1H), 11.70 (br s,
1H).
6-Bromo-2-quinolone:32 yield 64%; 1H NMR (DMSO-d6)
δ 6.54 (d, J ) 10 Hz, 1H), 7.24 (d, J ) 8 Hz, 1H), 7.63 (dd, J
) 2 Hz, 8 Hz, 1H), 7.88 (d, J ) 10 Hz, 1H), 7.92 (d, J ) 2 Hz,
1H), 11.85 (br s, 1H).
6-Cyano-2-quinolone. A mixture of 6-bromo-2-quinolone
(9.18 g, 41.0 mmol), N-methyl-2-pyrrolidinone (32 mL), and
CuCN (5.90 g, 65.9 mmol) was stirred at 20 °C overnight and
then at reflux temperature (202 °C) for 7 h. The mixture was
poured into water (250 mL) and filtered, and the solid was
washed twice with water. The solid was then mixed with 1 N
HCl (300 mL) and FeCl3·6 H2O (32.5 g, 120 mmol) and stirred
at 20 °C for 3 d. The mixture was filtered, and the solid was
washed twice with water, coevaporated with EtOH, and dried
under reduced pressure to give 6.37 g (91%) of the title
compound: 1H NMR (DMSO-d6) δ 6.63 (dd, J ) 2 Hz, 10 Hz,
1H), 7.40 (d, J ) 8 Hz, 1H), 7.88 (dd, J ) 2 Hz, 10 Hz, 1H),
7.94 (d, J ) 8 Hz, 1H), 8.24 (d, J ) 2 Hz, 1H), 12.13 (br s, 1H).
6-(1-Pyrazolyl)-2-quinolone. A mixture of 6-bromo-2-
quinolone (3.58 g, 16.0 mmol), DMF (15 mL), pyrazole (1.66
g, 24.4 mmol), K2CO3 (3.33 g, 24.1 mmol), and CuI (0.76 g,
3.99 mmol) was stirred at 160 °C for 22 h. The mixture was
poured into water (300 mL) and the product was isolated by
filtration. After washing with water the solid was coevaporated
with EtOH and then heated to reflux in a mixture of EtOH
(50 mL) and MeCN (50 mL). After standing at 20 °C overnight
the product was filtered off, washed with MeCN, and dried
under reduced pressure to yield 1.7 g (50%) of the title
compound as a green solid: 1H NMR (DMSO-d6) δ 6.50-6.68
(m, 2H), 7.39 (br s, 1H), 7.74 (br s, 1H), 7.97 (br s, 2H), 8.12
(br s, 1H), 8.47 (br s, 1H), 11.85 (br s, 1H).
2-(4-Ethylpiperazin-1-yl)quinoline dihydrochloride
1
(2b): yield 100%; mp 290 °C (EtOH); H NMR (DMSO-d6) δ
1.31 (t, J ) 7 Hz, 3H), 3.16 (m, 4H), 3.60-3.80 (m, 4H), 4.82
(m, 2H), 7.47 (m, 1H), 7.54 (m, 1H), 7.74 (m, 1H), 7.90 (m,
1H), 8.15 (m, 1H), 8.41 (m, 1H), 11.35 (br s, 1H); HPLC-MS
m/z 242 (MH+). Anal. (C15H19N3·2HCl) C, H, N.
2-(4-Isopropylpiperazin-1-yl)quinoline dihydrochlo-
ride (2c): yield 50%; mp 271-274 °C (EtOH); 1H NMR
(DMSO-d6) δ 1.31 (d, J ) 7 Hz, 6H), 3.19 (m, 2H), 3.52 (m,
3H), 3.72 (m, 2H), 4.79 (m, 2H), 7.45 (m, 2H), 7.68 (m, 1H),
7.86 (m, 1H), 8.03 (m, 1H), 8.31 (m, 1H), 11.45 (br s, 1H);
HPLC-MS m/z 256 (MH+). Anal. (C16H21N3·2HCl) C, H, N.
2-[4-(1-Ethylpropyl)piperazin-1-yl]quinoline dihydro-
1
chloride (2d): yield 48%; mp 260-263 °C (EtOH); H NMR
(DMSO-d6) δ 0.99 (t, J ) 7 Hz, 6H), 1.65 (m, 2H), 1.94 (m,
2H), 3.12 (br s, 1H), 3.33 (m, 2H), 3.57 (m, 2H), 3.93 (m, 2H),
4.83 (m, 2H), 7.44-7.58 (m, 2H), 7.76 (m, 1H), 7.92 (m, 1H),
8.25 (br s, 1H), 8.42 (m, 1H), 11.20 (br s, H); HPLC-MS m/z
284 (MH+). Anal. (C18H25N3·2HCl·H2O) C, H, N.
2-(4-Cyclopropylpiperazin-1-yl)quinoline dihydrochlo-
ride (2e): yield 16%; mp 240-242 °C (EtOH); 1H NMR
(DMSO-d6) δ 0.83 (m, 2H), 1.19 (m, 2H), 2.87 (br s, 1H), 3.30-
3.80 (m, 6H), 4.74 (m, 2H), 7.45 (m, 1H), 7.52 (d, J ) 8 Hz,
1H), 7.73 (m, 1H), 7.89 (d, J ) 8 Hz, 1H), 8.02 (br s, 1H), 8.38
(m, 1H), 11.22 (br s, 1H); HPLC-MS m/z 254 (MH+). Anal.
(C16H19N3·2HCl·H2O) C, H, N.
2-(4-Cyclopentylpiperazin-1-yl)quinoline dihydrochlo-
ride (2f): yield 13%; mp 272-275 °C (EtOH); 1H NMR (DMSO-
d6) δ 1.62 (m, 2H), 1.82 (m, 2H), 1.96 (m, 2H), 2.09 (m, 2H),
3.25 (m, 2H), 3.55-3.70 (m, 5H), 4.83 (m, 2H), 7.46-7.60 (m,
2H), 7.80 (m, 1H), 7.94 (m, 1H), 8.13 (m, 1H), 8.42 (m, 1H),
11.52 (br s, 1H); HPLC-MS m/z 282 (MH+). Anal. (C18H23N3·
2HCl·H2O) C, H, N.
General Procedure for the Preparation of Substituted
2-Chloroquinolines. 2-Chloro-6-trifluoromethylquino-
line.33 A mixture of 6-trifluoromethyl-2-quinolone (3.59 g, 16.8
mmol) and POCl3 (30 mL) was stirred at 110 °C for 2 h and
then at 20 °C overnight. The mixture was carefully poured
into a mixture of water and ice (400 mL) while being stirred
energetically. The product was isolated by filtration and dried
by coevaporation with MeCN/PhMe to yield 3.52 g (91%) of
the title compound as yellow solid: 1H NMR (DMSO-d6) δ 7.78
(d, J ) 8 Hz, 1H), 8.08 (m, 1H), 8.17 (m, 1H), 8.61 (br s, 1H),
8.67 (d, J ) 8 Hz, 1H).
(9aR)-2-Quinolin-2-yloctahydropyrido[1,2-a]pyra-
zine dihydrochloride (2g): yield 59%; mp 302-304 °C
1
(EtOH); H NMR (DMSO-d6) δ 1.40-1.55 (m, 1H), 1.65-2.10
1
2,7-Dichloroquinoline:34 yield 76%; H NMR (DMSO-d6)
(m, 5H), 2.92 (m, 1H), 3.25 (m, 1H), 3.35-3.90 (m, 5H), 4.90
(m, 2H), 7.49 (m, 1H), 7.59 (d, J ) 8 Hz, 1H), 7.77 (m, 1H),
7.92 (d, J ) 8 Hz, 1H), 8.32 (br s, 1H), 8.46 (m, 1H), 11.69 (br
s, 1H); HPLC-MS m/z 268 (MH+). Anal. (C17H21N3·2HCl·1.5
H2O) C, H, N.
δ 7.65 (d, J ) 9 Hz, 1H), 7.72 (d, J ) 9 Hz, 1H), 8.05 (br s,
1H), 8.12 (d, J ) 9 Hz, 1H), 8.51 (d, J ) 9 Hz, 1H).
2,5,7-Trichloroquinoline: yield 67%; 1H NMR (DMSO-d6)
δ 7.78 (d, J ) 9 Hz, 1H), 8.03 (br s, 1H), 8.09 (d, J ) 2 Hz,
1H), 8.59 (d, J ) 9 Hz, 1H).
6-Chloro-2-(4-cyclopropylpiperazin-1-yl)quinoline di-
2-Chloro-6-cyanoquinoline: yield 80%; 1H NMR (DMSO-
d6) δ 7.78 (d, J ) 9 Hz, 1H), 8.12 (m, 2H), 8.58 (d, J ) 9 Hz,
1H), 8.73 (s, 1H).
hydrochloride (2h): yield 16%; mp 234-235 °C (EtOH); H
1
NMR (DMSO-d6) δ 0.81 (m, 2H), 1.14 (br s, 2H), 2.88 (br s,
1H), 3.25-3.70 (m, 6H), 4.67 (m, 2H), 7.44 (d, J ) 8 Hz, 1H),