J. H. Lee et al. / Bioorg. Med. Chem. 15 (2007) 3499–3504
3503
(162 lL, 0.26 mmol) was added into the reaction mix-
ture and stirred at 60 ꢁC for 4 h. The reaction mixture
was cooled to room temperature and the reaction was
quenched by adding water (200 mL). Organic com-
pounds were extracted with dichloromethane (2·
50 mL), dried over Na2SO4, and concentrated in vacuo.
Flash column chromatography (5% MeOH/dichloro-
methane) gave the desired product 11a.
1-chloroethyl chloroformate (0.02 mL, 0.22 mmol) at
room temperature under N2 atmosphere and stirred un-
der reflux for 2 h. The reaction mixture was cooled to
room temperature and solvent was removed by rotary
evaporator. The residue was dissolved in methanol
(20 mL) at room temperature under N2 atmosphere
and stirred under reflux for 1 h. The reaction mixture
was cooled to room temperature and concentrated in va-
cuo. The residue was dissolved in dichloromethane
(20 mL) and water (20 mL), and then organic layer
was separated. Organic compounds were extracted with
dichloromethane (2· 20 mL). The combined organic
layer was dried over Na2SO4 and concentrated by rotary
evaporator. Flash column chromatography (10%
MeOH/dichloromethane) gave the desired product 12b.
5.2.1. 2-[4-Benzyl-2-(ethoxymethyl)piperazin-1-yl]-6-nitro-
quinoline (11a). 60 mg (56%) as a bright yellow oil: H
1
NMR (400 MHz, CDCl3) d 8.52 (d, 1H, J = 2.4 Hz),
8.28 (dd, 1H, J = 9.3, 2.7 Hz), 7.93 (d, 1H, J = 9.3 Hz),
7.64 (d, 1H, J = 9.2 Hz), 7.37–7.26 (m, 5H), 7.09 (d, 1H,
J = 9.3 Hz), 4.62 (t, 2H, J = 13.0 Hz), 3.81 (t, 1H,
J = 8.6 Hz), 3.65 (dd, 1H, J = 9.2, 2.6 Hz), 3.60 (d, 1H,
J = 13.2 Hz), 3.52 (d, 1H, J = 13.0 Hz), 3.33 (s, 3H),
3.30–3.23 (m, 1H), 3.09 (d, 1H, J = 14.0 Hz), 2.97 (d,
1H, J = 14.1 Hz), 2.25–2.05 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 158.5, 151.4, 141.6, 138.3, 138.0,
128.8, 128.2, 127.0, 124.2, 123.4, 121.0, 111.2, 67.7, 66.7,
62.6, 53.0, 52.8, 52.0, 40.7, 15.1; MS (FAB) m/z (relative
intensity) 407 [M+H]+, 154, 136 (100). HRMS (FAB) m/
z C23H27O3N4 [M+H]+ Calcd: 407.2083. Found: 407.2071.
5.3.1. 2-[(2-Methoxymethyl)piperazin-1-yl]-6-nitroquino-
line (12b). 87 mg (56%) as a bright yellow oil: H NMR
1
(400 MHz, CDCl3) d 9.04 (d, 1H, J = 2.4 Hz), 8.39 (dd,
1H, J = 9.2, 2.6 Hz), 8.01 (d, 1H, J = 12.2 Hz), 7.38–7.26
(m, 6H), 6.93 (s, 1H), 3.85 (t, 1H, J = 8.4 Hz), 3.71–3.55
(m, 5H), 3.29 (d, 1H, J = 12.0 Hz), 3.18 (s, 3H), 2.94 (q,
2H, J = 13.6 Hz), 2.65 (d, 1H, J = 12.0 Hz), 2.52 (t, 1H,
J = 12.2 Hz); 13C NMR (100 MHz, CDCl3) d 158.5,
151.5, 141.7, 138.4, 138.0, 128.8, 128.3, 127.2, 127.0,
124.2, 123.5, 121.0, 111.1, 70.6, 59.1, 50.3, 45.8, 45.3,
40.9; MS (FAB) m/z (relative intensity) 303 [M+H]+
(100), 287, 257. HRMS (FAB) m/z C15H18O3N4
[M+H]+ Calcd: 303.1457. Found: 303.1465.
5.2.2. 2-[4-Benzyl-2-(propoxymethyl)piperazin-1-yl]-6-nitro-
quinoline (11b). 62 mg (56%) as a bright yellow oil: H
1
NMR (400 MHz, CDCl3) d 8.51 (d, 1H, J = 2.4 Hz), 8.27
(dd, 1H, J = 9.3, 2.7 Hz), 7.92 (d, 1H, J = 9.2 Hz), 7.63
(d, 1H, J = 9.3 Hz), 7.41–7.24 (m, 5H), 7.09 (d, 1H,
J = 9.3 Hz), 4.60 (br s, 2H), 3.83 (t, 1H, J = 9.2 Hz),
3.67–3.59 (m, 2H), 3.49 (d, 1H, J = 13.2 Hz) 3.41–3.33
(m, 2H), 3.26 (t, 1H, J = 14.0 Hz), 3.12 (d, 1H,
J = 12.1 Hz), 2.98 (d, 1H, J = 14.0 Hz), 2.32–2.16 (m,
2H), 1.52–1.36 (m, 2H), 0.77 (t, 3H, J = 7.0 Hz); 13C
NMR (100 MHz, CDCl3) d 158.6, 151.4, 141.7, 138.2,
138.0, 128.8, 128.2, 127.1, 127.0, 124.2, 123.5, 121.0,
111.3, 73.1, 68.0, 62.7, 53.0, 52.1, 40.6, 22.8, 10.4; MS
(FAB) m/z 421 [M+H]+, 154. HRMS (FAB) m/z
C24H29O3N4 [M+H]+ Calcd: 421.2240. Found: 421.2248.
5.3.2. 2-[2-(Ethoxymethyl)piperazin-1-yl]-6-nitroquinoline
(12c). 39 mg (83%) as a bright yellow oil: 1H NMR
(400 MHz, CDCl3) d 8.54 (d, 1H, J = 2.4 Hz), 8.29
(dd, 1H, J = 9.3, 2.7 Hz), 7.97 (d, 1H, J = 9.3 Hz), 7.65
(d, 1H, J = 9.3 Hz), 7.09 (d, 1H, J = 9.4 Hz), 4.64 (br
s, 1H), 4.52 (d, 1H, J = 13.0 Hz), 3.88 (dd, 1H, J = 9.3,
2.7 Hz), 3.63 (dd, 1H, J = 9.2, 2.6 Hz), 3.53 (dd, 1H,
J = 9.2, 2.6 Hz), 3.50 (d, 2H, J = 7.0 Hz), 3.36 (d, 1H,
J = 12.2 Hz), 3.26 (dd, 1H, J = 9.2, 2.3 Hz), 3.20 (d,
1H, J = 11.5 Hz), 3.00 (dd, 1H, J = 9.3, 2.7 Hz), 2.88
(q, 1H, J = 8.4 Hz), 1.15 (t, 3H, J = 7.0 Hz); 13C NMR
(100 MHz, CDCl3) d 158.7, 151.5, 141.8, 138.4, 127.1,
124.2, 123.6, 121.1, 111.1, 68.2, 66.8, 51.0, 46.3, 45.8,
41.3, 15.3; MS (FAB) m/z 317 [M+H]+. HRMS (FAB)
m/z C16H21O3N4 [M+H]+ Calcd: 317.1614. Found:
317.1615.
5.2.3. 2-[4-Benzyl-2-(butoxymethyl)piperazin-1-yl]-6-nitro-
quinoline (11c). 55 mg (48%) as a bright yellow oil: H
1
NMR (400 MHz, CDCl3) d 8.51 (d, 1H, J = 2.4 Hz),
8.27 (dd, 1H, J = 9.3, 2.7 Hz), 7.91 (d, 1H, J = 9.1 Hz),
7.63 (d, 1H, J = 9.3 Hz), 7.39–7.26 (m, 5H), 7.09 (d, 1H,
J = 9.2 Hz), 4.60 (br s, 2H), 3.83 (t, 1H, J = 9.0 Hz),
3.68–3.58 (m, 2H), 3.49 (d, 1H, J = 13.0 Hz) 3.44–3.37
(m, 2H), 3.25 (t, 1H, J = 14.0 Hz), 3.11 (d, 1H,
J = 13.2 Hz), 2.98 (d, 1H, J = 14.1 Hz), 2.25–2.08 (m,
2H), 1.44–1.34 (m, 2H), 1.26–1.14 (m, 2H), 0.80 (t, 3H,
J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) d 158.6,
151.4, 141.7, 138.2, 138.0, 128.8, 128.3, 127.1, 127.0,
124.2, 123.5, 121.0, 111.3, 71.2, 68.1, 62.7, 53.0, 52.1,
40.6, 31.6, 19.1, 13.8; MS (FAB) m/z 435 [M+H]+, 154.
HRMS (FAB) m/z C25H31O3N4 [M+H]+ Calcd:
435.2396. Found: 435.2386.
5.3.3. 6-Nitro-2-(2-propoxymethylpiperazin-1-yl)quino-
line (12d). 31 mg (68%) as a bright yellow oil: 1H
NMR (400 MHz, CDCl3) d 8.52 (d, 1H, J = 2.4 Hz),
8.28 (dd, 1H, J = 9.3, 2.7 Hz), 7.94 (d, 1H, J = 9.4 Hz),
7.63 (d, 1H, J = 9.4 Hz), 7.09 (d, 1H, J = 9.4 Hz), 4.61
(br s, 1H), 4.51 (dd, 1H, J = 13.0 Hz), 3.86 (dd, 1H,
J = 9.3, 2.7 Hz), 3.63 (dd, 1H, J = 9.2, 2.6 Hz), 3.40 (t,
2H, J = 7.0 Hz), 3.36 (d, 1H, J = 14.0 Hz), 3.23 (dd,
1H, J = 9.2, 2.3 Hz), 3.17 (d, 1H, J = 11.5 Hz), 2.98
(dd, 1H, J = 9.3, 2.7 Hz), 2.86 (q, 1H, J = 8.3 Hz), 2.07
(br s, 1H), 1.45–1.58 (m, 2H), 0.84 (t, 3H, J = 7.0 Hz);
13C NMR (100 MHz, CDCl3) d 170.9, 158.7, 151.5,
141.7, 138.4, 127.0, 124.2, 123.5, 121.1, 111.1, 73.1,
68.5, 51.1, 46.5, 46.0, 41.4, 22.9, 10.5; MS (FAB) m/z
331 [M+H]+. HRMS (FAB) m/z C17H23O3N4 [M+H]+
Calcd: 331.1770. Found: 331.1778.
5.3. General procedure for the preparation of 2-[2-
(alkoxymethyl)piperazin-1-yl]-6-nitroquinoline (12b–12e)
To a solution of compound 9 (60 mg, 0.15 mmol) in
anhydrous dichloromethane (5 mL) was added slowly