Arch. Pharm. Chem. Life Sci. 2008, 341, 446–452
New 7-Hydroxyquinoline-3-Carboxylates
449
1
10a: Yield 95%, m.p.: 176–1788C, MS [MH+] (m/z): 427.2, H-
NMR (DMSO-d6) d: 8.5 (s, 1H, C4-H), 7.4 (d, 2H, Ph-H), 7.3–7.2 (m,
3H, Ph-H + C5-H), 7.1 (t, 1H, Ph-H), 4.7 (s, 2H, CH2S), 4.4 (s, 2H,
CH2N), 4.3 (q, 2H, J = 7.0 Hz, CH2CH3), 3.8 (s, 3H, OCH3), 2.4 (s, 6H,
N(CH3)2), 1.3 (t, 3H, J = 7.1 Hz, CH2CH3).
General procedure for the synthesis of ethyl 7-hydroxy-
6-methoxy-2-((arylthio)methyl)quinoline-3-carboxylate
9a–9f
To a solution of o-aminobenzaldehyde 7 (13.5 g, 0.053 mol) and
ethyl 3-oxo-4-(arylthio)butanoate 3 (0.053 mol) in isopropanol
(10 mL) was added piperidine (0.5 mL, 0.005 mol). The solution
was stirred at reflux for 12–15 hours. The mixture was cooled
down to room temperature. The solvent was removed under vac-
uum, and then 20 mL water was added. The water solution was
extracted with methylene chloride, and the organic phase was
washed with saturated sodium chloride solution and water. The
organic phase was dried over anhydrous sodium sulfate and
evaporated in vacuo to yield the crude compounds 8 as red oil.
The mixed acid (AcOH/HCl = 2/1, 25 mL) was poured into the red
oil 8 directly, and the solution was heated at 808C for 6 h. The
reaction mixture was cooled to room temperature, and the iso-
lated solids were filtered off, dried to give compounds 9 as a buff
to yellow powder.
1
10b: Yield 90%, m.p.: 149–1518C, MS [MH+] (m/z): 445.1, H-
NMR (DMSO) d: 8.5 (s, 1H, C4-H), 7.6 (q, 2H, J = 5.2 Hz, Ph-H), 7.4 (t,
2H, J = 8.8 Hz, Ph-H), 7.3 (s, 1H, C5-H), 4.7 (s, 2H, CH2S), 4.2 (q, 2H, J
= 7.1 Hz, CH2CH3), 3.9 (s, 2H, CH2N), 3.8 (s, 3H, OCH3), 2.1 (s, 6H,
N(CH3)2), 1.3 (t, 3H, J = 7.1 Hz, CH2CH3).
1
10c: Yield 91%, m.p.: 153–1558C, MS [MH+] (m/z): 457.2, H-
NMR (DMSO-d6) d: 8.5 (s, 1H, C4-H), 7.5 (s, 1H, C5-H), 7.1 (d, 2H, J =
8.6 Hz, Ph-H), 6.9 (d, 2H, J = 8.8 Hz, Ph-H), 4.6 (s, 2H, CH2S), 4.3 (q,
2H, J = 7.1 Hz, CH2CH3), 4.0 (s, 2H, CH2N), 3.8 (s, 3H, OCH3), 3.6 (s,
3H, OCH3), 2.3 (s, 6H, N(CH3)2), 1.3 (t, 3H, J = 7.1 Hz, CH2CH3).
1
10d: Yield 79%, m.p.: 143–1468C, MS [MH+] (m/z): 476.1, H-
NMR (DMSO-d6) d: 8.5 (s, 1H, C4-H), 7.4 (s, 1H, C5-H), 7.1 (d, 2H, J =
8.5 Hz, Ph-H), 7.0 (d, 2H, J = 8.5 Hz, Ph-H), 4.3 (q, 2H, J = 6.9 Hz,
CH2CH3), 4.2 (s, 2H, CH2S), 3.9 (s, 2H, CH2N), 3.7 (s, 3H, OCH3), 3.5
(s, 2H, SCH2), 2.6 (s, 6H, N(CH3)2), 1.3 (t, 3H, J = 6.9 Hz, CH2CH3).
9a: Yield 92%, m.p.: 182–1848C, MS [MH+] (m/z): 369.4, 1H-NMR
(DMSO-d6) d: 8.3 (s, 1H, C4-H), 7.2 (s, 1H, C8-H), 7.2–7.0 (m, 6H, Ph-
H + C5-H), 4.3 (s, 2H, CH2S), 4.2 (q, 2H, J = 7.1 Hz, CH2CH3), 3.5 (s,
3H, OCH3), 1.3 (t, 3H, J = 7.1 Hz, CH2CH3).
1
10e: Yield 96%, m.p.: 147–1498C, MS [MH+] (m/z): 441.1, H-
NMR (DMSO-d6) d: 8.4 (s, 1H, C4-H), 7.5 (s, 1H, C5-H), 7.2–7.1 (m,
3H, Ph-H), 6.9 (d, 2H, J = 7.1 Hz, Ph-H), 4.6 (s, 2H, CH2S), 4.5 (s, 2H,
CH2N), 4.3 (q, 2H, J = 7.1 Hz, CH2CH3), 3.8 (s, 3H, OCH3), 2.4 (s, 6H,
N(CH3)2), 2.2 (s, 3H, CCH3), 1.3 (t, 3H, J = 7.1 Hz, CH2CH3).
9b: Yield 85%, m.p.: 174–1768C, MS [MH+] (m/z): 387.2, 1H-NMR
(DMSO-d6) d: 8.5 (s, 1H, C4-H), 7.4 (s, 1H, C8-H), 7.3 (t, 2H, Ph-H), 7.1
(s, 1H, C5-H), 7.0 (q, 2H, J = 5.1 Hz, Ph-H), 4.4 (s, 2H, CH2S), 4.3 (q,
2H, J = 7.1 Hz, CH2CH3), 3.5 (s, 3H, OCH3), 1.3 (t, 3H, J = 7.1 Hz,
CH2CH3).
1
10f: Yield 89%, m.p.: 162–1658C, MS [MH+] (m/z): 463.0, H-
NMR (DMSO-d6) d: 8.3 (s, 1H, C4-H), 7.4–7.3 (m, 3H, Ph-H + C5-H),
7.2 (s, 1H, Ph-H), 4.7 (s, 2H, CH2S), 4.3 (q, 2H, J = 7.0 Hz, CH2CH3),
4.1 (s, 2H, CH2N), 3.7 (s, 3H, OCH3), 2.0 (s, 6H, N(CH3)2), 1.3 (t, 3H, J
= 7.0 Hz, CH2CH3).
9c: Yield 87%, m.p.: 186–1898C, MS [MH+] (m/z): 399.2, 1H-NMR
(DMSO-d6) d: 8.4 (s, 1H, C4-H), 7.3 (s, 1H, C8-H), 7.2 (d, 2H, J = 8.8 Hz,
Ph-H), 7.3 (s, 1H, C5-H), 7.0 (d, 2H, J = 8.8 Hz, Ph-H), 4.3 (s, 2H,
CH2S), 4.2 (q, 2H, J = 7.1 Hz, CH2CH3), 3.7 (s, 3H, OCH3), 3.5 (s, 3H,
OCH3), 1.3 (t, 3H, J = 7.1 Hz, CH2CH3).
General procedure for the synthesis of the target
compounds 11a–11g
To
9d: Yield 68%, m.p.: 162–1648C, MS [MH+] (m/z): 417.0, 1H-NMR
(DMSO-d6) d: 8.7 (s, 1H, C4-H), 7.3 (s, 1H, C8-H), 7.2 (s, 1H, C5-H), 7.1
(d, 2H, J = 8.4 Hz, Ph-H), 7.0 (d, 2H, J = 8.4 Hz, Ph-H), 4.3 (q, 2H, J =
7.0 Hz, CH2CH3), 4.0 (s, 2H, CH2S), 3.7 (s, 3H, OCH3), 3.4 (s, 2H,
SCH2), 1.3 (t, 3H, J = 7.0 Hz, CH2CH3).
a solution of 1H-imidazole or 2-methyl-1H-imidazole
(0.05 mol) and 36% HCl (4.3 mL, 0.05 mol) in 1,4-dioxane (30 mL)
was added 10 (0.01 mol). The reaction mixture was further
stirred at 60–808C for 2–3 hours. After cooling, the resulting
mixture was poured into water (100 mL), then the precipitate
was collected by filtration, washed with water and acetone. The
crude production was recrystallized from ethanol/water (3/1) to
obtain the desired compounds 11a–g.
9e: Yield 90%, m.p.: 185–1888C, MS [MH+] (m/z): 383.2, 1H-NMR
(DMSO-d6) d: 8.5 (s, 1H, C4-H), 7.3 (s, 1H, C8-H), 7.2–7.1 (m, 4H, Ph-
H + C5-H), 6.8 (s, 1H, Ph-H), 4.5 (s, 2H, CH2S), 4.3 (q, 2H, J = 7.1 Hz,
CH2CH3), 3.6 (s, 3H, OCH3), 2.2 (s, 3H, CCH3), 1.3 (t, 3H, J = 7.1 Hz,
CH2CH3).
9f: Yield 82%, m.p.: 187–1908C, MS [MH+] (m/z): 405.1, 1H-NMR
(DMSO-d6) d: 8.6 (s, 1H, C4-H), 7.3 (s, 1H, C8-H), 7.2 (s, 1H, C5-H),
6.9–6.8 (m, 2H, Ph-H), 6.8 (d, 1H, J = 8.9 Hz, Ph-H), 4.4 (s, 2H,
CH2S), 4.3 (q, 2H, J = 7.0 Hz, CH2CH3), 3.6 (s, 3H, OCH3), 1.3 (t, 3H, J
= 7.0 Hz, CH2CH3).
Ethyl 8-((1H-imidazole-1-yl)methyl)-7-hydroxy-6-
methoxy-2-((phenylthio)methyl)quinoline-3-carboxylate
11a
Yield 83%, m.p.: 148-1518C, MS [MH+] (m/z): 450.1, IR (KBr, cm– 1):
3415.8 (OH), 1703.1 (C=O); 1H-NMR (DMSO-d6) d: 8.5 (s, 1H, C4-H),
7.5 (s, 1H, imidazolyl-H), 7.4–7.2 (m, 6H, Ph-H + C5-H), 7.1 (s, 1H,
imidazolyl-H), 6.6 (s, 1H, imidazolyl-H), 5.4 (s, 2H, CH2N), 4.7 (s,
2H, CH2S), 4.3 (q, 2H, J = 7.1 Hz, CH2CH3), 3.8 (s, 3H, OCH3), 1.3 (t,
3H, J = 7.1 Hz, CH2CH3). Anal. calcd. for C24H23N3O4S: C 64.13, H
5.16, N 9.35. Found: C: 64.01, H 5.19, N 9.28.
General procedure for the synthesis of ethyl 7-hydroxy-8-
((dimethylamino)methyl)-6-methoxy-2-((arylthio)methyl)-
quinoline-3-carboxylate 10a–10f
A solution of 33% dimethylamine (3.8 mL, 0.025 mol) in acetic
acid was cooled to 108C, and then 37% formaldehyde (1.1 mL,
0.011 mol) was added and stirred at 108C for 30 min. Compound
9 (0.01 mol) was added to the reaction mixture, then heated to
508C for 3–5 hours. The solvent was evaporated in vacuo, and
poured into water (100 mL). The pH of the resulting mixture was
adjusted to 8 with 15% sodium hydroxide solution, and the solid
product was collected by filtration, washed with water. The
crude product was recrystallized from acetone to obtain com-
pound 10a–g.
Ethyl 7-hydroxy-6-methoxy-8-((2-methyl-1H-imidazole-1-
yl)methyl)-2-((phenylthio)methyl)quinoline-3-carboxylate
11b
Yield 76%, m.p.: 132–1348C, MS [MH+] (m/z): 464.1, IR (KBr, cm–1):
3430.0 (OH), 1705.8 (C=O); 1H-NMR (DMSO-d6) d: 8.7 (s, 1H, C4-H),
7.5 (s, 1H, C5-H), 7.3 (d, 2H, J = 7.1 Hz Ph-H), 7.2 (t, 2H, Ph-H), 7.1 (d,
1H, J = 7.1 Hz, Ph-H), 6.8 (s, 1H, imidazolyl-H), 6.5 (s, 1H, imida-
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