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M. Mizuno et al. / Tetrahedron 62 (2006) 8707–8714
CDCl3) d: 1.05 (t, J¼7.4 Hz, 3H), 3.28 (s, 3H), 3.84 (s, 3H),
4.00 (s, 3H), 4.06 (s, 3H), 4.12 (q, J¼7.2 Hz, 2H), 4.89 (d,
J¼11.4 Hz, 1H), 5.05 (d, J¼11.4 Hz, 1H), 6.91 (s, 1H),
7.14 (d, J¼8.4 Hz, 1H), 7.28 (dd, J¼8.4, 2.2 Hz, 1H), 7.40
(d, J¼2.2 Hz, 1H), 7.46 (s, 1H); MS (FAB): m/z 510
[M+H]+; Anal. Calcd for C23H24ClNO8S: C, 54.17; H,
4.74; N, 2.75. Found: C, 54.09; H, 4.66; N, 2.70.
62.06; H, 5.21; N, 12.06, Found: C, 62.08; H, 5.23; N,
12.05.
4.10. 2-Amino-9-(3,4-dimethoxyphenyl)-6,7-dimethoxy-
azolidino[3,4-b]quinolin-1-one (24)
To a suspension of ethyl 2-chloromethyl-4-(3,4-dimethoxy-
phenyl)-6,7-dimethoxyquinoline-3-carboxylate (23; 0.89 g,
2 mmol) in EtOH (10 mL) was added hydrazine hydrate
(0.50 g, 10 mmol), and the mixture was refluxed for 2.5 h.
After cooling, the resulting precipitates were collected by fil-
tration, washed with EtOH (5 mL), and dried in vacuo to
give 24 (0.74 g, 93.7%) as a pale yellow crystalline powder;
tR: 20.0 (23), 3.0 (24); mp 265.1 ꢀC; IR (KBr): 1695.6,
1502.7, 1249.9, 1232.6 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d: 3.83 (s, 3H), 3.90 (s, 3H), 4.00 (s, 3H), 4.08 (s, 3H),
4.37 (s, 2H), 4.66 (s, 2H), 7.00 (s, 1H), 7.06 (s, 2H), 7.16
(s, 1H), 7.48 (s, 1H); MS (FAB): m/z 396 [M+H]+; Anal.
Calcd for C21H21N3O5: C, 63.79; H, 5.35; N, 10.63. Found:
C, 63.51; H, 5.40; N, 10.40.
4.8. Ethyl 4-(3-mesyloxy-4-methoxyphenyl)-6,7-
dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-
3-carboxylate (15)
To a solution of 22 (4.08 g, 8 mmol) in DMF (41 mL) were
added 1H-1,2,4-triazole (0.61 g, 8.8 mmol) and potassium
carbonate (3.32 g, 24 mmol), and the mixture was stirred
for 4 h. After cooling, water (80 mL) and EtOH (40 mL)
were added and the resulting precipitates were collected
by filtration, washed with EtOH (15 mLꢁ2), and dried
in vacuo to give crude 15 (3.42 g, 78.8%) as a pale yellow
crystalline powder. The mother solution was extracted with
AcOEt (80 mL), and the organic extract was washed with
water (80 mL) and saturated NaCl solution (80 mL), dried
(MgSO4), and concentrated in vacuo. To the residue was
added EtOH (40 mL), and the resulting precipitates were col-
lected by filtration, washed with EtOH (15 mLꢁ2), and dried
in vacuo to give recovered 15 (0.58 g, 13.4%) as a pale
yellow crystalline powder. Both crude 15 and recovered 15
were purified together by chromatography on silica gel to
give 15 (3.83 g, 88.2%) as a pale yellow crystalline powder;
tR: 24.6 (22), 7.1 (15); mp 171.9 ꢀC; IR (KBr): 1714.8,
4.11. 9-(3,4-Dimethoxyphenyl)-6,7-dimethoxyoxolano-
[3,4-b]quinolin-1-one (25)
A solution of 23 (0.89 g, 2 mmol) in DMSO (10 mL) was
stirred for 5.5 h at 120 ꢀC. After cooling, water (20 mL)
was added and the resulting precipitates were collected by
filtration, washed with water (10 mL) and EtOH (5 mL),
and dried in vacuo to give 25 (0.62 g, 81.6%) as a yellow
crystalline powder; tR: 20.0 (23), 5.7 (25); mp 238.2 ꢀC
(lit.1d 241–242 ꢀC); IR (KBr): 1759.2, 1518.1, 1502.7,
1
1504.6, 1431.3, 1367.6, 1230.7, 1209.4, 1174.7 cmꢂ1; H
1
NMR (300 MHz, CDCl3) d: 0.91 (t, J¼7.0 Hz, 3H), 3.27
(s, 3H), 3.83 (s, 3H), 3.99 (s, 3H), 4.00 (q, J¼7.0 Hz, 2H),
4.05 (s, 3H), 5.69 (d, J¼14.8 Hz, 1H), 5.80 (d, J¼14.8 Hz,
1H), 6.89 (s, 1H), 7.12 (d, J¼8.4 Hz, 1H), 7.25 (dd, J¼8.4,
2.2 Hz, 1H), 7.37 (d, J¼1.8 Hz, 1H), 7.41 (s, 1H), 7.94 (s,
1H), 8.28 (s, 1H); MS (FAB): m/z 542 [M+H]+; Anal. Calcd.
for C25H26N4O8S$0.3H2O: C, 54.80; H, 4.89; N, 10.22.
Found: C, 54.76; H, 4.90; N, 9.94.
1483.4, 1251.9 cmꢂ1; H NMR (300 MHz, CDCl3) d: 3.85
(s, 3H), 3.91 (s, 3H), 4.01 (s, 3H), 4.10 (s, 3H), 5.38 (s,
2H), 7.02 (s, 1H), 7.07 (s, 2H), 7.23 (s, 1H), 7.49 (s, 1H);
MS (FAB): m/z 382 [M+H]+.
4.12. 2-Hydroxymethyl-4-(3,4-dimethoxyphenyl)-
6,7-dimethoxyquinoline-3-carbohydrazide (26)
To a suspension of 25 (0.19 g, 0.5 mmol) in EtOH (4 mL)
was added hydrazine hydrate (0.13 g, 2.5 mmol), and the
mixture was refluxed for 11 h. After cooling, AcOEt
(4 mL) was added and the resulting precipitates were col-
lected by filtration, washed with AcOEt (2 mLꢁ2), and
dried in vacuo to give 26 (0.18 g, 85.7%) as an ivory crystal-
line powder; tR: 5.7 (25), 2.2 (26); mp 240.9 ꢀC; IR (KBr):
4.9. Ethyl 4-(3-hydroxy-4-methoxyphenyl)-6,7-
dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-
3-carboxylate (1d)
To a suspension of 15 (25.0 g, 46.1 mmol) in EtOH (2.5 L)
was added cesium carbonate (60.1 g, 184 mmol), and the
mixture was refluxed for 30 min. After cooling and concen-
tration, 1 N NaOH (700 mL) was poured into the residue at
0 ꢀC and the resulting precipitates were removed by filtra-
tion. The mother solution was extracted with AcOEt
(700 mL), and the aqueous solution was adjusted to pH 7
with 1 N HCl (180 mL) and stirred at 0 ꢀC for 30 min.
The resulting precipitates were collected by filtration,
washed with water (200 mL) and EtOH (50 mL), and the
resulting crude powder was recrystallized from 95%
EtOH (1.5 L) to give 1d (14.3 g, 67.0%) as a white crystal-
line powder; tR: 7.1 (15), 4.5 (1d); mp 233.6 ꢀC; IR (KBr):
3287.0, 1657.0, 1518.1, 1504.6, 1248.0 cmꢂ1 1H NMR
;
(300 MHz, DMSO-d6) d: 3.70 (s, 3H), 3.77 (s, 3H), 3.85
(s, 3H), 3.97 (s, 3H), 4.21 (br s, 2H), 4.68 (d, J¼5.6 Hz,
2H), 5.02 (t, J¼5.2 Hz, 1H), 6.90 (s, 1H), 6.92 (d,
J¼8.4 Hz, 1H), 6.99 (s, 1H), 7.05 (d, J¼8.4 Hz, 1H), 7.47
(s, 1H), 9.29 (s, 1H); MS (FAB): m/z 414 [M+H]+; Anal.
Calcd for C21H23N3O6$0.3H2O: C, 60.22; H, 5.68; N,
10.03. Found: C, 60.13; H, 5.55; N, 10.00.
4.13. 2-Hydroxymethyl-4-(3,4-dimethoxyphenyl)-
6,7-dimethoxyquinoline-3-carboxylic acid (27)
2978.4, 1714.8, 1504.6, 1429.3, 1211.4 cmꢂ1 1H NMR
;
(300 MHz, CDCl3) d: 0.89 (t, J¼7.2 Hz, 3H), 3.80 (s,
3H), 3.96 (s, 3H), 3.98 (q, J¼7.2 Hz, 2H), 4.04 (s, 3H),
5.73 (s, 2H), 6.37 (s, 1H), 6.80 (d, J¼8.2 Hz, 1H), 6.98–
6.93 (3H, m), 7.40 (s, 1H), 7.94 (s, 1H), 8.30 (s, 1H); MS
(FAB): m/z 465 [M+H]+; Anal. Calcd for C24H24N4O6: C,
To a suspension of 25 (0.19 g, 0.5 mmol) in EtOH (4 mL)
was added sodium ethoxide (0.14 g, 2 mmol), and the mix-
ture was refluxed for 1 h. After cooling, 1 N HCl (3 mL)
was added and the resulting precipitates were collected by
filtration, washed with EtOH (4 mL), water (4 mL), and