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4.1.3.4. Methyl 2,3-dihydro-4-(3,4,5-trimethoxyphenyl)-5-(3-flu-
orophenyl)-3-oxopyrazole-1-carboxylate (11d). Yield: 97%; mp
203–205 °C (EtOAc); IR (KBr) 1761, 1587, 1511, 1439, 1415,
1339, 1244, 1127; 1H NMR (DMSO-d6) d 3.54 (6H, s), 3.62 (3H, s),
3.76 (3H, s), 6.51 (2H, s), 7.26 (3H, m), 7.46 (1H, m), 11.64 (1H,
br s); 13C NMR (DMSO-d6) d 54.0, 55.4, 60.0, 106.1, 112.5, 115.5
(d, J = 20.9 Hz), 117.1 (d, J = 22.4 Hz), 125.1, 126.3 (d, J = 2.0 Hz),
130.1 (d, J = 8.5 Hz), 133.6 (d, J = 8.8 Hz), 136.5, 141.0 (d,
J = 1.8 Hz), 149.7, 152.4, 160.6, 161.8 (d, J = 243.9 Hz); MS (ES+)
m/z (%) 403.1 (MH+, 67); Calcd for C20H19FN2O6: C, 59.70; H,
4.76; N, 6.96. Found: C, 59.66; H, 4.92; N, 6.90.
(DMSO-d6) d 53.7, 55.0, 55.4, 55.8, 56.3, 56.5, 98.1, 111.2, 111.5,
111.8, 112.0, 115.2, 120.8, 123.0, 139.0, 142.5, 147.7, 148.0,
149.7, 150.5, 152.3, 160.8; MS (ESI) m/z 445.1 (MH+, 100); Calcd
for C22H24N2O8: C, 59.45; H, 5.44; N, 6.30. Found: C, 59.64; H,
5.21; N, 6.35.
4.1.4. Conversion of 11 into 12
A methanolic solution of NaOH (2 N, 2.4 mL) was added to a
stirred mixture of 11 (2 mmol) in CH2Cl2/MeOH (9:1; 8 mL) at rt.
Stirring was continued at the same temperature for additional 1–
5 h and the reaction mixture was evaporated to dryness. The resi-
due was treated with water (5 mL), made acidic with HCl (1:2, v/v)
and extracted with EtOAc (3 ꢁ 30 mL). The combined EtOAc ex-
tracts were dried over anhydrous sodium sulfate and evaporated
to dryness to give the corresponding combretastatins 12.
4.1.3.5. Methyl 2,3-dihydro-4-(3,4,5-trimethoxyphenyl)-5-(naph-
thalen-1-yl)-3-oxopyrazole-1-carboxylate (11e). Yield: 100%;
mp 223–225 °C (EtOAc); IR (KBr) 2953, 1749, 1608, 1504, 1440,
1354, 1256, 1130; 1H NMR (DMSO-d6) d 3.25 (6H, s), 3.52 (3H, s),
3.62 (3H, s), 6.46 (2H, s), 7.52 (5H, m), 8.01 (2H, m), 11.81 (1H,
br s); 13C NMR (DMSO-d6) d 53.9, 55.0, 59.9, 105.2, 112.9, 124.7,
125.4, 125.5, 126.2, 127.1, 127.9, 128.3, 129.0, 129.4, 132.1,
132.9, 136.3, 140.5, 149.4, 152.2, 160.9; MS (ES+) m/z 435.2
(MH+, 100); Calcd for C24H22N2O6: C, 66.35; H, 5.10; N, 6.45. Found:
C, 66.14; H, 5.27; N, 6.36.
4.1.4.1. 1,2-Dihydro-5-(3-hydroxy-4-methoxyphenyl)-4-(3,4,5-
trimethoxyphenyl)pyrazol-3-one (12a). Yield: 100%; mp 253–
256 °C (EtOAc); IR (KBr) 3232, 1582, 1519, 1501, 1439, 1243,
1218, 1101; 1H NMR (DMSO-d6) d 3.60 (6H, s), 3.65 (3H, s), 3.77
(3H, s), 6.59 (2H, s), 6.82 (2H, m), 6.95 (1H, m), 9.08 (1H, br s),
10.06 (1H, br s), 11.65 (1H, br s); 13C NMR (DMSO-d6) d 55.6,
55.6, 60.0, 102.0, 106.1, 112.2, 115.2, 119.0, 123.4, 128.4, 135.5,
139.8, 146.3, 147.7, 152.4, 158.9; MS (ESI) m/z 373.1 (MH+, 100);
Calcd for C19H20N2O6: C, 61.28; H, 5.41; N, 7.52. Found: C, 61.03;
H, 5.51; N, 7.30.
4.1.3.6. Methyl 2,3-dihydro-4-(3,4,5-trimethoxyphenyl)-5-(naph-
thalen-2-yl)-3-oxopyrazole-1-carboxylate (11f). Yield: 89%; mp
212–215 °C (EtOAc); IR (KBr) 2943, 1750, 1593, 1508, 1436,
1352, 1249, 1123; 1H NMR (DMSO-d6) d 3.36 (6H, s), 3.55 (3H, s),
3.72 (3H, s), 6.51 (2H, s), 7.54 (3H, m), 7.93 (4H, m), 11.66 (1H,
br s); 13C NMR (DMSO-d6) d 53.9, 55.2, 59.9, 106.1, 112.5, 125.4,
126.4, 126.8, 127.4, 127.5, 127.7, 127.9, 128.8, 128.9, 132.4,
132.6, 136.3, 142.5, 149.8, 152.2, 160.7; MS (ES+) m/z 435.2
(MH+, 45); Calcd for C24H22N2O6: C, 66.35; H, 5.10; N, 6.45. Found:
C, 66.34; H, 5.14; N, 6.43.
4.1.4.2. 5-(3-Fluoro-4-methoxyphenyl)-1,2-dihydro-4-(3,4,5-tri-
methoxyphenyl)pyrazol-3-one (12b). Yield: 89%; mp 241–243 °C
(EtOAc); IR (KBr) 3266, 1583, 1531, 1498, 1416, 1269, 1240, 1119;
1H NMR (DMSO-d6) d 3.65 (6H, s), 3.68 (3H, s), 3.86 (3H, s), 6.60
(2H, s), 7.23 (3H, m), 11.04 (1H, br s); 13C NMR (DMSO-d6) d 55.7,
56.1, 60.1, 102.7, 106.5, 113.9 (d, J = 1.8 Hz), 115.0 (d, J = 19.2 Hz),
123.5 (d, J = 7.2 Hz), 124.2 (d, J = 3.2 Hz), 128.1, 135.9, 138.5, 147.0
(d, J = 10.5 Hz), 151.2 (d, J = 243.8 Hz), 152.6, 158.8; MS (ES+) m/z
375.1 (MH+, 29); HRMS Calcd for C19H20FN2O5 (MH+): 375.1356.
Found: 375.1356; Calcd for C19H19FN2O5: C, 60.96; H, 5.12; N,
7.48. Found: C, 60.94; H, 5.11; N, 7.30.
4.1.3.7. Methyl 2,3-dihydro-4-(3,4,5-trimethoxyphenyl)-5-(3,4-
dimethoxyphenyl)-3-oxopyrazole-1-carboxylate (11g). Yield:
95%; mp 205–208 °C (EtOAc); IR (KBr) 1764, 1584, 1438, 1414,
1351, 1248, 1139, 1126; 1H NMR (DMSO-d6) d 3.53 (6H, s), 3.61
(3H, s), 3.68 (3H, s), 3.74 (3H, s), 3.78 (3H, s), 6.53 (2H, s), 6.83
(1H, J1 = 8.4 Hz, J2 = 1.8 Hz, dd), 6.97 (1H, J1 = 8.4 Hz, d), 7.00 (1H,
J2 = 1.8 Hz, d), 11.50 (1H, br s); 13C NMR (DMSO-d6) d 53.8, 55.4,
55.5, 55.8, 59.9, 106.0, 111.4, 111.9, 114.0, 122.5, 123.4, 125.7,
136.3, 142.6, 148.4, 149.2, 149.7, 152.2, 160.5; MS (ESI) m/z
445.1 (MH+, 100); HRMS Calcd for C22H25N2O8 [M+H]+: 445.1611
Found: 445.1622; Calcd for C22H24N2O8: C, 59.45; H, 5.44; N,
6.30. Found: C, 59.58; H, 5.51; N, 6.24.
4.1.4.3. 1,2-Dihydro-4-(3,4,5-trimethoxyphenyl)-5-(4-methoxy-
phenyl)pyrazol-3-one (12c). Yield: 60%; mp 245–249 °C (EtOAc);
IR (KBr) 3265, 1616, 1590, 1528, 1512, 1251, 1123, 841; 1H NMR
(DMSO-d6) d 3.60 (6H, s), 3.65 (3H, s), 3.76 (3H, s), 6.56 (2H, s),
6.97 and 7.33 (4H, J = 8.7 Hz, AA‘XX’), 10.10 (1H, br s), 11.74 (1H,
br s); 13C NMR (DMSO-d6) d 55.2, 55.5, 60.0, 102.1, 106.1, 113.9,
123.0, 128.4, 129.1, 135.5, 139.5, 152.4, 158.9, 159.1; MS (ESI)
m/z 357.1 (MH+, 100); Calcd for C19H20N2O5: C, 64.04; H, 5.66; N,
7.86. Found: C, 63.82; H, 5.79; N, 7.72.
4.1.3.8. Methyl 2,3-dihydro-5-(3,4,5-trimethoxyphenyl)-4-(3,4-
dimethoxyphenyl)-3-oxopyrazole-1-carboxylate (11h). Yield:
92%; mp 210–215 °C (EtOAc); IR (KBr) 1757, 1584, 1545, 1438,
1350, 1251, 1240, 1131; 1H NMR (DMSO-d6) d 3.45 (3H, s), 3.68
(6H, s), 3.69 (3H, s), 3.70 (3H, s), 3.75 (3H, s), 6.67 (1H, s), 6.70
(1H, J1 = 1.8 Hz, d) 6.86 (1H, J2 = 8.4 Hz, d), 6.97 (1H, J1 = 8.4 Hz,
J2 = 1.8 Hz, dd), 11.46 (1H, s); 13C NMR (DMSO-d6) d 53.8, 54.8,
55.3, 56.1, 60.0, 107.7, 111.4, 111.9, 112.0, 121.0, 122.5, 126.7,
137.7, 141.9, 147.6, 147.8, 149.6, 152.6, 160.6; MS (ESI) m/z
445.1 (MH+, 100); Calcd for C22H24N2O8: C, 59.45; H, 5.44; N,
6.30. Found: C, 59.57; H, 5.30; N, 6.34.
4.1.4.4. 1,2-Dihydro-5-(3-fluorophenyl)-4-(3,4,5-trimethoxy-
phenyl)pyrazol-3-one (12d). Yield: 100%; mp 262–265 °C
(EtOAc); IR (KBr) 3352, 1585, 1518, 1468, 1413, 1236, 1128, 879;
1H NMR (DMSO-d6) d 3.63 (6H, s), 3.67 (3H, s), 6.57 (2H, s), 7.20
(3H, m), 7.44 (1H, m), 10.38 (1H, br s), 11.88 (1H, br s); 13C NMR
(DMSO-d6) d 55.6, 60.0, 103.2, 106.5, 114.2 (d, J = 22.6 Hz), 114.8
(d, J = 20.7 Hz), 123.8, 127.8, 130.5 (d, J = 6.2 Hz), 133.0, 135.9,
138.5, 152.6, 158.7, 162.0 (d, J = 243.4 Hz); MS (ES+) m/z (%)
345.1 (MH+, 100); HRMS Calcd for C18H18FN2O4 (MH+): 345.1251.
Found: 345.1252; Calcd for C18H17FN2O4: C, 62.79; H, 4.98; N,
8.14. Found: C, 62.66; H, 5.01; N, 7.93.
4.1.3.9. Methyl 2,3-dihydro-5-(2,4,5-trimethoxyphenyl)-4-(3,4-
dimethoxyphenyl)-3-oxopyrazole-1-carboxylate
(11i). Yield:
88%; mp 206–209 °C (EtOAc); IR (KBr) 1759, 1543, 1442, 1348,
1264, 1251, 1212, 1028; 1H NMR (DMSO-d6) d 3.50 (3H, s), 3.58
(3H, s), 3.68 (3H, s), 3.69 (3H, s), 3.74 (3H, s), 3.85 (3H, s), 6.75
(1H, s), 6.77 (1H, J1 = 1.8 Hz, d), 6.78 (1H, s), 6.84 (1H, J2 = 8.4 Hz,
d), 6.93 (1H, J1 = 1.8 Hz, J2 = 8.4 Hz, dd), 11.38 (1H, br s); 13C NMR
4.1.4.5. 1,2-Dihydro-4-(3,4,5-trimethoxyphenyl)-5-(naphthalen-
1-yl)pyrazol-3-one (12e). Yield: 92%; mp 290–294 °C (EtOAc); IR
(KBr) 3264, 1604, 1588, 1531, 1518, 1416, 1246, 1126; 1H NMR
(DMSO-d6) d 3.24 (6H, s), 3.51 (3H, s), 6.49 (2H, s), 7.53 (5H, m),
8.03 (2H, m), 10.65 (1H, br s), 11.81 (1H, br s); 13C NMR (DMSO-