220
Z.-H. Shi et al. / European Journal of Medicinal Chemistry 54 (2012) 210e222
The crude material was purified by column chromatography (25%
ethyl acetate in petroleum ether) to yield 26 (279 mg, 93% yield) as
a yellow solid. Mp 122e123 ꢀC. 1H NMR (CDCl3, 300 MHz): 3.70 (s,
3H, eOCH3), 3.96 (s, 3H, eOCH3), 5.07 (s, 2H, eOCH2Ph), 5.13 (s, 2H,
eOCH2Ph), 5.23 (s, 2H, eOCH2Ph), 6.43 (d, J ¼ 2.2 Hz, 1H, 6-H), 6.56
(d, J ¼ 2.2 Hz, 1H, 8-H), 6.92 (d, J ¼ 8.6 Hz, 1H, 50-H), 7.22e7.46 (m,
15H, aromatic H), 7.52 (dd, J ¼ 2.1, 8.6 Hz, 1H, 60-H), 7.68 (d,
J ¼ 2.1 Hz, 1H, 20-H). ESI-MS m/z: 601 [M þ H]þ, 623 [M þ Na]þ.
a yellow solid. Mp 102e103 ꢀC. 1H NMR (CDCl3, 300 MHz)
d 3.24 (s,
3H, eOCH3), 3.52 (s, 3H, eOCH3), 3.99 (s, 6H, 2ꢂ eOCH3), 5.20 (s,
2H, eOCH2Oe), 5.26 (s, 2H, eOCH2Oe), 6.48 (d, J ¼ 2.0 Hz, 1H, 6-H),
6.65 (d, J ¼ 2.0 Hz, 1H, 8-H), 7.00 (d, J ¼ 8.4 Hz, 1H, 50-H), 7.66 (d,
J ¼ 2.0 Hz, 1H, 20-H), 7.71 (dd, J ¼ 2.0, 8.4 Hz, 1H, 60-H), 12.57 (s, 1H,
5-OH). ESI-MS m/z: 419 [M þ H]þ, 441 [M þ Na]þ.
3.1.24. 2-(3,4-Dimethoxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-
one (22)
3.1.20. 3,7-Dihydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-
methoxy-4H-chromen-4-one (20)
To a stirring solution 28 (418 mg,1 mmol) of in CH2Cl2 (5 ml) and
ethyl ether (5 ml) was added hydrochloric acid (1 ml) at 0 ꢀC. The
reaction mixture was allowed to warm to room temperature and
stirred another 6 h, then the reaction mixture was diluted with
a large amount of ethyl acetate and washed with water and brine.
The ethyl acetate layer was dried over MgSO4, filtered and
concentrated and the crude material was purified by column
chromatography (50% ethyl acetate in petroleum ether) to yield 22
(300 mg, 91%) as a yellow solid. Mp 211e212 ꢀC. 1H NMR (DMSO-d6,
To a solution of 26 (100 mg, 0.17 mmol) dissolved in ethanol
(10 ml) and THF (10 ml) was added 10% Pd/C (2 mg) with vigorous
stirring. The reaction vessel was then evacuated and the atmosphere
replaced with hydrogen. After 12 h, the reaction mixturewas filtered
through celite and the filtrate concentrated. The crude material was
then chromatographed over silica gel (50% ethyl acetate in petro-
leum ether) to yield 20 (52 mg, 92%) as a yellow solid. Mp
240e241 ꢀC. 1H NMR (DMSO-d6, 300 MHz)
d
3.84 (s, 3H, eOCH3),
300 MHz) d 3.84 (s, 3H, eOCH3), 3.85 (s, 3H, eOCH3), 6.20 (d,
3.88 (s, 3H, eOCH3), 6.36 (d, J ¼ 2.0 Hz, 1H, 6-H), 6.55 (d, J ¼ 2.0 Hz,
1H, 8-H), 6.94 (d, J ¼ 8.4 Hz,1H, 50-H), 7.45 (dd, J ¼ 1.8, 8.4 Hz,1H, 60-
H), 7.51 (d, J ¼ 1.8 Hz,1H, 20-H), 8.77 (s,1H, 3-OH), 9.57 (s,1H, 40-OH),
10.69 (s, 1H, 7-OH). ESI-MS m/z: 331 [M þ H]þ, 353 [M þ Na]þ.
J ¼ 2.0 Hz, 1H, 6-H), 6.50 (d, J ¼ 2.0 Hz, 1H, 8-H), 7.14 (d, J ¼ 8.6 Hz,
1H, 50-H), 7.75 (d, J ¼ 2.0 Hz, 1H, 20-H), 7.80 (dd, J ¼ 2.0, 8.6 Hz, 1H,
60-H), 9.54 (s,1H, 3-OH),10.79 (s,1H, 7-OH),12.43 (s,1H, 5-OH). ESI-
MS m/z: 331 [M þ H]þ, 353 [M þ Na]þ.
3.1.21. 2-(2,2-Diphenylbenzo[d][1,3]dioxol-5-yl)-5-hydroxy-3,7-
dimethoxy-4H-chromen-4-one (27)
3.1.25. 2-(3,4-Bis(benzyloxy)phenyl)-7-(benzyloxy)-3,5-dimethoxy-
4H-chromen-4-one (29)
To a solution of 9 (233 mg, 0.5 mmol) in dry DMF (20 ml) was added
K2CO3 (2.06 g, 1.5 mmol, 3.0 equiv.) and iodomethane (0.083 ml,
1.3 mmol, 2.6 equiv.) at room temperature. After 12 h, the reaction
mixturewas thenpartitioned between 100 ml ethyl acetate and 100 ml
water. The ethyl acetate layer was then washed with brine (100 ml),
dried over MgSO4, filtered and concentrated. The crude material was
purified by column chromatography (25% ethyl acetate in petroleum
ether) to yield 27 (232 mg, 94% yield) as a yellow solid [16]. Mp
To a solution of 14 (286 mg, 0.5 mmol) in dry DMF (20 ml) was
added K2CO3 (414 mg, 3.0 mmol, 6.0 equiv.) and iodomethane
(0.16 ml, 2.5 mmol, 5.0 equiv.) at room temperature. After 12 h, the
reaction mixture was then partitioned between 100 ml ethyl
acetate and 100 ml water. The ethyl acetate layer was then washed
with brine (100 ml), dried over MgSO4, filtered and concentrated.
The crude material was purified by column chromatography (25%
ethyl acetate in petroleum ether) to yield 29 (273 mg, 91% yield) as
a yellow solid. Mp 132e134 ꢀC. 1H NMR (CDCl3, 300 MHz): 3.74 (s,
3H, eOCH3), 3.94 (s, 3H, eOCH3), 5.13 (s, 2H, eOCH2Ph), 5.25 (s, 4H,
2ꢂeOCH2Ph), 6.41 (d, J ¼ 2.4 Hz, 1H, 6-H), 6.52 (d, J ¼ 2.4 Hz, 1H, 8-
H), 7.02 (d, J ¼ 8.6 Hz,1H, 50-H), 7.30e7.49 (m,15H, aromatic H), 7.64
(dd, J ¼ 2.0, 8.6 Hz,1H, 60-H), 7.77 (d, J ¼ 2.0 Hz,1H, 20-H). ESI-MS m/
z: 601 [M þ H]þ, 623 [M þ Na]þ.
150e151 ꢀC (lit. [16] 149e151 ꢀC). 1H NMR (CDCl3, 300 MHz)
d 3.86 (s,
6H, 2ꢂ eOCH3), 6.34 (d, J¼ 2.0 Hz,1H, 6-H), 6.42 (d, J¼ 2.0 Hz,1H, 8-H),
7.00 (d, J ¼ 8.3 Hz, 1H, 50-H), 7.39 (m, 6H, aromatic H), 7.60 (m, 4H,
aromatic H), 7.66 (d, J ¼ 1.8 Hz, 1H, 20-H), 7.70 (dd, J ¼ 1.8, 8.3 Hz,1H, 60-
H), 12.61 (s, 1H, 5-OH). ESI-MS m/z: 495 [M þ H]þ, 517 [M þ Na]þ.
3.1.22. 2-(3,4-Dihydroxyphenyl)-5-hydroxy-3,7-dimethoxy-4H-
chromen-4-one (21)
3.1.26. 2-(3,4-Dihydroxyphenyl)-7-hydroxy-3,5-dimethoxy-4H-
chromen-4-one (23)
To a solution of 27 (100 mg, 0.20 mmol) dissolved in ethanol
(10 ml) and THF (10 ml) was added 10% Pd/C (2 mg) with vigorous
stirring. The reaction vessel was then evacuated and the atmosphere
replaced with hydrogen. After 12 h, the reaction mixturewas filtered
through celite and the filtrate concentrated. The crude material was
then chromatographed over silica gel (50% ethyl acetate in petro-
leum ether) to yield 21 (61 mg, 93%) as a yellow solid. Mp
To a solution of 29 (100 mg, 0.17 mmol) dissolved in ethanol
(10 ml) and THF (10 ml) was added 10% Pd/C (2 mg) with vigorous
stirring. The reaction vessel was then evacuated and the atmosphere
replaced with hydrogen. After 12 h, the reaction mixture was filtered
through celite and the filtrate concentrated. The crude material was
then chromatographed over silica gel (50% ethyl acetate in petro-
leum ether) to yield 23 (51 mg, 91%) as a yellow solid. Mp
229e230 ꢀC. 1H NMR (DMSO-d6, 300 MHz)
d 3.80 (s, 3H, eOCH3),
3.87 (s, 3H, eOCH3), 6.37 (d, J ¼ 2.0 Hz, 1H, 6-H), 6.71 (d, J ¼ 2.0 Hz,
1H, 8-H), 6.91 (d, J ¼ 8.4 Hz,1H, 50-H), 7.48 (dd, J ¼ 1.8, 8.4 Hz,1H, 60-
H), 7.59 (d, J ¼ 1.8 Hz,1H, 20-H), 9.35 (s,1H, 30-OH), 9.77 (s,1H, 40-OH),
12.69 (s, 1H, 5-OH). ESI-MS m/z: 331 [M þ H]þ, 353 [M þ Na]þ.
263e264 ꢀC. 1H NMR (DMSO-d6, 300 MHz)
d 3.70 (s, 3H, eOCH3),
3.80 (s, 3H, eOCH3), 6.34 (d, J ¼ 2.0 Hz, 1H, 6-H), 6.43 (d, J ¼ 2.0 Hz,
1H, 8-H), 6.87 (d, J ¼ 8.4 Hz,1H, 50-H), 7.37 (dd, J ¼ 2.2, 8.4 Hz,1H, 60-
H), 7.49 (d, J ¼ 2.2 Hz, 1H, 20-H), 9.28 (s, 1H, 30-OH), 9.56 (s, 1H, 40-
OH), 10.67 (s, 1H, 7-OH). ESI-MS m/z: 331 [M þ H]þ, 353 [M þ Na]þ.
3.1.23. 2-(3,4-Dimethoxyphenyl)-5-hydroxy-3,7-bis(methoxymethoxy)-
4H-chromen-4-one (28)
3.1.27. 3-(Benzyloxy)-2-(2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-
5,7-dimethoxy-4H-chromen-4-one (30)
To a solution of 11 (195 mg, 0.5 mmol) in dry DMF (20 ml) was
added K2CO3 (2.06 g, 1.5 mmol, 3.0 equiv.) and iodomethane
(0.083 ml,1.3 mmol, 2.6 equiv.) at room temperature. After 12 h, the
reaction mixture was then partitioned between 100 ml ethyl
acetate and 100 ml water. The ethyl acetate layer was then washed
with brine (100 ml), dried over MgSO4, filtered and concentrated.
The crude material was purified by column chromatography (25%
ethyl acetate in petroleum ether) to yield 28 (192 mg, 92% yield) as
To a solution of 17 (278 mg, 0.5 mmol) in dry DMF (20 ml) was
added K2CO3 (414 mg, 3.0 mmol, 6.0 equiv.) and iodomethane
(0.16 ml, 2.5 mmol, 5.0 equiv.) at room temperature. After 12 h, the
reaction mixture was then partitioned between 100 ml ethyl
acetate and 100 ml water. The ethyl acetate layer was then washed
with brine, dried over MgSO4, filtered and concentrated. The crude
material was purified by column chromatography (25% ethyl