Z.-Z. Zhou et al. / Bioorg. Med. Chem. 22 (2014) 1539–1547
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2H), 6.44 (d, J = 9.0 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 7.17 (d,
J = 8.6 Hz, 2H), 7.71 (d, J = 8.9 Hz, 1H), 12.74 (s, 1H, OH); 13C NMR
(100 MHz, CDCl3) d 7.45, 43.93, 55.19, 55.67, 101.87, 113.32,
113.72, 114.14, 126.57, 129.56, 130.27, 158.58, 162.47, 163.45,
202.6; ESI-MS m/z: 283.1 ([M+H]+).
4.1.2.4. 2-(3,4-Dimethoxyphenyl)-7-methoxy-8-methyl-3-phe-
nyl-4H-chromen-4-one (16c). Light yellow solid; 65% yield.
Mp 211.9–213.2 °C; 1H NMR (400 MHz, DMSO-d6) d 2.41 (s, 3H,
CH3), 3.47 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.97 (s, 3H, OMe), 6.74
(s, 1H), 6.83 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 7.28–7.37
(m, 6H), 8.13 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) d
8.04, 54.91, 55.46, 56.23, 109.22, 111.17, 112.91, 113.02, 116.53,
120.50, 122.36, 124.00, 124.87, 127.20, 128.09, 131.01, 133.82,
147.60, 150.50, 154.24, 160.14, 160.97, 175.89; ESI-MS m/z:
403.6 ([M+H]+), 425.5 ([M+Na]+); HR-ESI-MS for C25H23O5
([M+H]+) Calcd: 403.1540; Found: 403.1530.
4.1.1.4. 4,30,40-Trimethoxy-2-hydroxy-3-methyldeoxybenzoin
(14c).
85% yield. Mp 135.6–136.6 °C; 1H NMR (400 MHz, CDCl3)
d 2.07 (s, 3H, CH3), 3.83 (s, 3OMe), 4.13 (s, 2H, CH2), 6.42 (d,
J = 8.9 Hz, 1H), 6.79 (s, 3H), 7.70 (d, J = 8.9 Hz, 1H), 12.77 (s, 1H,
OH); 13C NMR (100 MHz, CDCl3) d 7.46, 44.42, 55.83, 101.88,
111.34, 112.36, 113.32, 113.73, 121.42, 127.04, 129.55, 148.07,
149.05, 162.48, 163.49, 202.48; ESI-MS m/z: 313.1 ([M+H]+),
335.13 ([M+Na]+).
4.1.2.5. 2-(4-Chlorophenyl)-7-methoxy-8-methyl-3-phenyl-4H-
chromen-4-one (16d).
White solid; 71% yield. Mp 234.0–
235.7 °C; 1H NMR (400 MHz, CDCl3) d 2.37 (s, 3H, CH3), 3.98 (s, 3
H, OMe), 7.02 (d, J = 8.8 Hz, 1H), 7.21–7.25 (m, 4H), 7.29–7.35 (m,
5H), 8.14 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 8.32,
56.15, 108.73, 113.73, 117.34, 122.22, 124.94, 127.73, 128.42,
128.45, 130.86, 131.21, 132.10, 132.85, 136.08, 155.07, 159.68,
161.52, 177.24; ESI-MS m/z: 400.0 ([M+Na]+); HR-ESI-MS for C23-
H18ClO3 ([M+H]+) Calcd: 377.0939; Found: 377.0926.
4.1.1.5. 40-Fluoro-2-hydroxy-4-methoxy-3-methyldeoxybenzoin
(14d).
75% yield. Mp126.7–127.7 °C; 1H NMR (400 MHz,
CDCl3) d 2.08 (s, 3H, CH3), 3.87 (s, 3H, OMe), 4.18 (s, 2 H, CH2),
6.45 (d, J = 9.0 Hz, 1H), 6.98–7.03 (m, 2H), 7.14–7.24 (m, 2H),
7.68 (d, J = 9.0 Hz, 1H), 12.66 (s, 1H, OH); 13C NMR (100 MHz,
CDCl3)
d 7.46, 43.81, 55.70, 101.97, 113.24, 113.83, 115.42,
115.64, 129.42, 130.20, 130.23, 130.80, 130.88, 160.67 (C-F),
162.47, 163.11 (C-F), 163.60, 201.92; ESI-MS m/z: 271.0 ([M+H]+),
293.0 ([M+Na]+).
4.1.2.6. 7-Methoxy-3-(4-methoxyphenyl)-8-methyl-2-phenyl-
4H-chromen-4-one (16e).
White solid; 57% yield. Mp
224.6–226.4 °C; 1H NMR (400 MHz, CDCl3) d 2.38 (s, 3H, CH3),
3.80 (s, 3H, OMe), 3.97 (s, 3H, OMe), 6.85 (d, J = 8.0 Hz, 2H), 7.01
(d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.28–7.34 (m, 3H), 7.43
(d, J = 7.6 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
4.1.2. Synthesis of 3-aryl-8-methylflavones 16a–m
4.1.2.1. General procedures.
A solution of compounds 14a–d
(1.0 mmol) and benzoyl chlorides 15a–e (2.7 mmol) in anhydrous
pyridine (5 mL) was stirred at room temperature for 5 h. The reac-
tion mixture was concentrated under reduced pressure, poured
into water (25 mL) and then extracted with ether (10 mL ꢁ 2).
The combined organic layer was washed subsequently with 5%
aqueous HCl (10 mL) and water (10 mL ꢁ 2), dried over anhydrous
Na2SO4 and concentrated to yield an oily residue. Purification was
accomplished by chromatography on a silica gel column, eluting
with petroleum ether–acetone (l0/l, v/v), to give crude esters. Then,
a solution of the crude esters in freshly distilled anhydrous glycerol
(8 mL) was heated at 260 °C for 2 h under the atmosphere of nitro-
gen. The reaction mixture, after cooled to room temperature, was
poured into water (20 mL), and adjusted to pH 10 with 4 N NaOH.
The resulting mixture was stirred at room temperature for 15 min
and allowed to stand at 0 °C for 24 h. The formed precipitate was
collected by filtration and re-crystallized from EtOH to give com-
pounds 16a–m.
CDCl3)
d 8.33, 55.24, 56.13, 108.58, 113.74, 113.84, 117.37,
121.53, 124.86, 125.23, 128.12, 129.56, 129.79, 132.44, 133.85,
155.14, 158.76, 160.76, 161.37, 177.71; ESI-MS m/z: 373.9
([M+H]+), 395.8 ([M+Na]+); HR-ESI-MS for C24H21O4 ([M+H]+)
Calcd: 373.1440; Found: 373.1439.
4.1.2.7.
chromen-4-one (16f).
7-Methoxy-2,3-bis(4-methoxyphenyl)-8-methyl-4H-
Light yellow solid; 51% yield. Mp
197.2–198.3 °C; 1H NMR (400 MHz, CDCl3) d 2.38 (s, 3H, CH3),
3.79 (s, 3H, OMe), 3.81 (s, 3H, OMe), 3.96 (s, 3H, OMe), 6.79 (d,
J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.8 Hz, 1H),
7.16 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 8.35, 55.25, 56.31, 56.11,
108.44, 113.56, 113.61, 113.92, 117.33, 120.60, 124.77, 125.66,
126.01, 131.16, 131.40, 155.03, 158.88, 160.65, 160.70, 161.26,
177.70; ESI-MS m/z: 403.8 ([M+H]+), 425.7 ([M+Na]+); HR-ESI-MS
for C25H23O5 ([M+H]+) Calcd: 403.1545; Found: 403.1556.
4.1.2.2. 7-Methoxy-8-methyl-2,3-diphenyl-4H-chromen-4-one
(16a).
4.1.2.8.
2-(3,4-Dimethoxyphenyl)-7-methoxy-3-(4-methoxy-
Light yellow
White solid; 65% yield. Mp 241.4–242.5 °C; 1H NMR
phenyl)-8-methyl-4H-chromen-4-one (16g).
solid; 54% yield. Mp 211.3–212.4 °C; 1H NMR (400 MHz, DMSO-
d6) d 2.32 (s, 3H, CH3), 3.44 (s, 3H, OMe), 3.75 (d, 6H, OMe ꢁ 2),
3.95 (s, 3H, OMe), 6.80 (s, 1H), 6.91–6.97 (m, 3H), 7.10 (d,
J = 8.4 Hz, 2H), 7.15 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H),
7.93 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) d 8.06,
54.94, 55.06, 55.44, 56.20, 109.12, 111.08, 112.82, 112.88, 113.64,
116.51, 120.05, 122.36, 124.01, 125.09, 125.64, 132.20, 147.59,
150.15, 154.20, 158.48, 159.99, 160.88, 176.13; ESI-MS m/z:
433.7 ([M+H]+), 455.7 ([M+Na]+); HR-ESI-MS for C26H25O6
([M+H]+) Calcd: 433.1651; Found: 433.1658.
(400 MHz, CDCl3) d 2.38 (s, 3H, CH3), 3.97 (s, 3H, OMe), 7.01 (d,
J = 7.2 Hz, 1H), 7.22–7.25 (m, 3H), 7.28–7.35 (m, 5H), 7.40 (d,
J = 7.6 Hz, 2H), 8.16 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) d 8.35, 56.17, 108.64, 113.78, 117.41, 122.02, 124.90,
127.51, 128.10, 128.26, 129.60, 129.91, 131.34, 133.16, 133.67,
155.16, 160.98, 161.42, 177.43; ESI-MS m/z: 343.4 ([M+H]+); HR-
ESI-MS for C23H19O3 ([M+H]+) Calcd: 343.1329; Found: 343.1314.
4.1.2.3. 7-Methoxy-2-(4-methoxyphenyl)-8-methyl-3-phenyl-
4H-chromen-4-one (16b).
White solid; 75% yield. Mp
194.5–196.5 °C; 1H NMR (400 MHz, DMSO-d6) d 2.31 (s, 3H, CH3),
3.75 (s, 3H, OMe), 3.95 (s, 3H, OMe), 6.87 (d, J = 8.8 Hz, 2H),
7.17–7.19 (m, 2H), 7.20 (d, J = 8.8 Hz, 1H), 7.30–7.35 (m, 5H),
7.94 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) d 8.12,
55.26, 56.24, 109.22, 112.89, 113.64, 116.54, 120.48, 124.05,
125.09, 127.27, 128.03, 130.97, 131.12, 133.51, 154.29, 160.40,
160.50, 160.96, 175.89; ESI-MS m/z: 373.5 ([M+H]+); HR-ESI-MS
for C24H21O4 ([M+H]+) Calcd: 373.1434; Found: 373.1429.
4.1.2.9. 3-(3,4-Dimethoxyphenyl)-7-methoxy-8-methyl-2-phe-
nyl-4H-chromen-4-one (16h).
Light yellow solid; 62% yield.
Mp 197.2–197.8 °C; 1H NMR (400 MHz, CDCl3) d 2.38 (s, 3H,
CH3), 3.73 (s, 3H, OMe), 3.87 (s, 3H, OMe), 3.96 (s, 3H, OMe), 6.80
(t, J = 8.0 Hz, 3H), 7.00 (d, J = 8.8 Hz, 1H), 7.28–7.34 (m, 3H), 7.44
(d, J = 6.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d 8.29, 55.79, 56.05, 108.56, 111.08, 113.69, 114.61,