JOURNAL OF CHEMICAL RESEARCH 2014 289
Apigenin: A solution of naringenin (5.0 g, 18 mmol) and iodine (5.0 g,
19 mmol) in pyridine (50 mL) was heated to 95 °C for 5 h. The mixture
was poured into ice water. The resulting precipitate was filtered,
and then washed with water, dilute hydrochloric acid and saturated
sodium thiosulfate. Recrystallisation of the dried residue from ethanol
afforded apigenin: 3.20 g; 66%; m.p. 345–350 °C (lit.23 344–346 °C).
Hesperetin from hesperidin: The same procedure as for naringenin
was used. Hesperetin was obtained as a yellow solid: 88%; m.p.
224–226 °C (lit.24 224–226 °C).
1181, 1074, 968, 830 cm–1; MS (m/z, EI): 372 (M+), 327, 315, 287, 259,
194, 135, 77, 57; HRMS (EI): m/z [M+] calcd for C20H20O7: 372.1209,
found: 372.1204.
Nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone) (2): The same procedure
as for 1 was used. 2 was obtained as yellow crystals: 80%; m.p.
112–113 °C (lit.13 112–113 °C); 1H NMR (CDCl3) δ 7.50 (dd, J=8.5 and
1.9 Hz, 1H, H-6′), 7.34 (s, 1H, H-2′), 6.92 (d, J=8.5 Hz, 1H, H-5′), 6.55
(s, 1H, H-3), 4.03 (s, 3H), 3.96 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.88 (s,
6H); 13C NMR (CDCl3) δ 177.3, 161.1, 151.9, 151.5, 149.2, 148.4, 147.7,
144.1, 123. 9, 119.9, 114.7, 111.2, 108.5, 106.7, 62.3, 62.0, 61.8, 61.7, 56.1,
55.9; MS (m/z, EI): 402 (M+), 387 (100), 371, 344, 326, 298, 283, 239,
225, 198, 197, 182, 162, 153, 139, 91, 83, 77; HRMS (EI): m/z [M+] calcd
for C21H22O8: 402.1315, found: 402.1314.
3-Hydroxytangeretin (3-hydroxy-5,6,7,8,4′-pentamethoxyflavone)
(3): To a solution of tangeretin (500 mg) and buffer NaHCO3 (1.9 g
NaHCO3, 4 g Na2CO3, 100 mL H2O) in CH2Cl2 (30 mL) and acetone
(25 mL), potassium hydrogen sulfate solution was added dropwise. The
mixture was left for 12 h at 5 °C±1°C, and then recharged with acetone
(25 mL) and buffer NaHCO3 (1.9 g NaHCO3, 4 g Na2CO3, 100 mL
H2O). After potassium hydrogen sulfate solution was added dropwise,
the mixture was kept again at 5 °C±1°C for another 12 h. The water
layer was then extracted with dichloromethane (3×50 mL). The
organic layers were combined and dried with anhydrous MgSO4. The
solution was filtered and p-toluenesulfonic acid (5 mg) was then added.
After stirring for 1 h, the mixture was evaporated and crystallised
by dichloromethane/methanol to afford 3 as yellow crystals: 350 mg
(67%); m.p. 130–132 °C (lit.13 134–135 °C); 1H NMR (CDCl3) δ 8.25 (d,
J=9.1 Hz, 2H, H-2′ and 6′), 7.31 (s, 1H, OH-3), 7.06 (d, J=9.1 Hz, 2H,
H-3′ and 5′), 4.13 (s, 3H), 4.04 (s, 3H), 3.99 (s, 3H), 3.96 (s, 3H), 3.90 (s,
3H); 13C NMR (CDCl3) δ 170.8, 159.8, 150.5, 146.5, 145.9, 142.4, 142.2,
136.9, 136.2, 128.1, 122.6, 113.1, 110.7, 61.3, 61.0, 60.8, 60.7, 54.4; IR
(KBr): ν 3452, 3292, 1564, 1602, 1462, 1402, 4264, 1209, 1184, 1057,
985, 835 cm–1; MS (m/z, ESI): 389 [M+1] +.
Diosmetin: The same procedure as for apigenin was used.
diosmetin was obtained as a yellow solid: 60%; m.p. 253–255 °C (lit.25
253–254 °C).
6,8-Dibromoapigenin (13): NBS (2.88 g, 16.2 mmol) was added to
a solution of apigenin (2.16 g, 8 mmol) in TFA (22 mL). The reaction
mixture was stirred for 5 h at room temperature, and then poured into
ice water. The resulting precipitate was filtered, washed with water
and dried under vacuum to afford a green crude solid which was
chromatographed on silica gel using petroleum ether/ethyl acetate
(4:1) as the eluent to afford 13 as a yellow solid: 3.15 g; 93%; m.p.
311–313 °C; 1H NMR (DMSO-d6) δ 12.96 (s, 1H), 10.81 (s, 1H), 10.37
(s, 1H), 7.93 (d, J=8.4 Hz, 2H, H-2′ and 6′), 6.93 (d, J=8.3 Hz, 2H, H-3′
and 5′), 6.49 (s, 1H, H-3).
6,8-Dibromodiosmetin (14): The same procedure as for 13 was
used. 14 was obtained as a yellow solid: 93%; m.p. 284–285 °C (lit.26
1
284–287 °C); H NMR (DMSO-d6) δ 9.56 (s, 1H), 7.65 (dd, J=8.6,
2.1 Hz, 1H, H-6′), 7.56 (d, J=2.2 Hz, 1H, H-2′), 7.13 (d, J=8.7 Hz, 1H,
H-5′), 7.00 (s, 1H, H-3), 3.89 (s, 3H, OCH3-4′).
6,8-Dimethoxyapiginin (11): Small pieces of clean sodium (Na)
(0.23 g) were added to methanol (12 mL) slowly. CuBr (0.002 g) was
mixed with MeONa/MeOH. When the colour of reaction solution
changed to blue, a solution of 6,8-dibromoapigenin (0.425 g) in
anhydrous DMF (20 mL) was added into the reaction solution
under nitrogen. The mixture was exposed to microwave irradiation
(700 W) at 120 °C for 1 h, and then cooled to room temperature.
After adjustment of the pH to 6 with hydrochloric acid (5%, 200 mL),
the mixture was filtered. The filtrate was extracted with ethyl
acetate (3×50 mL) and the organic layers were dried over anhydrous
Na2SO4. The solvent was evaporated to yield a crude oil that was
chromatographed on silica gel using petroleum ether/ethyl acetate
(3:1) as eluent to afford 11 as a yellow solid: 200 mg; 90%; m.p.
3-Hydroxynobiletein (3-hydroxy-5,6,7,8,3′,4′-hexamethoxyfavlone)
(4): The same procedure as for 3 was used. 4 was obtained as yellow
1
crystals: 64%; m.p. 133–134°C (lit.11 129–130°C); H NMR (CDCl3)
δ 7.85 (dd, J=10.6, 1.9 Hz, 2H, H-2′ and 6′), 6.96 (d, J=8.4 Hz, 1H,
H-5′), 5.23 (s, 1H, OH-3), 4.05 (s, 3H), 3.97 (s, 3H), 3.93 (s, 6H), 3.90
(s, 3H), 3.88 (s, 3H); 13C NMR (CDCl3) δ 171.804, 151.572, 150.366,
148.719, 147.521, 146.781, 143.417, 142.905, 137.718, 137.306, 123.704,
120.919, 111.589, 110.880, 109.964, 62.284, 61.910, 61.826, 61.681,
55.914, 55.784; IR (KBr): ν 3435, 3299, 2942, 2844, 1597, 1561, 1515,
1438, 1409, 1268, 1208, 1146, 1051, 1023, 975 cm–1; MS (m/z, ESI): 419
[M+1]+.
1
270–271 °C (lit.27 271–273 °C); H NMR (DMSO-d6) δ 12.81 (s, 1H),
10.41 (s, 1H), 10.03 (s, 1H), 7.80 (d, J=8.8 Hz, 2H, H-2′ and 6′), 6.95 (d,
J=8.8 Hz, 2H, H-3′ and 5′), 6.80 (s, 1H, H-3), 3.89 (s, 3H), 3.78 (s, 3H);
MS (m/z, EI): 330 (M+), 315, 287, 272, 197, 169, 113, 69; HRMS (EI): m/z
[M+] calcd for C17H14O7: 330.0740, found: 330.0745.
3,5,6,7,8,4′-Hexamethoxyflavone (5): Me2SO4 (0.2 mL, 1 equiv.)
was added dropwise to a stirred solution of 6, 8-dimethoxydiosmetin
(100 mg) in acetone (20 mL) and K2CO3 (144 mg) at room temperature
for 2 h. The mixture was filtered, and the filtrate was evaporated to
afford a crude solid which was crystallised from petroleum ether/ethyl
acetate (3:1) to afford yellow crystals: 84 mg; 81%; m.p. 133–135 °C
6,8-Dimethoxydiosmetin (12): The same procedure as for 11 was
used. 12 was obtain as pale yellow solid: 83%; m.p. 243–245 °C (lit.28
239–241 °C); 1H NMR (DMSO-d6) δ 12.79 (s, 1H), 10.45 (s, 1H), 9.59
(s, 1H), 7.57 (dd, J=8.6 and 2.3 Hz, 1H, H-6′), 7.48 (d, J=2.2 Hz, 1H,
H-2′), 7.12 (d, J=8.7 Hz, 1H, H-5′), 6.81 (s, 1H, H-3), 3.87 (d, J= 3.8 H z,
6H), 3.77 (s, 3H); 13C NMR (DMSO-d6) δ 182.7, 163.8, 151.7, 151.3,
148.8, 147.3, 145.9, 132.0, 128.4, 123.5, 119.1, 113.3, 112.7, 103.5, 103.5,
61.8, 60.6, 56.2; MS (m/z, EI): 360 (M+), 345 (100), 330, 315, 300, 287,
272, 229, 216, 197, 169, 149, 113, 83, 69; HRMS (EI): m/z [M+] calcd for
C18H16O8: 360.0845, found: 360.0845.
1
(lit.29 133–134 °C); H NMR (CDCl3) δ 8.16 (d, J=9.0 Hz, 2H, H-2′
and 6′), 7.04 (d, J=9.0 Hz, 2H, H-3′ and 5′), 4.10 (s, 3H), 4.01 (s, 3H),
3.98 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H); 13C NMR (CDCl3) δ
170.8, 150.6, 149.5, 147.9, 146.6, 145.8, 142.5, 142.0, 136.8, 136.4, 122.8,
120.0, 110.7, 110.0, 109.2, 61.3, 60.9, 60.8, 60.7, 55.0, 54.9; IR (KBr): ν
2946, 2843, 1650, 1607, 1587, 1512, 1462, 1363, 1265, 1181, 1074, 968,
830 cm–1; MS (m/z, EI): 402 (M+), 387 (100), 359, 344, 298, 225, 197,
182, 150, 136, 109, 83, 65.
Tangeretin (5,6,7,8,4′-pendamethoxyflavone) (1): Me2SO4 (0.1 mL,
3 equiv.) was added dropwise to stirred solution of 6,
8-dimethoxydiosmetin (120 mg) in acetone and K2CO3 (0.91 g,
6.48 mmol) at 65°C. The reaction was terminated after 5 h, and the
mixture was then filtered. The solution was evaporated to afford a
solid residue. The crude solid was chromatographed on silica gel using
petroleum ether/ethyl acetate (3:1) as eluent to afford light yellow
3,5,6,7,8,3′,4′-Heptamethoxylflavone (6): The same procedure as for
5 was used. 6 was obtained as yellow crystals: 83%; m.p. 130–131 °C
1
(lit.30 130.5–131.8 °C); H NMR (CDCl3) δ 7.77 (dd, J=8.5, 2.0 Hz,
1H, H-6′), 7.74 (d, J=2.0 Hz, 1H, H-2′), 6.94 (d, J=8.6 Hz, 1H, H-5′),
4.02 (s, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.90 (s, 3H), 3.87(s, 3H), 3.81 (s,
3H), 3.66 (s, 3H); 13C NMR (CDCl3) δ 172.9, 152.1, 150.3, 150.0, 147.7,
147.1, 145.7, 142.8, 139.7, 136.8, 122.4, 120.9, 114.0, 109.9, 99.0, 61.3,
60.9, 60.8, 60.7, 58.8, 55.0, 54.9; IR (KBr): ν 2938, 2840, 1648, 1590,
1521, 1463, 1363, 1273, 1217, 1177, 1138, 1049, 961 cm–1; MS (m/z, EI):
432 (M+), 404, 388, 373, 253, 236, 195, 181, 151 (100), 133, 108, 83, 69,
1
crystals of 1: 115 mg; 86%; m.p. 151–153 °C (lit.13 152–153 °C); H
NMR (CDCl3) δ 7.80 (d, J=8.8 Hz, 2H, H-2′ and 6′), 6.94 (d, J= 8.8 H z,
2H, H-3′ and 5′), 6.52 (s, 1H, H-3), 4.03 (s, 3H), 3.94 (s, 3H), 3.87 (s, 6H),
3.81 (s, 3H); 13C NMR (CDCl3) δ 176.3, 161.3, 160.1, 150.3, 147.3, 146.7,
143.0, 137.1, 126.7, 122.8, 113.8, 113.5, 105.6, 61.2, 61.0, 60.8, 60.6,
54.5; IR (KBr): ν 2946, 2843, 1650, 1607, 1587, 1512, 1462, 1363, 1265,
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