D. Ribeiro et al. / European Journal of Medicinal Chemistry 67 (2013) 280e292
283
1H, H-5), 7.74 (d, J 15.5 Hz,1H, H-
b
), 7.84 (d, J 15.5 Hz,1H, H-
a
),14.87
chromatography using ethyl acetate as eluent affording poly-
alkoxyflavones 10bed as yellowish oils in moderated yields: 10b,
36%, 0.10 g; 10c, 44%, 0.15 g; 10d, 44%, 0.13 g.
(s, 1H, 20-OH) ppm. 13C NMR:
d
55.8 (3-OCH3), 59.0 (C-400, C-4000 and
C-40000), 68.0 (C-20000), 68.1 (C-200), 68.6 (C-2000), 71.4 (C-300, C-3000 and C-
30000), 92.9 (C-100), 94.1 and 94.2 (C-1000 and 10000), 94.8 (C-50), 97.5 (C-
30), 107.4 (C-10), 111.0 (C-2), 115.8 (C-5), 122.1 (C-6), 125.7 (C-
a
),
2.7.1. 30-Hydroxy-40-methoxy-5,7-di[(2-methoxyethoxy)methoxy]
129.7 (C-1), 142.5 (C-
b
), 148.4 (C-4), 149.6 (C-þ3), 159.7 (C-60), 163.3
flavone (10b)
(C-40), 167.2 (C-20), 192.6 (C¼O) ppm. MS (ESI ) m/z (rel. int.): 589
1H NMR:
d
3.38 and 3.40 (2s, 2 ꢂ 3H, H-400 and00H0 -4000), 3.56e3.61
([M þ Na]þ, 100). HRMS (ESIþ), m/z: C28H39O12, calcd 567.2436
(m, 4H, H-300 and H-3000), 3.84e3.87 (m, 2H, H-2 ), 3.93e3.96 (m,
2H, H-200), 3.97 (s, 3H, 40-OCH3), 5.35 (s, 2H, H-1000), 5.42 (s, 2H, H-
100), 5.92 (brs, 1H, 30-OH), 6.56 (s, 1H, H-3), 6.77 (d, J 2.3 Hz, 1H, H-6),
6.89 (d, J 2.3 Hz, 1H, H-8), 6.94 (d, J 8.5 Hz, 1H, H-50), 7.42 (dd, J 8.5
and 2.2 Hz, 1H, H-60), 7.46 (d, J 2.2 Hz, 1H, H-20) ppm. 13C NMR:
[M
þ
H]þ, found: 567.2457; C28H38NaO12
, calcd 589.2256
[M þ Na]þ, found: 589.2265.
2.5.4. 20-Hydroxy-3,4-dimethoxy-40,60-di[(2-methoxyethoxy)
methoxy]chalcone (8d)
d
56.1 (40-OCH3), 58.9 and 59.1 (C-400 and C-4000), 68.1 (C-200), 68.2 (C-
1H NMR:
d
3.34 (s, 3H, H-4000), 3.39 (s, 3H, H-400), 3.52-3.55 (m,
2000), 71.5 (C-300 and C-3000), 93.3 (C-1000), 94.4 (C-100), 97.2 (C-8), 102.0
(C-6), 107.7 (C-3), 110.6 (C-10), 110.6 (C-50), 112.2 (C-20), 118.7 (C-60),
124.6 (C-10), 146.0 (C-30), 149.2 (C-40), 158.0 (C-7), 159.3 (C-9), 160.8
(C-2), 161.2 (C-5), 177.4 (C-4) ppm. MS (ESIþ) m/z (rel. int.): 477
([M þ H]þ, 34), 499 ([M þ Na]þ, 100), 975 ([2M þ Na]þ, 15). HRMS
(ESIþ), m/z: C24H29O10, calcd 477.1755 [M þ H]þ, found: 477.1753;
2H, H-3000), 3.55-3.58 (m, 2H, H-300), 3.80-3.83 (m, 2H, H-200), 3.83-
3.86 (m, 2H, H-2000), 3.93 (s, 6H, 3,4-OCH3), 5.28 (s, 2H, H-100), 5.38 (s,
2H, H-1000), 6.26 (d, J 2.4 Hz,1H, H-50), 6.34 (d, J 2.4 Hz,1H, H-30), 6.90
(d, J 8.3 Hz, 1H, H-5), 7.14 (d, J 1.9 Hz, 1H, H-2), 7.22 (dd, J 8.3 and
1.9 Hz, 1H, H-6), 7.75 (d, J 15.5 Hz, 1H, H-b), 7.83 (d, J 15.5 Hz, 1H, H-
a
), 13.09 (s, 1H, 20-OH) ppm. 13C NMR:
d
55.8 and 56.0 (3-OCH3 and
C
24H28NaO10, calcd 499.1575 [M þ Na]þ, found: 499.1573.
4-OCH3), 59.0 (C-4000), 59.1 (C-400), 68.2 (C-200), 68.7 (C-2000), 71.5 (C-
300 and C-3000), 93.0 (C-100), 94.3 (C-1000), 94.8 (C-50), 97.6 (C-30), 107.6
2.7.2. 30,5-Dihydroxy-40-methoxy-7-[(2-methoxyethoxy)methoxy]
flavone (9a)
(C-10), 110.2 (C-2), 111.1 (C-5), 122.8 (C-6), 125.2 (C-
a), 128.4 (C-1),
142.8 (C-
b
), 149.2 (C-3), 151.1 (C-þ4), 159.7 (C-60), 163.3 (C-40), 167þ.2
Mp 142e143 ꢀC (light yellow powder recrystallized from
(C-20), 192.7 (C¼O) ppm. MS (ESI ) m/z (rel. int.): 515 ([M þ Na] ,
ethanol). 1H NMR: 3.40 (s, 3H, H-400), 3.57e3.60 (m, 2H, H-300),
d
100). HRMS (ESI ), m/z: C25H33O10, calcd 493.2068 [M þ H]þ,
3.83-3.87 (m, 2H, H-200), 4.00 (s, 3H, 40-OCH3), 5.34 (s, 2H, H-100),
5.75 (s, 1H, 30-OH), 6.48 (d, J 2.2 Hz, 1H, H-6), 6.58 (s, 1H, H-3), 6.69
(d, J 2.2 Hz, 1H, H-8), 6.97 (d, J 8.0 Hz, 1H, H-50), 7.44 (d, J 2.2 Hz, 1H,
H-20), 7.45 (dd, J 8.0 and 2.2 Hz, 1H, H-60), 12.75 (s, 1H, 5-OH) ppm.
þ
found: 493.2084; C25H32NaO10, calcd 515.1888 [M þ Na]þ, found:
515.1880.
2.6. Synthesis of 30,5,7-trimethoxyflavone (10a)
13C NMR: 56.1 (40-OCH3), 59.1 (C-400), 68.2 (C-200), 71.5 (C-300), 93.3
d
(C-100), 94.3 (C-8), 100.1 (C-6), 104.7 (C-3), 106.3 (C-10), 110.7 (C-50),
112.3 (C-20), 119.2 (C-60), 124.4 (C-10), 146.0 (C-30), 149.6 (C-40), 157.6
(C-9), 162.0 (C-5), 162.9 (C-7), 163.9 (C-2), 182.5 (C-4) ppm. MS
(ESIþ) m/z (rel. int.): 489 ([M þ H]þ, 100). HRMS (ESIþ), m/z for
A catalytic amount of iodine (6 mg, 5.70 mmol) was added to a
solution of 20-hydroxy-3,40,60-trimethoxychalcone 8a (0.30 g,
0.95 mmol) in DMSO (10 mL). The solution was stirred at reflux,
under nitrogen atmosphere, for 30 min. After this period the reac-
tion was poured into ice (100 g), water (50 mL) and sodium thio-
sulfate (w0.5 g). The obtained solid was filtered and taken in
chloroform (100 mL). The organic layer was successively washed
with a sodium thiosulfate solution (20%, 2 ꢂ 100 mL) and water
(100 mL) and then dried through anhydrous sodium sulphate. The
solvent was evaporated to dryness and the residue was recrystal-
lized in ethanol to give 30,5,7-trimethoxyflavone (10a), a white solid,
C
20H21O8: calcd 389.1231 [M þ H]þ, found: 389.1229.
2.7.3. 30-Methoxy-40,5,7-tri[(2-methoxyethoxy)methoxy]flavone
(10c)
1H NMR:
d
3.38, 3.39 and 3.40 (3s, 3 ꢂ 3H, H-400, H-4000 and H-
40000), 3.56e3.61 (m, 6H, H-300, H-3000 and H-30000), 3.85e3.88 (m, 2H,
H-2000), 3.89-3.91 (m, 2H, H-20000), 3.93e3.97 (m, 2H, H-200), 4.00 (s,
3H, 30-OCH3), 5.37 (s, 2H, H-1000), 5.41 (s, 2H, H-10000), 5.43 (s, 2H, H-
100), 6.59 (s, 1H, H-3), 6.79 (d, J 2.3 Hz, 1H, H-6), 6.92 (d, J 2.3 Hz, 1H,
H-8), 7.31 (d, J 8.5 Hz, 1H, H-50), 7.36 (d, J 2.1 Hz, 1H, H-20), 7.48 (dd, J
in good yield (71%, 0.21 g). Mp 147e148 ꢀC. 1H NMR: 3.89 (s, 3H, 30-
d
OCH3), 3.92 (s, 3H, 7-OCH3), 3.96 (s, 3H, 5-OCH3), 5.38 (d, J 2.3 Hz,1H,
H-6), 6.57 (d, J 2.3 Hz, 1H, H-8), 6.68 (s, 1H, H-3), 7.05 (ddd, J 7.9, 2.6
and 1.4 Hz, 1H, H-40), 7.40e7.38 (m, 1H, H-20), 7.40 (t, J 7.9 Hz, 1H, H-
8.5 and 2.1 Hz, 1H, H-60) ppm. 13C NMR:
d
56.1 (30-OCH3), 58.9 and
59.0 (C-400, C-4000 and C-40000), 68.0 and 68.1 (C-200, C-2000 and C-20000),
71.4 (C-300, C-3000 and C-30000), 93.2 (C-1000), 94.1 (C-10000), 94.4 (C-100),
97.1 (C-8),102.1 (C-6),108.0 (C-3),109.0 (C-20),111.6 (C-10),115.7 (C-
50), 119.5 (C-60), 125.3 (C-10), 149.2 (C-40), 149.7 (C-30), 158.0 (C-7),
159.2 (C-9), 160.7 (C-2), 161.1 (C-5), 177.3 (C-4) ppm. MS (ESIþ) m/z
(rel. int.): 565 ([M þ H]þ,100), 587 ([M þ Na]þ, 94). HRMS (ESIþ), m/
50), 7.46 (dt, J 7.9 and 1.4 Hz, 1H, H-60) ppm. 13C NMR:
d 55.4 (5-
OCH3), 55.7 (7-OCH3), 56.4 (30-OCH3), 92.8 (C-8), 96.2 (C-6), 109.2
(C-3 and C-10), 111.3 (C-20), 116.9 (C-40), 118.3 (C-60), 130.0 (C-50),
132.8 (C-10), 159.9 (C-30), 159.9 (C-9), 160.4 (C-2), 160.9 (C-5), 164.0
(C-7), 177.6 (C-4) ppm. MS (ESIþ) m/z (rel. int.): 313 ([M þ H]þ, 100),
647 ([2M þ Na]þ, 77). MS (ESIþ) m/z (rel. int.): 301 ([M þ H]þ, 34).
HRMS (EI), m/z for C18H16O5: calcd 312.0998 [M]þ$, found: 312.0998.
z:
C
C28H37O12
,
calcd 565.2280 [M
þ
H]þ, found: 565.2264;
28H36NaO12, calcd 587.2099 [M þ Na]þ, found: 587.2077.
2.7. Synthesis of polyalkoxyflavones 10bed
2.7.4. 5-Hydroxy-30-methoxy-40,7-di[(2-methoxyethoxy)methoxy]
flavone (9b)
Sodium periodate (2.97 mmol) was added to a suspension of the
appropriated 20-hydroxychalcones 8bed (0.59 mmol) in DMSO
(10 mL). The reaction mixture was stirred under nitrogen at 100 ꢀC
for 8 h (for 8b), 48 h (for 8c) or 72 h (for 8d). Then, it was poured
into ice (100 g) and a sodium thiosulfate solution (10%, 50 mL).
The obtained precipitate was filtered, taken in ethyl acetate
(100 mL), washed with water (2 ꢂ 100 mL) and then dried over
anhydrous sodium sulphate. The solvent was evaporated to dryness
and the obtained oils were purified by preparative thin-layer
Mp 124e125 ꢀC (white powder recrystallized from ethanol). 1H
NMR:
d
3.38 and 3.39 (2 ꢂ s, 6H, H-400 and H-4000), 3.56e3.60 (m, 4H,
H-300 and H-3000), 3.84e3.91 (m, 4H, H-200 and H-2000), 4.00 (s, 3H, 30-
OCH3), 5.36 (s, 2H, H-100), 5.42 (s, 2H, H-1000), 6.48 (d, J 2.2 Hz, 1H, H-
6), 6.61 (s,1H, H-3), 6.73 (d, J 2.2 Hz,1H, H-8), 7.32 (d, J 8.6 Hz,1H, H-
50), 7.38 (d, J 2.1 Hz, 1H, H-20), 7.49 (dd, J 8.6 and 2.1 Hz, 1H, H-60),
12.73 (s, 1H, 5-OH) ppm. 13C NMR:
d
56.2 (30-OCH3), 59.0 and 59.1
(C-400 and C-4000), 68.1 (C-200), 68.2 (C-2000), 71.4 (C-300 and C-3000), 93.1
(C-100), 94.1 (C-1000), 94.2 (C-8), 100.3 (C-6), 105.0 (C-3 and C-10),