M. Freitas et al. / European Journal of Medicinal Chemistry 86 (2014) 153e164
155
35
37
d
31.9 (2-CH3), 61.0 (40-OCH3), 61.8 (60-OCH3), 112.9 (C-50), 113.7 (C-
39), 415 ([C
H
Cl37ClO6þH]þ, 32), 417 ([C19
H
Cl37ClO6þH]þ, 6),
19 18
18
35
35
30), 114.1 (C-10), 157.6 (C-60), 158.9 (C-40), 159.3 (C-20), 204.0 (C]O)
435 ([C
H
19 18
37
Cl35ClO6þNa]þ, 28), 437 ([C19
H
Cl37ClO6þNa]þ, 18),
18
35
ppm. MS (ESIþ) m/z (rel. int.): 265 ([C10
([C
([C
([C
H
H
H
Cl35ClO4þH]þ, 25), 267
439 ([C H
19 18
Cl37ClO6þNa]þ, 4). Anal. Calcd for C19H18Cl2O6
10
35
37
H
Cl37ClO4þH]þ, 19), 269 ([C10
Cl37ClO4þH]þ, 5), 287
(413.25): C 55.22, H 4.39; found: C 55.22, H 4.37%.
10 10
10
35
35
H
Cl35ClO4þNa]þ, 31), 289 ([C10
Cl37ClO4þNa]þ, 25), 291
10 10
10
37
H
Cl37ClO4þNa]þ, 6). Anal. Calcd for C10H10Cl2O4 (265.09): C
2.5. Synthesis of 30,40,5,7-tetramethoxyflavones 3a,c
10 10
45.31, H 3.80; found: C 44.88, H 4.07%.
30,40,5,7-Tetramethoxyflavones 3a,c were prepared accordingly
to a procedure we previously described for a similar substituted
methoxyflavone (30,5,7-trimethoxyflavone) [12]. These flavones
were obtained in good yields from the corresponding 3,4,40,60-
tetramethoxychalcones 2a,c: 3a 91% (white solid); 3c, 64% (white
solid).
2.3.5. 50-Chloro-20-hydroxy-40,60-dimethoxyacetophenone (1d)
Mp 89e90 ꢀC. 1H NMR:
d
2.70 (s, 3H, 2-CH3), 3.91 (s, 3H, 60-
OCH3), 3.92 (s, 3H, 40-OCH3), 6.30 (s, 1H, H-30), 13.50 (s, 1H, 20-OH)
ppm. 13C NMR:
d
31.2 (2-CH3), 56.4 (40-OCH3), 61.3 (60-OCH3), 96.9
(C-30), 107.8 (C-50), 109.5 (C-10), 159.0 (C-60), 161.2 (C-40), 164.4 (C-
20), 203.0 (C]O) ppm. MS (ESIþ) m/z (rel. int.): 231
35
37
([C
C
H
10 11
ClO4þH]þ, 14), 233 ([C10
H
11
ClO4þH]þ, 4). Anal. Calcd for
2.5.1. 30,40,5,7-Tetramethoxyflavone (3a)
10H11ClO4 (230.64): C 52.07, H 4.81; found: C 51.79, H 4.76%.
Mp 193e194 ꢀC (lit. [16] 193 ꢀC). NMR:
d 3.92 (s, 3H, 7-OCH3),
3.96 (2ꢂ s, 6H, 40-OCH3 and 50-OCH3), 3.98 (s, 3H, 30-OCH3), 6.38 (d,
J 2.3 Hz,1H, H-6), 6.56 (d, J 2.3 Hz,1H, H-8), 6.61 (s,1H, H-3), 6.96 (d,
J 8.5 Hz, 1H, H-50), 7.32 (d, J 2.1 Hz, 1H, H-20), 7.51 (dd, J 8.5 and
2.4. Synthesis of 20-hydroxychalcones 2aec
20-Hydroxychalcones 2aec were prepared accordingly to a
procedure we previously described for 20-hydroxychalcones with
other substituents [12] in good yields: 2a 87% (canary yellow solid);
2b, 74% (dark yellow solid), 2c, 73% (cottony orange solid).
2.1 Hz, 1H, H-60) ppm. 13C NMR:
d 55.7 (7-OCH3), 56.0 and 56.4 (4-
OCH3, 5-OCH3, 30-OCH3), 92.8 (C-8), 96.1 (C-6), 107.9 (C-3), 108.5 (C-
20), 109.1 (C-10), 111.0 (C-50), 119.5 (C-60), 124.0 (C-10), 149.2 (C-30),
152.0 (C-40), 160.0 (C-9), 160.6 (C-2), 160.8 (C-5), 164.0 (C-7), 177.6
(C-4) ppm. MS (ESIþ) m/z (rel. int.): 343 ([MþH]þ, 100), 365
([MþNa]þ, 14), 381 ([MþK]þ, 7), 707 ([2MþNa]þ, 85). Anal. Calcd
for C19H18O6 (342.34): C 66.66, H 5.30; found: C 66.47, H 5.35%.
2.4.1. 20-Hydroxy-3,4,40,60-tetramethoxychalcone (2a)
Mp 154e155 ꢀC. 1H NMR: 3.84 (s, 3H, 40-OCH3), 3.91 (s, 3H, 60-
d
OCH3), 3.93 (s, 3H, 4-OCH3), 3.94 (s, 3H, 3-OCH3), 5.97 (d, J 2.4 Hz,
1H, H-50), 6.11 (d, J 2.4 Hz, 1H, H-30), 6.90 (d, J 8.3 Hz, 1H, H-5), 7.13
(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
2.5.2. 6,8-Dichloro-30,40,5,7-tetramethoxyflavone (3c)
Mp 212e213 ꢀC. NMR:
d
3.98 (s, 3H, 40-OCH3), 3.99 (s, 3H, 30-
15.5 Hz, 1H, H-
ppm. 13C NMR (lit. [15]):
OCH3), 56.0 (4-OCH3), 91.2 (C-50), 93.8 (C-30), 106.3 (C-10), 110.4
(C-2), 111.1 (C-5), 122.6 (C-6), 125.4 (C- ), 128.6 (C-1), 142.6 (C- ),
b
), 7.81 (d, J 15.5 Hz, 1H, H-
a
), 14.21 (s, 1H, 20-OH)
OCH3), 4.00 (s, 3H, 5-OCH3), 4.04 (s, 3H, 7-OCH3), 6.69 (s, 1H, H-3),
d
55.7 (40-OCH3), 55.8 (60-OCH3), 55.8 (3-
7.01 (d, J 8.5 Hz, 1H, H-50), 7.46 (d, J 2.1 Hz, 1H, H-20), 7.61 (dd, J 8.5
and 2.1 Hz, 1H, H-60) ppm. 13C NMR:
d
56.0 (30-OCH3), 56.1 (40-
a
b
OCH3), 61.3 (7-OCH3), 62.1 (5-OCH3), 107.1 (C-3), 108.5 (C-20), 111.2
(C-50), 114.1 (C-8), 116.5 (C-10), 120.0 (C-60), 121.4 (C-6), 123.0 (C-10),
149.3 (C-30), 152.1 (C-9), 152.3 (C-40), 154.9 (C-5), 156.8 (C-7), 161.3
(C-2), 175.9 (C-4) ppm. MS (ESIþ) m/z (rel. int.): 411
149.1 (C-3), 151.0 (C-4), 162.4 (C-60), 166.0 (C-40), 168.4 (C-20), 192.4
(C]O) ppm. MS (ESIþ) m/z (rel. int.): 345 ([MþH]þ, 100), 367
([MþNa]þ, 23). Anal. Calcd for C19H20O6 (344.36): C 66.27, H 5.85;
found: C 66.24, H 5.92%.
35
35
([C
([C
([C
H
19 16
37
Cl35ClO6þH]þ, 40), 413 ([C19
H
16
35
Cl37ClO6þH]þ, 27), 415
H
Cl37ClO6þH]þ, 5), 433 ([C19
H
Cl35ClO6þNa]þ, 22), 435
19 16
16
37
35
2.4.2. 30-Chloro-20-hydroxy-3,4,40,60-tetramethoxychalcone (2b)
H
Cl37ClO6þNa]þ, 15), 437 ([C19
H
Cl37ClO6þNa]þ, 3). Anal.
19 16
16
Mp 189e190 ꢀC. 1H NMR:
d
3.94 (s, 3H, 4-OCH3), 3.95 (s, 3H, 3-
Calcd for C19H16Cl2O6.½CH3CH2OH (434.27): C 55.31, H 4.41; found:
35
OCH3), 3.98 (2ꢂ s, 6H, 40-OCH3 and 60-OCH3), 6.04 (s, 1H, H-50),
C 54.92, H 4.07%. HRMS (EI), m/z: C H
Cl35ClO6: calcd 410.0324
19 16
35
6.90 (d, J 8.3 Hz, 1H, H-5), 7.11 (d, J 1.9 Hz, 1H, H-2), 7.22 (dd, J 8.3 and
[M]þ, found: 410.0325; C19
found: 412.0307.
H
Cl37ClO6: calcd 412.0294 [M]þ,
16
1.9 Hz,1H, H-6), 7.73 (d, J 15.4 Hz, 1H, H-
14.84 (s, 1H, 20-OH) ppm. 13C NMR:
55.8, 56.0 and 56.2 (3-OCH3, 4-
OCH3, 40-OCH3 and 40-OCH3), 86.9 (C-50), 102.3 (C-10), 106.7 (C-30),
110.4 (C-2), 111.1 (C-5), 122.9 (C-6), 124.8 (C- ), 128.2 (C-1), 143.7 (C-
b), 7.80 (d, J 15.4 Hz,1H, H-a),
d
2.6. Synthesis of 8-chloro-30,40,5,7-tetramethoxyflavone (3b)
a
b
),149.1 (C-3), 151.3 (C-4),160.8 (C-60),161.2 (C-40), 162.2 (C-20), 192.6
2.6.1. Method I
35
(C]O) ppm. MS (ESIþ) m/z (rel. int.): 401 ([C19
H
ClO6þNa]þ, 64),
8-Chloro-30,40,5,7-tetramethoxyflavone (3b) was prepared in
moderate yield from 30-chloro-3,4,40,60-tetramethoxychalcone
(2b), as described for flavones 3a,c: 3b 54% (white solid).
19
37
35
38
37
403 ([C
H
ClO6þNa]þ, 23), 779 ([C38
H
H
Cl35ClO12þNa]þ, 50), 781
19 19
Cl37ClO12þNa]þ, 37), 783 ([C38
Cl37ClO12þNa]þ, 9). Anal.
35
([C
H
38 38
38
Calcd for C19H19ClO6.1/3CH3CH2OH (394.16): C 59.93, H 5.37; found: C
35
59.77, H 5.01%. HRMS (EI), m/z. C
found: 378.0862; C
H
19 19
ClO6: calcd 378.0870 [M]þ,
2.6.2. Method II
37
H
ClO6: calcd 380.0841 [M]þ, found: 380.0838.
To a
stirred solution of 30,40,5,7-tetramethoxyflavone (3a)
19 19
(98 mg, 0.26 mmol) in a (1:1) mixture of methanol:chloroform
(6 mL), at room temperature, it was added NaClO (10%, 0.53 mL)
and pH was adjusted to 6.2 with diluted hydrochloric acid. The
referred volume of NaClO was added four times with intervals of
2 h. Then, the reaction mixture was stirred, under nitrogen atmo-
sphere, overnight. The reaction mixture was extracted with chlo-
roform (100 mL), dried over anhydrous sodium sulphate and
evaporated to dryness. The obtained residue was purified by pre-
parative thin-layer chromatography using (1:1) mixture of chlor-
oform:ethyl acetate as eluent and recrystallized in ethanol
affording 8-chloro-30,40,5,7-tetramethoxyflavone (3b) in moderate
yield (34 mg, 32%).
2.4.3. 30,50-Dichloro-20-hydroxy-3,4,40,60-tetramethoxychalcone
(2c)
Mp 153e154 ꢀC. 1H NMR:
d
3.84 (s, 3H, 60-OCH3), 3.95 (s, 3H, 4-
OCH3), 3.96 (s, 3H, 3-OCH3), 4.00 (s, 3H, 40-OCH3), 6.92 (d, J 8.4 Hz,
1H, H-5), 7.16 (d, J 2.0 Hz, 1H, H-2), 7.28 (dd, J 8.4 and 2.0 Hz, 1H, H-
6), 7.80 (d, J 15.5 Hz,1H, H-
20-OH) ppm. 13C NMR: 56.0 (3-OCH3 and 4-OCH3), 51.0 (40-OCH3),
62.7 (60-OCH3), 110.2 (C-30), 111.1 (C-5), 113.3 and 113.9 (C-10 and C-
a), 7.94 (d, J 15.5 Hz,1H, H-b),13.74 (s,1H,
d
30), 114.4 (C-50), 122.7 (C-
a), 123.8 (C-6), 127.6 (C-1), 146.3 (C-b),
149.3 (C-3), 152.0 (C-4), 157.0 (C-60), 158.3 (C-40), 159.4 (C-20), 192.9
35
(C]O) ppm. MS (ESIþ) m/z (rel. int.): 413 ([C19
H
Cl35ClO6þH]þ,
18