J.L.C. Sousa et al. / European Journal of Medicinal Chemistry 119 (2016) 250e259
257
and both residues were purified by silica gel column chromatog-
raphy using CH2Cl2 as eluent.
4.1.8.2. (2E,4E)-5-[3,4-Bis(benzyloxy)phenyl]-1-(2-hydroxy-3,4-
dimethoxyphenyl)penta-2,4-dien-1-one (9b). Yellow solid (26 mg,
25% yield); Rf 0.35. Mp 159e161 ꢂC. 1H NMR (300.13 MHz, CDCl3):
d
13.33 (s, 1H, 20-OH), 7.66 (dd, J 14.7 and 10.3 Hz, 1H, H-
b
), 7.61 (d, J
9.2 Hz,1H, H-60), 7.49e7.32 (m,10H, 3,4-OCH2C6H5), 7.12 (d, J 2.0 Hz,
1H, H-2), 7.09 (d, J 14.7 Hz,1H, H- ), 7.05 (dd, J 8.4 and 2.0 Hz,1H, H-
6), 6.97e6.84 (m, 1H, H- ), 6.93 (d, J 8.4 Hz,
4.1.7.1. (E)-3,4-Dimethoxycinnamaldehyde
(102 mg, 53% yield); Rf 0.28. Mp 80e82 ꢂC. 1H NMR (300.13 MHz,
CDCl3): 9.66 (d, J 7.8 Hz, 1H, CHO), 7.42 (d, J 15.8 Hz, 1H, H- ), 7.17
(dd, J 8.3 and 2.0 Hz, 1H, H-6), 7.08 (d, J 2.0 Hz, 1H, H-2), 6.91 (d, J
8.3 Hz, 1H, H-5), 6.62 (dd, J 15.8 and 7.8 Hz, 1H, H- ), 3.94 (s, 3H, 4-
OCH3), 3.93 (s, 3H, 3-OCH3) ppm. 13C NMR (75.47 MHz, CDCl3):
193.5 (CHO), 152.8 (C- ), 151.9 (C-4), 149.3 (C-3), 126.9 (C-1), 126.6
(C-
(8a). White
solid
a
d
b
d
), 6.92e6.81 (m, 1H, H-g
1H, H-5), 6.52 (d, J 9.2 Hz, 1H, H-50), 5.20 (s, 4H, 3,4-OCH2Ph), 3.95
(s, 3H, 40-OCH3), 3.92 (s, 3H, 30-OCH3) ppm. 13C NMR (75.47 MHz,
a
CDCl3):
(C- ), 142.5 (C-d), 137.0 and 136.8 (C-1 of 3,4-OCH2C6H5), 136.7 (C-
d
192.4 (C]O), 158.3 (C-20,40), 150.4 (C-4), 149.1 (C-3), 145.1
d
b
b
a
), 123.3 (C-6), 111.0 (C-5), 109.7 (C-2), 55.9 and 55.8 (3,4-OCH3)
30),129.7 (C-1),128.6 (C-3,5 of 3,4-OCH2C6H5),127.99 and 127.97 (C-
4 of 3,4-OCH2C6H5), 127.4 and 127.2 (C-2,6 of 3,4-OCH2C6H5), 125.8
ppm. ESI-MS m/z (%): 215 ([MþNa]þ, 100), 193 ([MþH]þ, 95). ESI-
HRMS m/z calcd for [C11H12O3þH]þ: 193.0865, found: 193.0855.
(C-60), 125.1 (C- ), 122.1 (C-6), 115.7 (C-10), 114.5 (C-5),
g), 122.6 (C-a
113.4 (C-2), 102.7 (C-50), 71.5 and 71.0 (3,4-OCH2Ph), 60.7 (30-OCH3),
56.1 (40-OCH3) ppm. EI-MS m/z (%): 522 (Mþꢀ, 9), 431 ([MꢁC7H7]þ,
10), 181 (21), 91 (C7H7þ, 100). EI-HRMS m/z calcd for C33H30O6:
522.2042, found: 522.2059.
4.1.7.2. (E)-3,4-Bis(benzyloxy)cinnamaldehyde (8b). White solid
(220 mg, 64% yield); Rf 0.61. Mp 88e89 ꢂC. 1H NMR (300.13 MHz,
CDCl3):
OCH2C6H5), 7.35 (d, J 15.9 Hz, 1H, H-
7.11 (dd, J 8.2 and 2.0 Hz, 1H, H-6), 6.95 (d, J 8.2 Hz, 1H, H-5), 6.52
(dd, J 15.9 and 7.7 Hz, 1H, H- ), 5.23 (s, 2H, 4-OCH2Ph), 5.20 (s, 2H,
3-OCH2Ph) ppm. 13C NMR (75.47 MHz, CDCl3):
193.6 (CHO), 152.8
(C- ), 151.9 (C-4), 149.0 (C-3), 136.7 (C-1 of 3-OCH2C6H5), 136.5 (C-1
d
9.63 (d, J 7.7 Hz, 1H, CHO), 7.47e7.30 (m, 10H, 1,2-
b
), 7.14 (d, J 2.0 Hz, 1H, H-2),
4.1.9. Synthesis of polyalkoxy-3-hydroxy-2-styrylchromones 10a,b
a
An aqueous solution of H2O2 30 wt% (0.51 mL, 5.0 mmol) was
d
added to
a
solution of the appropriate 20-hydrox-
b
ycinnamylideneacetophenone 9a,b (0.20 mmol) and aqueous NaOH
4 M (0.25 mL,1.0 mmol) in a 1:1 mixture of MeOH and THF (6 mL) at
0 ꢂC. The reaction mixture was stirred at room temperature for 24 h.
After this period, it was poured onto ice (5 g) and H2O (15 mL) and
the pH was adjusted to 1 with diluted HCl. Then, the obtained pre-
cipitate was filtered off, taken in CH2Cl2 and dried over anhydrous
Na2SO4. The solvent was evaporated to dryness and the obtained
residues were recrystallized from a mixture of CH2Cl2/C6H14 (1:2).
of 4-OCH2C6H5), 128.6 (C-3,5 of 3,4-OCH2C6H5), 128.1 (C-4 of 3,4-
OCH2C6H5), 127.4 (C-1), 127.3 and 127.1 (C-2,6 of 3,4-OCH2C6H5),
126.8 (C-a), 123.7 (C-6), 114.1 (C-5), 113.8 (C-2), 71.4 (3-OCH2Ph),
70.9 (4-OCH2Ph) ppm. ESI-MS m/z (%): 383 ([MþK]þ, 7), 367
([MþNa]þ, 31), 345 ([MþH]þ, 100). ESI-HRMS: m/z calcd for
[C23H20O3þH]þ: 345.1491, found: 345.1491.
4.1.8. Synthesis of 20-hydroxycinnamylideneacetophenones 9a,b
To a solution of the appropriate 20-hydroxyacetophenone 1a,b
(0.20 mmol) in dry THF (4 mL) was added a solution of 1 M LiHMDS
in THF (1.0 mL, 1.0 mmol) under N2 at room temperature. The re-
action mixture was stirred for ca. 2 h. Then, a solution of the
appropriate cinnamaldehyde 8a,b (1.6 mmol) in dry THF (4 mL) was
added, and the reaction mixture was stirred at reflux for four days.
After this period, it was poured onto ice (5 g) and H2O (15 mL) and
the pH was adjusted to 1 with diluted HCl. Then, this aqueous
mixture was extracted with CH2Cl2 (2 ꢃ 15 mL), and the organic
layer was dried over anhydrous Na2SO4 and evaporated to dryness.
The obtained residues were purified by preparative thin layer
chromatography using CH2Cl2 as eluent.
4.1.9.1. (E)-7,8-Bis(benzyloxy)-2-(3,4-dimethoxystyryl)-3-hydroxy-
4H-chromen-4-one (10a). Yellow solid (68 mg, 63% yield); Rf 0.56
[CH2Cl2/EtOAc (9:1)]. Mp 205e207 ꢂC. 1H NMR (300.13 MHz,
CDCl3):
d 7.91 (d, J 9.1 Hz, 1H, H-5), 7.55e7.30 (m, 11H, 3-OH, 7,8-
OCH2C6H5), 7.37 (d, J 16.0 Hz, 1H, H-
b
), 7.16 (d, J 16.0 Hz, 1H, H-a),
7.10 (d, J 9.1 Hz, 1H, H-6), 7.07 (dd, J 8.7 and 2.7 Hz, 1H, H-60), 7.05 (d,
J 2.7 Hz,1H, H-20), 6.88 (d, J 8.7 Hz,1H, H-50), 5.29 (s, 2H, 7-OCH2Ph),
5.23 (s, 2H, 8-OCH2Ph), 3.95 (s, 3H, 30-OCH3), 3.94 (s, 3H, 40-OCH3)
ppm. 13C NMR (75.47 MHz, CDCl3):
d 172.1 (C]O), 155.8 (C-7), 150.3
(C-40), 149.8 (C-9), 149.3 (C-30), 145.7 (C-2), 137.2 (C-1 of 8-
OCH2C6H5), 136.8 (C-3), 136.2 (C-8), 136.1 (C-1 of 7-OCH2C6H5),
134.3 (C-b
), 129.0 (C-10), 128.8 and 128.5 (C-3,5 of 7,8-OCH2C6H5),
128.43 (C-2,6 of 8-OCH2C6H5), 128.37 and 128.3 (C-4 of 7,8-
4.1.8.1. (2E,4E)-1-[3,4-Bis(benzyloxy)-2-hydroxyphenyl]-5-(3,4-
dimethoxyphenyl)penta-2,4-dien-1-one (9a). Yellow solid (56 mg,
54% yield); Rf 0.33. Mp 143e144 ꢂC. 1H NMR (300.13 MHz, CDCl3):
OCH2C6H5), 127.4 (C-2,6 of 7-OCH2C6H5), 121.8 (C-60), 120.8 (C-5),
116.7 (C-10), 113.5 (C-a
), 111.6 (C-6), 111.1 (C-50), 109.2 (C-20), 75.9
(8-OCH2Ph), 71.4 (7-OCH2Ph), 56.0 (30,40-OCH3) ppm. EI-MS m/z
(%): 537 ([MþH]þ, 6), 536 (Mþꢀ, 16), 445 ([MꢁC7H7]þ, 10), 368 (12),
111 (10), 98 (14), 97 (16), 91 (C7Hþ7, 100), 83 (13). EI-HRMS m/z calcd
for C33H28O7: 536.1835, found: 536.1839.
d
13.40 (s, 1H, 20-OH), 7.69 (dd, J 14.6 and 10.4 Hz, 1H, H-
b
), 7.56 (d, J
9.2 Hz, 1H, H-60), 7.52e7.48 and 7.39e7.28 (2 m, 10H, 30,40-
OCH2C6H5), 7.10 (d, J 14.6 Hz, 1H, H- ), 7.09 (dd, J 8.3 and 2.0 Hz, 1H,
H-6), 7.04 (d, J 2.0 Hz,1H, H-2), 7.01 (d, J 15.5 Hz,1H, H- ), 6.98e6.87
a
d
(m, 1H, H-
g
), 6.87 (d, J 8.3 Hz, 1H, H-5), 6.51 (d, J 9.2 Hz, 1H, H-50),
4.1.9.2. (E)-2-[3,4-Bis(benzyloxy)styryl]-3-hydroxy-7,8-dimethoxy-
4H-chromen-4-one (10b). Yellow solid (55 mg, 51% yield); Rf 0.59
[CH2Cl2/EtOAc (9:1)]. Mp 180e182 ꢂC. 1H NMR (300.13 MHz,
5.18 (s, 2H, 40-OCH2Ph), 5.14 (s, 2H, 30-OCH2Ph), 3.95 (s, 3H, 3-
OCH3), 3.92 (s, 3H, 4-OCH3) ppm. 13C NMR (75.47 MHz, CDCl3):
d
192.4 (C]O), 158.8 (C-20), 157.7 (C-40), 150.4 (C-4), 149.2 (C-3),
CDCl3):
OCH2C6H5), 7.46 (d, J 16.2 Hz, 1H, H-b), 7.15 (d, J 16.2 Hz, 1H, H-a),
d
7.94 (d, J 9.1 Hz, 1H, H-5), 7.52e7.29 (m, 11H, 3-OH, 30,40-
145.2 (C-
b
), 142.6 (C-
d
), 137.6 (C-1 of 30-OCH2C6H5), 136.2 (C-1 of 40-
OCH2C6H5), 135.9 (C-30), 129.1 (C-1), 128.6 (C-2,6 of 30-OCH2C6H5),
128.2 (C-3,5 of 30,40-OCH2C6H5), 128.1 and 127.9 (C-4 of 30,40-
7.26 (overlapped with the solvent signal, 1H, H-20), 7.16 (dd, J 8.4
and 1.8 Hz, 1H, H-60), 7.04 (d, J 9.1 Hz, 1H, H-6), 6.95 (d, J 8.4 Hz, 1H,
H-50), 5.23 (s, 2H, 30-OCH2Ph), 5.21 (s, 2H, 40-OCH2Ph), 4.05 (s, 3H,
8-OCH3), 4.01 (s, 3H, 7-OCH3) ppm. 13C NMR (75.47 MHz, CDCl3):
OCH2C6H5), 127.2 (C-2,6 of 40-OCH2C6H5), 125.7 (C-60), 124.9 (C-
g),
122.5 (C-
a
),121.6 (C-6),115.7 (C-10),111.1 (C-5),109.1 (C-2),104.3 (C-
50), 74.7 (30-OCH2Ph), 70.7 (40-OCH2Ph), 56.0 and 55.9 (3,4-OCH3)
ppm. EI-MS m/z (%): 522 (Mþꢀ, 1), 431 ([MꢁC7H7]þ, 8), 416
([MeC7H7eCH3]þ, 28), 342 (13), 227 (15), 190 (19), 189 (35), 91
(C7Hþ7, 100). EI-HRMS m/z calcd for C33H30O6: 522.2042, found:
522.2050.
d
172.2 (C]O), 156.5 (C-7), 150.3 (C-40), 149.5 (C-9), 149.2 (C-30),
145.6 (C-2), 137.0, 136.92 and 136.89 (C-1 of 30,40-OCH2C6H5, C-3),
136.7 (C-8), 134.0 (C-b
), 129.6 (C-10), 128.6 (C-3,5 of 30,40-
OCH2C6H5), 128.0 and 127.9 (C-4 of 30,40-OCH2C6H5), 127.5 (C-2,6 of
30-OCH2C6H5), 127.2 (C-2,6 of 40-OCH2C6H5), 122.3 (C-60), 120.8 (C-