S. Li et al. / European Journal of Medicinal Chemistry 124 (2016) 1006e1018
1015
HRMS (ESI) m/z 426.1477 [MþNa]þ (calcd for 426.1476,
was added acetic anhydride (5 mmol) and stirred at room tem-
perature until the reaction was completed. The reaction mixture
was then diluted with dichloromethane (5 mL) and washed with
diluted hydrochloric acid and brine. The organic layer was then
dried over magnesium sulfate and concentrated to dryness to
afford intermediate 8p. Then 8p was reacted with compound 5 to
give compound 9p. Compound 9p was refluxed with the sulfuric
acid solution diluted in ethanol for 2 h. Finally, targeted product
10p was acquired.
C
25H22FNNaO3).
4.1.4.11. (E)-N-(4-(3,5-dimethoxystyryl)phenyl)-3-(2-fluorophenyl)
acrylamide(7k). Yield 83%, white solid, m.p. 187e190 ꢀC; IR (KBr)
3434, 1595, 1536, 1350, 1152, 839, 754 cmꢁ1 1H NMR (500 MHz,
DMSO)
n
;
d
10.41 (s, 1H), 7.89 (d, J ¼ 15.6 Hz, 1H), 7.78 (dd, J ¼ 6.1,
3.3 Hz, 1H), 7.73 (d, J ¼ 8.6 Hz, 2H), 7.61e7.54 (m, 3H), 7.47e7.43 (m,
2H), 7.24 (d, J ¼ 16.4 Hz, 1H), 7.11 (d, J ¼ 16.4 Hz, 1H), 6.91 (d,
J ¼ 15.6 Hz, 1H), 6.76 (d, J ¼ 2.1 Hz, 2H), 6.41 (t, J ¼ 2.1 Hz, 1H), 3.78
(s, 6H); 13C NMR (126 MHz, DMSO)
d
162.89, 160.62, 135.33, 133.38,
4.1.5.1. (E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,5-dimethoxystyryl)
phenyl)acrylamide (10p). 42%, pale yellow solid, m.p. 203e205 ꢀC;
131.12, 130.01, 128.46, 127.78, 127.66, 127.27, 127.02, 125.29, 119.39,
104.32, 99.70, 55.15; HRMS (ESI) m/z 426.1478 [MþNa]þ (calcd for
426.1476, C25H22FNNaO3).
IR (KBr)
(500 MHz, DMSO)
n ;
3299, 1597, 1534, 1272, 1204, 1149, 826 cmꢁ1 1H NMR
d
10.16 (s, 1H), 9.39 (br.s, 2H), 7.71 (d, J ¼ 7.1 Hz,
2H), 7.55 (d, J ¼ 7.2 Hz, 2H), 7.41 (d, J ¼ 15.6 Hz, 1H), 7.22 (d,
J ¼ 16.5 Hz, 1H), 7.09 (d, J ¼ 16.3 Hz, 1H), 7.02 (s, 1H), 6.92 (d,
J ¼ 8.1 Hz,1H), 6.77 (d, J ¼ 14.8 Hz, 3H), 6.55 (d, J ¼ 15.7 Hz,1H), 6.40
4.1.4.12. (E)-3-(2,4-difluorophenyl)-N-(4-(3,5-dimethoxystyryl)
phenyl)acrylamide (7l). Yield 78%, yellow solid, m.p. 196e198 ꢀC; IR
(KBr)
n
3315, 1667, 1591, 1530, 1208, 1153, 1061, 966, 872, 831 cmꢁ1
;
(d, J ¼ 1.8 Hz, 1H), 3.78 (s, 6H); 13C NMR (126 MHz, DMSO)
d 163.94,
1H NMR (500 MHz, DMSO)
d
10.38 (s,1H), 7.79 (dd, J ¼ 15.4, 8.6 Hz,
160.62, 145.57, 140.79, 139.26, 131.77, 128.55, 126.95, 120.74, 119.17,
118.29, 115.77, 113.97, 104.27, 99.65, 79.15, 79.09, 78.88, 78.62,
55.14; HRMS (ESI) m/z 440.1469 [MþNa]þ (calcd for 440.1468,
1H), 7.73 (d, J ¼ 8.5 Hz, 2H), 7.60 (d, J ¼ 16.6 Hz, 2H), 7.58 (d,
J ¼ 9.0 Hz, 2H), 7.42e7.35 (m, 1H), 7.23 (d, J ¼ 16.6 Hz, 2H), 7.10 (d,
J ¼ 16.4 Hz,1H), 6.91 (d, J ¼ 15.9 Hz,1H), 6.76 (d, J ¼ 2.0 Hz, 2H), 6.41
C25H23NNaO5).
(t, J ¼ 2.1 Hz, 1H), 3.78 (s, 6H); 13C NMR (126 MHz, DMSO)
d 163.13,
160.63, 139.22, 138.67, 132.22, 131.87, 128.48, 127.22, 127.02, 119.37,
112.51, 112.37, 104.70,104.31, 99.69, 55.15; HRMS (ESI) m/z 444.1378
[MþNa]þ (calcd for 444.1382, C25H21F2NNaO3).
4.1.6. General procedure for the preparation of compounds 12a-12i
The caffic acid derivitives (1 mmol), HATU (1.2 mmol) and N,N-
diisopropylethylamine (2 mmol) were dissolved in dichloro-
methane and stirred at room temperature for 30 min. Compound 11
(1 mmol) was then added to the solution, and stirred overnight. The
reaction mixture was extracted with dichloromethane. The organic
layer was washed with diluted hydrochloric acid, saturated sodium
bicarbonate solution and brine. Then it was dried with anhydrous
magnesium sulfate, and the solvent was evaporated in vacuum to
give the crude product, which was purified by chromatography on
silica gel.
4.1.4.13. (E)-3-(4-chlorophenyl)-N-(4-(3,5-dimethoxystyryl)phenyl)
acrylamide (7m). Yield 86%, white solid, m.p. 202e205 ꢀC; IR (KBr)
n
3434, 1659, 1589, 1535, 1202, 1154, 1066, 828 cmꢁ1 1H NMR
;
(500 MHz, DMSO)
d
10.33 (s, 1H), 7.74 (d, J ¼ 8.4 Hz, 2H), 7.68 (d,
J ¼ 8.4 Hz, 2H), 7.60 (dd, J ¼ 12.0, 8.3 Hz, 3H), 7.54 (d, J ¼ 8.3 Hz, 2H),
7.25 (d, J ¼ 16.4 Hz, 1H), 7.12 (d, J ¼ 16.4 Hz, 1H), 6.87 (d, J ¼ 15.7 Hz,
1H), 6.78 (d, J ¼ 1.8 Hz, 2H), 6.41 (t, J ¼ 2.1 Hz, 1H), 3.80 (s, 6H); 13
C
NMR (126 MHz, DMSO)
d 163.31, 160.63, 139.22, 138.87, 132.22,
131.91, 129.48, 127.19, 127.02, 119.37, 115.51, 104.86, 104.31, 99.68,
4.1.6.1. 4-(3,5-dimethoxystyryl)phenyl cinnamate (12a). Yield 93%,
55.16; HRMS (ESI) m/z 442.1181 [MþNa]þ (calcd for 442.1180,
white solid, m.p. 138e139 ꢀC; IR (KBr)
n
3432, 1731, 1633, 1594, 1311,
C
25H22ClNNaO3).
1145, 840 cmꢁ1
;
1H NMR (500 MHz, DMSO)
d
7.88 (d, J ¼ 16.0 Hz,
1H), 7.85e7.79 (m, 2H), 7.67 (d, J ¼ 8.6 Hz, 2H), 7.50e7.45 (m, 3H),
7.31 (d, J ¼ 16.4 Hz, 1H), 7.23 (d, J ¼ 8.5 Hz, 2H), 7.18 (d, J ¼ 16.4 Hz,
1H), 6.90 (d, J ¼ 16.0 Hz, 1H), 6.79 (d, J ¼ 2.0 Hz, 2H), 6.43 (t,
4.1.4.14. (E)-3-(4-bromophenyl)-N-(4-(3,5-dimethoxystyryl)phenyl)
acrylamide (7n). Yield 80%, white solid, m.p. 221e224 ꢀC; IR (KBr)
3435, 1659, 1589, 1155, 1069, 822 cmꢁ1; 1H NMR (500 MHz, DMSO)
n
J ¼ 2.0 Hz, 1H), 3.79 (s, 6H); 13C NMR (126 MHz, DMSO)
d 164.84,
d
10.31 (s, 1H), 7.72 (d, J ¼ 8.6 Hz, 2H), 7.66 (d, J ¼ 8.5 Hz, 2H), 7.57
160.66, 149.91, 146.45, 138.98, 134.68, 133.82, 128.96, 128.60, 127.97,
127.46,122.04,117.14,104.52, 99.95, 55.19; HRMS (ESI) m/z 387.1587
[MþH]þ (calcd for 387.1591, C25H23O4).
(dd, J ¼ 15.1, 6.4 Hz, 5H), 7.23 (d, J ¼ 16.4 Hz, 1H), 7.10 (d, J ¼ 16.4 Hz,
1H), 6.86 (d, J ¼ 15.7 Hz, 1H), 6.76 (d, J ¼ 2.1 Hz, 2H), 6.40 (t,
J ¼ 2.1 Hz, 1H), 3.78 (s, 6H); 13C NMR (126 MHz, DMSO)
d 163.22,
160.64, 138.87, 132.17, 131.94, 129.59, 128.50, 127.19, 127.02, 119.34,
104.32, 104.31, 99.68, 55.16; HRMS (ESI) m/z 464.0860 [7 M þ H]þ
(calcd for 464.0856, C25H23BrNO3).
4.1. 6 . 2. ( E ) - 4 - ( 3 , 5 - di me t h ox y s t y r yl ) ph e nyl 3- ( 3 , 4, 5 -
trimethoxyphenyl)acrylate (12d). Yield 87%, white solid, m.p.
157e159 ꢀC; IR (KBr)
n
3438, 1720, 1586, 1503, 1422, 1247, 1194,
1124, 840 cmꢁ1
;
1H NMR (500 MHz, DMSO)
d
7.81 (d, J ¼ 15.9 Hz,
4.1.4.15. (E)-N-(4-(3,5-dimethoxystyryl)phenyl)-3-(pyridin-2-yl)
1H), 7.67 (d, J ¼ 8.5 Hz, 2H), 7.31 (d, J ¼ 16.4 Hz, 1H), 7.23 (d,
J ¼ 8.5 Hz, 2H), 7.20e7.14 (m, 3H), 6.92 (d, J ¼ 15.9 Hz, 1H), 6.79 (d,
J ¼ 2.0 Hz, 2H), 6.43 (t, J ¼ 2.0 Hz, 1H), 3.84 (s, 6H), 3.79 (s, 6H), 3.72
acrylamide (7o). Yield 77%, yellow solid, m.p. 137e140 ꢀC; IR (KBr)
n
3333, 2990, 2833,1587,1584,1342,1200,1145,1063, 964, 827 cmꢁ1
;
1H NMR (500 MHz, DMSO)
d
10.45 (s, 1H), 8.65 (d, J ¼ 4.3 Hz, 1H),
(s, 3H); 13C NMR (126 MHz, DMSO)
d 163.51, 160.64, 153.09, 140.35,
7.87 (td, J ¼ 7.7,1.3 Hz,1H), 7.74 (d, J ¼ 8.5 Hz, 2H), 7.64 (d, J ¼ 9.3 Hz,
1H), 7.61e7.55 (m, 3H), 7.39 (dd, J ¼ 7.3, 4.9 Hz, 1H), 7.34 (d,
J ¼ 15.3 Hz, 1H), 7.23 (d, J ¼ 16.4 Hz, 1H), 7.11 (d, J ¼ 16.4 Hz, 1H),
6.76 (d, J ¼ 2.0 Hz, 2H), 6.41 (t, J ¼ 2.1 Hz, 1H), 3.78 (s, 6H); 13C NMR
139.25, 138.90, 132.01, 130.24, 128.54, 127.09, 127.01, 121.45, 119.24,
105.23, 104.30, 99.69, 60.08, 55.90, 55.16; HRMS (ESI) m/z 477.1913
[MþH]þ (calcd for 477.1908, C28H29O7).
(126 MHz, DMSO)
d
183.21, 160.64, 152.76, 149.85, 139.37,139.23,
4.1.6.3. (E)-4-(3,5-dimethoxystyryl)phenyl
phenyl)acrylate (12f). Yield 84%, white solid, m.p. 142e145 ꢀC; IR
(KBr)
3436, 1732, 1594, 1317, 1149, 1125, 1065, 836 cmꢁ1; 1H NMR
(500 MHz, DMSO)
3-(4-(trifluoromethyl)
138.72, 137.19, 132.22, 128.51, 127.21, 127.01, 125.84, 124.53, 124.20,
119.35, 104.31, 99.71, 55.15; HRMS (ESI) m/z 409.1526 [MþNa]þ
(calcd for 409.1523, C24H22N2NaO3).
n
d
8.08 (d, J ¼ 8.1 Hz, 2H), 7.98 (d, J ¼ 16.1 Hz, 1H),
7.85 (d, J ¼ 8.2 Hz, 2H), 7.70 (d, J ¼ 8.6 Hz, 2H), 7.34 (d, J ¼ 16.4 Hz,
1H), 7.27 (d, J ¼ 8.5 Hz, 2H), 7.21 (d, J ¼ 16.4 Hz, 1H), 7.08 (d,
J ¼ 16.1 Hz, 1H), 6.82 (d, J ¼ 2.0 Hz, 2H), 6.45 (t, J ¼ 2.0 Hz, 1H), 3.81
4.1.5. Procedure for the preparation of compound 10p
To a mixture of caffeic acid (6p, 1 mmol) and pyridine (1 mmol)