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Letters in Drug Design & Discovery, 2014, Vol. 11, No. 1
Ruan et al.
4.05 (ddd, 1H, J = 10.5, 7.0, 3.6 Hz), 3.88 (d, 6H, J = 4.0
Hz), 3.81 (s, 3H), 3.78 (d, 1H, J = 5.7 Hz), 3.76 (d, 1H, J =
7.7 Hz), 3.68 – 3.65 (m, 1H), 3.37 – 3.32 (m, 1H), 2.03 –
1.98 (m, 1H), 1.91 (dt, 2H, J = 9.8, 5.3 Hz), 1.61 – 1.57 (m,
1H). MS (ESI): 449.5(C26H28N2O5, [M+H]+). Anal. Calcd for
C26H28N2O5: C, 69.63; H, 6.29; N, 6.25. Found: C, 69.73; H,
6.29; N, 6.25%.
Calcd for C27H25N3O4: C, 71.19; H, 5.53; N, 9.22. Found: C,
71.19; H, 5.53; N, 9.22%.
C16: N-((E)-2-cyano-3-(2,4-dimethoxy-6-(4-methoxystyr-
yl)phenyl)acryloyl)nicotinamide
Yellow solid (38% yield). Mp 174-176 oC. 1H NMR (600
MHz, DMSO-d6) ꢁ 8.39 (s, 1H), 8.05 (s, 1H), 7.67 (d, 1H, J
= 23.8 Hz), 7.57 – 7.52 (m, 3H), 7.16 (d, 1H, J = 16.1 Hz),
7.11 (d, 1H, J = 3.4 Hz), 7.03 (d, 1H, J = 16.1 Hz), 6.94 (d,
4H, J = 7.6 Hz), 6.61 (s, 1H), 3.76 (s, 6H), 3.72 (s, 3H). MS
(ESI): 470.5(C27H23N3O5, [M+H]+). Anal. Calcd for
C27H23N3O5: C, 69.07; H, 4.94; N, 8.95. Found: C, 69.07; H,
4.94; N, 8.95%.
C13: (E)-3-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-2-
(pyrrolidine-1-carbonyl)acrylonitrile
Yellow solid (72% yield). Mp 173-175 oC. 1H NMR (600
MHz, CDCl3) ꢁ 12.67 (s, 1H), 12.25 (d, 2H, J = 8.6 Hz),
11.93 (d, 1H, J = 16.1 Hz), 11.74 (d, 1H, J = 16.1 Hz), 11.68
(s, 1H), 11.67 (s, 2H), 11.32 (d, 1H, J = 1.6 Hz), 8.60 (s,
3H), 8.56 (s, 3H), 8.50 (s, 3H), 8.35 (t, 2H, J = 6.3 Hz), 8.15
(t, 2H, J = 6.6 Hz), 6.63 – 6.56 (m, 4H). MS (ESI):
419.5(C25H26N2O4, [M+H]+). Anal. Calcd for C25H26N2O4:
C, 71.75; H, 6.26; N, 6.69. Found: C, 71.73; H, 6.26; N,
6.68%.
C17: (E)-2-cyano-3-(2,4-dimethoxy-6-(4-methoxystyryl)ph-
enyl)-N-(2-(thiophen-2-yl)ethyl)acrylamide
o
1
Yellow solid (76% yield). Mp 56-67 C. H NMR (600
MHz, CDCl3) ꢁ 13.29 (t, 1H, J = 5.5 Hz), 12.91 (s, 1H),
12.25 (d, 2H, J = 8.6 Hz), 12.03 (dd, 1H, J = 13.3, 4.6 Hz),
11.95 (d, 1H, J = 16.1 Hz), 11.76 – 11.70 (m, 1H), 11.69 –
11.67 (m, 3H), 11.67 (d, 1H, J = 5.1 Hz), 11.64 (d, 1H, J =
2.5 Hz), 11.33 (d, 1H, J = 1.7 Hz), 8.61 (s, 3H), 8.56 (s, 3H),
8.50 (s, 3H), 8.18 (dd, 2H, J = 12.9, 6.9 Hz), 7.78 (t, 2H, J =
7.1 Hz). MS (ESI): 475.6(C27H26N2O4S, [M+H]+). Anal.
Calcd for C27H26N2O4S: C, 68.33; H, 5.52; N, 5.90; S, 6.76.
Found: C, 68.33; H, 5.52; N, 5.90; S, 6.76%.
C14: (E)-2-cyano-3-(2,4-dimethoxy-6-(4-methoxystyryl)ph-
enyl)-N-(piperazin-1-yl)acrylamide
o
1
Yellow solid (69% yield). Mp 76-78 C. H NMR (600
MHz, CDCl3) ꢁ 12.67 (s, 1H), 12.25 (d, 2H, J = 8.6 Hz),
11.93 (d, 1H, J = 16.1 Hz), 11.74 (d, 1H, J = 16.1 Hz), 11.68
(s, 1H), 11.67 (s, 2H), 11.32 (d, 1H, J = 1.6 Hz), 8.60 (s,
3H), 8.56 (s, 3H), 8.50 (s, 3H), 8.35 (t, 2H, J = 6.3 Hz), 8.15
(t, 2H, J = 6.6 Hz), 6.63 – 6.56 (m, 6H). MS (ESI):
434.5(C25H27N3O4, [M+H]+). Anal. Calcd for C25H27N3O4:
C, 69.27; H, 6.28; N, 9.69. Found: C, 69.25; H, 6.28; N,
9.69%.
C18: (E)-N-(benzo[d]thiazol-2-yl)-2-cyano-3-(2,4-dimetho-
xy-6-(4-methoxystyryl)phenyl)acrylamide
o
1
Yellow solid (76% yield). Mp 56-67 C. H NMR (600
MHz, DMSO-d6) ꢁ 7.78 (s, 1H), 7.50 (d, 2H, J = 8.7 Hz),
7.10 (d, 1H, J = 16.1 Hz), 7.02 – 6.96 (m, 1H), 6.94 (d, 2H, J
= 8.7 Hz), 6.84 (d, 1H, J = 2.1 Hz), 6.50 (d, 1H, J = 2.1 Hz),
5.73 (s, 1H), 3.84 (s, 3H), 3.75 (d, 6H, J = 9.0 Hz), 3.72 (s,
3H). MS (ESI): 498.6(C28H23N3O4S, [M+H]+). Anal. Calcd
for C28H23N3O4S: C, 67.59; H, 4.66; N, 8.45; S, 6.44. Found:
C, 67.56; H, 4.66; N, 8.45; S, 6.44%.
General method of synthesis of compounds C15–C20
A solution of 2-cyanoacetamide (1 equiv), compound B
(1.0–1.5 equiv) was dissolve in methanol, then addition N-
methylpiperazine (0.05–1.05 equiv) and warm up to refluex
overnight. Then, the reaction is cooled to ambient tempera-
ture and extracted with dichloromethane (3 ꢀ 20 mL). The
organic phase is dried with anhydrous sodium sulfate. After
removal of the solvent on vacuum, white solid was obtained.
The solid was dissolved in methylene chloride, then add
EDCI (1.6 equiv) and (1.6 equiv) HOBt was added after 5
min. The reaction was stirred for 30 min and added (2.0
equiv) aromatic amine , heated to reflux for 10 h. Then, the
reaction is cooled to ambient temperature and extracted with
dichloromethane (3 ꢀ 20 mL). The organic phase is dried
with anhydrous sodium sulfate. After removal of the solvent
on vacuum, the crude product is purified with silica gel c-
hromatography (75% ethyl acetate in hexanes) to give the
title compound.
C19: (E)-2-cyano-3-(2,4-dimethoxy-6-(4-methoxystyryl)ph-
enyl)-N-(4-hydroxyphenethyl)acrylamide
o
1
Yellow solid (61% yield). Mp 80-81 C. H NMR (600
MHz, CDCl3) ꢁ 8.49 (s, 1H), 7.42 (t, 2H, J = 8.2 Hz), 7.25
(s, 1H), 7.04 (t, 2H, J = 15.4 Hz), 7.00 – 6.92 (m, 2H), 6.90 –
6.85 (m, 2H), 6.76 (d, 2H, J = 8.4 Hz), 6.73 (d, 1H, J = 2.1
Hz), 6.42 (t, 1H, J = 5.6 Hz), 6.40 (d, 1H, J = 2.1 Hz), 3.86
(t, 6H, J = 10.1 Hz), 3.81 (s, 3H), 3.60 (dd, 2H, J = 13.1, 6.9
Hz), 2.81 (t, 2H, J = 7.1 Hz). MS (ESI): 485.5(C29H28N2O5,
[M+H]+). Anal. Calcd for C29H28N2O5: C, 71.88; H, 5.82; N,
5.78. Found: C, 71.87; H, 5.82; N, 5.78%.
C20: (E)-N-(4-chlorophenyl)-2-cyano-3-(2,4-dimethoxy-6-
(4-methoxystyryl)phenyl)acrylamide
C15: (E)-2-cyano-3-(2,4-dimethoxy-6-(4-methoxystyryl)ph-
enyl)-N-(pyridin-2-ylmethyl)acrylamide
Yellow solid (79% yield). Mp 202-203 oC. 1H NMR (600
MHz, DMSO-d6) ꢁ 10.45 (s, 1H), 10.21 (s, 1H), 8.31 (s, 1H),
7.88 (s, 1H), 7.73 (d, 1H, J = 8.7 Hz), 7.27 (d, 2H, J = 8.6
Hz), 7.17 (d, 1H, J = 16.1 Hz), 7.10 (dd, 2H, J = 15.9, 9.9
Hz), 6.99 (s, 1H), 6.85 (s, 1H), 6.62 (s, 1H), 6.42 (s, 1H),
3.82 (s, 3H), 3.77 (s, 3H), 3.58 (s, 3H). MS (ESI): 475.9
(C27H23ClN2O4, [M+H]+). Anal. Calcd for C27H23ClN2O4: C,
68.28; H, 4.88; Cl, 7.46; N, 5.90. Found: C, 68.25; H, 4.88;
Cl, 7.46; N, 5.90%.
Yellow solid (52% yield). Mp 182-183 oC. 1H NMR (600
MHz, CDCl3) ꢁ 8.57 (d, 1H, J = 4.4 Hz), 8.51 (s, 1H), 7.73
(s, 1H), 7.69 (t, 1H, J = 7.1 Hz), 7.43 (d, 2H, J = 8.6 Hz),
7.31 (d, 1H, J = 7.8 Hz), 7.23 (dd, 1H, J = 11.7, 6.1 Hz),
7.01 (d, 1H, J = 16.0 Hz), 6.95 (d, 1H, J = 16.0 Hz), 6.87 (d,
2H, J = 8.6 Hz), 6.74 (d, 1H, J = 1.8 Hz), 6.41 (d, 1H, J =
1.7 Hz), 4.72 (d, 2H, J = 4.8 Hz), 3.88 (d, 6H, J = 1.2 Hz),
3.81 (s, 3H). MS (ESI): 456.5(C27H25N3O4, [M+H]+). Anal.