J. Hou et al. / European Journal of Medicinal Chemistry 46 (2011) 3190e3200
3197
(300 MHz, CDCl3)
d
: 7.61e7.63 (m, 4H), 7.15e7.39 (m, 8H), 6.53 (d,
J ¼ 8.4 Hz, 1H), 4.78 (s, 2H), 3.74 (s, 3H), 2.74e2.36 (m, 1H), 0.95 (d,
J ¼ 6.7 Hz, 3H), 0.74 (d, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz, DMSO-
J¼ 15.8Hz,1H), 6.11 (dd, J1 ¼7.9 Hz, J2 ¼15.8Hz,1H), 4.28(q, J ¼ 7.0 Hz,
1H), 3.00 (d, J ¼ 6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d: 135.9,134.6,
d6) d: 162.6, 159.4, 142.8, 135.7, 134.2, 130.7, 128.7, 128.3,127.9, 126.7,
133.5, 133.4, 132.4, 128.6, 128.2, 128.1, 128.0, 127.64, 127.59, 126.7,
126.4, 126.1, 125.6, 65.7, 41.5 (one peak less due to overlap).
125.9, 123.8, 119.1, 113.7, 76.7, 69.0, 65.1, 32.9, 18.9, 18.8 (one peak
less due to overlap).
6.1.5. General procedure for synthesis of compounds 1ce16c from
1be16b
6.1.5.6. (2E)-N-(4-Methoxybenzyloxy)-3-(1-((E)-4,4-dimethyl-1-
phenylpent-1en-3-yl)-1H-1,2,3-triazol-4-yl)acrylamide (6c). White
solid was obtained from 6b with the yield of 63%.1H NMR (400 MHz,
The obtained white solid terminal alkyne F (1.0 equiv.) was dis-
solved in THF (20 mL). Azido compound 1be16b (1.2 equiv.),
CuI$P(OEt)3 (1.0 equiv.) and DIPEA (2.0 equiv.) were added sequen-
tially. The reactionwas stirred overnight at rt, monitored by TLC. The
solvent was removed under reduced pressure, and the residue was
participated between DCM and saturated aqueous NH4Cl. The
aqueous layer was extracted twice with DCM, and the combined
organic extracts were dried with Na2SO4 and concentrated under
reduced pressure. The crude residue was purified with flash chro-
matograph (MeOH/DCM: from 1% to 5%) to give the title product.
DMSO-d6) d: 11.28 (s, 1H), 8.56 (s, 1H), 7.27e7.53 (m, 8H), 6.95 (d,
J ¼ 8.4 Hz, 2H), 6.83 (dd, J1 ¼ 9.2 Hz, J2 ¼ 15.7 Hz, 1H), 6.71 (d,
J¼ 15.7 Hz,1H), 6.59(d, J ¼15.7 Hz,1H), 5.13 (d, J ¼9.2 Hz,1H), 4.80 (s,
2H), 3.76 (s, 3H), 0.95 (s, 9H); 13C NMR (100 MHz, DMSO-d6)
d: 162.5,
159.3,142.2,135.7,134.9,130.7,128.6,128.2,127.8,126.7,124.7,124.0,
119.0,113.7, 76.6, 71.7, 55.1, 35.3, 26.4 (one peak less due to overlap).
6.1.5.7. (2E)-N-(4-Methoxybenzoxy)-3-(1-((E)-5-methyl-1-phenyl-
hex-1-en-3-yl)-1H-1,2,3-triazol-4-yl)acrylamide (7c). White solid
was obtained from 7b with the yield of 63%. 1H NMR (400 MHz,
6.1.5.1. (2E)-N-(4-Methoxybenzyloxy)-3-(1-((E)-4-phenylbut-3-en-
2-yl)-1H-1,2,3-triazol-4-yl)acrylamide (1c). White solid was ob-
tained from 1b with the yield of 94%. 1H NMR (400 MHz, DMSO-d6)
DMSO-d6) d: 11.3 (s, 1H), 8.56 (s, 1H), 7.26e7.51 (m, 8H), 6.95 (d,
J ¼ 8.4 Hz, 2H), 6.53e6.69 (m, 3H), 5.41e5.47 (m, 1H), 4.82 (s, 2H),
3.77 (s, 3H), 2.01e2.08 (m,1H),1.84e1.91 (m,1H),1.31e1.38 (m,1H),
0.95 (d, J ¼ 6.6 Hz, 3H), 0.89 (d, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz,
d: 11.31 (s, 1H), 8.50 (s, 1H), 7.45e7.52 (m, 3H), 7.24e7.36 (m, 5H),
6.94 (d, J ¼ 8.1, 2H), 6.53e6.65 (m, 3H), 5.50 (t, J ¼ 6.3 Hz, 1H), 4.81
DMSO-d6) d: 162.6, 159.4, 142.9, 135.7, 132.4, 130.7, 128.6, 128.2,
(s, 2H), 3.74 (s, 3H), 1.71 (d, J ¼ 6.7, 3H); 13C NMR (100 MHz, DMSO-
128.1, 127.8, 126.6, 123.5, 119.1, 113.7, 76.6, 61.0, 55.o, 43.2, 24.3, 22.1,
21.8 (one peak less due to overlap).
d6) d: 162.6, 159.4, 143.0, 135.7, 131.7, 130.7, 128.7, 128.3, 128.2, 127.9,
126.6, 123.4, 119.0, 113.7, 76.7, 58.0, 55.1, 20.6 (one peak less due to
overlap).
6.1.5.8. (2E)-N-(4-Methoxybenzyloxy)-3-(1-((E)-1-cyclobutyl-3-phe-
nylallyl)-1H-1,2,3-triazol-4yl)acrylamide (8c). White solid was ob-
tained from 8b with the yield of 81%. 1H NMR (400 MHz, DMSO-d6)
6.1.5.2. (2E)-N-(4-Methoxybenzyloxy)-3-(1-((E)-1-phenylpent-1-en-
3-yl)-1H-1,2,3-triazol-4-yl)acrylamide (2c). White solid was ob-
tained from 2b with the yield of 92%. 1H NMR (400 MHz, DMSO-d6)
d
: 11.26 (s, 1H), 8.48 (s, 1H), 7.26e7.48 (m, 8H), 6.94 (d, J ¼ 8.3 Hz,
2H), 6.44e6.69 (m, 3H), 5.31 (t, J ¼ 8.8 Hz, 1H), 4.79 (s, 2H), 3.76 (s,
d: 11.28 (s, 1H), 8.52 (s, 1H), 7.44e7.48 (m, 3H), 7.26e7.26 (m, 5H),
3H), 2.95e3.05 (m, 1H), 1.70e2.09 (m, 6H); 13C NMR (100 MHz,
6.94 (d, J ¼ 8.4 Hz, 2H), 6.53e6.65 (m, 3H), 5.26 (apparent q,
DMSO-d6) d: 162.5, 159.3, 142.7, 135.6, 133.1, 130.5, 128.5, 128.2,
128.0, 127.7, 126.5, 125.3, 123.4, 119.0, 113.6, 76.5, 67.2, 55.0, 38.2,
24.6, 24.5, 16.9.
J ¼ 7.3 Hz, 1H), 4.79 (s, 2H), 3.76 (s, 3H), 2..-2.13 (m, 2H), 0.83 (t,
J ¼ 7.3 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)
d: 162.6, 159.4, 142.9,
135.7, 132.7, 130.7, 128.7,128.3,128.2, 127.8, 127.5, 126.6, 123.7,119.0,
113.7, 76.7, 64.1, 55.1, 27.9, 10.2.
6.1.5.9. (2E)-N-(4-Methoxybenzyloxy)-3-(1-((E)-1-cyclopentyl-3-
phenylallyl)-1H-1,2,3-triazol-4-yl)acrylamide (9c). White solid was
obtained from 9b with the yield of 84%; 1H NMR (400 MHz, DMSO-
6.1.5.3. (2E)-N-(4-Methoxybenzyloxy)-3-(1-((E)-1-phenylhex-1-en-
3-yl)-1H-1,2,3-triazol-4-yl)acrylamide (3c). White solid was ob-
tained from 3b with the yield of 62%. 1H NMR (400 MHz, DMSO-d6)
d6)
d
: 11.27 (s,1H), 8.54 (s,1H), 7.26e7.48 (m, 8H), 6.95 (d, J ¼ 8.2 Hz,
1H), 6.56e6.70 (m, 3H), 5.12 (t, J ¼ 8.4 Hz, 1H), 4.80 (s, 2H), 3.76 (s,
3H), 2.56e2.67 (m, 1H), 1.75e1.79 (m, 1H), 1.36e1.62 (m, 6H),
d
: 11.27 (s, 1H), 8.52 (s, 1H), 7.26e7.48 (m, 8H), 6.94 (d, J ¼ 8.4 Hz,
2H), 6.53e6.66 (m, 3H), 5.35 (q, J ¼ 7.3 Hz, 1H), 4.79 (s, 2H), 3.76 (s,
1.12e1.18 (m, 1H); 13C NMR (100 MHz, DMSO-d6)
d: 162.5, 159.3,
3H),1.94e2.11 (m, 2H),1.14e1.29 (m, 2H), 0.90 (t, J ¼ 7.3 Hz, 3H); 13C
142.7,135.6,133.1,130.6,128.6,128.2,128.1,127.8,126.9,126.6,123.5,
119.0, 113.6, 76.6, 67.4, 55.0, 44.0, 29.24, 29.16, 24.9, 24.6.
NMR (100 MHz, DMSO-d6) d: 162.5, 159.4, 142.8, 135.7, 132.5, 130.7,
128.6, 128.2, 128.1, 127.8, 127.6, 126.6, 123.5, 119.0, 113.7, 76.6, 62.4,
55.1, 36.5, 18.6, 13.3.
6.1.5.10. (2E)-N-(4-Methoxybenzyloxy)-3-(1-((E)-1-phenylhexa-1,5-
dien-3-yl)-1H-1,2,3-triazole-4-yl)acrylamide (10c). White solid was
obtained from 10b with the yield of 84%. 1H NMR (400 MHz, DMSO-
6.1.5.4. (2E)-N-(4-Methoxybenzyloxy)-3-(1-((E)-1-phenylhept-1-en-
3-yl)-1H-1,2,3-triazol-4-yl)acrylamide (4c). White solid was ob-
tained from 4b with the yield of 73%. 1H NMR (400 MHz, DMSO-d6)
d6)
d
: 11.26 (s, 1H), 8.51 (s,1H), 7.26e7.47 (m, 8H), 6.94 (d, J ¼ 8.4 Hz,
2H), 6.54e6.65 (m, 3H), 5.65e5.75 (m, 1H), 5.44e5.50 (m, 1H),
d
: 11.27 (s, 1H), 8.52 (s, 1H), 7.26e7.48 (m, 8H), 6.95 (d, J ¼ 7.8 Hz,
5.01e5.10 (m, 2H), 4.78 (s, 2H), 3.76 (s, 3H), 2.82e2.87 (m, 2H); 13C
2H), 6.54e6.66 (m, 3H), 5.34 (apparent q, J ¼ 7.2 Hz, 1H), 4.79 (s,
2H), 3.76 (s, 3H), 2.01e2.10 (m, 2H), 1.10e1.37 (m, 4H), 0.85 (t,
NMR (100 MHz, DMSO-d6) d: 162.5, 159.3, 142.8, 135.6, 133.2, 132.6,
130.7, 128.7, 128.2, 127.8, 127.1, 126.6, 123.7, 119.0, 118.6, 113.7, 76.6,
61.9, 55.1, 38.8 (one peak less due to overlap).
J ¼ 7.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
d: 162.7, 159.4, 142.9,
135.7, 132.5, 130.6, 128.6, 128.3, 128.1, 127.9, 127.7, 126.6, 123.5, 119.1,
113.7, 76.7, 62.7, 55.0, 34.3, 27.4, 21.6, 13.7; HRMS (ESI) calcd for
C26H30N4O3 [M þ H]+ 447.2391 found 447.2385.
6.1.5.11. (2E)-N-(4-Methoxybenzyloxy)-3-(1-((E)-1,4-diphenylbut-3-
en-2-yl)-1H-1,2,3-triazol-4-yl) acrylamide (11c). White solid was
obtained from 11b with the yield of 89%. 1H NMR (400 MHz, DMSO-
6.1.5.5. (2E)-N-(4-Methoxybenzyloxy)-3-(1-((E)-4-methyl-1-phenyl-
pent-1-en-3-yl)-1H-1,2,3-triazol-4-yl)acrylamide (5c). White solid
was obtained from 5b with the yield of 79%. 1H NMR (400 MHz,
d6) d: 11.32 (br, 1H), 8.49 (s, 1H), 7.42e7.47 (m, 3H), 7.31e7.36 (m,
4H), 7.14e7.28 (m, 6H), 6.94 (d, J ¼ 8.3, 2H), 6.56e6.68 (m, 3H), 5.67
(q, J ¼ 7.3), 4.81 (s, 2H), 3.74 (s, 3H), 3.37e3.47 (m, one proton
DMSO-d6)
d: 11.28 (s, 1H), 8.52 (s, 1H), 7.43e7.48 (m, 3H), 7.25e7.3 5
overlap with H2O peak); 13C NMR (100 MHz, DMSO-d6)
d: 162.5,
(m, 5H), 6.93 (d, J ¼ 8.3 Hz, 2H), 6.55e6.72 (m, 3H), 5.01 (t,
159.4, 142.7,136.7,135.6,132.7,130.7,129.1, 128.7, 128.3, 128.2, 127.8,