V. Gembus et al. / European Journal of Medicinal Chemistry 58 (2012) 396e404
403
124.1, 123.0, 119.1, 49.9, 46.6, 37.9, 21.6 ppm; HRMS (ESI): calcd for
C
136.6,135.8,129.7,129.6,129.1,129.0,128.9,128.8,126.9,125.3, 64.2,
50.6, 50.5, 48.7, 48.5, 48.3, 48.2, 46.3, 46.2, 42.6, 39.4, 39.1, 37.9, 31.0,
30.9, 27.5, 27.4, 26.1, 21.5, 21.4, 20.4, 19.9, 19.8 ppm; HRMS (ESI):
calcd for C28H35N3OCl [M þ H]þ: 464.2469; found: 464.2462.
24H24N3O [M þ H]þ: 370.1919; found: 370.1908.
4.1.6.7. 4-Benzyl-N-cyclohexyl-3-m-tolyl-4,5-dihydro-1H-pyrazole-
1-carboxamide 9g. According to representative procedure (24 h at
60 ꢀC), the title compound was obtained as a white solid (71 mg,
76%) from the corresponding enone (0.25 mmol) and hydrazone
(0.375 mmol).
4.1.6.11. 3-(4-Chloro-3-methylphenyl)-4-(4-methylbenzyl)-N-
phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide 9k. According to
representative procedure (24 h at 50 ꢀC), the title compound was
obtained white solid (87.3 mg, 83%) from the corresponding enone
(0.25 mmol) and hydrazone (0.375 mmol).
Rf ¼ 0.25 (petroleum ether/EtOAc: 3/1); m.p. <50 ꢀC; IR (KBr):
ꢂ1
;
1H NMR
~
n
¼ 3321, 2930, 2854, 1649, 1527, 1401, 1328, 1140 cm
(300 MHz, CDCl3):
d
¼ 7.58e7.50 (m, 2H), 7.37e7.13 (m, 7H), 5.88
Rf ¼ 0.47 (petroleum ether/EtOAc: 3/1); m.p. <50 ꢀC; IR
~
(d, J ¼ 8.4 Hz, 1H), 4.00e3.61 (m, 4H), 3.07 (dd, J ¼ 13.9 Hz,
J ¼ 3.2 Hz, 1H), 2.61 (dd, J ¼ 14.1 Hz, J ¼ 9.8 Hz, 1H), 2.41 (s, 3H),
2.07e1.89 (m, 2H), 1.81e1.56 (m, 3H), 1.47e1.08 (m, 5H) ppm; 13C
(KBr):
n
¼ 3308, 1669, 1594, 1534, 1445, 1369, 1319, 1235, 1183,
1142, 1046 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼ 7.96 (s, 1H),
7.62 (d, J ¼ 1.5 Hz, 1H), 7.56e7.49 (m, 3H), 7.43 (d, J ¼ 8.3 Hz, 1H),
7.34e7.29 (m, 2H), 7.12e7.03 (m, 5H), 4.11e4.00 (m, 1H), 3.94e3.79
(m, 2H), 3.03 (dd, J ¼ 14.1 Hz, J ¼ 3.2 Hz,1H), 2.71e2.59 (m,1H), 2.45
NMR (75 MHz, CDCl3):
d
¼ 155.4, 154.9, 138.6, 138.4, 131.0, 130.6,
129.0, 128.8, 128.7, 127.2, 126.8, 123.9, 50.2, 48.9, 46.3, 37.8, 34.0,
25.8, 25.2, 21.6 ppm; HRMS (ESI): calcd for C24H30N3O [M þ H]þ:
376.2389; found: 376.2375.
(s, 3H), 2.32 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d
¼ 155.6,152.3,
138.6, 136.9, 136.7, 136.4, 134.8, 129.8, 129.6, 129.4, 129.3, 129.1,
129.0, 125.6, 123.2, 119.2, 50.1, 46.7, 37.7, 21.2, 20.4; HRMS (ESI):
calcd for C25H25N3OCl [M þ H]þ: 418.1686; found: 418.1671.
4.1.6.8. 4-Benzyl-3-(4-chloro-3-methylphenyl)-N-phenyl-4,5-dihydro-
1H-pyrazole-1-carboxamide 9h. According to representative proce-
dure (20 h at 50 ꢀC), the title compound was obtained as a white
solid (81 mg, 80%) from the corresponding enone (0.25 mmol) and
hydrazone (0.375 mmol).
4.1.6.12. 3-(4-Chloro-3-methylphenyl)-N-cyclohexyl-4-(4-methylbe-
nzyl)-4,5-dihydro-1H-pyrazole-1-carboxamide 9l. According to
representative procedure (24 h at 60 ꢀC), the title compound was
obtained as a colorless oil (80.6 mg, 76%) from the corresponding
enone (0.25 mmol) and hydrazone (0.375 mmol).
~
Rf ¼ 0.37 (petroleum ether/EtOAc: 3/1); m.p. <50 ꢀC; IR
~
(KBr):
n
¼ 3395, 1673, 1593, 1537, 1446, 1372, 1310, 1232, 1184,
1143, 1046 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼ 7.96 (s, 1H),
Rf ¼ 0.32 (petroleum ether/EtOAc: 3/1); IR (KBr):
n
¼ 3421, 2928,
1H
¼ 7.57 (s, 1H), 7.49 (dd, J ¼ 8.3 Hz,
7.63 (d, J ¼ 1.6 Hz, 1H), 7.58e7.49 (m, 3H), 7.43 (d, J ¼ 8.3 Hz, 1H),
7.37e7.21 (m, 5H), 7.20e7.13 (m, 2H), 7.10e7.01 (m, 1H), 4.11e4.03
(m, 1H), 3.97e3.83 (m, 2H), 3.09 (dd, J ¼ 14.3 Hz, J ¼ 3.3 Hz, 1H),
2.74e2.63 (m, 1H), 2.45 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
2852, 1667, 1519, 1446, 1383, 1321, 1257, 1137, 1049 cmꢂ1
NMR (300 MHz, CDCl3):
;
d
J ¼ 1.9 Hz, 1H), 7.37 (d, J ¼ 8.2 Hz, 1H), 7.10e7.02 (m, 4H), 5.85
(d, J ¼ 8.3 Hz, 1H), 4.02e3.91 (m, 1H), 3.82e3.62 (m, 3H), 2.97
(dd, J ¼ 14.1 Hz, J ¼ 2.4 Hz, 1H), 2.62e2.54 (m, 1H), 2.41 (s, 3H), 2.31
(s, 3H), 2.05e1.90 (m, 2H), 1.84e1.57 (m, 3H), 1.46e1.11 (m, 5H)
d
¼ 155.4, 152.3, 138.5, 137.8, 136.9, 136.3, 129.7, 129.2, 129.1, 129.0,
128.9, 127.0, 125.5, 123.1, 119.2, 50.1, 46.4, 38.0, 20.3 ppm; HRMS
(ESI): calcd for C24H23N3OCl [M þ H]þ: 404.1530; found: 404.1510.
ppm; 13C NMR (75 MHz, CDCl3):
d
¼ 154.7, 154.4, 136.6, 136.4, 135.7,
135.0, 129.7, 129.5, 129.4, 129.0, 128.9, 125.3, 50.4, 48.9, 46.3, 37.4,
34.0, 25.7, 25.2, 21.1, 20.2 ppm; HRMS (ESI): calcd for C25H31N3OCl
[M þ H]þ: 224.2156; found: 424.2157.
4.1.6.9. 4-Benzyl-3-(4-chloro-3-methylphenyl)-N-cyclohexyl-4,5-
dihydro-1H-pyrazole-1-carboxamide 9i. According to representa-
tive procedure (26 h at 60 ꢀC), the title compound was obtained as
a white solid (73 mg, 71%) from the corresponding enone
(0.25 mmol) and hydrazone (0.375 mmol).
4.1.6.13. 3-(4-Chloro-3-methylphenyl)-4-(4-methylbenzyl)-N-(1,3,3-
trimethylbicyclo[2.2.1]heptan-2-yl)-4,5-dihydro-1H-pyrazole-1-
carboxamide 9m. According to representative procedure (24 h at
80 ꢀC), the title compound was obtained as a white solid (60 mg,
63%) from the corresponding enone (0.20 mmol) and hydrazone
(0.212 mmol).
Rf ¼ 0.21 (petroleum ether/EtOAc: 3/1); m.p. <50 ꢀC; IR (KBr):
~
n
¼ 3421, 2928, 2852, 1665, 1515, 1450, 1385, 1359, 1321, 1257, 1159,
1137, 1047 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼ 7.54 (s, 1H), 7.46
(dd, J ¼ 8.3 Hz, J ¼ 1.9 Hz, 1H), 7.36 (d, J ¼ 8.2 Hz, 1H), 7.29e7.12
(m, 5H), 5.82 (d, J ¼ 8.3 Hz, 1H), 4.00e3.90 (m, 1H), 3.83e3.60
(m, 3H), 3.00 (dd, J ¼ 14.1 Hz, J ¼ 2.8 Hz, 1H), 2.64e2.56 (m, 1H),
2.39 (s, 3H), 2.03e1.89 (m, 2H),1.78e1.55 (m, 3H),1.43e1.10 (m, 5H)
Rf ¼ 0.35 (petroleum ether/EtOAc: 3/1); m.p. <50 ꢀC; IR (KBr):
~
3435, 2948, 2869, 1673, 1517, 1472, 1375, 1184, 1140,
n
¼
1046, 798 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
¼ 7.52e7.50 (m, 2H),
ppm; 13C NMR (75 MHz, CDCl3):
d
¼ 154.7, 154.4, 138.2, 136.7, 135.8,
7.40e7.37 (m, 1H), 7.10e7.02 (m, 4H), 6.07/6.05 (2d, J ¼ 9.8 Hz,
J ¼ 9.2 Hz, 1H), 4.04e3.94 (m, 1H), 3.84e3.75 (m, 2H), 3.54 (m, 1H),
2.97 (dd, J ¼ 14.1 Hz, J ¼ 3.4 Hz, 1H), 2.67e2.58 (m, 1H), 2.42 (s, 3H),
2.31 (s, 3H), 1.79e1.15 (m, 7H), 1.13e1.06 (4s, 6H), 0.80/0.83 (2s, 3H)
129.6, 129.0, 128.8, 126.9, 125.3, 50.4, 48.9, 46.2, 37.9, 34.2, 25.7,
25.2, 20.3 ppm; HRMS (ESI): calcd for C24H29N3OCl [M þ H]þ:
410.1999; found: 410.1985.
ppm; 13C NMR (75 MHz, CDCl3):
d
¼ 155.9, 154.3, 154.2,136.6, 136.4,
4.1.6.10. 4-Benzyl-3-(4-chloro-3-methylphenyl)-N-(1,3,3-trimethyl-
bicyclo[2.2.1]heptan-2-yl)-4,5-dihydro-1H-pyrazole-1-carboxamide
9j. According to representative procedure (48 h at 80 ꢀC), the title
compound was obtained as a colorless oil (65.2 mg, 57%) from the
corresponding enone (0.25 mmol) and hydrazone (0.27 mmol).
~
135.7, 135.0, 134.9, 129.8, 129.6, 129.4, 129.0, 128.9, 128.8, 125.3,
64.2, 64.1, 50.5, 48.7, 48.5, 48.2, 46.4, 46.3, 42.6, 42.5, 39.3, 39.1, 37.4,
30.9, 27.5, 27.4, 26.1, 21.4, 21.3, 21.1, 20.3, 19.8, 19.7 ppm; HRMS
(ESI): calcd for C29H37N3OCl [M þ H]þ: 478.2625; found: 478.2625.
Rf ¼ 0.5 (petroleum ether/EtOAc: 2/1); IR (KBr):
n
¼ 3434,
1H
¼ 7.55e7.47 (m, 2H), 7.39 (d, J ¼ 7.9 Hz,
4.1.6.14. 3-(4-Chloro-3-methylphenyl)-N-cyclohexyl-4-pentyl-4,5-
dihydro-1H-pyrazole-1-carboxamide 9n. According to representa-
tive procedure (48 h at 80 ꢀC), the title compound was obtained as
a white solid (75 mg, 77%) from the corresponding enone
(0.25 mmol) and hydrazone (0.375 mmol).
2948, 2869, 1674, 1517, 1472, 1375, 1184, 1145, 1046 cmꢂ1
NMR (300 MHz, CDCl3):
;
d
1H), 7.33e7.11 (m, 5H), 6.07/6.05 (2d, J ¼ 9.8 Hz, J ¼ 9.2 Hz, 1H),
4.04e3.94 (m, 1H), 3.87e3.75 (m, 2H), 3.54 (m, 1H), 3.03
(dd, J ¼ 14.3 Hz, J ¼ 3.2 Hz,1H), 2.72e2.61 (m,1H), 2.42 (s, 3H),1.80e
1.62 (m, 3H),1.55e1.16 (m, 4H),1.13e1.06 (4s, 6H), 0.84/0.80 (2s, 3H)
Rf ¼ 0.18 (petroleum ether/EtOAc: 4/1); m.p. ¼ 122 ꢀC; IR (KBr):
~
n
¼ 3284, 2930, 2852, 1653, 1536,1466,1449,1382,1357,1326, 1245,
ppm; 13C NMR (75 MHz, CDCl3):
d
¼ 156.0, 154.2, 154.1, 138.2, 138.1,
1186 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼ 7.54 (s, 1H), 7.42e7.34