366
M.N. Aboul-Enein et al. / European Journal of Medicinal Chemistry 47 (2012) 360e369
from methanol; yield 29%. IR (KBr, cmꢁ1): 3334 (NH), 3199 (NH),
2962 (C]C), 1692 (C]O), 1575 (C]N). 1H NMR (CDCl3):
1.2 (s, 9H,
OeCH2eO), 6.68e6.74 (m, 3H, H-4, H-6, H-7), 6.98 (s, 1H, H-40), 7.2
(d, J ¼ 7.7 Hz, 2H, H-30, H-50), 7.4 (d, J ¼ 6.9 Hz, 2H, H-20, H-60), 7.95
d
t-butyl), 5.99 (s, 2H, OeCH2eO), 6.29 (d, J ¼ 17.2 Hz, 1H,
CH ¼ CHph), 6.68 (d, J ¼ 17.2 Hz, 1H, CH ¼ CHph), 6.79 (d, J ¼ 8.0 Hz,
1H, H-7), 6.88 (dd, J ¼ 8.1, 1.7 Hz, 1H, H-6), 6.99 (d, J ¼ 1.7 Hz, 1H, H-
4), 7.19 (dd, J ¼ 8.6, 2.3 Hz, 1H, H-50), 7.36 (d, J ¼ 2.2 Hz, 1H, H-30),
8.30 (d, J ¼ 9.2 Hz,1H, H-60), 8.2 (s,1H, CONHph), 9.0 (s,1H, NNHCO)
(s, 1H, CONHph) ppm. 13C NMR (CDCl3):
d 28.1 (C(CH3)3), 38.1
(C(CH3)3), 42.5 (CHCH2), 59.9 (CHCH2), 101 (OeCH2eO), 105, 108,
118.9, 119, 122, 128, 137, 138, 147, 148 (CHar, Car), 152 (C]O), 163 (C]
N) ppm. HRMS: for C21H23N3O3.Hþ, calcd. 366.1812, found 366.1803.
ppm. 13C NMR (CDCl3):
d
28.2 (C(CH3)3), 38.5 (C(CH3)3), 101 (CH2),
6.1.6.2. (ꢀ)-(5RS)-(1,3-Benzodioxol-5-yl)-N-(4-bromophenyl)-3-tert-
butyl-4,5-dihydro-1H-pyrazole-1-carboxamide ((ꢀ)-8b). Off-white
solid, mp 141 ꢂC; reaction time 1 h; yield 56%. IR (KBr, cmꢁ1): 3394
105, 108, 115, 120, 122, 127.2, 127.7, 128.5, 129.3 (CHar, Car), 134
(CH ¼ CHph), 137 (CH ¼ CHph), 148.3, 148.6 (Car), 152.8 (C]N),
156.5 (C]O) ppm. HRMS: for C21H21Cl2N3O3.Hþ, calcd. 434.1033,
found 434.1024.
(NH), 2959 (C]C), 1687 (C]O), 1588 (C]N). 1H NMR (CDCl3):
d 1.2
(s, 9H, t-butyl), 2.79 (dd, J ¼ 5.4,18.3 Hz,1H, CHCH2), 3.4 (dd, J ¼ 10.7,
17.6 Hz, 1H, CHCH2), 5.3 (dd, J ¼ 5.4, 11.5 Hz, 1H, CHCH2), 5.9 (s, 2H,
OeCH2eO), 6.65e6.73 (m, 3H, H-4, H-6, H-7), 7.32e7.36 (m, 4H, H-
6.1.4.7. 2-[(1E)-1-(1,3-Benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-
ylidene]-N-(4-fluorophenyl)hydrazinecarboxamide
(7g). Yellow
20, H-30, H-50, H-60), 7.9 (s,1H, CONHph) ppm. 13C NMR (CDCl3):
d 28.1
solid, mp 110 ꢂC; reaction time 24 h; purified by column chroma-
tography using silica gel and chloroform followed by recrystalli-
zation from methanol; yield 25%. IR (KBr, cmꢁ1): 3346 (NH), 3211
(C(CH3)3), 34.1 (C(CH3)3), 42.5 (CHCH2), 59.9 (CHCH2), 101
(OeCH2eO), 105, 108, 115, 118, 120, 131, 136, 137, 147, 148 (CHar, Car),
151 (C]O), 164 (C]N) ppm. HRMS: for C21H22BrN3O3.Hþ, calcd.
444.0917, found 444.0908.
(NH), 2965 (C]C), 1679 (C]O), 1610 (C]N). 1H NMR (CDCl3):
d 1.15
(s, 9H, t-butyl), 5.9 (s, 2H, OeCH2eO), 6.2 (d, J ¼ 17.6 Hz, 1H,
CH ¼ CHph), 6.59 (d, J ¼ 17.6 Hz, 1H, CH ¼ CHph), 6.73 (d, J ¼ 8.4 Hz,
1H, H-7), 6.8 (dd, J ¼ 7.7,1.6 Hz,1H, H-6), 6.92 (d, J ¼ 1.6 Hz,1H, H-4),
6.95 (d, J ¼ 8.4 Hz, 2H, H-20, H-60), 7.36e7.39 (m, 2H, H-30, H-50),
7.93 (s, 1H, CONH ph), 8.1 (s, 1H, NNHCO) ppm. 13C NMR (CDCl3):
6.1.6.3. (ꢀ)-(5RS)-(1,3-Benzodioxol-5-yl)-3-tert-butyl-N-(4-chloro-
phenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide
((ꢀ)-8c). White
solid, mp 141 ꢂC; reaction time 8 h; yield 40%. IR (KBr, cmꢁ1): 3397
(NH), 2963 (C]C), 1658 (C]O), 1590 (C]N). 1H NMR (CDCl3):
d
1.2
d
28.3 (C(CH3)3), 38.4 (C(CH3)3), 101 (CH2), 105, 108, 115.4, 115.6,
(s, 9H, t-butyl), 2.79 (dd, J ¼ 5.4,18.4 Hz,1H, CHCH2), 3.4 (dd, J ¼ 12.3,
18.4 Hz, 1H, CHCH2), 5.3 (dd, J ¼ 5.4, 12.2 Hz, 1H, CHCH2), 5.9 (s, 2H,
OeCH2eO), 6.66e6.73 (m, 3H, H-4, H-6, H-7), 7.2 (t, J ¼ 6.9, 1.6 Hz,
2H, H-20, H-60), 7.4 (t, J ¼ 6.9, 2.3 Hz, 2H, H-30, H-50), 7.9 (s, 1H,
115.7, 121, 122, 129 (CHar, Car), 134 (CH ¼ CHph), 137 (CH ¼ CHph),
148.3, 148.6 (Car), 153 (C]N), 156 (C]O) ppm. HRMS: for
C21H22FN3O3.Hþ, calcd. 384.1718, found 384.1715.
CONHph) ppm. 13C NMR (CDCl3):
d 28.1 (C(CH3)3), 34.1 (C(CH3)3),
6.1.5. Synthesis of 2-[(1E)-1-(1,3-benzodioxol-5-yl)-4,4-
dimethylpent-1-en-3-ylidene]hydrazinecarboxamide (7h)
42.5 (CHCH2), 59.9 (CHCH2), 101 (OeCH2eO), 105, 108, 118, 120.6,
127.7, 128, 136, 137, 147, 148 (CHar, Car), 151 (C]O), 164 (C]N) ppm.
HRMS: for C21H22ClN3O3.Hþ, calcd. 400.1422, found 400.1409.
A solution of 6 (1.0 g, 0.0043 mol), semicarbazide hydrochloride
(0.5 g, 0.0043 mol) and anhydrous sodium acetate (0.35 g,
0.0043 mol) in absolute ethanol (40 mL) was stirred at room
temperature for 18 h. The reaction mixture was filtered and the
filtrate was evaporated under vacuum to afford 0.65 g (46%) of
crude 7h. The solid was recrystallized from ethanol to afford 0.54 g
(38%) of pure 7h as a yellowish white solid mp 144 ꢂC. IR (KBr,
cmꢁ1): 3373(NH), 3266, 3201 (NH2), 2970 (C]C), 1684 (C]O), 1581
6.1.6.4. (ꢀ)-(5RS)-(1,3-Benzodioxol-5-yl)-3-tert-butyl-N-(4-methyl-
phenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide
((ꢀ)-8d). White
Solid, mp 131 ꢂC; reaction time 1 h; yield 58%. IR (KBr, cmꢁ1): 3399
(NH), 2963 (C]C), 1681 (C]O), 1590 (C]N). 1H NMR (CDCl3):
d
1.2
(s, 9H, t-butyl), 2.3 (s, 3H, CH3), 2.77 (dd, J ¼ 6.1, 12.2 Hz, 1H, CHCH2),
3.4 (dd, J ¼ 12.9,18.4 Hz, 1H, CHCH2), 5.3 (dd, J ¼ 4.2, 11.5 Hz, 1H,
CHCH2), 5.9 (s, 2H, OeCH2eO), 6.67e6.74 (m, 3H, H-4, H-6, H-7), 7.0
(d, J ¼ 8.4 Hz, 2H, H-20, H-60), 7.3 (d, J ¼ 6.1 Hz, 2H, H-30, H-50), 7.8 (s,
(C]N). 1H NMR (CDCl3):
d 1.1 (s, 9H, t-butyl), 5.9 (s, 2H, OeCH2eO),
6.25 (d, J ¼ 17.2 Hz, 1H, CH ¼ CHph), 6.61 (d, J ¼ 17.2 Hz, 1H,
CH ¼ CHph), 6.77 (d, J ¼ 8.1 Hz,1H, H-7), 6.84 (dd, J ¼ 1.7, 8.0 Hz,1H,
H-6), 6.98 (d, J ¼ 1.1 Hz, 1H, H-4), 8.0 (s, 1H, NH) ppm. 13C NMR
1H, CONHph) ppm. 13C NMR (CDCl3):
d 20.0 (CH3), 28.1 (C(CH3)3),
34.1 (C(CH3)3), 42.5 (CHCH2), 60.0 (CHCH2), 101 (CH2), 105, 108, 118,
126, 129, 132, 136, 137, 146, 148 (CHar, Car), 153 (C]O), 163 (C]N)
ppm. HRMS: for C22H25N3O3.Hþ,calcd. 380.1969, found 380.1975.
(CDCl3):
d 28.3 (C(CH3)3), 38.3 (C(CH3)3), 101 (CH2), 105, 108, 115
(CHar), 122 (Car), 129 (CH ¼ CHph), 137 (CH ¼ CHph), 148.3, 148.5
(Car), 155 (C]N), 157 (C]O) ppm. HRMS: for C15H19N3O3.Hþ, calcd.
290.1499, found 290.1501.
6.1.6.5. (ꢀ)-(5RS)-(1,3-Benzodioxol-5-yl)-3-tert-butyl-N-(2-methylp-
henyl)-4,5-dihydro-1H-pyrazole-1-carboxamide
((ꢀ)-8e). White
6.1.6. General procedure for synthesis of (ꢀ)-N-aryl-(5RS)-(1,3-
benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazole-1-
carboxamides (ꢀ)-8aeh
solid, mp 122 ꢂC; reaction time 1 h; yield 50%. IR (KBr, cmꢁ1): 3401
(NH), 2965 (C]C), 1688 (C]O), 1588 (C]N). 1H NMR (CDCl3):
d
1.2
(s, 9H, t-butyl), 2.3 (s, 3H, CH3), 2.77 (dd, J ¼ 5.4, 17.6 Hz, 1H, CHCH2),
3.4 (dd, J ¼ 12.2,18.4 Hz, 1H, CHCH2), 5.3 (dd, J ¼ 5.4, 11.5 Hz, 1H,
CHCH2), 5.9 (s, 2H, OCH2O), 6.7e6.74 (m, 3H, H-4, H-6, H-7), 6.9e7.9
(m, 4H, H-20, H-30, H-40, H-50), 8.0 (s, 1H, CONHph) ppm. 13C NMR
20% Aqueous NaOH (1 mL) was added to a solution of 6 (1.0 g,
0.0043 mol) and the appropriate arylsemicarbazide 3aeg or sem-
icarbazide hydrochloride (0.004 mol) in ethanol (10 mL). The
reaction mixture was stirred under reflux for appropriate time (TLC
controlled). The solvent was evaporated under vacuum to afford
crude (ꢀ)-8aeh. The crude products were recrystallized from
ethanol to afford (ꢀ)-8aeh as pure solids.
(CDCl3):
d 17.0 (CH3), 28.1 (C(CH3)3), 34.1 (C(CH3)3), 42.5 (CHCH2),
60.0 (CHCH2), 101 (CH2), 105, 108, 119, 119.8, 122, 126, 126.8, 130, 137,
137.1, 147, 148 (CHar, Car), 152 (C]O), 163 (C]N) ppm. HRMS: for
C22H25N3O3.Hþ, calcd. 380.1969, found 380.1961.
6.1.6.1. (ꢀ)-(5RS)-(1,3-Benzodioxol-5-yl)-3-tert-butyl-N-phenyl-4,5-
dihydro-1H-pyrazole-1-carboxamide ((ꢀ)-8a). Yellow solid, mp
138 ꢂC; reaction time 24 h; yield 23%. IR (KBr, cmꢁ1): 3382 (NH),
6.1.6.6. (ꢀ)-(5RS)-(1,3-Benzodioxol-5-yl)-3-tert-butyl-N-(2,4-dichlo-
rophenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide
((ꢀ)-8f). White
solid, mp 150 ꢂC; reaction time 1 h; yield 47%. IR (KBr, cmꢁ1): 3399
2961 (C]C), 1689 (C]O), 1597 (C]N). 1H NMR (CDCl3):
d
1.2 (s, 9H,
(NH), 2963 (C]C),1681 (C]O),1590 (C]N). 1H NMR (CDCl3):
d
1.2 (s,
t-butyl), 2.77 (dd, J ¼ 5.4, 17.6 Hz, 1H, CHCH2), 3.4 (dd, J ¼ 12.3,
9H, t-butyl), 2.79 (dd, J ¼ 5.3, 18.4 Hz, 1H, CHCH2), 3.4 (dd, J ¼ 12.2,
18.4 Hz, 1H, CHCH2), 5.3 (dd, J ¼ 4.6, 11.5 Hz, 1H, CHCH2), 5.9 (s, 2H,
18.4 Hz, 1H, CHCH2), 5.3 (t, J ¼ 6.1, 4.6 Hz, 1H, CHCH2), 5.9 (s, 2H,