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M. Alvarado et al. / Bioorg. Med. Chem. 21 (2013) 1708–1716
4.04 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz) d 160.5 (CO), 155.9 and
155.1 (C-3 and C-5), 137.7 (C-100), 136.3 and 136.2 (C-40 and C-400),
130.8 130.3, 129.6 and 127.1 (C-20 C-30 C-200 and C-300), 125.3 (C-10),
53.4 (CH3). MS (EI): m/z (%) 347 (66), 210 (62), 125 (100) and 90
(22); elemental analysis C16H11Cl2N3O2, Calcd: C, 55.19; H, 3.18;
N, 12.07. Found: C, 55.21; H, 3.46; N, 12.20.
CH2CH2CH2NCH2CH2), 1.81–1.73 (m, 4H, CH2CH2CH2NCH2CH2),
1.48–1.44 (m, 2H, CH2CH2CH2NCH2CH2); 13C NMR (CDCl3,
75 MHz) d 159.0 (CO), 146.7 (C-3), 144.8 (C-5), 139.6 (C-10),
129.6 (C-100), 129.1, 128.7 and 128.5 (C-30, C-200 and C-300), 128.6
(C-400), 128.3 (C-40), 125.5 (C-20), 108.6 (C-4), 57.3 (CH2CH2CH2
NCH2CH2), 25.3 (CH2CH2CH2NCH2CH2), 23.3 (CH2CH2CH2NCH2
CH2). IR (KBr) m
/cmꢀ1: 3436, 3285, 2927, 2856, 1671, 1498, 768
4.1.7. General procedure for the synthesis of 8a–8h
and 696. MS (EI): m/z (%) 263 (89), 247 (100), 219 (24), and 84
(40); elemental analysis C21H22N4O, Calcd: C, 72.81; H, 6.40; N,
16.17. Found: C, 72.63; H, 6.48; N, 16.35.
To a solution of the corresponding amine (5 equiv) in dry DCM
was added a solution of Al(Me)3 in heptane (2 M, 5 equiv) under N2
atmosphere. The mixture was stirred at rt for 1 h. Then, a solution
of alkyl carboxylate (1 equiv) in dry DCM was added dropwise. The
mixture was refluxed for 14–48 h, and then was carefully poured
onto 1 N HCl. The biphasic solution was heated to 40 °C for
30 min and cooled to rt. The organic layer was separated, dried
over MgSO4 and evaporated. The residue was purified by flash
chromatography (eluent n-hexane/EtOAc, 9:1 for pyrazoles and
1:1 for triazoles), except 8b which was recrystallized from hexane.
4.1.7.4. N-Oleyl-1,5-diphenyl-4-methyl-1H-pyrazole-3-carbox-
amide (8d).
N-Oleyl-1,5-diphenyl-4-Methyl-1H-pyrazole-3-
carboxamide (8d) was prepared from 7b (300 mg, 0.97 mmol),
oleylamine (1.61 mL, 4.89 mmol) and Al(Me)3 (2.44 mL,
4.89 mmol). Yield 347 mg (68%) as a yellow oil. Rf: (n-hexane/
EtOAc 1:9) 0.25. 1H NMR (CDCl3, 300 MHz) d 7.28–7.07 (m, 10H,
Ph), 7.02–6.98 (m, 1H, NH), 5.29–5.26 (m, 2H, CH@CH), 3.36 (q,
2H, J = 6.7 Hz, NHCH2), 2.31 (s, 3H, CH3), 1.95–1.91 (m, 4H,
CH2CH@CHCH2), 1.57–1.52 (m, 2H, CH2CH3), 1.25–1.19 (m, 22H,
oleyl), 0.81 (t, 3H, J = 6.8 Hz, CH3); 13C NMR (CDCl3, 75 MHz) d
163.0 (CO), 144.2 (C-3), 142.2 (C-5), 139.6 (C-10), 129.9, 129.8
and 129.7 (C-100 and CH@CH), 130.0, 128.8 and 128.5 (C-30, C-200
and C-300), 128.4 (C-400), 127.5 (C-40), 124.9 (C-20), 118.4 (C-4),
38.9 (NHCH2), 31.9, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3 and 29.2
(oleyl), 27.2 and 27.0 (CH2CH@CHCH2), 22.6 (CH2CH3), 14.1
4.1.7.1.
(8a).
N-Oleyl-1,5-diphenyl-1H-pyrazole-3-carboxamide
N-Oleyl-1,5-diphenyl-1H-pyrazole-3-carboxamide (8a)
was prepared from oleylamine (1.68 mL, 5.13 mmol), Al(Me)3
(2.56 mL, 5.13 mmol) and 7a (300 mg, 1.02 mmol) Yield 440 mg
(84%) as a yellow oil. Rf: (n-hexane/EtOAc 1:9) 0.20. 1H NMR
(CDCl3, 300 MHz) d 7.40–7.26 (m, 8H, Ph), 7.22–7.19 (m, 2H, Ph),
7.05 (s, 1H, H-4), 7.00 (bt, 1H, J = 5.5 Hz, NH), 5.39–5.39 (m, 2H,
CH@CH), 3.44 (q, 2H, J = 6.9 Hz, NHCH2), 2.04–1.98 (m, 4H,
CH2CH@CHCH2), 1.63–1.53 (m, 2H, CH2CH3), 1.30–1.25 (m, 22H,
oleyl), 0.87 (t, 3H, J = 6.5 Hz, CH3); 13C NMR (CDCl3, 75 MHz) d
161.7 (CO), 147.4 (C-3), 144.9 (C-5), 139.6 (C-10), 129.9, 129.8
and 129.7 (C-100 and CH@CH), 129.0, 128.7, 128.6, 128.5 and
128.2 (C-30 C-40 C-200 C-300 and C-400), 125.4 (C-20), 108.0 (C-4),
39.2 (NHCH2), 31.9 and 31.8 (CH2CH2CH3 and NHCH2CH2), 29.7,
29.6, 29.5, 29.4, 29.3, 29.2 and 29.0 (oleyl), 27.2 and 27.0
(CH2CH3), 9.4 (CH3). IR (film)
m
/cmꢀ1: 3421, 3344, 2924, 2853,
1673, 1598, 1538, 1501, 1467, 1457, 1445, 1361, 774 and 700.
MS (EI): m/z (%) 527 (22), 261 (100), 233 (20); elemental analysis
C35H49N3O, Calcd: C, 79.65; H, 9.36; N, 7.96. Found: C, 79.40; H,
9.37; N, 7.90.
4.1.7.5. N-Hexadecyl-1,5-diphenyl-4-methyl-1H-pyrazole-3-car-
boxamide (8e).
N-Hexadecyl-1,5-diphenyl-4-methyl-1H-pyr-
(CH2CH@CHCH2), 22.7 (CH2CH3), 14.1 (CH3). IR (film)
m
/cmꢀ1
:
azole-3-carboxamide (8e) was prepared from 7b (200 mg,
0.65 mmol), hexadecylamine (780 mg, 3.26 mmol) and Al(Me)3
(1.63 mL, 3.26 mmol). Yield 170 mg (53%) as a yellow solid. Rf:
(n-hexane/EtOAc 1:9) 0.25. Mp = 64–65 °C. 1H NMR (CDCl3,
300 MHz) d 7.35–7.20 (m, 8H, Ph), 7.17–7.14 (m, 2H, Ph), 7.08–
7.04 (m, 1H, NH), 3.43 (q, 2H, J = 6.6 Hz, NHCH2), 2.37 (s, 3H,
CH3), 1.64–1.57 (m, 2H, CH2CH3),1.25 (br s, 26H, hexadecyl), 0.88
(t, 3H, J = 6.8 Hz, CH2CH3); 13C NMR (CDCl3, 75 MHz) d 162.0
(CO), 143.3 (C-3), 141.2 (C-5), 138.7 (C-10), 128.7 (C-100), 129.0,
127.8 and 127.5 (C-30 C-200 and C-300), 126.7 (C-400), 126.6 (C-40),
124.0 (C-20), 117.4 (C-4), 38.0 (NHCH2), 30.9 (CH2CH2CH3), 28.8,
28.7, 28.6 and 28.3 (hexadecyl), 26.0 (NHCH2CH2CH2), 21.7
3315, 3103, 2923, 2853, 1643, 1557, 1541, 1499, 1430, 1369, 765
and 699. MS (EI): m/z (%) 513 (27) and 247 (100); elemental anal-
ysis C34H47N3O, Calcd: C, 79.49; H, 9.22; N, 8.18. Found: C, 79.28;
H, 9.13; N, 7.99.
4.1.7.2. N-Hexadecyl-1,5-diphenyl-1H-pyrazole-3-carboxamide
(8b).
N-Hexadecyl-1,5-diphenyl-1H-pyrazole-3-carboxamide
(8b) was prepared from 7a (300 mg, 1.02 mmol), hexadecylamine
(1.23 g, 5.13 mmol) and Al(Me)3 (2.56 mL, 5.13 mmol). Yield
475 mg (99%) as a white solid. Rf: (n-hexane/EtOAc 4:1) 0.43.
Mp = 75–76 °C. 1H NMR (CDCl3, 300 MHz) d 7.37–7.21 (m, 10 H,
Ph), 7.00 (s, 1H, H-4), 6.47–6.43 (m, 1H, NH), 3.44 (q, 2H,
J = 6.6 Hz, NHCH2), 1.63–1.56 (m, 2H, CH2CH3), 1.25 (br s, 26H,
hexadecyl), 0.89–0.85 (m, 3H, CH3); 13C NMR (CDCl3, 75 MHz) d
161.8 (CO), 147.4 (C-3), 144.9 (C-5), 139.6 (C-10), 129.7 (C-100),
129.1, 128.7 and 128.5 (C-30, C-200 and C-300), 128.6 (C-400), 128.2
(C-40), 125.4 (C-20), 108.0 (C-4), 39.2 (NHCH2), 31.9 (CH2CH2CH3),
29.7, 29.6, 29.5, and 29.3 (hexadecyl), 27.0 (NHCH2CH2CH2), 22.7
(CH2CH2CH3), 13.1 (CH2CH3), 8.4 (CH3). IR (KBr)
m
/cmꢀ1: 3429,
3317, 2917, 2849, 1647, 1540 and 698. MS (EI): m/z (%) 501 (20),
261 (100) and 240 (36); elemental analysis C33H47N3O, Calcd: C,
78.99; H, 9.44; N, 8.37. Found: C, 78.75; H, 9.40; N, 8.28.
4.1.7.6.
carboxamide (8f).
pyrazole-3-carboxamide (8f) was prepared from 7b (300 mg,
0.97 mmol), 1-aminopiperidine (520 L, 4.89 mmol) and Al(Me)3
N-Piperidinyl-1,5-diphenyl-4-methyl-1H-pyrazole-3-
N-Piperidinyl-1,5-diphenyl-4-methyl-1H-
(CH2CH2CH3), 14.1 (CH3). IR (KBr)
m
/cmꢀ1: 3430, 3317, 2919,
2851, 1642, 1499, 766 and 699. MS (EI): m/z (%) 247 (100); elemen-
tal analysis C32H45N3O, Calcd: C, 78.80; H, 9.30; N, 8.62. Found: C,
78.60; H, 9.16; N, 8.55.
l
(2.44 mL, 4.89 mmol). Yield 240 mg (68%) as a yellow solid. Rf:
(n-hexane/EtOAc 1:9) 0.50. Mp = 195–196 °C. 1H NMR (CDCl3,
300 MHz) d 7.76 (br s, 1H, NH), 7.35–7.26 (m, 6H, Ph), 7.23–7.20
(m, 2H, Ph), 7.15–7.12 (m, 2H, Ph), 2.88 (t, 4H, J = 5.1 Hz,
CH2CH2CH2NCH2CH2), 2.36 (s, 3H, CH3), 1.82–1.72 (m, 4H,
CH2CH2CH2NCH2CH2), 1.48–1.42 (m, 2H, CH2CH2CH2NCH2CH2);
13C NMR (CDCl3, 75 MHz) d 160.3 (CO), 143.5 (C-3), 142.2 (C-5),
139.6 (C-10), 129.6 (C-100), 130.0 128.8 and 128.5 (C-30, C-200 and
C-300), 128.4 (C-400), 127.7 (C-40), 125.0 (C-20), 119.0 (C-4), 57.1
(CH2CH2CH2NCH2CH2), 25.5 (CH2CH2CH2NCH2CH2), 23.4 (CH2CH2
4.1.7.3. N-Piperidinyl-1,5-diphenyl-1H-pyrazole-3-carboxamide
(8c).
(8c) was prepared from 7a (300 mg, 1.02 mmol), 1-aminopiperi-
dine (540 L, 5.13 mmol) and Al(Me)3 (2.56 mL, 5.13 mmol). Yield
N-Piperidinyl-1,5-diphenyl-1H-pyrazole-3-carboxamide
l
451 mg (91%) as a yellow solid. Rf: (n-hexane/EtOAc 1:9) 0.30.
Mp = 147–148 °C. 1H NMR (CDCl3, 300 MHz) d 7.70 (br s, 1H,
NH), 7.40–7.34 (m, 4H, Ph), 7.32–7.27 (m, 4H, Ph), 7.22–7.18 (m,
2H, Ph), 7.09 (s, 1H, H-4), 2.87 (t, 4H, J = 5.1 Hz,
CH2NCH2CH2), 9.3 (CH3). IR (KBr)
m
/cmꢀ1: 3435, 2929, 1688,