Ligustrazine Derivatives. Part 8: Design, Synthesis, and Preliminary Biological Evaluation
Medicinal Chemistry, 2014, Vol. 10, No. 1 83
CDC13, ꢀ ppm): 167.33 (C=O), 149.73, 147.92, 147.78,
144.85 (pyrazine-C), 134.46, 131.53, 128.62, 127.06 (ben-
zene-C), 41.43 (CH2) 21.56, 21.45, 20.06 (CH3); ESI-MS:
256.0 (M+H)+.
(E)-3-(4-chlorophenyl)-N-((3,5,6-trimethylpyrazin-2-yl)me-
thyl)acrylamide (8f)
Flash column chromatography: ethyl acetate/cyclohexane
= 4:1; yield 50%; white crystal; mp: 169-171 °C; IR (KBr,
cm-1): 3264.29 (NH), 1619.16, 1543.28, 1493.85, 1442.58
(C=N, C=C), 1651.74 (C=O); 1H-NMR (600 MHz, CDCl3, ꢀ
ppm): 7.32 (s, 1H, NH), 7.65 (d, H, C=CH, J = 15.60 Hz),
6.55 (d, 1H, C=CH, J = 15.60 Hz), 7.48 (d, 2H, Ar-H, J =
8.45 Hz), 7.35 (d, 2H, Ar-H, J = 8.44 Hz), 4.61 (s, 2H, CH2);
2.53-2.51(m, 9H, CH3 x 3); 13C-NMR (150 MHz, CDC13, ꢀ
ppm): 165.55 (C=O), 133.36, 135.50 (C=CH), 41.26 (CH2),
20.08, 21.41, 21.45 (CH3); ESI-MS: 316.3 (M+H)+.
2-phenyl-N-((3,5,6-trimethylpyrazin-2-yl)methyl)acetamide
(8b)
Flash column chromatography: ethyl acetate/cyclohexane
= 4:1; yield 53%; yellow crystal; mp: 125-126 °C; IR (KBr,
cm-1): 3377.86 (NH), 1507.64, 1496.82, 1454.64 (C=N,
C=C), 1662.40 (C=O); 1H-NMR (600 MHz, CDCl3, ꢀ ppm):
7.17 (s, H, NH), 7.40-7.33 (m, 5H, Ar-H), 4.43 (d, 2H, CH2,
J = 4.1 Hz), 2.46 (s, 3H, CH3), 2.42 (s, 3H, CH3), 2.34 (s,
3H, CH3); 13C-NMR (150 MHz, CDC13, ꢀ ppm): 171.13
(C=O), 144.57, 147.50, 147.73, 149.51 (pyrazine-C), 127.31,
128.97, 129.70, 134.91 (benzene-C), 41.02, 43.84 (CH2),
19.91, 21.21, 21.34 (CH3); ESI-MS: 270.5 (M+H)+.
(E)-3-(4-fluorophenyl)-N-((3,5,6-trimethylpyrazin-2-yl)me-
thyl)acrylamide (8g)
Flash column chromatography: ethyl acetate/cyclohexane
= 4:1; yield 52%; white crystal; mp: 160-161 °C; IR (KBr,
cm-1): 3266.11 (NH), 1618.59, 1540.61, 1510.52, 1444.70
(C=N, C=C), 1652.47 (C=O); 1H-NMR (600 MHz, CDCl3, ꢀ
ppm): 7.31 (s, 1H, NH), 7.65 (d, H, C=CH, J = 15.60 Hz),
6.51 (d, H, C=CH, J = 15.61 Hz), 7.54 (m, 2H, Ar-H), 7.07
(m, 2H, Ar-H), 4.62 (s, 2H, CH2), 2.54(s, 3H, CH3), 2.54(s,
3H, CH3), 2.51(s, 3H, CH3); 13C-NMR (150 MHz, CDC13, ꢀ
ppm): 165.71 (C=O), 139.90, 131.08 (C=CH), 41.22 (CH2),
20.09, 21.38, 21.45 (CH3), C: 163.53 (1JC-F = 248.55 Hz), C:
120.27 (4JC-F = 1.5 Hz), CH: 115.85 (2JC-F = 21.5 Hz), CH:
129.64 (3JC-F = 8.6 Hz); ESI-MS: 300.6 (M+H)+.
3-chloro-N-((3,5,6-trimethylpyrazin-2-yl)methyl)benzamide
(8c)
Flash column chromatography: ethyl acetate/cyclohexane
= 4:1; yield 45%; white crystal; mp: 110-111 °C; IR (KBr,
cm-1): 3406.14 (NH), 1523.23, 1565.89, 1523.23 (C=N,
1
C=C), 1671.43 (C=O); H-NMR (600 MHz, CDCl3, ꢀ ppm):
7.98 (s, H, NH), 7.89 (t, H, Ar-H), 7.76 (dd, 1H, Ar-H, J1 =
1.11 Hz, J2 = 7.73 Hz), 7.50 (m, 1H, Ar-H ), 7.40 (m, 1H,
Ar-H), 4.67 (d, 2H, CH2, J = 4.51 Hz), 2.56 (s, 3H, CH3),
2.54 (s, 3H, CH3), 2.53 (s, 3H, CH3); 13C-NMR (150 MHz,
CDC13, ꢀ ppm): 165.99 (C=O), 144.61, 147.84, 148.00,
149.96 (pyrazine-C), 125.09, 127.55, 129.93, 133.14,
134.79, 136.15 (benzene-C), 41.41 (CH2), 20.00, 21.40,
21.49 (CH3); ESI-MS: 290.5 (M+H)+.
(E)-3-(4-bromophenyl)-N-((3,5,6-trimethylpyrazin-2-yl)me-
thyl)acrylamide (8h)
Flash column chromatography: ethyl acetate/cyclohexane
= 4:1; yield 45%; white crystal; mp: 165-166 °C; IR (KBr,
cm-1): 3261.65 (NH), 1651.52, 1617.67, 1543.39, 1488.76
(C=N, C=C), 1757.39 (C=O); 1H-NMR (600 MHz, CDCl3, ꢀ
ppm): 7.79 (d, H, C=CH, J = 15.92), 7.63 (d, H, C=CH, J =
15.59 Hz), 7.52 (d, 2H, Ar-H, J = 8.36 Hz), 7.40 (d, 2H, Ar-
H, J = 8.36 Hz), 7.34 (s, H, NH), 4.62 (d, 2H, CH2, J = 4.0
Hz), 2.63 (s, 3H, CH3), 2.55 (s, 3H, CH3), 2.53 (s, 3H, CH3);
13C-NMR (150 MHz, CDC13, ꢀ ppm): 165.54 (C=O),
117.28, 123.81 (C=CH), 41.23 (CH2), 20.07, 21.33, 21.42
(CH3); ESI-MS: 362.4 (M+H)+.
N-((3,5,6-trimethylpyrazin-2-yl)methyl)nicotinamide (8d)
Flash column chromatography: ethyl acetate/cyclohexane
= 4:1; yield 40%; white crystal; mp: 125-129 °C; IR (KBr,
cm-1): 3275.19 (NH), 1591.62, 1548.10, 1438.75 (C=N,
1
C=C), 1642.60 (C=O), H-NMR (600 MHz, CDCl3, ꢀ ppm):
8.23 (s, H, NH), 7.45 (m, H, Ar-H), 8.25 (dt, 1H, Ar-H, J1 =
7.86 Hz, J2 = 1.98 Hz), 8.75 (dd, 1H, Ar-H, J1 = 4.81 Hz, J2 =
1.63 Hz), 9.12 (m, 1H, Ar-H), 4.68 (d, 2H, CH2, J = 4.08
Hz), 2.58 (s, 3H, CH3), 2.54-2.53 (m, 6H, CH3 x 2); 13C-
NMR (150 MHz, CDC13, ꢀ ppm): 165.36 (C=O), 123.60,
130.08, 135.27, 144.28, 147.71 (pyridine-C), 41.31 (CH2),
20.00, 21.46, 21.54 (CH3); ESI-MS: 257.6 (M+H)+.
N-((3,5,6-trimethylpyrazin-2-yl)methyl)isonicotinamide (8i)
Flash column chromatography: ethyl acetate/cyclohexane
= 4:1; yield 38%; yellow crystal; mp: 119-120 °C; IR (KBr,
cm-1): 3275.81 (NH), 1591.52, 1547.44, 1478.53 (C=N,
2-(((3,5,6-trimethylpyrazin-2-yl)methyl)carbamoyl)phenyl
acetate (8e)
1
C=C), 1642.22 (C=O), H-NMR (600 MHz, CDCl3, ꢀ ppm):
8.06 (s, H, NH), 7.45 (m, H, Ar-H), 8.25 (dt, 1H, Ar-H, J1 =
7.86 Hz, J2 = 1.98 Hz), 8.75 (dd, 1H, Ar-H, J1 = 4.81 Hz, J2 =
1.63 Hz), 9.12 (m, 1H, Ar-H), 4.68 (d, 2H, CH2, J = 3.75
Hz), 2.54 (s, 9H, 3 ꢀ CH3); 13C-NMR (150 MHz, CDC13, ꢀ
ppm): 165.34 (C=O), 123.59, 130.13, 135,26, 144.26, 147.73
(pyridine-C), 41.30 (CH2), 19.99, 21.45, 21.51 (CH3); ESI-
MS: 257.4 (M+H)+.
Flash column chromatography: ethyl acetate/cyclohexane
= 4:1; yield 46%; yellow crystal; mp: 113-114 °C; IR (KBr,
cm-1): 3443.58 (NH), 1523.88, 1606.85, 1479.13 (C=N,
C=C), 1758.85 (C=O), 1653.75 (C=O); 1H-NMR (600 MHz,
CDCl3, ꢀ ppm): 8.11 (s, H, NH), 7.93 (dd, H, Ar-H, J1 = 1.67
Hz, J2 = 7.7 6Hz), 7.51 (dt, 1H, Ar-H, J1 = 1.68 Hz, J2 = 7.66
Hz), 7.35 (dt, 1H, Ar-H, J1 = 1.06 Hz, J2 = 7.60 Hz), 7.15
(dd, 1H, Ar-H, J1 = 0.98 Hz, J2 = 8.12 Hz ), 4.66 (s, 2H,
CH2), 2.53 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.52 (s, 3H,
CH3), 2.31 (s, 3H, COCH3); 13C-NMR (150 MHz, CDC13, ꢀ
ppm): 165.34, 169.09 (C=O), 41.78 (CH2), 20.09, 21.23,
21.37, 21.44 (CH3); ESI-MS: 314.4 (M+H)+.
(E)-3-(4-methoxyphenyl)-N-((3,5,6-trimethylpyrazin-2-yl)
methyl)acrylamide (8j)
Flash column chromatography: ethyl acetate/cyclohexane
= 4:1; yield 48%; white crystal; mp: 185-187 °C; IR (KBr,
cm-1): 3285.87 (NH), 1615.61, 1603.50, 1576.22, 1567.12