H.-J. Zhang et al. / Bioorg. Med. Chem. 19 (2011) 4513–4519
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4.2. General procedure for synthesis of cinnamic acids
1H), 3.84 (s, 3H), 4.03–4.17 (m, 2H), 6.75 (d, J = 15.36 Hz, 1H), 6.92–
6.96 (m, 2H), 7.02 (s, 1H), 7.10 (d, J = 7.68 Hz, 1H), 7.28–7.34 (m,
1H), 7.66 (d, J = 15.36 Hz, 1H). ESI-MS: 346.1 (C17H20N3O5,
[M+H]+). Anal. Calcd for C17H19N3O5: C, 59.12; H, 5.55; N, 12.17.
Found: C, 58.81; H, 5.75; N, 11.95.
A mixture of aromatic aldehydes (3.2 mmol), malonic acid
(3.87 mmol), piperidine (0.387 mmol) was dissolved in pyridine
and stirred on 80–90 °C for 24 h. The pyridine was removed at
the vacuum. The reaction mixture was poured in water and
washed with HCl, the precipitate was filtered and washed with
hexane about three times, and dried under vacuum to afford the
cinnamic acids (Scheme 1)
4.3.6. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3-
(3-fluorophenyl)acrylate (3f)
White powder, yield 66.2%, mp: 133–136 °C, 1H NMR (300 MHz,
CDCl3, d ppm): 1.41 (d, J = 7.09 Hz, 3H), 2.42 (s, 3H), 4.13–4.18 (m,
1H), 4.34–4.36 (m, 1H), 4.61–4.66 (m, 1H), 6.56 (d, J = 15.36 Hz,
1H), 7.24–7.26 (m, 1H), 7.39 (d, J = 8.24 Hz, 1H), 7.56 (t,
J = 6.93 Hz, 2H), 7.71 (s, 1H), 7.97 (s, 1H). ESI-MS: 334.1
(C16H17FN3O4, [M+H]+). Anal. Calcd for C16H16FN3O4: C, 57.65; H,
4.84; N, 12.61. Found: C, 58.05; H, 4.62; N, 12.34.
4.3. General procedure for synthesis of cinnamic acid
secnidazole ester derivatives
Equimolar amount of secnidazole (1.0 mmol) and cinnamic
acid (1.0 mmol) were dissolved in dichloromethane, DCC
(1.5 mmol) and DMAP (0.5 mmol) as catalyst and stirred at 50–
60 °C for 24 h. The reaction mixture was extracted with ethyl ace-
tate and saturated sodium bicarbonate, respectively. Then, the or-
ganic layer was collected and crystallized to get the product
(Scheme 1).
4.3.7. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3-
(3-bromophenyl)acrylate (3g)
Light yellow powder, yield 67.2%, mp: 102–104 °C, 1H NMR
(300 MHz, CDCl3, d ppm): 1.43 (d, J = 6.57 Hz, 3H), 2.54 (s, 3H),
4.09–4.16 (m, 1H), 4.32–4.40 (m, 1H), 4.63–4.69 (m, 1H), 6.27
(d, J = 15.90 Hz, 1H), 7.26 (t, J = 7.86 Hz, 1H), 7.41 (d,
J = 7.68 Hz, 1H), 7.51 (t, J = 7.97 Hz, 2H), 7.64 (s, 1H), 7.94 (s,
1H). ESI-MS: 394.0 (C16H17BrN3O4, [M+H]+). Anal. Calcd for
4.3.1. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl
cinnamate (3a)
Light grey powder, yield 60.9%, mp: 136–139 °C, 1H NMR
(300 MHz, CDCl3, d ppm): 1.42 (d, J = 4.62 Hz, 3H), 2.49 (s, 3H),
3.76–3.78 (m, 1H), 4.10–4.14 (m, 2H), 6.75 (d, J = 9.24 Hz, 1H),
7.02 (s, 1H), 7.37–7.39 (m, 3H), 7.48–7.50 (m, 2H), 7.67 (s,
1H). ESI-MS: 316.1 (C16H18N3O4, [M+H]+). Anal. Calcd for
C16H16BrN3O4: C, 48.75; H, 4.09; N, 10.66. Found: C, 48.89; H,
3.98; N, 11.12.
4.3.8. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3-
(3-methoxyphenyl)acrylate (3h)
C16H17N3O4: C, 60.94; H, 5.43; N, 13.33. Found: C, 60.67; H,
5.56; N, 13.45.
White powder, yield 72.9%, mp: 148–151 °C, 1H NMR (300 MHz,
CDCl3, d ppm): 1.42 (d, J = 6.66 Hz, 3H), 2.40 (s, 3H), 3.82 (s, 3H),
4.04 (d, J = 7.50 Hz, 2H), 4.12–4.16 (m, 1H), 6.73 (d, J = 15.39 Hz,
1H), 6.91–6.94 (m, 2H), 7.00 (s, 1H), 7.09 (d, J = 7.50 Hz, 1H),
7.26–7.33 (m, 1H), 7.64 (d, J = 15.36 Hz, 1H). ESI-MS: 346.1
(C17H20N3O5, [M+H]+). Anal. Calcd for C17H19N3O5: C, 59.12; H,
5.55; N, 12.17. Found: C, 59.33; H, 4.98; N, 12.52.
4.3.2. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3-
(2-fluorophenyl)acrylate (3b)
White powder, yield 65.6%, mp: 106–107 °C, 1H NMR (300 MHz,
CDCl3, d ppm): 1.42 (d, J = 4.62 Hz, 3H), 2.54 (s, 3H), 4.29–4.37 (m,
1H), 4.64–4.71 (m, 1H), 5.38–5.43 (m, 1H), 6.39 (d, J = 16.08 Hz,
1H), 7.08–7.19 (m, 2H), 7.34–7.41 (m, 1H), 7.49 (t, J = 7.50 Hz,
1H), 7.71 (d, J = 16.26 Hz, 1H), 7.93 (s, 1H). ESI-MS: 334.1
(C16H17FN3O4, [M+H]+). Anal. Calcd for C16H16FN3O4: C, 57.65; H,
4.84; N, 12.61. Found: C, 57.67; H, 4.87; N, 12.77.
4.3.9. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3-
(4-fluorophenyl)acrylate (3i)
White powder, yield 66.7%, mp: 145–147 °C, 1H NMR (300 MHz,
CDCl3, d ppm): 1.39 (d, J = 8.69 Hz, 3H), 2.04 (s, 3H), 3.48 (s, 1H),
3.71–3.81 (m, 1H), 4.08–4.15 (m, 1H), 6.66 (d, J = 15.36 Hz, 1H),
6.95 (s, 1H), 7.07 (t, J = 8.68 Hz, 2H), 7.45–7.49 (m, 2H), 7.64 (d,
J = 15.18 Hz, 1H). ESI-MS: 334.1 (C16H17FN3O4, [M+H]+). Anal. Calcd
for C16H16FN3O4: C, 57.65; H, 4.84; N, 12.61. Found: C, 57.23; H,
5.01; N, 12.49.
4.3.3. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3-
(2-chlorophenyl)acrylate (3c)
White powder, yield 61.1%, mp: 125–127 °C, 1H NMR (300 MHz,
CDCl3, d ppm): 1.44 (d, J = 6.42 Hz, 3H), 2.55 (s, 3H), 4.30–4.38 (m,
1H), 4.64–4.70 (m, 1H), 5.38–5.43 (m, 1H), 6.27 (d, J = 16.08 Hz,
1H), 7.25–7.35 (m, 2H), 7.40–7.43 (m, 1H), 7.55–7.58 (m, 1H),
7.93 (s, 1H), 8.00 (d, J = 16.08 Hz, 1H). ESI-MS: 350.1
(C16H17ClN3O4, [M+H]+). Anal. Calcd for C16H16ClN3O4: C, 54.94;
H, 4.61; N, 12.01. Found: C, 54.69; H, 4.81; N, 12.45.
4.3.10. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3-
(4-chlorophenyl)acrylate (3j)
White powder, yield 56.1%, mp: 217–219 °C, 1H NMR (300 MHz,
CDCl3, d ppm): 1.43 (d, J = 8.23 Hz, 3H), 1.92 (s, 3H), 3.36 (s, 1H),
3.71–3.78 (m, 1H), 4.08–4.15 (m, 1H), 6.66 (d, J = 15.36 Hz, 1H),
6.84 (s, 1H), 7.35 (d, J = 8.58 Hz, 2H), 7.41 (d, J = 8.61 Hz, 2H),
7.62 (d, J = 15.39 Hz, 1H). ESI-MS: 350.1 (C16H17ClN3O4, [M+H]+).
Anal. Calcd for C16H16ClN3O4: C, 54.94; H, 4.61; N, 12.01. Found:
C, 54.89; H, 4.81; N, 12.04.
4.3.4. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3-
(2-bromophenyl)acrylate (3d)
White powder, yield 57.0%, mp: 112–115 °C, 1H NMR (300 MHz,
CDCl3, d ppm): 1.44 (d, J = 6.39 Hz, 3H), 2.55 (s, 3H), 4.09 (d,
J = 8.40 Hz, 1H), 4.30–4.38 (m, 1H), 4.64–4.70 (m, 1H), 5.36–5.44
(m, 1H), 6.23 (d, J = 15.99 Hz, 1H), 7.21–7.26 (m, 1H), 7.33 (t,
J = 7.13 Hz, 1H), 7.54–7.57 (m, 1H), 7.59–7.62 (m, 1H), 7.93 (s,
1H). ESI-MS: 394.0 (C16H17BrN3O4, [M+H]+). Anal. Calcd for
C16H16BrN3O4: C, 48.75; H, 4.09; N, 10.66. Found: C, 48.61; H,
4.51; N, 11.15.
4.3.11. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3-
(4-bromophenyl)acrylate (3k)
White powder, yield 62.1%, mp: 220–222 °C, 1H NMR (300 MHz,
CDCl3, d ppm): 1.40 (d, J = 7.98 Hz, 3H), 2.05 (s, 3H), 3.74–3.76 (m,
1H), 4.08–4.13 (m, 2H), 6.54 (d, J = 15.00 Hz, 1H), 6.80 (s, 1H), 7.01–
7.06 (m, 1H), 7.23–7.26 (m, 2H), 7.62 (d, J = 5.13 Hz, 1H), 7.80 (d,
J = 15.00 Hz, 1H). ESI-MS: 394.0 (C16H17BrN3O4, [M+H]+). Anal.
Calcd for C16H16BrN3O4: C, 48.75; H, 4.09; N, 10.66. Found: C,
48.87; H, 4.31; N, 10.49.
4.3.5. (E)-1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3-
(2-methoxyphenyl)acrylate (3e)
White powder, yield 59.2%, mp: 158–162 °C, 1H NMR (300 MHz,
CDCl3, d ppm): 1.59 (d, J = 7.21 Hz, 3H), 1.98 (s, 3H), 3.76–3.80 (m,