4.2. Synthesis
General Procedure for the synthesis of Compounds 1–5
The respective carboxylic acid, used as starting material (3 mmol), was dissolved in dry CH
2Cl
2. For Compounds
3 and
4 a small quantity of DMF (up to 0.5 mL) was added, due to reduced solubility of the carboxylic acid. Then, ethyl 3-piperidinecarboxylate (3.6 mmol) and N,N-dimethylaminopyridine (DMAP, 3.6 mmol) were added. After 15 min N,N dicyclohexylcarbodiimide (DCC, 3.6 mmol) was added and the mixture was stirred at room temperature overnight. Thereinafter, the mixture was filtered, washed successively with HCl (5%), NaHCO
3 (5%) and saturated NaCl solution and the organic layer was dried over Na
2SO
4. Finally, the solvent was evaporated under reduced pressure and the final compounds were isolated with flash column chromatography using mixtures of ethyl acetate and petroleum ether as eluents [
28].
Synthesis of Compound 6
Cinnamyl chloride (3 mmol) was dissolved in dry CH2Cl2 and mixed with ethyl 3-piperidinecarboxylate (3.6 mmol) and DMAP (3.6 mmol). The mixture was stirred at ambient temperature overnight, washed successively with HCl (5%), NaHCO3 (5%) and saturated NaCl solution, and the organic layer was dried over Na2SO4. Finally, the solvent was removed under reduced pressure and the final compound was isolated with flash column chromatography using a mixture of petroleum ether and ethyl acetate as eluents.
Ethyl 1-(3,5-di-tert-butyl-4-hydroxybenzoyl)piperidine-3-carboxylate (1): Flash Column Chromatography (ethyl acetate/petroleum ether 1/2). Yellow powder, yield 73%, mp 47–49 °C. 1H-NMR (CDCl3). δ(ppm): 7.72 (s, 2H, aromatic), 5.41 (s, 1H, -OH), 4.13 (q J: 7.1 Hz, 2H, -OCH2-CH3), 3.07–3.15 (m, 1H, 6-piperidine), 2.92–2.99 (m, 1H, 6-piperidine), 2.56 (t J: 10.8, 1H, 3-piperidine), 2.12 (dd J: 16.3 Hz, 12.7 Hz, 2H, 2-piperidine), 1.49–1.81 (m, 4H, 4/5-piperidine), 1.43 (s, 18H, -C(CH3)3), 1.24 (t J: 7.1 Hz, 3H, -OCH2-CH3). 13C-NMR (CDCl3). δ(ppm): 173.07 (1C, -COOCH2CH3), 171.63 (1C, -CO-NH-), 155.37 (1C, 4-aromatic), 136.67 (2C, 3/5-aromatic), 126.29 (1C, 1-aromatic), 124.53 (2C, 2/6-aromatic), 60.64 (1C, -OCH2CH3), 45.67 (2C, 2/6-piperidine), 41.82 (1C, 3-piperidine), 34.35 (2C, -C(CH3)3), 30.11 (6C, -C(CH3)3), 27.57 (1C, 4-piperidine), 24.66 (1C, 5-piperidine), 14.20 (1C, -OCH2CH3). Anal. Calculated for C23H35NO4: C, 70.92; H, 9.06; N, 3.60%. Found C, 70.72; H, 9.08; N, 3.71%.
(E)-Ethyl 1-(3-(3,5-di-tert-butyl-4-hydroxyphenyl)acryloyl)piperidine-3-carboxylate (2): Flash Column Chromatography (ethyl acetate/petroleum ether 1/3). Yellow powder, yield 82%, mp 158–161 °C. 1H-NMR (CDCl3). δ(ppm): 7.61 (d J: 15.3 Hz, 1H, Ph-CH=CH), 7.34 (s, 2H, aromatic), 6.73 (d J: 15.3 Hz, 1H, Ph-CH=CH) 5.44 (s, 1H, -OH), 4.15 (q J: 7.1 Hz, 2H, -OCH2CH3), 3.94–4.05 (m, 1H, 6-piperidine), 3.43–3.60 (m, 1H, 6-piperidine), 2.88–3.17 (m, 2H, 2-piperidine), 2.52 (t, J: 10.0 Hz, 1H, 3-piperidine), 2.05–2.10 (m, 1H, 5-piperidine), 1.72–1.84 (m, 2H, 4-piperidine), 1.52–1.58 (m, 1H, 5-piperidine), 1.45 (s, 18H, -C(CH3)3), 1.26 (t J: 7.1 Hz, 3H, -OCH2CH3). 13C-NMR (CDCl3). δ(ppm): 173.67 (1C, -COOCH2CH3), 166.12 (1C, -CO-NH-), 155.46 (1C, 4-aromatic), 143.24 (1C, Ph-CH=CH-), 136.20 (2C, 3/5-aromatic), 126.62 (1C, 1-aromatic), 124.96 (2C, 2/6-aromatic), 113.89 (1C, Ph-CH=CH-), 60.67 (1C, -OCH2CH3), 45.96 (2C, 2/6-piperidine), 41.96 (1C, 3-piperidine), 34.30 (2C, -C(CH3)3), 30.17 (6C, -C(CH3)3), 27.43 (1C, 4-piperidine), 24.68 (1C, 5-piperidine), 14.17 (1C, -OCH2CH3). Anal. Calculated for C25H37NO4: C, 72.26; H, 8.97; N, 3.37. Found C, 72.54; H, 9.01; N, 3.09%.
(E)-Ethyl 1-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)piperidine-3-carboxylate (3): Flash Column Chromatography (ethyl acetate/petroleum ether 1/1). Yellow oily liquid, yield 64%. 1H-NMR (CDCl3). δ(ppm): 7.59 (d J: 15.3 Hz, 1H, Ph-CH=CH), 7.09 (d J: 8.1 Hz, 1H, 6-aromatic), 6.99 (s, 1H, 2-aromatic), 6.90 (d J: 8.1 Hz, 1H, 5-aromatic), 6.77 (d J: 15.3 Hz, 1H, Ph-CH=CH), 5.41 (s, 1H, -OH), 4.15 (q J: 7.1 Hz, 2H, -OCH2CH3), 3.92 (s, 3H, Ph-OCH3), 3.10–3.19 (m, 1H, 6-piperidine), 2.52 (t, J: 9.7 Hz, 1H, 3-piperidine), 2.03–2.17 (m, 1H, 6-piperidine), 1.48–1.97 (m, 6H, 2/4/5-piperidine), 1.26 (t J: 7.1 Hz, 3H, -OCH2CH3). 13C-NMR (CDCl3). δ(ppm): 172.89 (1C, -COOCH2CH3), 166.85 (-CO-NH-), 147.67 (1C, 4-aromatic), 142.27 (1C, 3-aromatic), 137.64 (1C, Ph-CH=CH), 127.84 (1C, 1-aromatic), 121.90 (1C, 6-aromatic), 114.70 (1C, Ph-CH=CH), 114.66 (1C, 5-aromatic), 109.86 (1C, 2-aromatic), 60.79 (1C, -OCH2CH3), 55.99 (1C, Ph-OCH3), 45.11 (2C, 2/6-piperidine), 43.86 (1C, 3-piperidine), 27.43 (1C, 4-piperidine), 25.56 (1C, 5-piperidine), 14.17 (1C, -OCH2CH3). Anal. Calculated for C18H23NO5: C, 64.85; H, 6.95; N, 4.20%. Found C, 64.99; H, 7.18; N, 3.82%.
(E)-Ethyl 1-(3-(4-hydroxy-3,5-dimethoxyphenyl)acryloyl)piperidine-3-carboxylate (4): Flash Column Chromatography (ethyl acetate/petroleum ether 1/1). Yellow powder, yield 65%, mp 59–61 °C. 1H-NMR (CDCl3). δ(ppm): 7.57 (d J:15.3 Hz, 1H, Ph-CH=CH), 6.76 (s, 2H, aromatic), 6.74 4 (d J:15.3 Hz, 1H, Ph-CH=CH), 4.15 (q J: 7.1 Hz, 2H, -OCH2CH3), 3.92 (s, 6H, Ph-OCH3), 3.11–3.20 (m, 1H, 6-piperidine), 2.53 (t J: 9.7 Hz, 1H, 3-piperidine), 1.53–2.09 (m, 7H, 2/4/5/6-piperidine), 1.26 (t J: 7.1 Hz, 3H, -OCH2CH3). 13C-NMR (CDCl3). δ(ppm): 173.11 (1C, -COOCH2CH3), 166.73 (1C, -CO-NH-), 147.16 (2C, 3/5-aromatic), 143.25 (1C, 4-aromatic), 136.54 (1C, Ph-CH=CH), 126.78 (1C, 1-aromatic), 114.93 (1C, Ph-CH=CH), 104.83 (2C, 2/6-aromatic), 60.76 (1C, -OCH2CH3), 56.38 (2C, Ph-OCH3), 41.56 (2C, 2/6-piperidine), 36.72 (1C, 3-piperidine), 27.43 (2C, 4/5-piperidine), 14.18 (1C, -OCH2CH3). Anal. Calculated for C19H25NO6: C, 62.80; H, 6.93; N, 3.85%. Found C, 63.12; H, 7.26; N, 3.67%.
(E)-Ethyl 1-(3-(3,4-dimethoxyphenyl)acryloyl)piperidine-3-carboxylate (5): Flash Column Chromatography (ethyl acetate/petroleum ether 1/1). Yellow oily liquid, yield 78%. 1H-NMR (CDCl3). δ(ppm): 7.61 (d J: 15.3 Hz, 1H, Ph-CH=CH), 7.11 (d J: 8.3 Hz, 1H, 6-aromatic), 7.03 (s, 1H, 2-aromatic), 6.86 (d J: 8.3 Hz, 1H, 5-aromatic), 6.80 (d J: 15.3 Hz, 1H, Ph-CH=CH), 4.15 (q J: 7.1 Hz, 2H, -OCH2CH3), 3.97-4.08 (m 1H, 6-piperidine), 3.92 (s, 3H, Ph-OCH3), 3.90 (s, 3H, Ph-OCH3), 3.45–3.60 (m, 1H, 6-piperidine), 3.12–3.19 (m, 1H, 2-piperidine), 2.52 (t J: 9.8 Hz, 1H, 3-piperdidine), 2.05–2.11 (m, 1H, 2-piperidine), 1.52–1.89 (m, 4H, 4/5-piperidine), 1.26 (t J: 7.1Hz, 3H, -OCH2CH3). 13C-NMR (CDCl3). δ(ppm): 173.66 (1C, -COOCH2CH3), 166.78 (1C, -CO-NH-), 150.47 (1C, 4-aromatic), 149.07 (1C, 3-aromatic), 142.79 (1C, Ph-CH=CH), 128.28 (1C, 1-aromatic), 121.77 (1C, 6-aromatic), 114.97 (1C, Ph-CH=CH), 111.03 (1C, 5-aromatic), 109.87 (1C, 2-aromatic), 60.74 (1C, -OCH2CH3), 55.94 (2C, Ph-OCH3), 52.83 (1C, 2-piperidine), 44.12 (1C, 6-piperidine), 43.09 (1C, 3-piperidine), 27.44 (1C, 4-piperidine), 24.02 (1C, 5-piperidine), 14.19 (1C, -OCH2CH3). Anal. Calculated for C19H25NO5: C, 65.59; H, 7.25; N, 4.03%. Found C, 65.38; H, 7.00; N, 4.13%.
Ethyl 1-cinnamoylpiperidine-3-carboxylate (6): Flash Column Chromatography (ethyl acetate/petroleum ether 1/3). Colorless oily liquid, yield 85%. 1H-NMR (CDCl3). δ(ppm): 7.68 (d J: 15.4 Hz, 1H, Ph-CH=CH), 7.51–7.57 (m, 2H, aromatic), 7.33–7.41 (m, 2H, aromatic), 6.94 (d J: 15.4 Hz, 1H, Ph-CH=CH), 4.17 (q J: 7.1 Hz, 2H, -OCH2CH3), 4.03–4.10 (m, 1H, 6-piperidine), 3.18–3.38 (m, 2H, 2/6-piperidine), 2.52 (t J: 9.8 Hz, 1H, 3-piperdidine), 2.06–2.14 (m, 1H, 2-piperidine), 1.52–1.86 (m, 4H, 4/5-piperidine), 1.27 (t J: 7.1 Hz, 3H, -OCH2CH3). 13C-NMR (CDCl3). δ(ppm): 172.99 (1C, -COOCH2CH3), 166.68 (1C, -CO-NH-), 142.23 (1C, Ph-CH=CH), 135.27 (1C, 1-aromatic), 129.60 (1C, 4-aromatic), 128.76 (2C, 3/5-aromatic), 127.77 (2C, 2/6-aromatic), 117.19 (1C, Ph-CH=CH), 60.79 (1C, -OCH2CH3), 52.59 (1C, 2-piperidine), 46.40 (1C, 6-piperidine), 41.60 (1C, 3-piperidine), 27.36 (1C, 4-piperidine), 24.54 (1C, 5-piperidine), 14.19 (1C, -OCH2CH3). Anal. Calculated for C17H23NO3: C, 71.06; H, 7.37; N, 4.87%. Found C, 71.33; H, 7.76; N, 4.75%.