4.2.4. General Procedure for the Synthesis of Compounds 1c–5c
The corresponding amide of proline (1 mmol) was dissolved in dry dichloromethane, using a small amount of DMF (up to 0.5 mL) to increase the solubility. Then, methyl 4-aminobutanoate hydrochloride (1.2 mmol), N,N-dimethylaminopyridine (DMAP, 1.2 mmol), and N,N dicyclohexylcarbodiimide (DCC, 1.2 mmol, after 15 min) were added, and the mixture was stirred overnight (at room temperature). The resulting mixture was purified with filtration and washed with HCl (5%), NaHCO3 (5%), and a saturated NaCl solution and dried over Na2SO4. Finally, the solvent was distilled off under a low pressure, followed by the purification of the final product via flash column chromatography.
(E)-methyl 1-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)pyrrolidine-2-carboxylate (1a): Flash column chromatography (ethyl acetate/petroleum ether 3/1). Yellow powder, yield of 57%, mp. of 118–121 °C.
IR (nujol): 3405 (O-H), 3217 (N-H), 1708 (C=O ester), 1630 (C=O amide), 1600, 1574 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.64 (d J: 15.4 Hz, 1H, Ph-CH=CH-), 7.10 (d J: 8.2 Hz, 1H, 6-aromatic) 6.98 (s, 1H, 2-aromatic), 6.90 (d J: 8.2 Hz, 1H, 5-aromatic), 6.58 (d J: 15.4 Hz, 1H, Ph-CH=CH-), 4.61 (dd J: 8.0, 3.2 Hz, 1H, 2-pyrrolidine), 3.91 (s, 3H, Ph-OCH3), 3.67–3.73, 3.82–3.89 (m, 2H, 5-pyrrolidine), 3.75 (s, 3H, -OCH3) 2.09–2.26 (m, 2H, 3-pyrrolidine), 1.53–1.79 (m, 2H, 4-pyrrolidine).
13C-NMR (CDCl3): 172.25 (1C, -
COOCH
3), 165.18 (1C, -
CO-N), 147.47 (1C, 4-aromatic), 146.64 (1C, 3-aromatic), 143.09 (1C, Ph-
CH=C), 127.99 (1C, 1-aromatic), 122.16 (1C, 6-aromatic), 115.30 (1C, Ph-CH=
CH), 114.71 (1C, 5-aromatic), 109.95 (1C, 2 aromatic), 59.02 (1C, 2-pyrrolidine), 55.95 (1C, Ph-O
CH
3), 52.28 (1C, -O
CH
3), 46.94 (1C, 5-pyrrolidine), 29.19 (1C, 3-pyrrolidine), 24.86 (1C, 4-pyrrolidine) (See
Supplementary File).
(E)-1-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)pyrrolidine-2-carboxylic acid (1b): Yellow powder, yield of 93%, mp. of 169–172 °C).
IR (nujol): 3405 (O-H), 3250 (COO-H), 3206 (N-H), 1732 (C=O carboxylic), 1633 (C=O amide), 1603, 1572 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 10.26 (s, 1H, -COOH), 7.76 (d J: 15.3 Hz, 1H, Ph-CH=CH-), 7.14 (d J: 8.2 Hz, 1H, 6-aromatic), 7.01 (s, 1H, 2-aromatic), 6.94 (d J: 8.2 Hz, 1H, 5-aromatic), 6.54 (d J: 15.3 Hz, 1H, Ph-CH=CH-), 4.74 (dd J: 7.9, 3.1 Hz, 1H, 2-pyrrolidine), 3.94 (s, 3H, Ph-OCH3), 3.69–3.80, (m, 2H, 5-pyrrolidine), 2.05–2.12 (m, 2H, 3-pyrrolidine), 1.83–2.01 (m, 2H, 4-pyrrolidine).
13C-NMR (CDCl3): 171.79 (1C, -COOH), 168.64 (1C, -CO-N), 148.23 (1C, 4-aromatic), 146.75 (1C, 3-aromatic), 145.58 (1C, Ph-CH=C), 126.91 (1C, 1-aromatic), 122.71 (1C, 6-aromatic), 114.90 (1C, Ph-CH=CH), 113.45 (1C, 5-aromatic), 110.31 (1C, 2 aromatic), 60.73 (1C, 2-pyrrolidine), 58.01 (1C, Ph-OCH3), 47.92 (1C, 5-pyrrolidine), 28.85 (1C, 3-pyrrolidine), 24.83 (1C, 4-pyrrolidine).
(E)-methyl 4-(1-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)pyrrolidine-2-carboxamido)butanoate (1c): Flash column chromatography (ethyl acetate/acetone 3/1). Yellow powder, yield of 24%, mp. of 167–170 °C.
IR (nujol): 3405 (O-H), 3215 (N-H), 1712 (C=O ester), 1634, 1627 (C=O amide), 1600, 1572 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.65(d J: 15.3 Hz, 1H, Ph-CH=CH-), 7.44 (s, 1H, -NH) 7.11 (d J: 8.2 Hz, 1H, 6-aromatic), 7.00 (s, 1H, 2-aromatic) 6.92 (d J: 8.2 Hz, 1H, 5-aromatic), 6.58 (d J: 15.3 Hz, 1H, Ph-CH=CH-), 4.72 (dd J: 7.9, 3.1 Hz, 1H, 2-pyrrolidine), 3.93 (s, 3H, Ph-OCH3), 3.60–3.63, 3.73–3.79 (m, 2H, 5-pyrrolidine), 3.64 (s, 3H, -OCH3), 3.21–3.31 (m, 2H, -NH-CH2-CH2-), 2.35 (t J: 7.4 Hz, 2H, -CH2-C=O) 2.09–2.18, 2.23–2.29 (m, 2H, 3-pyrrolidine), 1.77–1.88 (m, 4H, 4-pyrrolidine, -ΝH-CH2-CH2-).
13C-NMR (CDCl3): 173.65 (1C, -COOCH3), 171.29 (1C, -CO-NH), 166.64 (1C, -CO-N), 147.72 (1C, 4-aromatic), 146.27 (1C, 3-aromatic), 143.46 (1C, Ph-CH=C), 127.40 (1C, 1-aromatic), 122.33 (1C, 6-aromatic), 115.20 (1C, Ph-CH=CH), 114.80 (1C, 5-aromatic), 109.99 (1C, 2-aromatic), 60.00 (1C, 2-pyrrolidine), 55.97 (1C, Ph-OCH3), 51.80 (1C, -OCH3), 47.48 (1C, 5-pyrrolidine), 38.77 (1C, -NH-CH2), 31.38 (1C, -CH2-COOCH3), 26.97 (1C, 3-pyrroldine), 25.02 (1C, 4-pyrroldine), 24.72 (1C, -C-CH2-C).
Anal. calculated for C20H26N2O6: C, 61.53; H, 6.71; N, 7.18%. Found: C, 61.93; H, 7.08; N, 6.89%.
(E)-methyl 1-(3-(4-hydroxy-3,5-dimethoxyphenyl)acryloyl)pyrrolidine-2-carboxylate (2a): Flash column chromatography (ethyl acetate). Yellow oil, yield of 68%.
IR (nujol): 3415 (O-H), 3227 (N-H), 1711 (C=O ester), 1638 (C=O amide), 1602, 1575 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.62 (d J: 15.3 Hz, 1H, Ph-CH=CH-), 6.75 (s, 2H, aromatic), 6.57 (d J: 15.3 Hz, 1H, Ph-CH=CH-), 4.62 (dd J: 8.6, 4.1 Hz, 1H, 2-pyrrolidine), 3.91 (s, 6H, Ph-OCH3), 3.69–3.74, 3.85–3.89 (m, 2H, 5-pyrrolidine), 3.75 (s, 3H, -OCH3) 2.01–2.26 (m, 4H, 3,4-pyrrolidine).
13C-NMR (CDCl3): 172.88 (1C, -COOCH3), 165.01 (1C, -CO-N), 147.13 (2C, 3,5-aromatic), 143.27 (1C, Ph-CH=C), 136.70 (1C, 4-aromatic), 126.61 (1C, 1-aromatic), 115.75 (1C, Ph-CH=CH), 104.73 (2C, 2,6-aromatic), 59.01 (1C, 2-pyrrolidine), 56.36 (2C, Ph-OCH3), 52.23 (1C, -OCH3), 46.96 (1C, 5-pyrrolidine), 29.17 (1C, 3-pyrrolidine), 24.86 (1C, 4-pyrrolidine).
(E)-1-(3-(4-hydroxy-3,5-dimethoxyphenyl)acryloyl)pyrrolidine-2-carboxylic acid (2b): Yellow powder, yield of 86%, mp. of 94–98 °C.
IR (nujol): 3405 (O-H), 3275 (COO-H), 3202 (N-H), 1736 (C=O carboxylic), 1632 (C=O amide), 1602, 1570 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.73 (d J: 15.3 Hz, 1H, Ph-CH=CH-), 6.76 (s, 2H, aromatic), 6.52 (d J: 15.3 Hz, 1H, Ph-CH=CH-), 4.72 (dd J: 8.6, 4.1 Hz, 1H, 2-pyrrolidine), 3.91 (s, 6H, Ph-OCH3), 3.76–3.87 (m, 2H, 5-pyrrolidine), 3.70 (s, 3H, -OH) 2.48–2.54 (m, 1H, 3-pyrrolidine), 1.96–2.12 (m, 3H, 3-pyrrolidine, 4-pyrrolidine).
13C-NMR (CDCl3): 172.09 (1C, -COOH), 168.03 (1C, -CO-N), 147.24 (2C, 3,5-aromatic), 145.54 (1C, Ph-CH=C), 137.23 (1C, 4-aromatic), 125.90 (1C, 1-aromatic), 113.95 (1C, Ph-CH=CH), 105.40 (2C, 2,6-aromatic), 60.50 (1C, 2-pyrrolidine), 56.40 (2C, Ph-OCH3), 48.83 (1C, 5-pyrrolidine), 27.20 (1C, 3-pyrrolidine), 24.79 (1C, 4-pyrrolidine).
(E)-methyl 4-(1-(3-(4-hydroxy-3,5-dimethoxyphenyl)-acryloyl)pyrrolidine-2-carboxamido)-butanoate (2c): Flash column chromatography (ethyl acetate/acetone 3/1). Yellow powder, yield of 58%, mp. of 158–159 °C.
IR (nujol): 3408 (O-H), 3223 (N-H), 1704 (C=O ester), 1644, 1631 (C=O amide), 1602, 1578 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.63 (d J:15.3 Hz, 1H, Ph-CH=CH-), 7.42 (s, 1H, -NH) 7.00 (s, 2H, aromatic), 6.57 (d J: 15.3 Hz, 1H, Ph-CH=CH-), 4.70 (dd J: 8.5, 4.1 Hz, 1H, 2-pyrrolidine), 3.92 (s, 6H, Ph-OCH3), 3.73–3.79 (m, 1H, 5-pyrrolidine), 3.64 (s, 3H, -OCH3), 3.19–3.36 (m, 3H, -NH-CH2-CH2-, 5-pyrrolidine), 2.34 (t J: 7.4 Hz, 2H, -CH2-C=O) 1.85–1.89, 2.01, 2.06 (m, 2H, 3-pyrrolidine), 1.77–1.85 (m, 4H, 4-pyrroldine, -ΝH-CH2-CH2-).
13C-NMR (CDCl3): 173.64 (1C, -COOCH3), 171.24 (1C, -CO-NH), 166.50 (1C, -CO-N), 147.20 (2C, 3,5-aromatic), 143.68 (1C, Ph-CH=C), 136.96 (1C, 4-aromatic), 126.35 (1C, 1-aromatic), 115.50 (1C, Ph-CH=CH), 105.09 (2C, 2,6-aromatic), 60.01 (1C, 2-pyrrolidine), 56.41 (2C, Ph-OCH3), 56.35 (1C, -OCH3), 47.55 (1C, 5-pyrrolidine), 38.80 (1C, -NH-CH2), 31.41 (1C, -CH2-COOCH3), 26.94 (1C, 3-pyrrolidine), 25.01 (1C, 4-pyrrolidine), 24.72 (1C, -C-CH2-C).
Anal. calculated for C21H28N2O7: C, 59.99; H, 6.71; N, 6.66%. Found: C, 60.08; H, 6.88; N, 6.54%.
(E)-methyl 1-(3-(3,4-dimethoxyphenyl)acryloyl)pyrrolidine-2-carboxylate (3a): Flash column chromatography (ethyl acetate/petroleum ether 3/1). Colorless oil, yield of 78%.
IR (nujol): 3226 (N-H), 1709 (C=O ester), 1636 (C=O amide), 1601, 1568 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.65 (d J: 15.5 Hz, 1H, Ph-CH=CH-), 7.10 (d J: 8.2 Hz, 1H, 6-aromatic) 7.02 (s, 1H, 2-aromatic), 6.84 (d J: 8.2 Hz, 1H, 5-aromatic), 6.59 (d J: 15.4 Hz, 1H, Ph-CH=CH-), 4.61 (dd J: 8.5, 4.2 Hz, 1H, 2-pyrrolidine), 3.90 (s, 3H, Ph-OCH3), 3.89 (s, 3H, Ph-OCH3) 3.68–3.72, 3.83–3.88 (m, 2H, 5-pyrrolidine), 3.74 (s, 3H, -OCH3) 2.09–2.27 (m, 2H, 3-pyrrolidine), 1.93–2.06 (m, 2H, 4-pyrrolidine).
13C-NMR (CDCl3): 172.88 (1C -COOCH3), 165.11 (1C -CO-N), 150.67 (1C, 4-aromatic), 149.07 (1C, 3-aromatic), 142.91 (1C, Ph-CH=C), 128.07 (1C, 1-aromatic), 122.09 (1C, 6-aromatic), 115.67 (1C, Ph-CH=CH), 111.06 (1C, 2-aromatic), 110.01 (1C, 5-aromatic), 59.02 (1C, 2-pyrrolidine), 55.93 (2C, Ph-OCH3), 52.21 (1C, -OCH3), 46.94 (1C, 5-pyrrolidine), 29.16 (1C, 3-pyrrolidine), 24.84 (1C, 4-pyrrolidine).
(E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)pyrrolidine-2-carboxylic acid (3b): White powder, yield of 95%, mp. of 186–188 °C.
IR (nujol): 3285 (COO-H), 3217 (N-H), 1732 (C=O carboxylic), 1631 (C=O amide), 1599, 1567 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.78 (d J: 15.3 Hz, 1H, Ph-CH=CH-), 7.16 (d J: 8.2 Hz, 1H, 6-aromatic) 7.04 (s, 1H, 2-aromatic), 6.88 (d J: 8.2 Hz, 1H, 5-aromatic), 6.55 (d J: 15.3 Hz, 1H, Ph-CH=CH-), 4.74 (dd J: 8.5, 4.2 Hz, 1H, 2-pyrrolidine), 3.92 (s, 6H, Ph-OCH3), 3.65–3.71, 3.75–3.82 (m, 2H, 5-pyrrolidine), 2.06–2.15 (m, 2H, 3-pyrrolidine), 1.92–2.01 (m, 2H, 4-pyrrolidine).
13C-NMR (CDCl3): 171.49 (1C, -COOH), 168.57 (1C, -CO-N), 148.23 (1C, 4-aromatic), 146.75 (1C, 3-aromatic), 145.58 (1C, Ph-CH=C), 126.91 (1C, 1-aromatic), 122.71 (1C, 6-aromatic), 114.90 (1C, Ph-CH=CH), 113.45 (1C, 2-aromatic), 110.31 (1C, 5-aromatic), 60.73 (1C, 2-pyrrolidine), 58.11 (2C, Ph-OCH3), 47.92 (1C, 5-pyrrolidine), 28.85 (1C, 3-pyrrolidine), 24.83 (1C, 4-pyrrolidine).
(E)-methyl 4-(1-(3-(3,4-dimethoxyphenyl)acryloyl)pyrrolidine-2-carboxamido)butanoate (3c): Flash column chromatography (ethyl acetate/petroleum ether 3/1). Yellow powder, yield of 78% mp. of 158–159 °C.
IR (nujol): 3220 (N-H), 1715 (C=O ester), 1631, 1619 (C=O amide), 1598, 1564 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.68 (d J: 15.4 Hz, 1H, Ph-CH=CH-), 7.45 (s, 1H, -NH) 7.14 (d J: 8.2 Hz, 1H, 6-aromatic), 7.05 (s, 1H, 2-aromatic) 6.88 (d J: 8.2 Hz, 1H, 5-aromatic), 6.61 (d J: 15.4 Hz, 1H, Ph-CH=CH-), 4.72 (d J: 7.9 Hz, 1H, 2-pyrrolidine), 3.93 (s, 6H, Ph-OCH3), 3.92 (s, 6H, Ph-OCH3), 3.73–3.79 (m, 1H, 5-pyrrolidine), 3.65 (s, 3H, -OCH3), 3.20–3.35 (m, 3H, -NH-CH2-CH2-, 5-pyrrolidine), 2.35 (t J: 7.4 Hz, 2H, -CH2-C=O) 2.01, 2.20 (m, 2H, 3-pyrrolidine), 1.75–1.88 (m, 4H, 4-pyrrolidine, -ΝH-CH2-CH2-).
13C-NMR (CDCl3): 173.66 (1C, -COOCH3), 171.27 (1C, -CO-NH), 166.61 (1C, -CO-N), 150.91 (1C, 4-aromatic), 149.16 (1C, 3-aromatic), 143.31 (1C, Ph-CH=C), 127.85 (1C, 1-aromatic), 122.22 (1C, 6-aromatic), 115.52 (1C, Ph-CH=CH), 111.12 (1C, 5-aromatic), 110.06 (1C, 2-aromatic), 60.01 (1C, 2-pyrrolidine, 55.96 (2C, Ph-OCH3), 51.61 (1C, -OCH3), 47.51 (1C, 5-pyrrolidine), 38.77 (1C, -NH-CH2), 31.40 (1C, -CH2-COOCH3), 26.98 (1C, 3-pyrrolidine), 25.03 (1C, 4-pyrrolidine), 24.73 (1C, -C-CH2-C).
Anal. calculated for C21H28N2O6: C, 62.36; H, 6.98; N, 6.93%. Found: C, 62.48; H, 7.36; N, 6.99%.
Methyl 1-cinnamoylpyrrolidine-2-carboxylate (4a): Flash column chromatography (ethyl acetate/petroleum ether 1/1). White powder, yield of 90%, mp. of 88–89 °C.
IR (nujol): 3222 (N-H), 1709 (C=O ester), 1628 (C=O amide), 1601, 1572 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.72 (d J: 15.4 Hz, 1H, Ph-CH=CH-), 7.49–7.53 (m, 2H, aromatic), 7.32–7.43 (m, 3H, aromatic), 6.75 (d J: 15.4 Hz, 1H, Ph-CH=CH-), 4.62 (dd J: 7.7, 3.1 Hz, 1H, 2-pyrrolidine), 3.75 (s, 3H, -OCH3) 3.69–3.73, 3.84–3.88 (m, 2H, 5-pyrrolidine), 2.09–2.17, 2.20–2.27 (m, 2H, 3-pyrrolidine), 1.98–2.08 (m, 2H, 4-pyrrolidine).
13C-NMR (CDCl3): 172.81 (1C, -COOCH3), 164.86 (1C, -CO-N), 142.92 (1C, Ph-CH=C), 135.10 (1C, 1-aromatic), 129.74 (1C, 4-aromatic), 128.77 (2C, 3,5-aromatic), 127.92 (2C, 2,6-aromatic), 117.92 (1C, Ph-CH=CH), 59.04 (1C, 2-pyrrolidine), 52.23 (1C, -OCH3), 46.95 (1C, 5-pyrrolidine), 29.16 (1C, 3-pyrrolidine), 24.95 (1C, 4-pyrrolidine).
1-cinnamoylpyrrolidine-2-carboxylic acid (4b): White powder, yield of 92%, mp. of 180–182 °C.
IR (nujol): 3287 (COO-H), 3214 (N-H), 1732 (C=O carboxylic), 1634 (C=O amide), 1602, 1571 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.62 (d J: 15.5 Hz, 1H, Ph-CH=CH-), 7.44–7.53 (m, 2H, aromatic), 7.29–7.43 (m, 3H, aromatic), 6.75 (d J: 15.5 Hz, 1H, Ph-CH=CH-), 4.54 (dd J: 8.1, 3.3 Hz, 1H, 2-pyrrolidine), 3.57–3.73, 3.76–3.88 (m, 2H, 5-pyrrolidine), 1.99–2.24 (m, 4H, 3,4-pyrrolidine).
13C-NMR (CDCl3): 178.48 (1C, -COOH), 169.69 (1C, -CO-N), 147.21 (1C, Ph-CH=C), 139.72 (1C, 1-aromatic), 134.51 (1C, 4-aromatic), 133.55 (2C, 3,5-aromatic), 132.61 (2C, 2,6-aromatic), 123.02 (1C, Ph-CH=CH), 63.98 (1C, 2-pyrrolidine), 51.84 (1C, 5-pyrrolidine), 33.67 (1C, 3-pyrrolidine), 29.46 (1C, 2-pyrrolidine).
(E)-methyl 4-(1-cinnamoylpyrrolidine-2-carboxamido)butanoate (4c): Flash column chromatography (ethyl acetate). White powder, yield of 75%, mp. of 76–78 °C.
IR (nujol): 3215 (N-H), 1716 (C=O ester), 1634, 1623 (C=O amide), 1605, 1577 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 7.72 (d J: 15.5 Hz, 1H, Ph-CH=CH-), 7.50–7.58 (m, 2H, aromatic), 7.33–7.45 (m, 3H, aromatic), 6.75 (d J: 15.5 Hz, 1H, Ph-CH=CH-), 4.70 (dd J: 8.0, 3.3 Hz, 1H, 2-pyrrolidine), 3.64 (s, 3H, -OCH3), 3.58–3.62, 3.73–3.79 (m, 2H, 5-pyrrolidine), 3.17–3.36 (m, 2H, -NH-CH2-CH2-), 2.34 (t J: 7.4 Hz, 2H, -CH2-C=O), 2.00–2.20 (m, 2H, 3-pyrrolidine), 1.77–1.90 (m, 4H, 4-pyrrolidine, -NH-CH2-CH2-).
13C-NMR (CDCl3): 173.64 (1C, -COOCH3), 171.18 (1C, -CO-NH), 166.31 (1C, -CO-N), 143.28 (1C, Ph-CH=C), 134.86 (1C, 1-aromatic), 129.98 (1C, 4-aromatic), 128.85 (2C, 3,5-aromatic), 127.97 (2C, 2,6-aromatic), 117.83 (1C, Ph-CH=CH), 60.05 (1C, 2-pyrrolidine), 51.59 (1C, -OCH3), 47.51 (1C, 5-pyrrolidine), 38.79 (1C, -NH-CH2), 31.39 (1C, -CH2-COOCH3), 27.05 (1C, 3-pyrrolidine), 25.02 (1C, 4-pyrrolidine), 24.70 (1C, -C-CH2-C).
Anal. calculated for C19H24N2O4: C, 62.53; H, 6.89; N, 4.56%. Found: C, 62.79; H, 7.12; N, 4.66%.
Methyl 1-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl)pyrrolidine-2-carboxylate (5a): Flash column chromatography (ethyl acetate/petroleum ether 2/3). Colorless oil, yield of 73%.
IR (nujol): 3401 (O-H), 3229 (N-H), 1720 (C=O ester), 1633 (C=O amide), 1608, 1570 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 4.36 (dd J: 11.1, 5.6 Hz, 1H, 2-pyrrolidine), 3.41–3.48, 4.04–4.16 (m, 2H, 5-pyrrolidine), 3.58, 3.71 (s, 3H, -OCH3), 2.49–2.73 (m, 4H, 3,4-chroman), 2.17 (s, 3H, Ph-CH3), 2.16 (s, 3H, Ph-CH3), 2.06, 2.10 (s, 3H, Ph-CH3), 1.68–1.96 (m, 4H, 3,4-pyrrolidine), 1.54, 1.61 (s, 3H, 2-CH3).
13C-NMR (CDCl3): 173.19/172.95 (1C, -COOCH3), 172.79/172.50 (1C, -CO-N), 145.31/145.23 (1C, 9-chroman), 144.68/144.44 (1C, 6-chroman), 121.54/121.50 (1C, 5-chroman), 121.29/121.20 (1C, 8-chroman), 118.94/118.77 (1C, 7-chroman), 118.24/118.20 (1C, 10-chroman), 78.81/78.67 (1C, 2-chroman), 60.80/60.39 (1C, 2-pyrrolidine), 52.01/51.84 (1C, -OCH3), 48.12/47.98 (1C- 5-pyrrolidine), 30.52/30.51 (1C, 3-pyrrolidine), 27.81/27.58 (1C, 3-chroman), 26.06/25.43 (1C, 4-pyrrolidine), 24.96/24.41 (1C, 4-chroman), 21.06/20.67 (1C, 2-CH3), 12.24/12.20 (1C, 5-CH3), 12.16/12.13 (1C, 8-CH3), 11.28/11.25 (1C, 7-CH3).
2-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl)pyrrolidine-1-carboxylic acid (5b): White powder, yield of 97%, mp. of 135–138 °C.
IR (nujol): 3401 (O-H), 3280 (COO-H), 3220 (N-H), 1741 (C=O carboxylic), 1639 (C=O amide), 1606, 1570 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 4.42 (dd J: 11.1, 5.6 Hz, 1H, 2-pyrrolidine), 3.38–3.50, 4.03–4.09 (m, 2H, 5-pyrrolidine), 2.51–2.73 (m, 4H, 3,4-chroman), 2.16 (s, 3H, Ph-CH3), 2.14 (s, 3H, Ph-CH3), 2.04, 2.08 (s, 3H, Ph-CH3), 1.63–2.01 (m, 4H, 3,4-pyrrolidine), 1.56, 1.61 (s, 3H, 2-CH3).
13C-NMR (CDCl3): 175.58/175.09 (1C, -COOH), 174.80/174.27 (1C, -CO-N), 145.42/145.36 (1C, 9-chroman), 144.51/144.28 (1C, 6-chroman), 121.51 (1C, 5-chroman), 121.40 (1C, 8-chroman), 119.10/119.02 (1C, 7-chroman), 118.08/118.03 (1C, 10-chroman), 78.89/78.78 (1C, 2-chroman), 60.86/60.42 (1C, 2-pyrrolidine), 48.44/48.31 (1C, 5-pyrrolidine), 30.61/30.46 (1C, 3-pyrrolidine), 27.04/26.97 (1C, 3-chroman), 25.94/25.50 (1C, 4-pyrrolidine), 25.01/24.38 (1C, 4-chroman), 21.02/20.67 (1C, 2-CH3), 12.25/12.21 (1C, 5-CH3), 12.15/12.11 (1C, 8-CH3), 11.27/11.18 (1C, 7-CH3).
Methyl 4-(1-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl)pyrrolidine-2-carboxamido)-butanoate (5c): Flash column chromatography (ethyl acetate/acetone 8/1). Yellow powder, yield of 45%, mp. of 59–61 °C.
IR (nujol): 3401 (O-H), 3227 (N-H), 1712 (C=O ester), 1638, 1628 (C=O amide), 1608, 1570 (C-C aromatic) cm−1.
1H-NMR (CDCl3): 4.42 (dd J: 11.1, 5.6 Hz, 1H, 2-pyrrolidine), 3.66, 3.68 (s, 3H, -OCH3), 3.24–3.29, 3.43–3.52 (m, 2H, 5-pyrrolidine), 2.70–2.79, 3.08–3.16 (m, 2H, -NH-CH2-CH2-) 2.49–2.68 (m, 4H, 3,4-chroman), 2.34 (t J: 7.4 Hz, 2H, -CH2-C=O), 2.18, 2.20 (s, 3H, Ph-CH3), 2.14, 2.15 (s, 3H, Ph-CH3), 2.04, 2.08 (s, 3H, Ph-CH3), 1.89–2.02 (m, 2H, 3-pyrrolidine), 1.66–1.84 (m, 2H, 4-pyrrolidine), 1.58, 1.61 (s, 3H, 2-CH3).
13C-NMR (CDCl3): 174.40 (1C, -COOCH3), 173.64 (1C, -CO-NH), 171.42 (1C, -CO-N), 145.83 (1C, 9-chroman), 144.81 (1C, 6-chroman), 123.45 (1C, 5-chroman), 121.75/121.40 (1C, 8-chroman), 120.68/120.32 (1C, 7-chroman), 118.16 (1C, 10-chroman), 78.75 (1C, 2-chroman), 61.47/60.96 (1C, 2-pyrrolidine), 51.90/51.61 (1C, -OCH3), 48.26/48.17 (1C, 5-pyrrolidine), 38.68/38.50 (1C, -NH-CH2), 31.78/31.30 (1C, -CH2-COOCH3), 31.09/30.85 (3-pyrrolidine), 27.99 (3-pyrrolidine), 25.76/25.52 (4-pyrrolidine), 24.75/24.60 (4-chroman), 24.38/24.29 (1C, -C-CH2-C), 21.48/20.97 (1C, 2-CH3), 12.39 (1C, 5-CH3), 12.25/12.13 (1C, 8-CH3), 11.54/11.28 (1C, 7-CH3).
Anal. calculated for C24H34N2O6: C, 64.55; H, 7.67; N, 6.66%. Found: C, 64.38; H, 7.29; N, 6.13%.