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E. A. Correa et al. / Bioorg. Med. Chem. 18 (2010) 3299–3306
3.1.9. Preparation of 5-(40-hydroxy-30-methoxyphenyl)-2E-4E-
pentadien isobutyl amide (6)
reaction was monitored by TLC (PE/EtOAc, 2:1) and the crude
material purified with column chromatography (silica gel) petro-
leum ether/EtOAc, 4:1–2:1 and gave 215 mg [0.87 mmol] as a
white solid (87%). Mp 116–118 °C. IR (KBr cmꢀ1): 3294, 2958,
1650, 1253, 1038, 931, 810. 1H NMR (CDCl3, 400 MHz) d (ppm):
0.91 (6H, d, J = 6.7 Hz, H-300-400), 1.82 (1H, m, H-200), 3.18 (2H, t,
J = 6.5 Hz, H-100), 5.91 (2H, s, –O–CH2–O–), 6.38 (1H, d,
J = 15.5 Hz, H-2), 6.64 (1H, t, J = 6.7 Hz, –NH), 6.69 (1H, d,
J = 8.0 Hz, H-50), 6.89 (dd, J = 1.7, 7.9 Hz, H-60), 7.49 (1H,
d, J = 15.7 Hz, H-3). 13C NMR (CDCl3, 100 MHz) d (ppm): 20.2 (C-
300-400), 28.7 (C-200), 47.2 (C-100), 101.4 (–O–CH2–O–), 106.4 (C-20),
108.4 (C-50), 119.4 (C-2), 123.7 (C-60), 129.4 (C-10), 140.3 (C-3),
148.2 (C-30), 148.9 (C-40), 166.5 (–NH–C@O). ESI-TOF MS m/z:
248.1 [M+H] for C14H17NO3.
130.3 mg [0.59 mmol] of 5-(40-hydroxy-30-methoxyphenyl)-2E-
4E-pentadienoic acid (16) were mixed with DIC (1 equiv) and HOBt
(1 equiv) in DCM (25 mL) and stirred for 10 min, 43.2 mg of isobu-
tylamine were added at room temperature and when the reaction
was completed the crude residue was purified with silica gel
(DCM/acetone 100.0–50:50) and gave 145.3 mg [0.53 mmol] of a
yellow solid. (89%). Mp 133–135 °C. IR (KBr cmꢀ1) 3358, 2926,
1652, 1514, 1279, 1147, 1033, 996. 1H NMR (CDCl3, 400 MHz) d
(ppm): 0.91 (6H, d, J = 6.7 Hz, H300-400), 1.81 (1H, m, H.200), 3.16
(2H, t, J = 6.4, H-100), 3.81 (3H, s, –OCH3), 6.04 (1H, d, J = 14.9 Hz,
H-2), 6.49 (1H, t, J = 6.08 Hz, –NH), 6.73 (1H, dd, J = 10.4, 15.6, H-
4), 6.80 (1H, d, J = 15.2 Hz), 6.89 (1H, d, J = 8.3 Hz, H-50), 6.93 (1H,
d, J = 2.0 Hz, H-20), 6.99 (1H, dd, J = 1.9, 8.3 Hz, H-60), 7.38 (1H,
dd, J = 10.4, 14.8 Hz, H-3). 13C NMR (CDCl3, 100 MHz) d (ppm):
20.2 (C-300-400), 28.4 (C-200), 47.2 (C-100), 55.5 (–OCH3), 109.2 (C-20),
115.0 (C-50), 120.9 (C-2), 122.9 (C-60), 124.0 (C-4), 128.7 (C-10),
139.3 (C-5), 141.2 (C-3), 146.9 (C-30), 147.1 (C-40), 166.8 (–NH–
C@O). ESI-TOF MS m/z: 276.2 [M+H]; HRMS 275.1519 for
C16H21NO3.
3.1.13. Preparation of 3-(40-hydroxy-30-methoxyphenyl)-2E-
propenoic acid piperidin amide (11)
Using the methodology for 3-(40-hydroxy-30-methoxyphenyl)-
2E-propenoic acid morpholin amide (2) preparation, 151.6 mg
[0.78 mmol] of ferulic acid and 66.4 mg [0.78 mmol] of piperidine
were subjected to reaction and the crude was purified with column
chromatography (Silica gel DCM/acetone 100:0–95:5) to give
159 mg [0.61 mmol] of yellow crystals (78%). Mp 125–127 °C. IR
(KBr cmꢀ1): 3307, 2975, 1647, 1590, 1286, 1033, 833. 1H NMR
(CDCl3, 400 MHz) d (ppm): 1.56 (4H, m, H-300-500), 1.62 (2H, m, H-
400), 3.56–3.62 (4H, m, H200-600), 3.84 (3H, s, –O–CH3), 6.72 (1H, d,
J = 15.4 Hz, H-2), 6.89 (1H, d, J = 8.2 Hz, H-50), 6.95 (1H, d,
J = 1.9 Hz, H-20), 7.02 (1H, dd, J = 1.8, 8.3 Hz, H-600), 7.56 (1H,
d, J = 15.4 Hz, H-3). 13C NMR (CDCl3, 100 MHz) d (ppm): 24.3
(C-400), 25.5 (C-300), 26.5 (C-500), 43.3 (C-200), 47.0 (C-600), 55.7
(–O–CH3), 110.1 (C-20), 114.5 (C-2), 115.0 (C-50), 121.7 (C-60),
127.4 (C-10), 142.7 (C-3), 147.1 (C-30), 147.7 (C-40), 165.8
(–NH–C@O). ESI-TOF MS m/z: 262.1 [M+H] for C15H19NO3.
3.1.10. Preparation of 5-(30,40-methylendioxy phenyl)-pentanoic
acid piperidine amide (tetrahydro piperine 8)
To piperine (1) (100 mg, 0.35 mmol) in dichloromethane (DCM,
20 mL) was added a catalytic amount of Pd/C (5%) and hydrogen
was bubbled over 12 h, giving 100.6 mg [0.34 mmol] of a colourless
oil (97%). IR (KBr cmꢀ1): 2926, 1635, 1489, 1437, 1246, 1037, 936,
1
852. H NMR (CDCl3, 300 MHz) d (ppm) 1.52–1.63 (10H, m, H-200,
H-300, H-400, H-3, H-4), 2.33 (2H, br s, H-2), 2.54 (2H, br s, H-5),
3.45 (4H, br s, H-100-H-500), 5.89 (2H, s, –O–CH2–O–), 6.66 (3H, m,
13
H-20, H-50, H-60). C NMR (CDCl3, 75 MHz) d (ppm) 25.2 (C-200, C-
400), 25.6 (C-300), 32.2 (C-3), 34.1 (C-2), 36.2 (C-4, C-5), 101.4 (–O–
CH2–O–), 108.7 (C-50), 109.5 (C-20), 121.8 (C-60), 136.8 (C-10),
146.2 (C-40), 148.2 (C-30), 171.9 (–NH–C@O). ESI-TOF MS m/z:
290.1681 [M+H] for C17H23NO3.
3.1.14. Preparation of 3-(40-hydroxy-30-methoxyphenyl)-2E-
propenoic acid morpholine amide (12)
To a solution of ferulic acid (purchased from Sigma–Aldrich)
(500 mg [2.6 mmol]) in DCM (25 mL), DIC (1 equiv) and HOBt
(1 equiv) were added and the mixture stirred for 10 min. Mor-
pholine (226.5 mg [2.6 mmol]) was added to the mixture and al-
lowed to react for 4 h. After the reaction was completed the
solvent was evaporated and the residue dissolved in EtOAc
washed with NaHCO3 solution (10%), water and citric acid solu-
tion (5%), the organic layer was dried over anhydrous sodium
sulphate, filtrated and the solvent evaporated, the crude product
was further purified by column chromatography (DCM/EtOAc,
3:1, 2:1, 1:1, 1:2) giving 530 mg [2.02 mmol] of a white solid
(78%). Mp 167–169 °C. IR (KBr cmꢀ1): 3150, 2963, 1644, 1585,
3.1.11. Preparation of 3-(30,40-methylenedioxyphenyl)-2E-
propenoic acid piperidine amide (9)
To
a
stirred solution of 3-(30,40-methylendioxyphenyl)-2E-
propenoic acid (Ferulic acid, purchased from Sigma–Aldrich)
192 mg [1 mmol], DIC (1 equiv) and HOBt (1 equiv) in DCM
(25 mL), piperidine 85.2 mg [1 mmol] was added at room temper-
ature, the reaction was checked by TLC (DCM/acetone, 9:1) when
the starting material was consumed the reaction was stopped and
the crude product purified using silica gel (DCM/acetone, 100:0–
93:7), 244.2 mg [0.94 mmol] of an amorphous white solid were
obtained (94%). Mp 88–90 °C. IR (KBr cmꢀ1): 2937, 1638, 1590,
1434, 1245, 1140, 1044, 819. 1H NMR (CDCl3, 400 MHz)
d
1515, 1270, 1111, 1037, 821. 1H NMR (CDCl3, 400 MHz)
d
(ppm): 1.59 (4H, m, H-300-400), 1.65 (2H, m, H-400), 3.60 (4H, br s,
H-200-600), 5.97 (2H, s, –O–CH2–O–), 6.73 (1H, d, J = 15.4 Hz, H-2),
6.79 (1H, d, J = 8.0 Hz, H-50), 6.99 (1H, dd, J = 1.7, 8.0 Hz, H.60),
7.03 (1H, d, J = 1.7 Hz, H-20), 7.56 (1H, d, J = 15.5 Hz, H-3). 13C
NMR (CDCl3, 100 MHz) d (ppm): 24.5 (C-400), 25.4 (C-300), 26.5
(C-500), 43.1 C-200), 46.6 (C-600), 101.3 (–O–CH2–O–), 106.1 (C-20),
108.2 (C-50), 115.5 (C-2), 123.3 (C-60), 129.6 (C-10), 141.6 (C-3),
147.9 (C-30), 148.5 (C-40), 165.2 (–NH–C@O). ESI-TOF MS m/z:
260.1 [M+H] for C15H17NO3.
(ppm): 3.72 (8H, br s, H-200, 300, 500, 600), 3.93 (3H, s, –OCH3),
6.64 (1H, d, J = 15.3 Hz, H-2), 6.86 (1H, d, J = 8.1 Hz, H-50), 6.93
(1H, d, J = 2.2 Hz, H-20), 6.98 (1H, dd, J = 1.9, 8.2 Hz, H-60), 7.56
(1H, d, J = 15.2 Hz, H-3). 13C NMR (CDCl3, 100 MHz) d (ppm):
42.4 (C-200, C-600), 55.9 (–OCH3), 66.8 (C-300, C-500), 109.9 (C-20),
113.7 (C-1), 114.8 (C-50), 121.9 (C-60), 127.5 (C-10), 143.5 (C-2),
146.7 (C-30), 147.5 (C-40), 166.1 (–NH–C@O). ESI-TOF MS m/z:
264.1 [M+H] for C14H17NO4.
3.1.15. Preparation of 3-(40-hydroxy-30-methoxyphenyl)-2E-
propenoic acid thiomorpholine amide (13)
3.1.12. Preparation of 3-(30,40-methylendioxyphenyl)-2E-
propenoic acid isobutyl amide (10)
Ferulic acid (2.6 mmol) and thiomorpholine (2.6 mmol) were al-
lowed to react under the same conditions and reagents as for 3-(40-
hydroxy-30-methoxyphenyl)-2E-propenoic acid morpholin amide;
the crude product was purified with silical gel (DCM/EtOAc, 3:1,
2:1, 1:1, 1:2) and gave 560.3 mg [2.00 mmol] of a pale yellow solid
(77%). Mp 153–155 °C. IR (KBr cmꢀ1): 3100, 2918, 1634, 1514,
With the same conditions for 3-(30,40-methylendioxyphenyl)-
2E-propenoic acid piperidine amide (9) synthesis, 192 mg
[1 mmol] of 3-(30,40-methylendioxyphenyl)-2E-propenoic acid
was mixed with DIC (1 equiv) and HOBt (1 equiv) and isobutyl-
amine 73.1 mg [1 mmol] was added to the stirred solution, the