H. Zhu et al. / European Journal of Medicinal Chemistry 121 (2016) 181e193
189
yielded 3-allyl-4-hydroxybenzaldehyde (3) (996 mg, 33.2%) as a
5.1.4.4. (3E,5E)-3,5-Bis(3-allyl-4-hydroxybenzylidene)-1-
brown liquid.
propylpiperidin-4-one (4d). Yellow power. Yield: 30%. m.p:
172.9e175.2 ꢀC. 1H NMR (600 MHz, DMSO-d6)
d (ppm): 10.01 (2H, s,
AreOH), 7.49 (2H, s, H-
b
, H-
b
0), 7.26 (2H, d, J ¼ 8.4 Hz, H-6, H-60),
5.1.4. General procedure for synthesis of 4ael
7.20 (2H, s, H-2, H-20), 6.90 (2H, d, J ¼ 8.4 Hz, H-5, H-50), 6.01e5.95
(2H, m, A,B-ArCH2CH]CH2), 5.08e5.03 (4H, m, A,BeArCH2CH]
CH2), 3.71 (4H, s, piperidoneeCH2eNeCH2), 3.31 (4H, s, A,B-
ArCH2CH]CH2), 2.47 (2H, t, J ¼ 7.2 Hz, NeCH2CH2CH3), 1.43e1.37
To a solution of 3-allyl-4-hydroxybenzaldehyde (3) (1.0 mmol)
in glacial acetic acid (10 mL) added piperidone or different
substituted piperidone (0.5 mmol) in glacial acetic acid (4.0 mL).
The reaction mixture was stirred for two days at room temperature.
The resulting mixture was treated with saturated NaHCO3 aqueous
solution to adjust pH to 7.0, and extracted by EtOAc (3 ꢁ 20 mL). The
combined organic layers were washed with brine and dried over
anhydrous MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was further purified by chromatography on silica
gel to give the desired symmetric allylated MACs 4ael.
(2H, m, NeCH2CH2CH3), 0.80 (3H, t, J ¼ 7.2 Hz, NeCH2CH2CH3). 13
C
NMR (150 MHZ, DMSO-d6)
d
(ppm): 186.2 (eCOe), 156.4 ꢁ 2 (C-4,
C-40), 136.8 ꢁ 2 (C-
b, C-
b
0), 134.9 ꢁ 2 (C-
a
, C-a
0), 132.8 ꢁ 2
(A,BeArCH2CH]CH2), 130.8 ꢁ 2 (C-2, C-20), 130.3 ꢁ 2 (C-3, C-30),
126.5
ꢁ
2
(C-1, C-10), 125.9
ꢁ
2
(C-6, C-60), 115.6
ꢁ
2
(A,BeArCH2CH]CH2), 115.3 ꢁ 2 (C-5, C-50), 58.6 (NeCH2CH2CH3),
54.4 ꢁ 2 (piperidoneeCH2eNeCH2), 33.5 ꢁ 2 (A,BeArCH2CH]
CH2), 19.8 (NeCH2CH2CH3), 11.7 (NeCH2CH2CH3). ESI-MS, m/z:
428.3 (MꢂH)ꢂ. HRMS (ESI): calcd for C28H31NO3 [MþH]þ: 430.2377,
found: 430.2396.
5.1.4.1. (3E,5E)-3,5-Bis(3-allyl-4-hydroxybenzylidene)piperidin-4-
one (4a). Yellow power. Yield:25%. m.p: 196.2e198.3 ꢀC. 1H NMR
(600 MHz, DMSO-d6) d (ppm): 9.97 (2H, s, AreOH), 7.47 (2H, s, H-b,
H-
b
0), 7.19 (2H, d, J ¼ 8.4 Hz, H-6, H-60), 7.18 (2H, s, H-2, H-20), 6.89
5.1.4.5. (3E,5E)-3,5-Bis(3-allyl-4-hydroxybenzylidene)-1-
(2H, d, J ¼ 8.4 Hz, H-5, H-50), 6.01e5.94 (2H, m, A,B-ArCH2CH]
CH2), 5.08e5.03 (4H, m, A,B-ArCH2CH]CH2), 3.94 (4H, s, piper-
idoneeCH2eNeCH2), 3.31(4H, s, A,BeArCH2CH]CH2), 1.99 (1H, s,
isopropylpiperidin-4-one (4e). Yellow power. Yield: 30%. m.p:
205.3e207.2 ꢀC. 1H NMR (600 MHz, DMSO-d6)
d (ppm): 9.99 (2H, s,
AreOH), 7.47 (2H, s, H-
b
, H-
b
0), 7.23 (2H, d, J ¼ 7.8 Hz, H-6, H-60),
eNH). 13C NMR (150 MHz, DMSO-d6)
d (ppm): 186.9 (eCOe),
b
7.21 (2H, s, H-2, H-20), 6.90 (2H, d, J ¼ 7.8 Hz, H-5, H-50), 6.02e5.95
(2H, m, A,B-ArCH2CH]CH2), 5.09e5.04 (4H, m, A,B-ArCH2CH]
CH2), 3.75 (4H, s, piperidoneeCH2eNeCH2), 3.31 (4H, s, A,B-
ArCH2CH]CH2), 2.91e2.87 (1H, m, NeCH(CH3)2), 1.02 (6H, d,
156.3 ꢁ 2 (C-4, C-40), 136.8 ꢁ 2 (C-
b
, C-
a, C-a
0), 134.2 ꢁ 2 (C- 0),
132.7 ꢁ 2 (A,BeArCH2CH]CH2), 132.6 ꢁ 2 (C-2, C-20), 130.4 ꢁ 2 (C-
3, C-30), 126.5 ꢁ 2 (C-1, C-10), 126.1 ꢁ 2 (C-6, C-60), 115.6 ꢁ 2
(A,BeArCH2CH]CH2), 115.2 ꢁ 2 (C-5, C-50), 47.5 ꢁ 2 (piperidone-
CH2eNeCH2), 33.6 ꢁ 2 (A,BeArCH2CH]CH2). ESI-MS, m/z: 385.9
(MꢂH)ꢂ. HRMS(ESI): calcd for C25H25NO3 [MþH]þ: 388.1907,
found: 388.1909.
J ¼ 6.6 Hz, NeCH(CH3)2). 13C NMR (150 MHz, DMSO-d6)
d (ppm):
186.7 (eCOe), 156.3 ꢁ 2 (C-4, C-40), 136.8 ꢁ 2 (C-
b, C-b
0), 134.3 ꢁ 2
(C-
a
, C-
a
0), 132.6 ꢁ 2 (A,B-ArCH2CH]CH2), 131.5 ꢁ 2 (C-2, C-20),
130.3 ꢁ 2 (C-3, C-30), 126.5 ꢁ 2 (C-1, C-10), 125.9 ꢁ 2 (C-6, C-60),
115.7
ꢁ
2
(A,B-ArCH2CH]CH2), 115.3
ꢁ
2
(C-5, C-50), 53.1
5.1.4.2. (3E,5E)-3,5-Bis(3-allyl-4-hydroxybenzylidene)-1-
(NeCH(CH3)2), 50.1 ꢁ 2 (piperidoneeCH2eNeCH2), 33.4 ꢁ 2 (A,B-
methylpiperidin-4-one (4b). Yellow power. Yield: 30%. m.p:
ArCH2CH]CH2), 18.1
ꢁ
2 (NeCH(CH3)2). ESI-MS, m/z: 428.1
185.9e187.6 ꢀC. 1H NMR (600 MHz, DMSO-d6)
d (ppm): 10.01 (2H, s,
(MꢂH)ꢂ. HRMS (ESI): calcd for C28H31NO3 [MþH]þ: 430.2377,
AreOH), 7.48 (2H, s, H-
b
, H-
b
0), 7.21 (2H, d, J ¼ 8.4 Hz, H-6, H-60),
found: 430.2396.
7.20 (2H, s, H-2, H-20), 6.90 (2H, d, J ¼ 8.4 Hz, H-5, H-50), 6.01e5.94
(2H, m, A,B-ArCH2CH]CH2), 5.08e5.03 (4H, m, A,BeArCH2CH]
CH2), 3.67 (4H, s, piperidoneeCH2eNeCH2), 3.31 (4H, s, A,B-
ArCH2CH]CH2), 2.38 (3H, s, NeCH3). 13C NMR (150 MHz, DMSO-d6)
5.1.4.6. (3E,5E)-3,5-Bis(3-allyl-4-hydroxybenzylidene)-1-
cyclopropylpiperidin-4-one (4f). Yellow power. Yield: 40%. m.p:
82.5e85.1 ꢀC. 1H NMR (600 MHz, DMSO-d6)
AreOH), 7.49 (2H, s, H-b, H-b
d (ppm): 10.01 (2H, s,
d
(ppm): 185.9 (eCOe), 156.4 ꢁ 2 (C-4, C-40), 136.7 ꢁ 2 (C-
b, C-b
0),
0), 7.22 (2H, d, J ¼ 8.4 Hz, H-6, H-60),
7.21 (2H, s, H-2, H-20), 6.92 (2H, d, J ¼ 8.4 Hz, H-5, H-50), 6.02e5.95
(2H, m, A,BeArCH2CH]CH2), 5.08e5.04 (4H, m, A,BeArCH2CH]
CH2), 3.89 (4H, s, piperidoneeCH2eNeCH2), 3.31 (4H, s,
A,BeArCH2CH]CH2), 1.99e1.96 (1H, m, NeCHeCyclopropyl),
0.47e0.44 (2H, m, NeCH2eCH2eCyclopropyl), 0.28e0.25 (2H, m,
134.8 ꢁ 2 (C-
a
, C-a
0), 132.9 ꢁ 2 (A,BeArCH2CH]CH2), 130.7 ꢁ 2 (C-
2, C-20), 130.1 ꢁ 2 (C-3, C-30), 126.5 ꢁ 2 (C-1, C-10), 125.8 ꢁ 2 (C-6, C-
60), 115.6 ꢁ 2 (A,BeArCH2CH]CH2), 115.3 ꢁ 2 (C-5, C-50), 56.6 ꢁ 2
(piperidone-CH2eNeCH2),
45.4
(NeCH3),
33.5
ꢁ
2
(A,BeArCH2CH]CH2). ESI-MS, m/z: 400.0 (MꢂH)ꢂ. HRMS (ESI):
calcd for C25H25NO3 [MþH]þ: 388.1907, found: 388.1909.
NeCH2eCH2eCyclopropyl). 13C NMR (150 MHz, DMSO-d6)
d (ppm):
186.1 (eCOe), 156.4 ꢁ 2 (C-4, C-40), 136.7 ꢁ 2 (C-
b, C-b
0), 134.9 ꢁ 2
5.1.4.3. (3E,5E)-3,5-Bis(3-allyl-4-hydroxybenzylidene)-1-
(C-
a
, C-
a
0), 132.9 ꢁ 2 (A,BeArCH2CH]CH2), 130.8 ꢁ 2 (C-2, C-20),
ethylpiperidin-4-one (4c). Yellow power. Yield: 30%. m.p:
130.1 ꢁ 2 (C-3, C-30), 126.6 ꢁ 2 (C-1, C-10), 125.9 ꢁ 2 (C-6, C-60),
115.7 ꢁ 2 (A,BeArCH2CH]CH2), 115.3 ꢁ 2 (C-5, C-50), 54.5 ꢁ 2
(piperidoneeCH2eNeCH2), 37.5 (NeCHeCyclopropyl), 33.5 ꢁ 2
(A,B-ArCH2CH]CH2), 6.4 ꢁ 2 (NeCH2eCH2eCyclopropyl). ESI-MS,
m/z: 426.1 (MꢂH)ꢂ. HRMS (ESI): calcd for C28H29NO3 [MþH]þ:
428.2220, found: 428.2229.
181.3e183.2 ꢀC. 1H NMR (600 MHz, DMSO-d6)
d (ppm): 10.01 (2H, s,
Ar-OH), 7.49 (2H, s, H-
b
, H-
b
0), 7.22 (2H, d, J ¼ 8.4 Hz, H-6, H-60), 7.21
(2H, s, H-2, H-20), 6.90 (2H, d, J ¼ 8.4 Hz, H-5, H-50), 6.01e5.95 (2H,
m, A,B-ArCH2CH]CH2), 5.08e5.03 (4H, m, A,B-ArCH2CH]CH2),
3.71 (4H, s, piperidoneeCH2eNeCH2), 3.32 (4H, d, J ¼ 6.6 Hz,
A,BeArCH2CH]CH2), 2.56 (2H, q, J ¼ 7.2 Hz, NeCH2CH3), 0.99 (3H,
t, J ¼ 7.2 Hz, NeCH2CH3). 13C NMR (150 MHz, DMSO-d6)
d
(ppm):
5.1.4.7. (3E,5E)-3,5-Bis(3-allyl-4-hydroxybenzylidene)-1-(phenyl-
186.3 (eCOe), 156.4 ꢁ 2 (C-4, C-40), 136.8 ꢁ 2 (C-
b, C-b
0), 134.8 ꢁ 2
sulfonyl)piperidin-4-one (4g). Yellow power. Yield: 35%. m.p:
(C-
a
, C-
a
0), 132.7 ꢁ 2 (A,B-ArCH2CH]CH2), 130.8 ꢁ 2 (C-2, C-20),
84.7e87.0 ꢀC. 1H NMR (600 MHz, DMSO-d6)
d
(ppm): 10.18 (2H, s,
130.3 ꢁ 2 (C-3, C-30), 126.5 ꢁ 2 (C-1, C-10), 125.9 ꢁ 2 (C-6, C-60),
AreOH), 7.74e7.71 (1H, m, eNeSO2eAreH-4), 7.60e7.59 (4H, m,
115.7 ꢁ 2 (A,BeArCH2CH]CH2), 115.3 ꢁ 2 (C-5, C-50), 53.9 ꢁ 2
NeSO4eAreH-2,3,5,6), 7.48 (2H, s, H-b, H-b
0), 7.22 (2H, dd,
(piperidoneeCH2eNeCH2), 50.7 (NeCH2CH3), 33.5
ꢁ
2
J1 ¼ 8.4 Hz, J2 ¼ 1.8 Hz, H-6, H-60), 7.14 (2H, s, H-2, H-20), 6.95 (2H, d,
J ¼ 8.4 Hz, H-5, H-50), 6.05e5.98 (2H, m, A,B-ArCH2CH]CH2),
5.14e5.08 (4H, m, A,B-ArCH2CH]CH2), 4.49 (4H, s, piper-
idoneeCH2eNeCH2), 3.35 (4H, s, A,B-ArCH2CH]CH2). 13C NMR
(A,BeArCH2CH]CH2), 12.10 (NeCH2CH3). ESI-MS, m/z: 414.1
(MꢂH)ꢂ. HRMS (ESI): calcd for C27H29NO3 [MþH]þ: 416.2220,
found: 416.2246.