New Agonists of PPARꢀ Based on Stilbene and Chalcone Scaffolds
Medicinal Chemistry, 2014, Vol. 10, No. 1 61
132.87 (CH Ar), 138.64 (O=CC Ar), 144.37 (=CH), 157.99
(CArO), 166.10 (EtOC=O), 175.07 (=CC=O).
r.t. for 10-15 h. The solvent was removed under reduced
pressure and the residue was poured into water (20 mL) and
acidified with conc HCl at 0 °C. The aqueous layer was ex-
tracted with dichloromethane (3 ꢀ 20 mL) and then the or-
ganic layer was dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by crystallization
with cyclohexane or chloroform affording desired acids 17-
26 with good yields.
Ethyl{4-[(1E)-3-oxo-3-phenylprop-1-enyl]phenoxy}
acetate (12). Yellow solid, 79% yield, m.p. 62-63 °C. IR
(KBr) 1766 cm-1; 1H NMR (CDCl3) ꢁ 1.30 (t, 3H, J = 6.9 Hz,
CH3CH2), 4.28 (q, 2H, J = 6.9 Hz, CH2CH3), 4.67 (s, 2H,
OCH2CO), 6.82 (d, 2H, J = 8.2 Hz, CH Ar), 7.43 (d, 1H, J =
15.3 Hz, =CH), 7.48-7.60 (m, 4H, CH Ar), 7.75 (d, 1H, J =
15.3 Hz, =CH), 7.99 (d, 2H, J = 8.2 Hz, CH Ar); 13C NMR
2-Methyl-2-{4-[(E)-2-phenylvinyl]phenoxy}propanoic
acid (17). White solid, 94% yield, m.p. 190-192 °C. IR
(CDCl3)
ꢁ
14.40 (CH3CH2), 61.82 (CH2CH3), 65.49
1
(OCH2CO), 115.27 (CH Ar), 120.57 (=CHC=O), 128.36 (C
ArC=), 128.67, 128.83, 130.47 and 132.90 (CH Ar), 133.95
(O=CC Ar), 144.97 (=CHC Ar), 159.94 (C ArO), 168.57
(EtOC=O), 190.78 (C=OAr).
(KBr) 3280, 1706 cm-1; H NMR (acetone-d6) ꢁ 1.59 (s, 6H,
C(CH3)2), 6.90 (d, 2H, J = 8.7 Hz, CH Ar), 7.07-7.37 (m, 7H,
CH Ar and HC=CH), 7.49-7.58 (m, 2H, CH Ar); 13C NMR
(acetone-d6) ꢁ 25.09 (C(CH3)2), 79.14 (C(CH3)2), 119.20,
126.47 (CH Ar), 127.07 (HC=CH), 127.43 and 127.56 (CH
Ar), 128.24 (HC=CH), 128.84 (CH Ar), 131.33, 137.97 and
155.91 (C Ar), 175.17 (C=O).
Ethyl
2-{4-[(anilinocarbonyl)amino]phenoxy}-2-
methylpropanoate (13). White solid, 63% yield, m.p. 112-
114 °C. IR (KBr) 3322, 1726, 1657 cm-1, H NMR (CDCl3)
1
ꢁ 1.26 (t, 3H, J = 7.2 Hz, CH3CH2), 1.55 (s, 6H, C(CH3)2),
4.23 (q, 2H, J = 7.2 Hz, CH2CH3), 6.78 (d, 2H, J = 9.0 Hz,
CH Ar), 7.01-7.06 (m, 2H, CH Ar), 7.14 (d, 2H, J = 9.0 Hz,
CH Ar), 7.25-7.28 (m, 3H, CH Ar); 13C NMR (CDCl3) ꢁ
14.33 (CH3CH2), 25.52 ((CH3)2C), 61.81 (CH2CH3), 79.74
(C(CH3)2), 120.6, 120.87, 122.92, 124.03 and 129.37 (CH
Ar), 132.71 and 138.41 (C Ar), 152.12 (O=CNH), 154.04
(CArO), 174.64 (OC=O).
Ethyl{4-[(E)-2-phenylvinyl]phenoxy}acetic acid (18).
White solid, 51% yield, m.p. 206-207 °C. IR (KBr) 3210,
1
1706 cm-1; H NMR (DMSO) 4.78 (s, 2H, OCH2CO), 6.90
(m, 2H, CH Ar), 7.05-7.19 (m, 3H, CH Ar and HC=CH),
7.34 (t, 2H, CH Ar), 7.50-7.56 (m, 4H, CH Ar) 13C NMR
(DMSO) ꢁ 65.16 (OCH2CO), 115.28, 126.87 (CH Ar),
127.05 (HC=CH), 127.92 and 128.41 (CH Ar), 128.59
(HC=CH), 129.35 (CH Ar), 130.83 and 137.99 (C Ar),
158.12 (C ArO), 170.84 (C=O).
Ethyl {4-[(anilinocarbonyl)amino]phenoxy}acetate
(14). White solid, 74% yield, m.p. 162-164 °C. IR (KBr)
1735, 1642 cm-1; 1H NMR (acetone-d6) ꢁ 1.25 (t, 3H, J = 7.2
Hz, CH3CH2), 4.20 (q, 2H, J = 7.2 Hz, CH2CH3), 4.67 (s, 2H,
OCH2CO), 6.88 (d, 2H, J = 9.3 Hz, CH Ar), 6.96-6.99 (m,
2H, CH Ar), 7.44 (d, 2H, J = 9.3 Hz, CH Ar), 7.51-7.54 (m,
2H, CH Ar), 7.95 (s, 1H, NH), 8.03 (m, 1H, NH); 13C NMR
(acetone-d6) ꢁ 14.03 (CH3CH2), 66.91 (OCH2CO), 118.42,
119.53, 121.31 and 128.91 (CH Ar), 134.01 (NHC Ar),
139.72 (NHC Ar), 148.92 (C ArO), 152.73 (HNC=O),
173.10 (EtOC=O).
2-Methyl-2-{4-[(2E)-3-phenylprop-2-enoyl]phenoxy}
propanoic acid (19). Yellow solid, 91% yield, m.p.
149-151 °C. IR (KBr) 3300, 1733, 1635 cm-1; 1H NMR
(CD3OD) ꢁ 1.66 (s, 6H, C(CH3)2), 6.97 (d, 2H, J = 9.0 Hz,
CH Ar), 7.42-7.44 (m, 3H, CH Ar), 7.73-7.76 (m, 4H, CH
Ar and HC=CH), 8.06 (d, 2H, J = 9.0 Hz, CH Ar); 13C NMR
(CD3OD) ꢁ 20.60 ((CH3)2C), 79.25 (C(CH3)2), 117.63 (CH
Ar), 121.60 (HC=CH), 128.51, 128.88 and 130.45 (CH Ar),
131.34 (O=CC Ar), 135.19 (C ArC=), 144.39 (HC=CH),
160.43 (C ArO), 175.81 (HOC=O), 189.51 (ArC=O).
{4-[(2E)-3-Phenylprop-2-enoyl]phenoxy}acetic
acid
Ethyl 2-(4-benzoylphenoxy)-2-methylpropanoate (15).
(20). Yellow solid, 46% yield, m.p. 174-175 °C. IR (KBr)
White solid, 29% yield, m.p. 85-87 °C. IR (KBr) 1725, 1654
1
3448, 1734, 1708 cm-1; H NMR (DMSO) ꢁ 4.82 (s, 2H,
1
cm-1; H NMR (CDCl3) ꢁ 1.23 (t, 3H, J = 6.9 Hz, CH3CH2),
OCH2CO), 7.06 (d, 2H, J = 9.0 Hz, CH Ar), 7.43-7.45 (m,
3H, CH Ar), 7.70 (d, 1H, J = 15.6 Hz, HC=C), 7.85-7.89 (m,
2H, CH Ar), 8.12 (d, 1H, J = 15.6 Hz, =CH), 8.15 (d, 2H, J =
9.0 Hz, CH Ar); 13C NMR (DMSO) ꢁ 65.23 (OCH2CO),
115.22 (CH Ar), 122.66 (=CHC=O), 129.52, 129.59 and
131.16 (CH Ar), 131.50 (O=CCAr), 131.55 (CH Ar), 135.48
(CArCH=), 143.95 (ArCH=), 162.39 (CArO), 170.49
(HOC=O), 188.07 (ArC=O).
1.67 (s, 6H, C(CH3)2), 4.23 (q, 2H, J = 6.9 Hz, CH2CH3),
6.86 (d, 2H, J = 9.0 Hz, CH Ar), 7.45-7.59 (m, 3H, CH Ar),
7.38 (d, 2H, J = 9.0 Hz, CH Ar), 7.61 (m, 2H, CH Ar); 13C
NMR (CDCl3) ꢁ 14.28 (CH3CH2), 24.90 ((CH3)2C), 60.71
(CH2CH3), 78.72 ((CH3)2C), 115.02, 128.63 and 128.70 (CH
Ar), 129.54 (C Ar), 129.84 and 132.31 (CH Ar), 138.22 and
158.67 (C Ar), 170.12 (EtOC=O), 195.98 (ArC=OAr).
Ethyl (4-benzoylphenoxy)acetate (16). White solid,
2-Methyl-2-{4-[(1E)-3-oxo-3-phenylprop-1-enyl]
1
94% yield, m.p. 82-84 °C. IR (KBr) 1725, 1654 cm-1; H
phenoxy}propanoic acid (21). Yellow solid, 66% yield,
NMR (CDCl3) ꢁ 1.31 (t, 3H, J = 7.2Hz, CH3CH2), 4.29 (q,
2H, J = 7.2 Hz, CH2CH3), 4.70 (s, 2H, OCH2CO), 6.97 (d,
2H , J = 9.0 Hz, CH Ar), 7.44-7.60 (m, 3H, CH Ar), 7.75 (m,
2H, CH Ar), 7.83 (d, 2H, J = 9.0 Hz, CH Ar); 13C NMR
1
m.p. 200 °C (dec). IR (KBr) 3443, 1665, 1605 cm-1; H
NMR (CD3OD) ꢁ 1.44 (s, 6H, C(CH3)2), 6.79 (d, 2H, J = 8.7
Hz, CH Ar), 7.13 (d, 1H, J = 15.2 Hz, =CH), 7.43-7.57 (m,
5H, CH Ar), 7.76 (d, 1H, J = 15.2 Hz, =CH), 7.93 (d, 2H, J =
8.7 Hz, CH Ar); 13C NMR (CD3OD) ꢁ 26.03 ((CH3)2C),
78.85 (C(CH3)2), 119.62 (O=CCH=), 123.05 (CArC=),
128.57(CArC=), 129.11, 129.93 and 133.10 (CH Ar), 138.75
(O=CC Ar), 145.21 (=CH), 155.88 (CArO), 175.89
(HOC=O), 191.31 (=CC=O).
(CDCl3)
ꢁ
14.40 (CH3CH2), 61.87 (CH2CH3), 65.45
(OCH2CO), 114.38, 128.46 and 130.00 (CH Ar), 131.34 and
132.29 (C Ar), 132.77 (CH Ar), 138.26, 161.47 (C Ar),
168.53 (EtOC=O), 195.71 (ArC=OAr).
General procedure for the preparation of acids 17-26.
A solution of NaOH 1N (3.9 mmol) was added to esters 7-16
(3.0 mmol) in EtOH (20 mL), and the mixture was stirred at
{4-[(1E)-3-Oxo-3-phenylprop-1-enyl]phenoxy}acetic
acid (22). Yellow solid, 80% yield, m.p. 200 °C (dec). IR