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A. Reyes-Ramírez et al. / European Journal of Medicinal Chemistry 46 (2011) 2699e2708
filtered and purified by flash column chromatography on silica gel
(hexane-EtOAc, 9:1) to give the final products 16e19. For 1.0 g of
crude reaction, 30 g of silica gel were packed in the column.
4.1.6. Synthesis of 1,3-diphenylpropanes 20e22
4.1.6.1. 4-[3-(4-Methoxyphenyl)propyl]phenol (20). Chalcone 16
(3.0 g) was dissolved in a solution of H2SO4 (2.0 mL) in EtOH
(100 mL) and hydrogenated at 60 lb/in2 (60 ꢀC) over 10% palladium
on carbon (0.3 g) for 4 h; the catalyst was filtered and the solvent
removed in vacuo. The resulting solution was then tried with 50 mL
of water and the crude products were extracted with EtOAc
(2 ꢃ 25 mL). The combined organic layers were washed with brine
(20 mL), and dried (Na2SO4). After solvent removal, the residue was
purified by flash chromatography to give diphenylpropane 20:
(2.67 g, yield 92.4%) as yellow powder; mp 48 ꢀC; UV (MeOH) lmax
4.1.5.1. (2E)-1-(4-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-
one (16). Compound 16 (1.96 g, yield 77.4%) was obtained as yellow
powder; mp 190 ꢀC; UV (MeOH) lmax 344, 236 nm; IR (KBr) vmax
3123, 2839, 1645, 1563, 1429, 1166 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
3.89 (3H, s, CH3O-4), 4.89 (1H, s, HO-40), 6.96e6.98 (4H, m, H-3, H-
30, H-5, H-50), 7.45 (1H, d, J ¼ 15.6 Hz, ]CH-
a
), 7.63 (2H, d, J ¼ 8.7 Hz,
), 8.03 (2H, d, J ¼ 8.7 Hz, H-
55.4 (CH3O-4), 114.4 (C-3, C-
), 127.7 (C-1), 130.1 (C-10), 130.7 (C-2,
H-2, H-6), 7.81 (1H, d, J ¼ 15.9 Hz, ]CH-
b
20, H-60); 13C NMR (100 MHz, CDCl3)
5), 115.4 (C-30, C-50), 119.5 (C-
d
277, 226 nm; IR (KBr) vmax 3418, 2941, 1608, 1512, 1353, 1216 cmꢂ1
;
a
1H NMR (400 MHz, CDCl3)
d 1.80e1.90 (2H, m, H-8), 2.50e2.60 (4H,
C-6),131.0 (C-20, C-60),144.1 (C-
b
),159.7 (C-4),161.6 (C-40),188.9 (C]
m, H-7, H-70), 3.78 (3H, s, CH3O-40), 4.41 (1H, br s, HO-4), 6.73 (2H,
d, J ¼ 8.8 Hz, H-3, H-5), 6.82 (2H, d, J ¼ 8.8 Hz, H-30, H-50), 7.02 (2H,
d, J ¼ 8.8 Hz, H-2, H-6), 7.08 (2H, d, J ¼ 8.8 Hz, H-20, H-60); 13C NMR
O); EM-IE (m/z) 254 [Mþ (100)], 239 (21), 161 (18), 121 (20). HREIMS
[M]þ(m/z) 254.0950 (calcd for C16H14O3 254.0943).
(100 MHz, CDCl3) d
33.4 (C-8), 34.8 (C-7, C-70), 55.3 (CH3O-40), 113.7
4.1.5.2. (2E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3-hydroxy-5-meth-
oxyphenyl)prop-2-en-1-one (17). Chalcone17 (2.16 g, yield 72.0%)
was obtained as yellow powder; mp 161 ꢀC; UV (MeOH) lmax 356,
(C-30, C-50), 115.1 (C-3, C-5), 129.3 (C-20, C-60), 129.4 (C-2, C-6), 134.þ4
(C-10), 134.5 (C-1), 153.5 (C-4), 157.5 (C-40); EM-IE (m/z) 242 [M
(71)], 135 (18), 121 (100), 107 (24). HREIMS [M]þ(m/z) 242.1301
(calcd for C16H18O2 242.1307).
207 nm; IR (KBr) vmax 3476, 3263, 2840, 1646, 1562, 1266 cmꢂ1
;
1H NMR (400 MHz, CD3OD)
d 3.82 (3H, s, CH3O-4), 3.91 (3H, s,
CH3O-50), 6.60 (1H, t, J ¼ 2.1 Hz, H-40), 6.98 (1H, d, J ¼ 8.3 Hz, H-
4.1.6.2. 4-[3-(1,3-Benzodioxol-5-yl)propyl]phenol (21). Compound
19 (1.5 g, 5.6 mmol) was dissolved in a solution of H2SO4 (1.0 mL) in
EtOH (50 mL), and hydrogenated at 60 lb/in2 (60 ꢀC) over 10%
palladium on carbon (0.15 g) for 4 h. The catalyst was filtered off
and the filtrate evaporated. The resulting solution was then tried
with 25 mL of water and the crude products were extracted with
EtOAc (2 ꢃ 25 mL). The combined organic layers were washed with
brine (20 mL), and dried (Na2SO4). After solvent removal, the
residue was purified by flash chromatography to give diphenyl-
propane 21 (1.48 g, yield 58%) as yellow powder; mp 84 ꢀC: UV
(MeOH) lmax 281, 209 nm; IR (KBr) vmax 3477, 3368, 2928, 1586,
5), 7.01e7.03 (2H, m, H-20, H-60), 7.19 (1H, dd, J ¼ 8.3, 2.1 Hz, H-6),
7.21 (1H, d, J ¼ 2.1 Hz, H-2), 7.41 (1H, d, J ¼ 15.7 Hz, ]CH-
a
), 7.67
54.5
(CH3O-50), 54.9 (CH3O-4), 104.6 (C-60), 105.5 (C-40), 107.6 (C-20),
111.1 (C-5), 113.7 (C-2), 119.4 (C- ), 122.14 (C-6), 127.9 (C-1), 140.7
(C-10), 145.4 (C-
(1H, d, J ¼ 15.7 Hz, ]CH-
b d
); 13C NMR (100 MHz, CD3OD)
a
b
), 146.6 (C-3), 150.5 (C-4), 158.7 (C-30), 161.2 (C-
50), 191.0 (C]O); EM-IE (m/z) 300 [Mþ (100)], 285 (34), 177 (35),
142 (41). HREIMS [M]þ(m/z) 300.0980 (calcd for C17H16O5
300.0998).
4.1.5.3. (2E)-1-(3-hydroxy-5-methoxyphenyl)-3-(4-hydroxy-3-meth-
oxyphenyl)prop-2-en-1-one (18). Chalcone 18 (1.91 g, yield 63.7%)
was obtained as yellow powder; mp 161e162 ꢀC; UV (MeOH) lmax
1500, 1483, 1244 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 1.26 (2H, m,
H-8), 2.82 (4H, s, H-7, H-70), 4.63 (1H, br s, HO-3), 5.92 (2H,
s, eOCH2Oe), 6.61 (1H, dd, J ¼ 8.0, 1.6 Hz, H-60), 6.64e6.68 (3H, m,
H-2, H-20, H-4), 6.72 (1H, d, J ¼ 8.0 Hz, H-50), 6.75 (1H, d, J ¼ 7.6 Hz,
H-6), 7.14 (1H, dt, J ¼ 7.6, 2.4 Hz, H-5); 13C NMR (100 MHz, CDCl3)
360, 207 nm; IR (KBr) vmax 3407, 2943, 1648, 1565, 1428, 1149 cmꢂ1
;
1H NMR (400 MHz, CD3OD)
d 3.83 (3H, s, CH3O-3), 3.93 (3H, s,
CH3O-50), 6.60 (1H, t, J ¼ 2.0 Hz, H-40), 6.84 (1H, d, J ¼ 8.4 Hz, H-6),
7.04 (1H, t, J ¼ 2.0 Hz, H-20), 7.06 (1H, t, J ¼ 2.0 Hz, H-60), 7.22 (1H,
dd, J ¼ 8.4, 2.0 Hz, H-5), 7.33 (1H, d, J ¼ 2.0 Hz, H-2), 7.46 (1H, d,
d
37.4 (C-8), 37.9 (C-7, C-70), 100.7 (eOCH2Oe), 108.1 (C-50), 112.5
(C-20), 112.8 (C-4), 115.3 (C-2), 120.9 (C-6), 121.1 (C-60), 129.5 (C-5),
135.5 (C-10), 143.6 (C-1), 145.6 (C-40), 147.5 (C-30), 155.4 (C-3); EM-IE
(m/z) 256 [Mþ (60)], 149 (100), 119 (16). HREIMS [M]þ(m/z)
256.1090 (calcd for C16H16O3 256.1099).
J ¼ 15.6 Hz, ]CH-
(100 MHz, CD3OD)
105.4 (C-40), 107.6 (C-60), 110.8 (C-2), 115.2 (C-5), 118.8 (C-
a
d
), 7.71 (1H, d, J ¼ 15.6 Hz, ]CH-
b
); 13C NMR
54.5 (CH3O-50), 55.1 (CH3O-3), 104.7 (C-20),
), 123.5
), 148.0 (C-4), 149.7 (C-3),
a
(C-6), 126.8 (C-1), 140.3 (C-10), 145.9 (C-
b
4.1.6.3. 4-[3-(3-Hydroxy-5-methoxyphenyl)propyl]-2-methoxyphen-
ol (22). Compound 22 (crystalline solid, mp 77 ꢀC, 0.25 g, yield
54.2%) was prepared from chalcone 18 (0.48 g) following the
method described for 21. UV (MeOH) lmax 279, 207 nm; IR (KBr)
158.6 (C-30), 161.1 (C-50), 191.2 (C]O); EM-IE (m/z) 300 [Mþ (100)],
177 (28), 145 (23). HREIMS [M]þ(m/z) 300.0980 (calcd for C17H16O5
300.0998).
vmax 3355, 3039, 2931, 1611, 1591, 1513, 1455, 1196, 813 cmꢂ1 1H
;
4.1.5.4. (2E)-3-(1,3-benzodioxol-5-yl)-1-(3-hydroxyphenyl)prop-2-en-
NMR (400 MHz, CDCl3)
d
1.89 (2H, q, J ¼ 7.6 Hz, H-8), 2.55 (2H, t,
1-one (19). To
a
solution of (1.36 g, 10 mmol) 40-hydrox-
J ¼ 7.6 Hz, H-7), 2.56 (2H, t, J ¼ 7.6 Hz, H-70), 3.76 (3H, s, CH3O-30),
3.86 (3H, s, CH3O-5), 5.49 (2H, br s, HO-3, HO-40), 6.24 (2H, m, H-2,
H-4), 6.32 (1H, d, J ¼ 3.0 Hz, H-20), 6.67 (2H, m, H-6, H-60), 6.83 (1H,
yacetophenone (27c), (1.5 g, 10 mmol) of 3,4-(methylenedioxy)
benzaldehyde (24c) in ethanol (15 mL), an aqueous solution of KOH
(40%, 5 mL) was added slowly. The mixture was stirred and heated to
reflux for 10 h, and then the suspension was poured into ice-water.
The precipitate was filtered and dried to yield (E)-30-hydroxy-3,4-
methylenedioxydiphenylpropenone (19) (1.7 g, 63.7%) as an amor-
phous yellow powder; UV (MeOH) lmax 361, 206 nm; IR (KBr) vmax
d, J ¼ 8.0 Hz, H-50). 13C NMR (100 MHz, CDCl3)
d 32.8 (C-8), 35.0 (C-7,
C-70), 35.4 (C-7, C-70), 55.2 (CH3O-30), 55.9 (CH3O-5), 98.2 (C-4),
106.8 (C-6), 107.9 (C-2), 111.0 (C-20), 114.2 (C-50), 120.9 (C-60), 134.2
(C-10), 143.6 (C-1), 145.1 (C-40), 146.3 (C-30), 156.6 (C-3), 160.8 (C-5);
EM-IE (m/z) 288 [Mþ (9)], 150 (4), 138 (100), 122 (4), 77 (7), 65 (4).
HREIMS [M]þ(m/z) 288.3378 (calcd for C17H20O4 288.3380).
3406, 2945, 1644, 1563 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 5.18 (1H,
br s, HO-30), 6.07 (2H, s, eOCH2Oe), 6.89 (1H, d, J ¼ 7.9 Hz, H-5), 6.92
(1H, dd, J ¼ 7.3, 3.8 Hz, H-40), 7.09 (1H, dd, J ¼ 8.2, 1.6 Hz, H-60), 7.18
(1H, dd, J ¼ 7.9,1.8 Hz, H-6), 7.27 (1H, d, J ¼ 2.0 Hz, H-2), 7.37 (1H, dd,
4.2. Biological study
J ¼ 5.6, 4.9 Hz, H-20), 7.45 (1H, d, J ¼ 15.6 Hz, ]CH-
a
),7.59 (1H, t,
4.2.1. Phosphodiesterase activity assay
Phosphodiesteraseactivitywasmeasuredaccordingtothemethod
described by Rivero and coworkers with some modifications [12].
J ¼ 7.8 Hz, H-50),7.88 (1H, d, J ¼ 15.8 Hz, ]CH-
b
). HREIMS [M]þ(m/z)
268.2639 (calcd for C16H12O4 268.2640).