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R. Romagnoli et al. / European Journal of Medicinal Chemistry 45 (2010) 5781e5791
temperature, poured in a 0.1 N aqueous HCl solution (10 mL) and
extracted with EtOAc (20 mL). The organic phase was washed twice
with 0.1 N aqueous HCl solution (5 mL), brine (5 mL), dried over
Na2SO4 and concentrated at reduced pressure to furnish a residue
that was purified by flash chromatography on silica gel
(EtOAcepetroleum ether 1.5e8.5).
(CDCl3)d: 2.04 (s, 3H), 3.76 (s, 6H), 3.81 (s, 3H), 6.94 (s, 2H), 7.10 (d,
J ¼ 7.4 Hz, 2H), 7.22 (d, J ¼ 7.4 Hz, 2H), 7.48 (m, 2H), 7.82 (dd, J ¼ 7.2
and 1.0 Hz, 1H), 7.94 (dd, J ¼ 7.2 and 1.0 Hz, 1H). Anal. calcd for
C25H22O4S: C, 71.75; H, 5.30; found: C, 71.58; H, 5.13.
5.1.6.5. (3-(4-Methoxyphenyl)benzo[b]thiophen-2-yl)(3,4,5-trime-
thoxyphenyl)methanone (3e). Following general procedure C, the
residue was purified by chromatography on silica gel (EtOAcepetro-
leumether2e8)to furnishcompound3easayellowoil, yield: 56%.1H
5.1.5.1. (3-Bromobenzo[b]thiophen-2-yl)(3,4,5-trimethoxyphenyl)
methanone (9a). Following general procedure B, the product was
isolated as a purple solid, yield: 85%, mp 105e106 ꢂC 1H NMR
NMR (CDCl3)
d
: 3.76 (s, 6H), 3.77 (s, 3H), 3.81 (s, 3H), 6.79 (d, J ¼ 8.6 Hz,
(CDCl3)
d: 3.90 (s, 6H), 3.92 (s, 3H), 7.22 (s, 2H), 7.55 (m, 2H), 7.86
2H), 6.93 (s, 2H), 7.22 (d, J ¼ 8.6 Hz, 2H), 7.47 (m, 2H), 7.82 (dd, J ¼ 7.4
and 1.0 Hz, 1H), 7.96 (dd, J ¼ 7.4 and 1.0 Hz, 1H). Anal. calcd for
C25H22O5S: C, 69.11; H, 5.10; found: C, 68.89; H, 4.89.
(dd, J ¼ 6.0 and 3.0 Hz, 1H), 7.98 (dd, J ¼ 7.4 and 1.0 Hz, 1H).
5.1.5.2. (3-Bromo-6-methylbenzo[b]thiophen-2-yl)(3,4,5-trimethox-
yphenyl)methanone (9b). Following general procedure B, the
product was isolated as a purple solid, yield: 67%, mp 130e131 ꢂC
5.1.6.6. (3,4,5-Trimethoxyphenyl)(3-(4-(methylthio)phenyl)benzo[b]
thiophen-2-yl)methanone (3f). Following general procedure C, the
residue was purified by chromatography on silica gel (EtOAcepetro-
leum ether 1.5e8.5) to furnish compound 3f as a yellow solid, yield:
1H NMR (CDCl3)
d: 2.54 (s, 3H), 3.89 (s, 6H), 3.93 (s, 3H), 7.20 (s, 2H),
7.33 (d, J ¼ 8.4 Hz, 1H), 7.66 (d, J ¼ 0.8 Hz, 1H), 7.86 (dd, J ¼ 8.4 Hz,
1H).
62%, mp 91e92 ꢂC 1H NMR (CDCl3)
d: 3.77 (s, 9H), 3.83 (s, 3H), 6.94 (s,
2H), 7.16 (d, J ¼ 8.6 Hz, 2H), 7.24 (d, J ¼ 8.6 Hz, 2H), 7.47 (m, 2H), 7.82
(dd, J ¼ 7.4 and 1.2 Hz,1H), 7.96 (dd, J ¼ 7.4 and 1.2 Hz,1H). Anal. calcd
for C25H22O4S2: C, 66.64; H, 4.92; found: C, 66.41; H, 4.69.
5.1.6. General procedure (C) for the preparation of compounds
(3aej)
A mixture of benzo[b]thiophene derivative 9a (0.5 mmol),
potassium carbonate (104 mg, 0.75 mmol, 1.5 equiv), the appro-
priate aryl boronic acid (1 mmol, 2 equiv) and tetrakis (triphenyl-
phosphine)palladium (13.5 mg, 0.012 mmol) in dry toluene (10 mL)
was stirred at 100 ꢂC under nitrogen for 18 h, cooled to ambient
temperature and evaporated in vacuo. The residue was dissolved
with dichloromethane (20 mL), and the resultant solution was
washed sequentially with a 2 M aqueous K2CO3 solution (5 mL),
water (5 mL) and brine (5 mL). The organic layer was dried, filtered
and evaporated, and the residue was purified by flash chromatog-
raphy on silica gel.
5.1.6.7. (3-(2-Methoxyphenyl)benzo[b]thiophen-2-yl)(3,4,5-trime-
thoxyphenyl)methanone (3g). Following general procedure C, the
residue was purified by chromatography on silica gel (EtOAcepetro-
leumether2e8)to furnish compound 3gasayellowoil, yield: 45%.1H
NMR (CDCl3)
d
: 3.75 (s, 6H), 3.78 (s, 3H), 3.79 (s, 3H), 6.79 (d, J ¼ 8.2 Hz,
1H), 6.86 (dd, J ¼ 8.6 and 1.0 Hz,1H), 6.93 (s, 2H), 7.24 (m, 2H), 7.42 (m,
2H), 7.64 (dd, J ¼ 7.2 and 0.8 Hz, 1H), 7.91 (dd, J ¼ 7.4 and 1.0 Hz, 1H).
Anal. calcd for C25H22O5S: C, 69.11; H, 5.10; found: C, 68.88; H, 4.92.
5.1.6.8. (3,4,5-Trimethoxyphenyl)(3-(2,4-dimethoxyphenyl)benzo[b]
thiophen-2-yl)methanone (3h). Following general procedure C, the
residue was purified by chromatography on silica gel (EtOAcepetro-
leumether2e8)tofurnishcompound 3hasayellowoil,yield:52%.1H
5.1.6.1. (3,4,5-Trimethoxyphenyl)(3-phenylbenzo[b]thiophen-2-yl)
methanone (3a). Following general procedure C, the residue was
purified by chromatography on silica gel (EtOAcepetroleum ether
1.5e8.5) to furnish compound 3a as a yellow oil, yield: 57%. 1H
NMR (CDCl3)d: 3.76 (s, 3H), 3.79 (s, 3H), 3.81 (s, 6H), 3.84 (s, 3H), 6.72
(d, J ¼ 8.4 Hz,1H), 6.78 (d, J ¼ 8.4 Hz,1H), 6.94 (s, 2H), 7.19 (s,1H), 7.50
(m,2H), 7.74(dd,J¼ 7.4and1.0Hz,1H), 7.90(dd,J¼ 7.4 and 1.0 Hz, 1H).
Anal. calcd for C26H24O6S: C, 67.22; H, 5.21; found: C, 67.02; H, 4.96.
NMR (CDCl3)d: 3.76 (s, 6H), 3.81 (s, 3H), 6.92 (s, 2H), 7.27 (m, 5H),
7.48 (m, 2H), 7.82 (dd, J ¼ 7.4 and 1.0 Hz, 1H), 7.94 (dd, J ¼ 7.4 and
1.0 Hz, 1H). Anal. calcd for C24H20O4S: C, 71.27; H, 4.98; found: C,
71.03; H, 4.69.
5.1.6.9. (3,4,5-Trimethoxyphenyl)(3-(2,5-dimethoxyphenyl)benzo[b]
thiophen-2-yl)methanone (3i). Following general procedure C, the
residue was purified by chromatography on silica gel (EtOAcepetro-
leum ether 4e6) to furnish compound 3i as a yellow oil, yield: 49%.1H
5.1.6.2. (3-(4-Fluororophenyl)benzo[b]thiophen-2-yl)(3,4,5-trime-
thoxyphenyl)methanone (3b). Following general procedure C, the
residue was purified by chromatography on silica gel (EtOAcepetro-
leum ether 1.5e8.5) to furnish compound 3b as a pink oil, yield: 63%.
NMR (CDCl3)d: 3.55 (s, 3H), 3.71 (s, 3H), 3.76 (s, 6H), 3.81 (s, 3H), 6.66
(d, J ¼ 8.4 Hz,1H), 6.72 (d, J ¼ 8.4 Hz,1H), 6.82 (s,1H), 6.94 (s, 2H), 7.44
(m,2H), 7.82(dd,J¼ 7.4and1.0Hz,1H), 7.94(dd,J¼ 7.4and1.0Hz,1H).
Anal. calcd for C26H24O6S: C, 67.22; H, 5.21; found: C, 66.93; H, 4.98.
1H NMR (CDCl3)
d: 3.77 (s, 6H), 3.84 (s, 3H), 6.95 (s, 2H), 7.04 (d,
J ¼ 8.8 Hz, 2H), 7.32 (m, 2H), 7.51 (m, 2H), 7.74 (dd, J ¼ 7.4 and 1.0 Hz,
1H), 7.97 (dd, J ¼ 7.4 and 1.0 Hz, 1H). Anal. calcd for C24H19FO4S: C,
68.23; H, 4.53; found: C, 67.95; H, 4.38.
5.1.6.10. (3-(4-Methoxy-3-methylphenylamino)benzo[b]thiophen-2-
yl)(3,4,5-trimethoxyphenyl)methanone (3j). Following general proce-
dure C, the residue was purified by chromatography on silica gel
(EtOAcepetroleum ether 1.5e8.5) to furnish compound 3j as a yellow
5.1.6.3. (3-(4-Chlorophenyl)benzo[b]thiophen-2-yl)(3,4,5-trimethox-
yphenyl)methanone (3c). Following the general procedure C, the
residue purified by chromatography on silica gel (EtOAcepetro-
leum ether 1.5e8.5) to furnish compound 3c as a yellow oil, yield:
oil, yield: 62%. 1H NMR (CDCl3)
d: 2.11 (s, 3H), 3.75 (s, 3H), 3.79 (s, 6H),
3.86 (s, 3H), 6.62 (d, J ¼ 7.4 Hz, 1H), 6.88 (s, 2H), 7.23 (s, 1H), 7.54 (m,
2H), 7.82 (dd, J ¼ 7.4 and 1.0 Hz, 1H), 7.92 (dd, J ¼ 7.4 and 1.0 Hz, 1H),
10.8 (bs, 1H). Anal. calcd for C26H24O5S: C, 69.62; H, 5.39; found: C,
69.47; H, 5.18.
61%. 1H NMR (CDCl3)
d: 3.78 (s, 6H), 3.85 (s, 3H), 6.76 (s, 2H), 7.24 (m,
2H), 7.49 (m, 4H), 7.82 (dd, J ¼ 7.4 and 1.0 Hz, 1H), 7.94 (dd, J ¼ 7.4
and 1.0 Hz, 1H). Anal. calcd for C24H19ClO4S: C, 65.67; H, 4.36;
found: C, 65.47; H, 4.18.
5.1.6.11. (3-(4-Ethoxyphenyl)benzo[b]thiophen-2-yl)(3,4,5-trimethox-
yphenyl)methanone (3k). Following general procedure C, the residue
was purified by chromatography on silica gel (EtOAcepetroleum ether
2e8) to furnish compound 3k as a yellow oil, yield: 59%. 1H NMR
5.1.6.4. (3,4,5-Trimethoxyphenyl)(3-p-tolylbenzo[b]thiophen-2-yl)
methanone (3d). Following general procedure C, the residue was
purified by chromatography on silica gel (EtOAcepetroleum ether
2e8) to furnish compound 3d as a yellow oil, yield: 62%. 1H NMR
(CDCl3)d: 1.38 (t, J ¼ 7.2 Hz, 3H), 3.76 (s, 6H), 3.81 (s, 3H), 3.96 (q,