Journal of Medicinal Chemistry
Article
sealed, purged, and backfilled with nitrogen. The reaction mixture
subjected to microwave irradiation for 2 h at 150 °C. Upon com-
pletion, the reaction was diluted with EtOAc and washed with water
and brine. The combined organic layer was dried over anhydrous
MgSO4, filtered, and concentrated in vacuo to give a red brown
residue, which was purified by column chromatography (SiO2, 0−30%
EtOAc/heptane) to afford (E)-tert-butyl 3-(4-((6-methoxy-2-(4-
(trifluoromethyl)phenyl)benzo[b]thiophen-3 yl)oxy)phenyl)acrylate
(59.4 mg, 86% yield). 1H NMR (400 MHz, CD3OD) δ ppm =
1.42−1.61 (m, 9H), 3.77−3.98 (m, 3H), 6.31 (d, J = 15.66 Hz, 1H),
6.87−7.04 (m, 3H), 7.28 (d, J = 9.09 Hz, 1H), 7.46 (d, J = 2.53
Hz, 1H), 7.47−7.57 (m, 3H), 7.65 (d, J = 8.08 Hz, 2H), 7.89 (d, J =
8.08 Hz, 2H). LC/MS ESI m/z 471.4 [M + H]+.
thiophen-3-yl)oxy)phenyl)acrylate using the procedure described for
the synthesis of 53d, step 2. H NMR (400 MHz, CD3OD) δ ppm =
1
1.37 (s, 6H), 3.09 (s, 2H), 6.40 (d, J = 15.66 Hz, 1H), 6.71 (dd, J =
8.59, 2.02 Hz, 1H), 6.79 (d, J = 8.59 Hz, 2H), 6.98 (d, J = 2.02
Hz, 1H), 7.04 (d, J = 8.59 Hz, 1H), 7.16−7.23 (m, 1H), 7.28 (t, J =
7.58 Hz, 2H), 7.35 (d, J = 16.17 Hz, 1H), 7.37−7.41 (m, 2H), 7.44
(d, J = 9.09 Hz, 2H). HRMS ESI m/z 445.1465 [M + H]+.
(E)-3-(4-((6-Hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-
yl)oxy)phenyl)acrylic Acid (53h). Step 1: The intermediate was
prepared in 85% yield from (E)-tert-butyl 3-(4-((6-methoxybenzo[b]-
thiophen-3-yl)oxy)phenyl)acrylate and 1-bromo-2-isopropylbenzene
using the procedure described for the synthesis of 53d, step 1. LC/
MS ESI m/z 445.0 [M − t-Bu + H]+.
Step 2: The title compound was prepared in 35% yield from tert-
butyl (E)-3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-
3-yl)oxy)phenyl)acrylate using the procedure described for the
Step 2: To a 2-dram vial containing (E)-tert-butyl 3-(4-((6-
methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3 yl)oxy)-
phenyl)acrylate (59.4 mg, 0.113 mmol) in anhydrous DCM (1.5 mL)
at 0 °C was added BBr3 (1.0 M in DCM, 451 μL, 0.451 mmol) dropwise.
The resulting mixture was stirred at 0 °C for 1 h, after which the
reaction was quenched with 3 drops of water, diluted with DCM, and
extracted with sat. aq. NaHCO3 (added a few drops of 2-propanol).
The organic layer was dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo to afford the curde material, which was purified by
reverse phase HPLC (neutral conditions, 3% 1-propanol in 10−100%
CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)-
phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (33.8 mg,
1
synthesis of 53d, step 2. H NMR (400 MHz, CD3OD) δ ppm =
1.16 (d, J = 6.57 Hz, 6H), 3.23 (m, 1H), 6.31 (d, J = 15.66 Hz, 1H),
6.82−6.88 (m, 3H), 7.09−7.15 (m, 1H), 7.22−7.38 (m, 5H), 7.45
(d, J = 8.59 Hz, 2H), 7.57 (d, J = 16.17 Hz, 1H). 13C NMR (100 MHz,
CD3OD) δ ppm = 24.68, 31.65, 108.86, 115.94, 117.17, 117.84,
123.05, 126.62, 126.82, 126.88, 126.95, 130.05, 130.46, 130.78, 130.95,
132.51, 139.99, 141.70, 145.69, 150.19, 157.33, 161.41, 170.83. HRMS
ESI m/z 431.1309 [M + H]+.
(E)-3-(4-((2-(4-Fluoro-2-methylphenyl)-6-hydroxybenzo[b]-
thiophen-3-yl)oxy)phenyl)-acrylic Acid (53i). Step 1: The inter-
mediate was prepared in 95% yield from (E)-tert-butyl 3-(4-((6-
methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate and 1-bromo-4-
fluoro-2-methylbenzene using the procedure described for the
synthesis of 53d, step 1. LC/MS ESI m/z 435.3 [M − t-Bu + H]+.
Step 2: The title compound was prepared in 63% yield from tert-
butyl (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]-
thiophen-3-yl)oxy)phenyl)acrylate using the procedure described for
1
66% yield) as a white solid. H NMR (400 MHz, CD3OD) δ ppm =
6.36 (d, J = 16.17 Hz, 1H), 6.78−6.89 (m, 1H), 6.98 (d, J = 8.59
Hz, 2H), 7.17−7.30 (m, 2H), 7.51−7.70 (m, 5H), 7.88 (d, J = 8.08
Hz, 2H). HRMS ESI m/z 457.0710 [M + H]+.
(E)-3-(4-((6-Hydroxy-2-(o-tolyl)benzo-[b]thiophen-3-yl)oxy)-
phenyl)acrylic Acid (53e). Step 1: The intermediate was prepared in
97% yield from (E)-tert-butyl 3-(4-((6-methoxybenzo[b]thiophen-3-
yl)oxy)phenyl)acrylate and 1-bromo-2-methylbenzene using the pro-
cedure described for the synthesis of 53d, step 1. LC/MS ESI m/z
417.3 [M − t-Bu + H]+.
Step 2: The title compound was prepared in 52% yield from tert-
butyl (E)-3-(4-((6-methoxy-2-(o-tolyl)benzo[b]thiophen-3-yl)oxy)-
phenyl)acrylate using the procedure described for the synthesis of
53d, step 2. 1H NMR (400 MHz, CD3OD) δ ppm = 2.35 (s, 3H), 6.34
(d, J = 15.66 Hz, 1H), 6.76−6.82 (m, 2H), 6.84 (dd, J = 8.84, 2.27
Hz, 1H), 7.13 (d, J = 8.08 Hz, 1H), 7.16−7.38 (m, 8H). 13C NMR
(100 MHz, CD3OD) δ ppm = 20.82, 108.88, 115.93, 117.13, 117.85,
123.05, 126.63, 126.83, 127.13, 129.92, 130.11, 130.93, 131.45, 132.18,
132.30, 139.10, 140.03, 141.62, 145.69, 157.37, 161.29, 170.82. HRMS
ESI m/z 403.0995 [M + H]+.
1
the synthesis of 53d, step 2. H NMR (400 MHz, CD3OD) δ ppm =
2.35 (s, 3H), 6.32 (d, J = 15.66 Hz, 1H), 6.81−6.92 (m, 4H), 6.98
(dd, J = 9.60, 2.53 Hz, 1H), 7.24 (d, J = 2.02 Hz, 1H), 7.27 (d, J = 8.59
Hz, 1H), 7.31 (dd, J = 8.59, 5.56 Hz, 1H), 7.42−7.49 (m, 2H), 7.56
(d, J = 16.17 Hz, 1H). 13C NMR (100 MHz, CD3OD) δ ppm = 20.87,
108.89, 113.59, 113.80, 116.02, 117.15, 117.80, 117.93, 118.02, 123.10,
125.36, 127.00, 130.98, 134.01, 134.10, 140.04, 142.05, 145.65, 157.49,
161.22, 163.09, 165.54, 170.79. HRMS ESI m/z 421.0911 [M + H]+.
(E)-3-(4-((6-Hydroxy-2-(2-(trifluoromethyl)-phenyl)benzo[b]-
thiophen-3-yl)oxy)phenyl)-acrylic Acid (53j). Step 1: The inter-
mediate was prepared in 78% yield from (E)-tert-butyl 3-(4-((6-
methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate and 1-bromo-2-
(trifluoromethyl)benzene using the procedure described for the
synthesis of 53d, step 1. LC/MS ESI m/z 471.4 [M − t-Bu + H]+.
Step 2: The title compound was prepared in 59% yield from tert-
butyl (E)-3-(4-((6-methoxy-2-(2-(trifluoromethyl)phenyl)benzo[b]-
thiophen-3-yl)oxy)phenyl)acrylate using the procedure described for
(E)-3-(4-((2-(2-Ethylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)-
oxy)phenyl)-acrylic Acid (53f). Step 1: The intermediate was prepared
in 89% yield from (E)-tert-butyl 3-(4-((6-methoxybenzo[b]thiophen-
3-yl)oxy)phenyl)acrylate and 1-bromo-2-ethylbenzene using the
procedure described for the synthesis of 53d, step 1. LC/MS ESI
m/z 431.4 [M − t-Bu + H]+.
1
the synthesis of 53d, step 2. H NMR (400 MHz, CD3OD) δ ppm =
6.32 (d, J = 15.66 Hz, 1H), 6.78−6.91 (m, 3H), 7.16−7.28 (m, 2H),
7.45 (d, J = 9.09 Hz, 2H), 7.49−7.62 (m, 4H), 7.70−7.81 (m, 1H).
13C NMR (100 MHz, CD3OD) δ ppm = 108.68, 116.11, 117.42,
Step 2: The title compound was prepared in 42% yield from tert-
butyl (E)-3-(4-((2-(2-ethylphenyl)-6-methoxybenzo[b]thiophen-3-
yl)oxy)phenyl)acrylate using the procedure described for the synthesis
1
of 53d, step 2. H NMR (400 MHz, CD3OD) δ ppm = 1.14 (t, J =
118.06, 123.27, 123.39, 126.27, 127.53, 127.58, 127.63, 127.68, 130.27,
130.48, 130.93, 131.33, 131.38, 131.63, 132.95, 135.09, 140.31, 143.10,
145.59, 157.67, 161.24, 170.82. HRMS ESI m/z 457.0702 [M + H]+.
(E)-3-(4-((2-(4-Fluoro-2-(trifluoromethyl)-phenyl)-6-hydroxy-
benzo[b]thiophen-3-yl)oxy)phenyl)acrylic Acid (53k). Step 1: The
intermediate was prepared in 94% yield from (E)-tert-butyl 3-(4-((6-
methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate and 1-bromo-4-
fluoro-2-(trifluoromethyl)benzene using the procedure described for
the synthesis of 53d, step 1. LC/MS ESI m/z 489.3 [M − t-Bu + H]+.
Step 2: The title compound was prepared in 36% yield from tert-
butyl (E)-3-(4-((2-(4-fluoro-2-(trifluoromethyl)phenyl)-6-
methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate using the proce-
7.58 Hz, 3H), 2.73 (q, J = 7.58 Hz, 2H), 6.34 (d, J = 15.66 Hz, 1H),
6.79 (d, J = 8.59 Hz, 2H), 6.85 (dd, J = 8.59, 2.02 Hz, 1H), 7.09−7.17
(m, 1H), 7.22 (d, J = 2.02 Hz, 1H), 7.23−7.30 (m, 5H), 7.34 (d, J =
9.09 Hz, 2H). 13C NMR (100 MHz, CD3OD) δ ppm = 16.08, 27.78,
108.83, 115.84, 117.03, 123.17, 124.87, 126.41, 126.75, 127.14, 129.89,
130.02, 130.15, 131.52, 131.63, 132.59, 139.94, 140.50, 141.92, 145.42,
157.28, 160.35, 175.75. HRMS ESI m/z 417.1148 [M + H]+.
(E)-3-(4-((2-(2-(tert-Butyl)phenyl)-6-hydroxybenzo[b]thiophen-3-
yl)oxy)phenyl)-acrylic Acid (53g). Step 1: The intermediate was
prepared in 53% yield from (E)-tert-butyl 3-(4-((6-methoxybenzo[b]-
thiophen-3-yl)oxy)phenyl)acrylate and 1-bromo-2-(tert-butyl)benzene
using the procedure described for the synthesis of 53d, step 1. LC/MS
ESI m/z 459.4 [M − t-Bu + H]+.
1
dure described for the synthesis of 53d, step 2. H NMR (400 MHz,
DMSO-d6) δ ppm = 6.37 (d, J = 15.66 Hz, 1H), 6.84−6.92 (m, 3H),
7.15 (d, J = 8.59 Hz, 1H), 7.35 (d, J = 2.02 Hz, 1H), 7.49 (d, J = 16.17
Hz, 1H), 7.53−7.62 (m, 3H), 7.68 (dd, J = 8.59, 5.56 Hz, 1H),
Step 2: The title compound was prepared in 20% yield from tert-
butyl (E)-3-(4-((2-(2-(tert-butyl)phenyl)-6-methoxybenzo[b]-
W
J. Med. Chem. XXXX, XXX, XXX−XXX