Benzofuran Derivatives
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5291
quenched by addition of brine (400 mL), and the mixture was
extracted with ethyl acetate. The combined organic layer was
sequentially washed with water, 5% citric acid, water, and
brine and dried over MgSO4. Removal of the solvent afforded
an oily residue, which was purified by silica gel chromatog-
raphy (AcOEt/n-hexane ) 1/2) to afford 37 (15.0 g, 78%).
Colorless oil; 1H NMR (CDCl3) δ 1.45-1.90 (6H, m), 3.56 (1H,
m), 3.69 (3H, s), 3.76 (2H, s), 3.90 (1H, m), 4.01 (3H, s), 4.70
(1H, d, J ) 13.0 Hz), 4.72 (1H, t, J ) 3.0 Hz), 4.85 (1H, d, J )
13.0 Hz), 6.81 (1H, dd, J ) 1.0, 8.0 Hz), 7.11-7.20 (2H, m); IR
(neat) 1742 cm-1 (COOMe); LR-MS (EI) 334 (M+).
2-[7-Methoxy-2-(tetrahydropyran-2-yloxymethyl)ben-
zofuran-3-yl]ethanol (38). By the procedure used in 26,
compound 38 (51%) was prepared from 37. Pale-yellow oil;
1H NMR (CDCl3) δ 1.49-1.87 (6H, m), 2.98 (2H, t, J )
6.0 Hz), 3.57 (1H, m), 3.87 (2H, t, J ) 6.0 Hz), 3.92 (1H, m),
4.01 (3H, s), 4.64 (1H, d, J ) 13.0 Hz), 4 81 (1H, t, J )
3.0 Hz), 4.86 (1H, d, J ) 13.0 Hz), 6.83 (1H, dd, J ) 1.0,
8.0 Hz), 7.12 (1H, dd, J ) 1.0, 8.0 Hz), 7.17 (1H, t, J )
8.0 Hz); IR (neat) 1734 cm-1 (COOMe); LR-MS (EI) 306 (M+).
m), 2.33 (2H, q, J ) 7.0 Hz), 2.40 (2H, t, J ) 7.0 Hz), 2.69
(2H, t, J ) 7.0 Hz), 3.54 (1H, m), 3.80 (3H, s), 3.88 (1H, m),
4.52 (1H, d, J ) 13.0 Hz), 4.68 (1H, t, J ) 3.0 Hz), 4.71 (1H,
d, J ) 13.0 Hz), 4.87 (2H, s), 6.73 (1H, dd, J ) 1.0, 8.0 Hz),
6.84 (1H, dd, J ) 1.0, 8.0 Hz), 7.05 (1H, t, J ) 8.0 Hz), 7.16-
7.29 (m, 6H), 7.33 (m, 4H); LR-MS (FAB, positive) 597 (M+
Na).
+
[3-[2-(1,1-Diphenylbutylsulfanyl)ethyl]-2-(tetrahydro-
pyran-2-yloxymethyl)benzofuran-7-yloxy]acetic Acid
Methyl Ester (40d). By the procedure used in 40b, compound
40d (86%) was synthesized from 39. Colorless oil; 1H NMR
(CDCl3) δ 0.82 (3H, t, J ) 7.0 Hz), 1.14 (2H, m), 1.45-1.88
(6H, m), 2.25 (2H, m), 2.41 (2H, t, J ) 7.0 Hz), 2.68 (2H, t,
J ) 7.0 Hz), 3.53 (1H, m), 3.80 (3H, s), 3.88 (1H, m), 4.52 (1H,
d, J ) 13.0 Hz), 4.68 (1H, t, J ) 3.0 Hz), 4.70 (1H, d, J )
13.0 Hz), 4.87 (2H, s), 6.73 (1H, dd, J ) 1.0, 8.0 Hz), 6.84 (1H,
dd, J ) 1.0, 8.0 Hz), 7.45 (1H, t, J ) 8.0 Hz), 7.16-7.28 (6H,
m), 7.34 (4H, m); LR-MS (FAB, positive) 611 (M+ + Na).
{2-(Tetrahydropyran-2-yloxymethyl)-3-[2-(2,2,2-triflu-
oro-1,1-diphenylethylsulfanyl)ethyl]benzofuran-7-yloxy}-
acetic Acid Methyl Ester (40e). By the procedure used in
40b, compound 40e (56%) was synthesized from 39. Colorless
[3-(2-Hydroxyethyl)-2-(tetrahydropyran-2-yloxymeth-
yl)benzofuran-7-yloxy]acetic Acid Methyl Ester (39). To
a stirred mixture of t-BuOK (9.71 g, 87 mmol) and 38 (7.67 g,
25 mmol) in DMF (150 mL) was added n-PrSH (8.50 mL,
94 mmol), and the reaction mixture was stirred at 140 °C for
1 h. The solvent was removed under reduced pressure, and
the residue was poured into 5% citric acid and extracted with
ethyl acetate. The combined organic layer was sequentially
washed with water and brine and dried over MgSO4. Removal
of the solvent afforded an oily residue, which was dissolved in
DMF (100 mL). To this solution was added K2CO3 (10.23 g,
74 mmol) and methyl bromoacetate (5.0 mL, 54 mmol), and
the reaction mixture was stirred at room temperature for
15 h. The solvent was removed under reduced pressure, and
the residue was poured into 5% citric acid and was extracted
with ethyl acetate. The combined organic layer was sequen-
tially washed with water and brine and dried over MgSO4.
Removal of the solvent afforded an oily residue, which was
purified by silica gel chromatography (AcOEt/n-hexane ) 1/1,
1
oil; H NMR (CDCl3) δ 1.42-1.95 (6H, m), 2.59 (2H, m), 2.78
(2H, m), 3.56 (1H, m), 3.80 (3H, s), 3.89 (1H, m), 4.53 (1H, d,
J ) 13.0 Hz), 4.68 (1H, t, J ) 3.3 Hz), 4.72 (1H, d, J )
13.0 Hz), 4.87 (2H, s), 6.73 (1H, dd, J ) 0.8, 7.9 Hz), 6.78 (1H,
dd, J ) 0.8, 7.9 Hz), 7.03 (1H, t, J ) 8.0 Hz), 7.25-7.30 (6H,
m), 7.36-7.42 (4H, m); LR-MS (EI) 614 (M+).
General Procedure for Deprotection of the THP
Group.
[3-[2-(1,1-Diphenylethylsulfanyl)ethyl]-2-hy-
droxymethylbenzofuran-7-yloxy]acetic Acid Methyl
Ester (41b). To a stirred solutoin of 40b (550 mg, 0.98 mmol)
in THF (10 mL) and MeOH (10 mL) was added pyridinium
p-toluenesulfonate (103 mg, 0.41 mmol), and the reaction
mixture was stirred at 80 °C for 6.5 h. The solvent was
removed under reduced pressure, and the residue was poured
into 5% citric acid and was extracted with ethyl acetate. The
combined organic layer was sequentially washed with water
and brine and was dried over MgSO4. Removal of the solvent
afforded an oily residue, which was purified by silica gel
1
then 2/1) to afford 39 (7.54 g, 84%). Pale-yellow oil; H NMR
(CDCl3) δ 1.47-1.88 (6H, m), 2.31 (1H, t, J ) 3.0 Hz), 2.98
(2H, t, J ) 6.0 Hz), 3.81 (3H, s), 3.83-3.96 (3H, m), 4.65 (1H,
d, J ) 13.0 Hz), 4.81 (1H, t, J ) 3.0 Hz), 4.85 (1H, d, J )
13.0 Hz), 4.90 (2H, s), 6.78 (1H, dd, J ) 1.5, 7.5 Hz), 7.14 (1H,
t, J ) 7.5 Hz), 7.18 (1H, dd, J ) 1.5, 7.5 Hz); IR (neat)
1763 cm-1 (COOMe); LR-MS (EI) 364 (M+).
chromatography (AcOEt/n-hexane
) 1/1) to afford 41b
1
(387 mg, 83%). Colorless oil; H NMR (CDCl3) δ 2.00 (3H, s),
2.26 (1H, t, J ) 6.5 Hz), 2.60 (2H, m), 2.69 (2H, m), 3.81 (3H,
s), 4.63 (2H, d, J ) 6.5 Hz), 4.88 (2H, s), 6.74 (1H, dd, J ) 1.0,
7.0 Hz), 6.92 (1H, dd, J ) 1.0, 7.0 Hz), 7.07 (1H, t, J )
7.0 Hz), 7.16-7.29 (6H, m), 7.34 (m, 4H); LR-MS (FAB,
positive) 477 (M+ + H).
[3-[2-(1,1-Diphenylethylsulfanyl)ethyl]-2-(tetrahydro-
pyran-2-yloxymethyl)benzofuran-7-yloxy]acetic Acid
Methyl Ester (40b). Compound 39 was mesylated by the
procedure used in 28. And by the procedure used in 23d,
compound 40b (80% in two steps) was synthesized from 39.
Colorless oil; 1H NMR (CDCl3) δ 1.47-1.82 (6H, m), 2.04 (3H,
s), 2.57 (2H, t, J ) 7.0 Hz), 2.77 (2H, t. J ) 7.0 Hz), 3.54 (1H,
m), 3.80 (3H, s), 3.89 (1H, m), 4.55 (1H, d, J ) 13.0 Hz), 4.68
(1H, t, J ) 3.0 Hz), 4.73 (1H, d, J ) 13.0 Hz), 4.87 (2H, s),
6.74 (1H, dd, J ) 1.0, 8.0 Hz), 6.89 (1H, dd, J ) 1.0, 8.0 Hz),
7.06 (1H, t. J ) 8.0 Hz), 7.18-7.30 (6H, m), 7.39 (4H, m);
LR-MS (FAB, positive) 583 (M+ + Na).
[3-(2-Benzhydrylsulfanylethyl)-2-(tetrahydropyran-2-
yloxymethyl)benzofuran-7-yloxy]acetic Acid Methyl
Ester (40a). By the procedure used in 40b, compound 40a
(73%) was synthesized from 39. Colorless oil; 1H NMR (CDCl3)
δ 1.47-1.82 (6H, m), 2.66 (2H, t, J ) 7.0 Hz), 2.95 (2H, t, J )
7.0 Hz), 3.54 (1H, m), 3.80 (3H, s), 3.89 (1H, m), 4.54 (1H, d,
J ) 13.0 Hz), 4.68 (1H, t, J ) 3.0 Hz), 4.72 (1H, d, J )
13.0 Hz), 4.88 (2H, s), 5.15 (1H, s), 6.78 (1H, dd, J ) 1.0,
8.0 Hz), 6.83 (1H, dd, J ) 1.0, 8.0 Hz), 7.08 (1H, t, J )
8.0 Hz), 7.19-7.33 (6H, m), 7.37-7.41 (4H, m); LR-MS (FAB,
positive) 569 (M+ + Na).
[3-(2-Benzhydrylsulfanylethyl)-2-hydroxymethylben-
zofuran-7-yloxy]acetic Acid Methyl Ester (41a). Com-
pound 41a (73%) was prepared from 40a. Colorless oil;
1H NMR (CDCl3) δ 2.15 (1H, t, J ) 7.0 Hz), 2.67 (2H, t, J )
7.0 Hz), 2.92 (2H, t, J ) 7.0 Hz), 3.80 (3H, s), 4.68 (2H, d, J )
7.0 Hz), 4.88 (2H, s), 5.04 (1H, s), 6.81 (1H, dd, J ) 1.0,
8.0 Hz), 6.89 (1H, dd, J ) 1.0, 8.0 Hz), 7.11 (1H, t, J )
8.0 Hz), 7.18-7.36 (10H, m); LR-MS (FAB, positive) 463
(M+ + H).
[3-[2-(1,1-Diphenylpropylsulfanyl)ethyl]-2-hydroxy-
methylbenzofuran-7-yloxy]acetic Acid Methyl Ester (41c).
Compound 41c (78%) was prepared from 40c. Colorless oil;
1H NMR (CDCl3) δ 0.73 (3H, t, J ) 7.0 Hz), 2.27 (1H, t, J )
6.0 Hz), 2.31 (2H, q, J ) 7.0 Hz), 2.47 (2H, m), 2.55 (2H, m),
3.81 (3H, s), 4.59 (2H, d, J ) 6.0 Hz), 4.88 (2H, s), 6.74 (1H,
dd, J ) 1.0, 8.0 Hz), 6.88 (1H, dd, J ) 1.0, 8.0 Hz), 7.06 (1H,
t, J ) 8.0 Hz), 7.14-7.32 (10H, m); LR-MS (FAB, positive) 491
(M+ + H).
[3-[2-(1,1-Diphenylbutylsulfanyl)ethyl]-2-hydroxy-
methylbenzofuran-7-yloxy]acetic Acid Methyl Ester (41d).
Compound 41d (91%) was prepared from 40d. Colorless oil;
1H NMR (CDCl3) δ 0.80 (3H, t, J ) 7.0 Hz), 1.11 (2H, m), 2.23
(2H, m), 2.26 (1H, t, J ) 6.5 Hz), 2.48 (2H, m), 2.55 (2H, m),
3.81 (3H,s), 4.59 (2H, d, J ) 6.5 Hz), 4.88 (2H, s), 6.74 (1H,
dd, J ) 1.0, 8.0 Hz), 6.88 (1H, dd, J ) 1.0, 8.0 Hz), 7.06 (1H,
t, J ) 8.0 Hz), 7.15-7.32 (10H, m); LR-MS (FAB, positive) 505
(M+ + H).
[3-[2-(1,1-Diphenylpropylsulfanyl)ethyl]-2-(tetra-
hydropyran-2-yloxymethyl)benzofuran-7-yloxy]acetic
Acid Methyl Ester (40c). By the procedure used in 40b,
compound 40c (40%) was synthesized from 39. Colorless oil;
1H NMR (CDCl3) δ 0.77 (3H, t, J ) 7.0 Hz), 1.45-1.82 (6H,