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M. Saitoh et al. / Bioorg. Med. Chem. 17 (2009) 2017–2029
147 °C; 1H NMR (DMSO-d6) d 3.86 (3H, s), 4.62 (2H, s), 7.25 (2H, d,
J = 8.4 Hz), 7.67–7.79 (4H, m), 8.11 (1H, s), 9.37 (1H, t, J = 1.2 Hz);
Anal. Calcd for C18H13F3N4O2SÁ0.1H2O: C, 52.96; H, 3.26; N, 13.72.
Found: C, 52.94; H, 3.28; N, 13.42.
7.52–7.58 (1H, m), 7.66–7.74 (2H, m), 7.95 (2H, d, J = 0.9 Hz),
8.08 (1H, t, J = 0.9 Hz), 8.16 (1H, s); Anal. Calcd for C24H17F3N4O2S:
C, 59.75; H, 3.55; N, 11.61. Found: C, 59.73; H, 3.52; N, 11.54.
6.53. 3-[({5-[1-(4-Methoxyphenyl)-1H-benzimidazol-6-yl]-
6.47. 6-(5-{[4-Methoxy-3-(trifluoromethyl)benzyl]sulfanyl}-
1,3,4-oxadiazol-2-yl)quinoline (20r)
1,3,4-oxadiazol-2-yl}sulfanyl)methyl]benzonitrile (20x)
Colorless solid (24%): mp 157–158 °C; 1H NMR (CDCl3) d 3.92
(3H, s), 4.51 (2H, s), 7.11 (2H, d, J = 8.9 Hz), 7.39–7.48 (3H, m),
7.55–7.61 (1H, m), 7.71–7.80 (2H, m), 7.95 (2H, s), 8.05–8.09 (1H,
m), 8.16 (1H, s); Anal. Calcd for C24H17N5O2S: C, 65.59; H, 3.90;
N, 15.94. Found: C, 65.34; H, 3.66; N, 16.04.
The compound 20r was prepared in a manner similar to that de-
scribed for 20p.
Colorless solid (74%): mp 130–131 °C; 1H NMR (CDCl3) d 3.89
(3H, s), 4.53 (2H, s), 6.98 (1H, d, J = 8.5 Hz), 7.50 (1H, dd, J = 4.1,
8.3 Hz), 7.64–7.69 (2H, m), 8.20–8.27 (2H, m), 8.32 (1H, dd,
J = 1.9, 8.9 Hz), 8.46 (1H, d, J = 1.9 Hz), 9.01 (1H, dd, J = 1.7,
4.1 Hz); Anal. Calcd for C20H14F3N3O2S: C, 57.55; H, 3.38; N,
10.07. Found: C, 57.44; H, 3.35; N, 10.11.
6.54. 1-Methyl-6-(5-{[3-(trifluoromethyl)benzyl]sulfanyl}-
1,3,4-oxadiazol-2-yl)-1H-benzimidazole (20y)
The compounds 20s–x were prepared in a manner similar to
that described for 20c.
To a solution of 18h (0.20 g, 1.05 mmol) and Et3N (0.18 ml,
1.26 mmol) in EtOH was added carbon disulfide (0.16 ml,
2.63 mmol), and the mixture was heated at reflux overnight. The
mixture was cooled to 0 °C, added KOH (85%) (58.9 g, 1.05 mmol)
and 3-(trifluoromethyl)benzyl chloride (0.16 ml, 1.03 mmol), and
the mixture was stirred overnight at room temperature. The reac-
tion mixture was diluted with EtOAc and the organic layer was
washed with water and brine, dried over MgSO4 and concentrated
in vacuo. The residue was purified by silica gel column chromatog-
raphy (hexane–EtOAc) to give 20y (49.9 mg, 12%) as a colorless so-
lid: mp 126–127 °C; 1H NMR (CDCl3) d 3.92 (3H, s), 4.57 (2H, s),
7.44–7.51 (1H, m), 7.54–7.60 (1H, m), 7.68–7.77 (2H, m), 7.85–
7.93 (2H, m), 7.99 (1H, br s), 8.09 (1H, br s); Anal. Calcd for
C18H13F3N4OS: C, 55.38; H, 3.86; N, 14.35. Found: C, 55.18; H,
3.45; N, 14.11.
6.48. 2-[3-(4-Methoxyphenyl)-1-benzofuran-5-yl]-5-{[4-
methoxy-3-(trifluoromethyl)benzyl]sulfanyl}-1,3,4-oxadiazole
(20s)
Colorlesssolid (91%): mp162–163 °C;1H NMR(CDCl3) d 3.88 (6H,
s), 4.50 (2H, s), 6.96 (1H, d, J = 8.1 Hz), 7.02–7.07 (2H, m), 7.55–7.60
(2H, m), 7.61–7.66 (3H, m), 7.80 (1H, s), 8.00 (1H, dd, J = 1.7, 8.7 Hz),
8.43 (1H, dd, J = 0.6, 1.7 Hz). Anal. Calcd for C26H19F3N2O4S: C, 60.93;
H, 3.74; N, 5.47. Found: C, 60.95; H, 3.95; N, 5.36.
6.49. 2-[3-(4-Methoxyphenyl)-1-benzofuran-5-yl]-5-{[3-
(trifluoromethyl)benzyl]sulfanyl}-1,3,4-oxadiazole (20t)
Colorless solid (94%); mp 119–120 °C; 1H NMR (CDCl3) d 3.88
(3H, s), 4.56 (2H, s), 7.02–7.07 (2H, m), 7.46 (1H, t, J = 7.7 Hz),
7.54–7.59 (3H, m), 7.63 (1H, dd, J = 0.6, 8.7 Hz), 7.69–7.74 (2H,
m), 7.80 (1H, s), 7.99 (1H, dd, J = 1.7, 8.7 Hz), 8.42 (1H, dd, J = 0.6,
1.7 Hz); Anal. Calcd for C25H17F3N2O3S: C, 62.23; H, 3.55; N, 5.81.
Found: C, 62.23; H, 3.66; N, 5.77.
6.55. 2-(2,3-Dihydro-1-benzofuran-5-yl)-5-[2-(3-
fluorophenyl)ethyl]-1,3,4-oxadiazole (21)
To a solution of 18a (0.50 g, 2.81 mmol) and 3-(3-fluoro-
phenyl)propionic acid (0.47 g, 2.81 mmol) was added POCl3
(3 ml), and the mixture was stirred overnight at 100 °C. The reac-
tion mixture was cooled to room temperature, poured into a mix-
ture of cold water and saturated aqueous NaHCO3 solution, and the
water layer was extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(hexane–EtOAc) to give 21 (0.51 g, 59%) as a colorless solid: mp
85–86 °C; 1H NMR (CDCl3) d 3.07–3.22 (4H, m), 3.28 (2H, t,
J = 8.8 Hz), 4.66 (2H, t, J = 8.8 Hz), 6.86 (1H, d, J = 8.7 Hz), 6.89–
7.06 (3H, m), 7.19–7.32 (1H, m), 7.77 (1H, dd, J = 1.7, 8.3 Hz),
7.86 (1H, d, J = 1.7 Hz); LC–MS (ESI+) 311; Anal. Calcd for
C18H15FN2O2: C, 69.67; H, 4.87; N, 9.03. Found: C, 69.66; H, 4.98;
N, 9.01.
6.50. 3-[({5-[3-(4-Methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-
oxadiazol-2-yl}sulfanyl)methyl]benzonitrile (20u)
Colorless solid (87%); 145–146 °C; 1H NMR (CDCl3) d 3.88 (3H,
s), 4.52 (2H, s), 7.03–7.07 (2H, m), 7.45 (1H, dt, J = 0.4, 7.7 Hz),
7.54–7.60 (3H, m), 7.63 (1H, dd, J = 0.6, 8.7 Hz), 7.74–7.81 (3H,
m), 7.99 (1H, dd, J = 1.7, 8.7 Hz), 8.41 (1H, dd, J = 0.6, 1.7 Hz); Anal.
Calcd for C25H17N3O3S: C, 68.32; H, 3.90; N, 9.56. Found: C, 68.36;
H, 3.87; N, 9.56.
6.51. 1-(4-Methoxyphenyl)-6-(5-{[4-methoxy-3-
(trifluoromethyl)benzyl]sulfanyl}-1,3,4-oxadiazol-2-yl)-1H-
benzimidazole (20v)
6.56. 2-(2,3-Dihydro-1-benzofuran-5-ylcarbonyl)-N-(3-
fluorobenzyl)hydrazinecarboxamide (22)
Colorless solid (34%): mp 163–164 °C; 1H NMR (CDCl3) d 3.88
(3H, s), 3.91 (3H, s), 4.49 (2H, s), 6.95 (1H, d, J = 8.3 Hz), 7.11 (2H,
d, J = 9.0 Hz), 7.43 (2H, d, J = 9.0 Hz), 7.59–7.67 (2H, m), 7.95 (2H,
d, J = 1.0 Hz), 8.09 (1H, t, J = 1.0 Hz), 8.16 (1H, s); Anal. Calcd for
C25H19F3N4O3S: C, 58.59; H, 3.74; N, 10.93. Found: C, 58.38; H,
3.87; N, 10.69.
To a solution of 18a (0.50 g, 2.81 mmol) in pyridine (5 ml) was
added 3-fluorobenzyl isocyanate (0.85 g, 5.61 mmol) and the mix-
ture was stirred overnight at room temperature. The reaction mix-
ture was diluted with EtOAc and the organic layer was washed
with water and brine, dried over MgSO4 and concentrated in vacuo.
The product was washed with EtOAc to give 22 (0.60 g, 65%) as a
colorless solid: mp 200–201 °C; 1H NMR (DMSO-d6) d 3.21 (2H, t,
J = 8.7 Hz), 4.25 (2H, d, J = 6.0 Hz), 4.60 (2H, t, J = 8.7 Hz), 6.83
(1H, d, J = 8.3 Hz), 6.96–7.17 (4H, m), 7.27–7.40 (1H, m), 7.68–
7.76 (1H, m), 7.81 (1H, s), 7.96 (1H, s), 9.99 (1H, s). Anal. Calcd
for C17H16FN3O3: C, 62.00; H, 4.90; N, 12.76. Found: C, 61.92; H,
4.84; N, 12.69.
6.52. 1-(4-Methoxyphenyl)-6-(5-{[3-
(trifluoromethyl)benzyl]sulfanyl}-1,3,4-oxadiazol-2-yl)-1H-
benzimidazole (20w)
Colorless solid (61%): mp 174–175 °C; 1H NMR (CDCl3) d 3.92
(3H, s), 4.55 (2H, s), 7.11 (2H, d, J = 8.9 Hz), 7.40–7.49 (3H, m),