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A. Kakefuda et al. / Bioorg. Med. Chem. 10 (2002) 1905–1912
AcOEt=8/1) to give N-(2-methoxyphenyl)thiobutyr-
amide (1.54 g, 57%) as a yellow syrup. A suspension of
the thiobutyramide obtained above (1.53 g, 7.31 mmol),
K2CO3 (3.03 g, 21.9 mmol), and MeI (1.23 mL, 19.7
mmol) in CH3CN (25 mL) was stirred at 50 ꢀC for 3 h.
After cooling at room temperature, the mixture was
concentrated in vacuo. The residue was partitioned
between AcOEt (200 mL) and H2O (150 mL). The
organic layer was washed with saturated NaClaq. (150
mL), and dried and concentrated in vacuo. The residue
was purified by column chromatography on silica gel
(hexane/AcOEt=20/1) to give 8i (1.33 g, 81%) as a
yellow syrup. A solution of 8i (0.818 g, 3.66 mmol) and
4-biphenylcarboxylic hydrazide (0.457 g, 2.15 mmol) in
DMF (8 mL) was stirred at 120 ꢀC for 26 h. After cool-
ing at room temperature, the mixture was concentrated
in vacuo. The residue was purified by column chroma-
tography on silica gel (CHCl3/MeOH=50/1) to give
crude 9i as a yellow syrup. The syrup was crystallized
from AcOEt–hexane to give 9i (0.168 g, 21%) as a col-
orless powder: mp 145–146 ꢀC; 1H NMR (400 MHz,
DMSO-d6) d 0.86 (3H, t, J=7.4 Hz), 1.51–1.63 (2H, m),
2.44 (3H, t, J=7.4 Hz), 3.70 (3H, s), 7.12 (1H, dt,
J=7.6, 1.2 Hz), 7.29 (1H, dd, J=8.4, 1.2 Hz), 7.34–7.39
(1H, m), 7.42–7.47 (4H, m), 7.54–7.60 (1H, m), 7.63–
7.68 (4H, m);MS (FAB) m/z 370 (MH+). Anal. calcd
for C24H23N3O: C, 78.02;H, 6.27;N, 11.37. Found: C,
77.98;H, 6.57;N, 11.40.
3.33 (3H, s), 5.07 (2H, s), 6.96 (2H, d, J=8.7 Hz), 7.09
(1H, t, J=7.2 Hz), 7.25–7.43 (9H, m), 7.51–7.57 (1H,
m), 7.54 (1H, dt, J=7.4, 1.7 Hz);MS (FAB) m/z 372
(MH+). Anal. calcd for C23H21N3O2: C, 74.37;H, 5.70;
N, 11.31. Found: C, 74.37;H, 5.73;N, 11.28.
4-(2-Methoxyphenyl)-3-methyl-5-[4-(pyrrol-1-yl)phenyl]-
1,2,4-triazole (9e). (65%);mp 181–183 ꢀC (AcOEt–hex-
1
ane); H NMR (400 MHz, CDCl3) d 2.29 (3H, s), 3.73
(3H, s), 6.32 (1H, t, J=2.0 Hz), 7.00–7.15 (5H, m), 7.28
(2H, d, J=9.0 Hz), 7.45–7.55 (3H, m), 7.54 (1H, dt,
J=7.4, 1.7 Hz);MS (FAB) m/z 331 (MH+). Anal. calcd
for C20H18N4O: C, 72.71;H, 5.49;N, 16.96. Found: C,
72.70;H, 5.62;N, 16.83.
4-(2-Methoxyphenyl)-3-methyl-5-[4-(piperidino)phenyl]-
1,2,4-triazole (9f). (42%);mp 125–126 ꢀC (AcOEt–hex-
1
ane); H NMR (400 MHz, CDCl3) d 1.50–1.65 (6H, m),
2.24 (3H, s), 3.05–3.15 (4H, m), 3.73 (3H, s), 6.75 (2H,
d, J=9.0 Hz), 6.95–7.10 (3H, m), 7.25–7.30 (2H, m),
7.45–7.50 (1H, m);MS (FAB) m/z 349 (MH+). Anal.
calcd for C21H24N4O: C, 72.39;H, 6.94;N, 16.08.
Found: C, 72.16;H, 6.94;N, 16.06.
4-(2-Methoxyphenyl)-3-methyl-5-[4-(morphorino)phenyl]-
1,2,4-triazole (9g). (31%);mp 190–192 ꢀC (AcOEt–hex-
1
ane); H NMR (400 MHz, CDCl3) d 2.25 (3H, s), 3.14
(4H, t, J=5.0 Hz), 3.73 (3H, s), 3.81 (4H, t, J=5.0 Hz),
6.74 (2H, d, J=9.0 Hz), 6.95–7.15 (3H, m), 7.32 (2H, d,
J=9.0 Hz), 7.45–7.52 (1H, m);MS (FAB) m/z 351
(MH+). Anal. calcd for C20H22N4O2: C, 68.55;H, 6.33;
N, 15.99. Found: C, 68.28;H, 6.51;N, 15.96.
Compounds 9a–h and 9j were prepared by a procedure
similar to that described for 9i. Yields referred to the
final cyclization step.
5-(3-Biphenyl)-4-(2-methoxyphenyl)-3-methyl-1,2,4-tri-
azole (9a). (70%);mp 112–113 ꢀC (Et2O–hexane); 1H
NMR (400 MHz, DMSO-d6) d 2.18 (3H, s), 3.69 (3H, s),
7.14 (1H, dt, J=7.7, 1.2 Hz), 7.30–7.50 (10H, m), 7.56–
7.69 (2H, m);MS (FAB) m/z 342 (MH+). Anal. calcd
for C22H19N3O: C, 77.40;H, 5.61;N, 12.31. Found: C,
77.69;H, 5.55;N, 12.26.
5-(4-Biphenyl)-3-ethyl-4-(2-methoxyphenyl)-1,2,4-triazole
ꢀ
1
(9h). (59%);mp 122–123 C (AcOEt–hexane); H NMR
(400 MHz, DMSO-d6) d 1.14 (3H, t, J=7.5 Hz), 2.43–
2.51 (2H, m), 3.71 (3H, s), 7.12 (1H, t, J=7.7 Hz), 7.29
(1H, d, J=8.4 Hz), 7.34–7.47 (6H, m), 7.54–7.67 (5H,
m);MS (FAB) m/z 356 (MH+). Anal. calcd for
C23H21N3O: C, 77.72;H, 5.96;N, 11.82. Found: C,
77.78;H, 6.09;N, 11.82.
5-(2-Biphenyl)-4-(2-methoxyphenyl)-3-methyl-1,2,4-tri-
azole (9b). (17%);mp 142–143 ꢀC (Et2O–hexane); 1H
NMR (400 MHz, DMSO-d6) d 2.04 (3H, s), 3.44 (3H, s),
6.33 (1H, d, J=7.8 Hz), 6.74 (1H, t, J=7.7 Hz), 6.92–
6.96 (3H, m), 7.23–7.33 (5H, m), 7.38–7.51 (3H, m);MS
(FAB) m/z 342 (MH+). Anal. calcd for C22H19N3O: C,
77.40;H, 5.61;N, 12.31. Found: C, 77.67;H, 5.53;N,
12.28.
4-(2-Benzyloxyphenyl)-5-(4-biphenyl)-3-methyl-1,2,4-tri-
azole (9j). (66%);mp 171–172 ꢀC (AcOEt–hexane); H
1
NMR (400 MHz, CDCl3) d 2.31 (3H, s), 4.95 (1H, d,
J=13.0 Hz), 5.06 (1H, d, J=13.0 Hz), 6.95–7.15 (4H,
m), 7.20–7.60 (14H, m);MS (FAB) m/z 418 (MH+).
Anal. calcd for C28H23N3O: C, 80.55;H, 5.55;N, 10.06.
Found: C, 80.25;H, 5.50;N, 9.91.
4-(2-Methoxyphenyl)-3-methyl-5-(4-phenoxyphenyl)-
1,2,4-triazole (9c). (72%);mp 149–150 ꢀC (AcOEt–hex-
ane); H NMR (400 MHz, DMSO-d6) d 2.13 (3H, s),
3.70 (3H, s), 6.89–6.93 (2H, m), 7.00–7.04 (2H, m), 7.09
(1H, dt, J=7.7, 1.1 Hz), 7.16–7.21 (1H, m), 7.27 (1H,
dd, J=8.4, 0.9 Hz), 7.31–7.44 (5H, m), 7.54 (1H, dt,
J=7.4, 1.7 Hz);MS (FAB) m/z 358 (MH+). Anal. calcd
for C22H19N3O2: C, 73.93;H, 5.36;N, 11.76. Found: C,
73.80;H, 5.35;N, 11.77.
5-(4-Biphenyl)-4-(2-hydroxyphenyl)-3-methyl-1,2,4-tri-
azole (10). To a solution of 9j (0.100 g, 0.240 mmol) in
MeOH (10 mL) was added 10% Pd/C (w/w, 0.080 g),
and the mixture was stirred under hydrogen atmosphere
at room temperature for 2 h. The catalyst was removed
by filtration and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography on
silica gel (CHCl3/MeOH=10/1) to give crude 10 as a col-
orless solid. The solid was recrystallized from AcOEt–
hexane to give 10 (0.055 g, 70%) as a colorless powder: mp
>300 ꢀC; 1H NMR (400 MHz, DMSO-d6) d 2.17 (3H, s),
6.95 (1H, t, J=8.0 Hz), 7.07 (1H, t, J=8.0 Hz), 7.30–7.53
(7H, m), 7.60–7.65 (4H, m), 10.33 (1H, s);MS (FAB) m/z
1
5-(4-Benzyloxyphenyl)-4-(2-methoxyphenyl)-3-methyl-
1,2,4-triazole (9d). (64%);mp 157–158 ꢀC (AcOEt–hex-
1
ane); H NMR (400 MHz, DMSO-d6) d 2.12 (3H, s),