Y. Yonetoku et al. / Bioorg. Med. Chem. 14 (2006) 5370–5383
5381
7.36 (2H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.61
(1H, d, J = 3.9 Hz), 7.66 (1H, s); FAB-MS m/z 400
[(M+H)+].
J = 3.9 Hz), 7.46 (2H, d, J = 8.7 Hz), 7.55 (2H, d,
J = 8.3 Hz); FAB-MS m/z 400 [(M+H)+].
5.36. 40-Chloro-5-(1,5-dimethyl-3-trifluoromethyl-1H-
pyrazol-5-yl)thiophene-2-carboxanilide (17c)
5.31. 40-Chloro-5-(1-isopropyl-3-trifluoromethyl-1H-pyr-
azol-5-yl)thiophene-2-carboxanilide (16h)
The title compound was prepared from 19e by a proce-
dure similar to that described for 7a and 8a (35% from
16c): H NMR (DMSO-d6) d 2.15 (3H, s), 3.91 (3H,
s), 7.44 (2H, d, J = 9.2 Hz), 7.50 (1H, d, J = 4.3 Hz),
7.77 (2H, d, J = 9.1 Hz), 8.14 (1H, d, J = 3.7 Hz),
10.50 (1H, s); FAB-MS m/z 400 [(M+H)+].
1H NMR (CDCl3) d 1.54 (6H, d, J = 6.8 Hz), 4.78 (1H,
sept, J = 6.6 Hz), 6.64 (1H, s), 7.17 (1H, d, J = 3.9 Hz),
7.35 (2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.61
(1H, d, J = 3.4 Hz), 7.67 (1H, s); FAB-MS m/z 414
[(M+H)+].
1
5.32. 40-Chloro-3-(1-methyl-3-trifluoromethyl-1H-pyra-
zol-5-yl)benzanilide (16i)
The following compounds were prepared using similar
methods.
1H NMR (DMSO-d6) d 4.21 (3H, s), 7.03 (1H, s), 7.43
(2H, d, J = 8.8 Hz), 7.71(1H, t, J = 7.8 Hz), 7.82 (2H,
d, J = 8.8 Hz), 7.83–7.87 (1H, m), 8.04–8.08 (1H, m),
8.14 (1H, t, J = 1.5 Hz), 10.43 (1H, s); FAB-MS m/z
380 [(M+H)+].
5.37. 5-(1-Benzyl-3-trifluoromethyl-1H-pyrazol-5-yl)-40-
chlorothiophene-2-carboxanilide (17d) (3.5% from 16d)
1H NMR (CDCl3) d 5.53 (2H, s), 6.76 (1H, s), 7.01 (1H,
d, J = 3.9 Hz), 7.05–7.09 (2H, m), 7.30–7.36 (5H, m),
7.51 (1H, d, J = 3.9 Hz), 7.55 (2H, d, J = 9.3 Hz), 7.60
(1H, s); FAB-MS m/z 462 [(M+H)+].
5.33. 40-Chloro-5-(1,3-dimethyl-1H-pyrazol-5-yl)thio-
phene-2-carboxanilide (16b)
5.38. 5-{5-[(4-Chloroanilino)methyl]-2-thienyl}-1-methyl-
3-trifluoromethyl-1H-pyrazole (20)
A
mixture of 5-(1,3-dimethyl-1H-pyrazol-5-yl)thio-
phene-2-carboxylic acid (12b, 202 mg, 0.909 mmol,
accompanied with regioisomer), oxalyl chloride
(127 lL, 1.45 mmol), and DMF (1 drop) in THF
(5 mL) was stirred for 2 h at room temperature. The
mixture was concentrated in vacuo, and the residue
in THF (3 mL) was added dropwise to an ice-cooled
mixture of 4-chloroaniline (139 mg, 1.09 mmol), Et3N
(190 lL, 1.36 mmol), and THF (2 mL). The whole
was stirred for 20 h at room temperature then H2O
was added and extracted with AcOEt, washed with
brine, dried, and concentrated in vacuo. The residue
was purified by column chromatography (toluene/
AcOEt = 9:1–4:1) and recrystallized from AcOEt–hex-
ane to give 16b (20 mg, 6.6%) as a colorless powder:
1H NMR (DMSO-d6) d 2.17 (3H, s), 3.91 (3H, s),
6.41 (1H, s), 7.43 (2H, d, J = 8.8 Hz), 7.47 (1H, d,
J = 3.9 Hz), 7.77 (2H, d, J = 8.8 Hz), 8.05 (1H, d,
J = 3.9 Hz), 10.41 (1H, s); FAB-MS m/z 332
[(M+H)+].
A mixture of 4-chloroaniline (65 mg, 0.512 mmol), 5-(1-
methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-
carboxaldehyde (19, 127 mg, 0.488 mmol), NaB-
H(OAc)3 (259 mg, 1.22 mmol), and AcOH (0.1 mL) in
ClCH2CH2Cl (2 mL) was stirred for 2.5 h at room tem-
perature. Saturated aqueous NaHCO3 was added and
extracted with AcOEt. The extract was washed with
brine, dried, and concentrated in vacuo. The residue
was purified by column chromatography (hexane/
AcOEt = 5:1) to give 20 (156 mg, 86%) as a pale yellow
1
solid: H NMR (CDCl3) d 3.99 (3H, s), 4.18 (1H, br s),
4.53 (2H, d, J = 4.9 Hz), 6.59 (1H, s), 6.61 (2H, d,
J = 8.7 Hz), 7.02 (1H, d, J = 3.9 Hz), 7.06 (1H, d,
J = 3.9 Hz), 7.14 (2H, d, J = 8.8 Hz); FAB-MS m/z 372
[(M+H)+].
5.39. 5-(1-Methyl-3-trifluoromethyl-1H-pyrazol-5-
yl)thiophen-2-ylamine monohydrochloride (21)
The following compounds were prepared according to
this method, substituting aqueous NaHCO3 or pyridine
for Et3N as appropriate.
A mixture of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-
905 mg,
5-yl)thiophene-2-carboxylic acid
3.28 mmol), diphenylphosphoryl
(12j,
azide
(741 lL,
3.44 mmol), and Et3N (479 lL, 3.44 mmol) in toluene
(20 mL) was stirred at 50 ꢁC for 30 min. It was cooled
at room temperature, then t-BuOH (486 mg, 6.55 mmol)
in toluene (1 mL) was added and the whole was stirred
at 80 ꢁC for 5 h. H2O was added to the mixture, extract-
ed with AcOEt, washed with brine, dried, and concen-
trated in vacuo. The residue was purified by column
chromatography (hexane/AcOEt = 6:1–4:1) to give
t-butyl [5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-
thiophen-2-yl]-carbamate (223 mg) as a pale yellow sol-
id. This carbamate was added to a mixture of trifluoro-
acetic acid (5 mL) and CH2Cl2 (5 mL), and the whole
was stirred for 2 days at room temperature. It was
concentrated in vacuo, and the residue was added to
5.34. 40-Chloro-5-(1-methyl-5-trifluoromethyl-1H-pyra-
zol-3-yl)thiophene-2-carboxanilide (16j)
1H NMR (DMSO-d6) d 4.01 (3H, s), 7.42 (2H, d,
J = 9.2 Hz), 7.46 (1H, s), 7.63 (1H, d, J = 3.7 Hz), 7.77
(1H, d, J = 9.1 Hz), 7.99 (1H, d, J = 4.3 Hz), 10.37
(1H, s); FAB-MS m/z 386 [(M+H)+].
5.35. 40-Chloro-N-methyl-5-(1-methyl-3-trifluoromethyl-
1H-pyrazol-5-yl)thiophene-2-carboxanilide (16k)
1H NMR (DMSO-d6) d 3.35 (3H, s), 3.96 (3H, s), 6.55
(1H, d, J = 3.9 Hz), 7.03 (1H, s), 7.31 (1H, d,