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J = 8 Hz), 7.02 (s, 1H, pyrazole-CH), 7.65–7.70 (m, 2H), 8.02–8.04 (m,
1H), 8.10 (s, 1H), 10.65 (s, 1H, –CONH–), 13.09 (s, 1H, pyrazole-NH);
MS (FAB+), 324 [M+Na]+, m/z 302 [M+H]+; HPLC: tR = 5.04 min.
1H, J1 = J2 = 8 Hz), 7.76 (dd, 1H, J1 = J2 = 8 Hz), 7.86 (d, 1H,
J = 8 Hz), 10.61 (s, 1H, –CONH–), 12.72 (s, 1H, pyrazole-NH); MS
(FAB+), 324 [M+Na]+, m/z 302 [M+H]+; HPLC: tR = 4.62 min.
4.13. 3-(4-(Trifluoromethyl)phenyl)-1H-pyrazol-5-amine (11d)
4.15.3. N-(3-(3-Chlorophenyl)-1H-pyrazol-5-yl)-2-mercaptoace-
tamide (12g)
3-Oxo-3-(4-(trifluoromethyl)phenyl)propanenitrile (10d, 2.0 g,
9.3 mmol) was dissolved in absolute ethanol (4.4 mL). Anhydrous
hydrazine (344 lL, 11.3 mmol) was added dropwise and the solu-
tion was stirred at room temperature for 1 h and then heated to re-
flux for an additional 1 h. The reaction mixture was cooled to room
temperature and cold H2O (4 mL) was added until the product pre-
cipitated. The product was collected on fritted glass, washed with
cold H2O (2 ꢀ 5 mL) and dried under high vacuum to provide
1.89 g (90%) of the desired b-ketonitrile as an off-white powder.
HPLC: tR = 3.77 min.
In a similar manner as above, 3-(3-chlorophenyl)-1H-pyrazol-5-
amine (11g, 50 mg, 0.26 mmol) was converted to 68 mg (98%) of
the 2-mercaptoacetamide as white crystals. 1H NMR (DMSO-d6) d
2.35 (br s, 1H, –SH), 3.35 (s, 2H, –CH2–), 6.83 (s, 1H, pyrazole-
CH), 7.26–7.29 (m, 1H), 7.36 (dd, 1H, J1 = J2 = 8 Hz), 7.60 (dd, 1H,
J1 = 8 Hz, J2 = 1 Hz), 7.74 (dd, 1H, J1 = J2 = 2 Hz), 10.96 (s, 1H,
–CONH–), 12.15 (s, 1H, pyrazole-NH); MS (FAB+), 290 [M+Na]+;
HPLC: tR = 4.67 min.
4.15.4. N-(3-(4-Fluorophenyl)-1H-pyrazol-5-yl)-2-mercaptoace
tamide (12h)
4.14. N-(3-(4-(Trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-2-
In a similar manner as above, 3-(4-fluorophenyl)-1H-pyrazol-5-
amine (11h, 4.6 g, 26 mmol) was converted to 5.55 g (85%) of the
2-mercaptoacetamide as white crystals. 1H NMR (DMSO-d6) d
2.50 (br s, 1H, –SH), 3.30 (s, 2H, –CH2–), 6.88 (s, 1H, pyrazole-
CH), 7.29 (dd, 2H, J1 = J2 = 8 Hz), 7.77 (dd, 2H, J1 = 8 Hz, J2 = 6 Hz),
10.59 (s, 1H, –CONH–), 12.86 (s, 1H, pyrazole-NH); MS (FAB+),
274 [M+Na]+; HPLC: tR = 4.08 min.
mercaptoacetamide (12d)
3-(4-(Trifluoromethyl)phenyl)-1H-pyrazol-5-amine (11d, 1.89 g,
8.3 mmol) was weighed into a clean, oven-dried vial. Dry toluene
(3.3 mL) and thioglycolic acid (870 lL, 12.5 mmol) were added
and the vial was purged with argon, sealed, and heated to 110 °C
in an aluminum block for 18 h. After cooling to room temperature,
the product crystallized from the reaction mixture. The product
was collected on fritted glass and washed successively with satd
NaHCO3 (2 ꢀ 5 mL), H2O (2 ꢀ 5 mL), 1 N HCl (2 ꢀ 5 mL) and diethyl
ether (2 ꢀ 5 mL). After drying under high vacuum, 2.04 g (82%) of
the 2-mercaptoacetamide was obtained as a white powder. 1H
NMR (DMSO-d6) d 2.90 (t, 1H, –SH, J = 8 Hz), 3.30 (d, 2H, –CH2–,
J = 8 Hz), 7.04 (s, 1H, pyrazole-CH), 7.80 (d, 2H, J = 8 Hz), 7.94 (d,
2H, J = 8 Hz), 10.64 (s, 1H, –CONH–), 13.13 (s, 1H, pyrazole-NH);
MS (FAB+), 324 [M+Na]+, m/z 302 [M+H]+; HPLC: tR = 5.09 min.
4.15.5. N-(3-(4-Bromophenyl)-1H-pyrazol-5-yl)-2-
mercaptoacetamide (12i)
In a similar manner as above, 3-(4-bromophenyl)-1H-pyrazol-
5-amine (11i, 238 mg, 1.0 mmol) was converted to 236 mg (76%)
of the 2-mercaptoacetamide as white crystals. 1H NMR (DMSO-
d6) d 2.88 (t, 1H, –SH, J = 8 Hz), 3.28 (d, 2H, –CH2–, J = 8 Hz), 6.87
(s, 1H, pyrazole-CH), 7.62 (d, 2H, J = 9 Hz), 7.67 (d, 2H, J = 9 Hz),
10.67 (s, 1H, –CONH–), 12.92 (s, 1H, pyrazole-NH); MS (FAB+),
334, 336 [M+Na]+; HPLC: tR = 4.83 min.
4.15. General method
4.15.6. N-(3-p-Tolyl-1H-pyrazol-5-yl)-2-mercaptoacetamide (12j)
In a similar manner as above, 3-p-tolyl-1H-pyrazol-5-amine
(11j, 257 mg, 1.5 mmol) was converted to 315 mg (85%) of the 2-
mercaptoacetamide as white crystals. 1H NMR (DMSO-d6) d 2.31
(s, 3H, –CH3), 2.88 (t, 1H, –SH, J = 8 Hz), 3.29 (d, 2H, –CH2–,
J = 8 Hz), 6.83 (s, 1H, pyrazole-CH), 7.24 (d, 2H, J = 8 Hz), 7.59 (d,
2H, J = 8 Hz), 10.55 (s, 1H, –CONH–), 12.77 (s, 1H, pyrazole-NH);
MS (FAB+), 270 [M+Na]+, m/z 248 [M+H]+; HPLC: tR = 4.44 min.
The appropriately substituted aminopyrazole (2.0 mmol) was
weighed into a clean, oven-dried vial. Thioglycolic acid (3.0 mmol)
and dry toluene were added to give a final concentration of the
aminopyrazole of 2 M. The vial was then purged with argon, sealed,
and heated to 110 °C in an aluminum block heater/stirrer until the
reaction was complete as determined by HPLC analysis (18–48 h).
After cooling to room temperature, the product crystallized from
the reaction mixture. Crystalline products were collected on fritted
glass and washed successively with satd NaHCO3 (2 ꢀ 5 mL), H2O
(2 ꢀ 5 mL), 1 N HCl (2 ꢀ 5 mL), and diethyl ether (2 ꢀ 5 mL).
4.15.7. N-(3-(4-Methoxyphenyl)-1H-pyrazol-5-yl)-2-
mercaptoacetamide (12k)
In a similar manner as above, 3-(4-methoxyphenyl)-1H-pyra-
zol-5-amine (11k, 568 mg, 3.0 mmol) was converted to 676 mg
(86%) of the 2-mercaptoacetamide as white crystals. 1H NMR
(DMSO-d6) d 2.89 (t, 1H, –SH, J = 8 Hz), 3.29 (d, 2H, –CH2–,
J = 8 Hz), 3.79 (s, 3H, –CH3–), 6.77 (s, 1H, pyrazole-CH), 7.00 (d,
2H, J = 9 Hz), 7.65 (d, 2H, J = 9 Hz), 10.54 (s, 1H, –CONH–), 12.75
(s, 1H, pyrazole-NH); MS (FAB+), 286 [M+Na]+, m/z 264 [M+H]+;
HPLC: tR = 3.98 min.
4.15.1. N-(3-(Phenyl)-1H-pyrazol-5-yl)- 2-mercaptoacetamide
(12e)
In a similar manner as above, 3-phenyl-1H-pyrazol-5-amine
(11e, 2.5 g, 15.7 mmol) was converted to the 2-mercaptoacetamide
analog (2.98 g, 82%) as white crystals. 1H NMR (DMSO-d6) d 12.86
(s, 1H, pyrazole-NH), 10.58 (s, 1H, –CONH–), 7.72 (d, 2H, J = 7 Hz),
7.45 (dd, 2H, J1 = J2 = 7 Hz), 7.34 (dd, 1H, J1 = J2 = 7 Hz), 6.87 (s, 1H,
pyrazole-CH), 3.30 (d, 2H, –CH2–, J = 8 Hz), 2.90 (t, 1H, –SH,
J = 8 Hz); MS (FAB+), 256 [M+Na]+, m/z 234 [M+H]+; HPLC tR:
3.98 min.
4.15.8. N-(3-(4-Nitrophenyl)-1H-pyrazol-5-yl)-2-
mercaptoacetamide (12l)
4.15.2. N-(3-(2-(Trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-2-
mercaptoacetamide (12f)
In a similar manner as above, 3-(4-nitrophenyl)-1H-pyrazol-5-
amine (11l, 1.0 g, 4.9 mmol) was converted to 1.32 g (97%) of the
2-mercaptoacetamide as yellow crystals. 1H NMR (DMSO-d6)
d 2.92 (s, 1H, –SH), 3.31 (s, 2H, –CH2–), 7.12 (s, 1H, pyrazole-
CH), 8.01 (d, 2H, J = 8 Hz), 8.29 (d, 2H, J = 8 Hz), 10.70 (s, 1H,
–CONH–), 13.26 (s, 1H, pyrazole-NH); MS (FAB+), 301 [M+Na]+,
m/z 279 [M+H]+; HPLC: tR = 4.28 min.
In a similar manner as above, 3-(2-(trifluoromethyl)phenyl)-
1H-pyrazol-5-amine (11f, 100 mg, 0.44 mmol) was converted to
45 mg (34%) of the 2-mercaptoacetamide as a white powder. 1H
NMR (DMSO-d6) d 2.89 (t, 1H, –SH, J = 8 Hz), 3.29 (d, 2H, –CH2–,
J = 8 Hz), 6.71 (s, 1H, pyrazole-CH), 7.59 (d, 1H, J = 8 Hz), 7.66 (dd,