Nov-Dec 2007
Synthesis and Chemistry of N-Arylated Pyrano[2,3-c]pyrazoles
1393
(s, 3H); ms (API-ES+) m/z 364 ([M+H+]+, 100). Anal. Calcd.
for C14H7F6N3O2: C, 46.29; H, 1.94; N, 11.57. Found: C,
46.18; H, 2.00; N, 11.51.
temperature. After 3 h no starting remained (tlc). The solution
was then treated with 1.0 N hydrochloric acid (approximately 10
mL) to give a Ph of 3-4. The mixture was diluted to 40 mL with
water, was chilled in ice, and the solid was collected and
vacuum dried to give 1.01 g (87%) of the titled compound; ir
(potassium bromide) 1679 (s), 1649 (s) cm-1; 1H nmr ꢀ
(deuteriochloroform) pyrazolone tautomer 7.85 (d, 2H, J = 8.9
Hz), 7.33 (d, 2H, J = 8.9 Hz), 4.23 (s, 2H), 3.12 (s, 3H), 2.97 (s,
3H), 2.46 (s, 3H), 2.44 (s, 3H); ms (API-ES-) ms 320 ([M+2-
H+]+, 30), 318 ([M-H+]+, 100);. A portion was recrystallized
from hexanes/ethyl acetate to give the analytical sample, mp
130-1 °C. Anal. Calcd. for C16H18ClN3O2: C, 60.09; H, 5.67; N,
13.14. Found: C, 59.93; H, 5.56; N, 12.98.
3-[5-Methyl-1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-3-
(5-trifluoromethyl-[1,3,4]thiadiazol-2-yloxy)-1H-pyrazol-4-
yl]-3-phenyl-acrylamide (16). To a solution of 116 mg (0.513
mmol) of 15 (R = H) in 0.8 mL of dry DMF cooled in a dry
ice/isopropanol bath was added dropwise 0.500 mL (0.500
mmol) of 1.0 M lithium hexamethyldisilazide in THF. After 30
min a solution of 188 mg (1.00 mmol) of the 2-chloro-5-
trifluoromethyl-1,3,4-thiadiazole [7] in 0.5 mL of DMF was
added dropwise via syringe. The contents were stirred overnight
at room temperature. The volatiles were removed in vacuo, the
residue was partitioned between diethyl ether and saturated
sodium bicarbonate and the layers were separated. The aqueous
phase was extracted once with diethyl ether and the combined
organics were dried (MgSO4). Concentration gave 224 mg
which was chromatographed on silica gel to give 47 mg (17%)
of 16; 1H nmr ꢀ deuteriochloroform) 7.59-7.34 (m, 5H), 6.90 (s,
1H), 5.88 (br s, 1H), 5.36 (br s, 1H), 2.53 (s, 3H); ms (API-ES+)
m/z 548 ([M+H+]+, 100). Anal. Calcd. for C19H11F6N7O2S2: C,
41.68; H, 2.03; N, 17.91. Found: C, 41.95; H, 2.07; N, 17.42.
3-(5-Hydroxy-3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-but-
2-enoic acid methyl ester (17a). To a mixture of 121 mg (0.501
mmol) of 1d in 3 mL of methanol was added 1.0 mL (1.0 mmol) of
1.0 N sodium hydroxide. After stirring at room temperature for one
hour, tlc indicated no starting material remaining. Hydrochloric acid
(1.0N, 1.00 mmol) was added and the methanol was removed in
vacuo. The residue was extracted two times with diethyl ether, the
combined extracts were washed with brine and were dried (MgSO4).
Concentration gave a material which was chromatographed by
reverse-phase (C18 amide linker-modified) using gradient elution
(0.1% acetic acid in 60:40 water/acetonitrile to 100% acetonitrile) to
give 65 mg (47%) of the titled compound, mp 91-5 °C; ir
3-[1-(4-Chloro-phenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-
(4)-ylidene]-butyric acid methyl ester (17b). To a mixture
cooled in ice of 1.0 g (3.64 mmol) of 1c in 22 mL of methanol
was added dropwise 7.4 mL (14.8 mmol) of 2.0 N sodium
hydroxide. The contents were stirred at room temperature
overnight, were cooled, and were treated with 7.4 mL of 2.0 N
hydrochloric acid to give pH 4. The mixture was concentrated
in vacuo to remove most of the methanol and was then diluted
with water and extracted two times with diethyl ether. The
combined extracts were dried (MgSO4). Concentration gave
1
1.15 g (quantitative); H nmr ꢀ (CDCl3) pyrazolone tautomer
7.90 (d, 2H, J = 8.9 Hz), 7.33 (d, 2H, J = 8.9 Hz), 4.19 (s, 2H),
3.74 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H); ms (API-ES-) m/z 307
([M+2-H+]+, 36), 305 ([M-H+]+, 100).
A portion was
recrystallized from ethyl acetate to give the analytical sample,
mp 121-123.5 °C. Anal. Calcd. for C15H15ClN2O3: C, 58.73; H,
4.93; N, 9.13. Found: C, 58.80; H, 5.01; N, 9.14.
REFERENCES
[1] a) Kuo, S.; Huang, L.; Nakamura, H. J. Med. Chem., 1984, 27,
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206; (c) Sato, Y.; Shimoji, Y.; Endo, K.; Nishino, H.; Koike, H.;
Kumakura, S. Yakugaku Zasshi, 1978, 98, 335; Chem. Abstr., 1978, 89,
43223; (d) Guo, M. Chinese Patent, CN 1,093,088, 1994; Chem. Abstr.,
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Japanese Patent, JP 52077088, 1977; H Chem. Abstr., 1977, 87, 201529;
(f) Sato, Y.; Shimoji, Y.; Kumakura, S.; Takagi, H. Japanese Patent, JP
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Metwally, M. A.; Amer, F. A. Bollettino Chimico Farmaceutico, 1995,
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R. K.; Dhindsa, G. S.; Kaushik, B.; Singh, S. P.; Dhawan, S. N. Indian
J. Chem., Sec. B, 1986, 25B, 569; (j) Ueda, T.; Mase, H.; Oda, N.;Ito, I.
Chem. Pharm. Bull., 1981, 29, 3522.
[2] Khan, M. A.; Cosenza, A. G.; Ellis, G. P. J. Heterocyclic
Chem., 1982, 19, 1077 and references cited therein.
[3] Huang, L. J.; Kuo, S. C.; Hwang, J. C.; Chan, S. C.; Wu, L.
T.; Ko, F. N.; Teng, C. M. Zhonghua Yaoxue Zazhi, 1993, 45, 409;
Chem. Abstr., 1994, 121, 57377.
[4] Berger, S.; Braun, S.; Kalinowski, H.-O. NMR Spectroscopy
of the Non-Metallic Elements,” John Wiley & Sons, New York, NY,
1997, pp. 161-163.
[5] Baddar, F. G.; El-Newaihy, M. F.; Salem, M. R. J. Chem. Soc.
(C), 1969, 5, 836.
1
(potassium bromide) 3433 (br), 1705 cm-1; H nmr ꢀ (deuterio-
chloroform) 13.5 (br s, 1H), 8.26 (m,1H), 7.89 (m, 2H), 7.19 (m,
1H), 6.02 (q, 1H, J = 1.3 Hz), 3.73 (s, 3H), 2.59 (d, 3H, J = 1.3 Hz),
2.38 (s, 3H); MS (API-ES-) 272 ([M-H+]+, 100);. A portion was
recrystallized from diethyl ether/ethyl acetate to give the analytical
sample, mp 97-98.5 °C. Anal. Calcd. for C14H15N3O3: C, 61.52; H,
5.53; N, 15.38. Found: C, 61.27; H, 5.35; N, 15.16.
3-[3-Hydroxy-5-methyl-1-(4-trifluoromethyl-pyrimidin-2-
yl)-1H-pyrazol-4-yl]-but-2-enoic acid dimethylamide (19c).
To a mixture of 94 mg (0.303 mmol) of 2c in 1.0 mL of THF
was added 136 mg (1.21 mmol) of 40% aqueous dimethylamine.
After 2 h at room temperature tlc indicated no starting material
remaining. The solution was treated with 1.21 mL of 1.0 N
hydrochloric acid causing precipitation of a white solid which
was collected and dried in vacuo to give 75 mg (70%) of the
titled compound; 1H nmr ꢀ (deuteriochloroform) 8.93 (d, 1H, J =
5.0 Hz), 7.36 (d, 1H, J = 4.9 Hz), 6.21 (br s, 1H), 2.90 (s, 3H),
2.61 (s, 3H), 2.14 (d, 3H, J = 1.6 Hz); ms (API-ES-) m/z 354
([M-H+]+, 100). A portion was recrystallized from chloroform/
hexanes to give the analytical sample, mp 178 °C (dec). Anal.
Calcd. for C15H16F3N5O2: C, 50.70; H, 4.54; N, 19.71. Found:
C, 50.87; H, 4.53; N, 19.17.
3-[1-(4-Chloro-phenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-
(4)-ylidene]-N,N-dimethyl-butyramide (18b). To a mixture
cooled in an ice bath of 1.00 g (3.64 mmol) of 1c in 5 mL of
THF was added dropwise 1.64 g (14.6 mmol) of 40% aqueous
dimethylamine. The contents were allowed to warm to room
[6] Carrillo, J. R.; Cossio, F. P.; Diaz-Ortiz, A.; Gomez-
Escalonilla, M. J.; de la Hoz, A.; Lecea, B.; Moreno, A.; Prieto, P.
Tetrahedron 2001, 57, 4179.
[7] Forster, H; Hofer, W. J.; Schmidt, R. R.; Ene, L. German
Patent DE 3,218,482, 1983; Chem. Abstr. 1984, 100, 85705.