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M. A. P. Martins et al.
PAPER
(2) (a) Gombos, Z.; Nyitrai, J.; Doleschall, G.; Kolonits, P.;
night at r.t. The solvent was evaporated in a rotary evaporator and
the residue was extracted with CHCl3 (15 mL). The organic layer
was washed with H2O (3 × 15 mL), dried (MgSO4), and the solvent
was removed in a rotary evaporator to afford the product in satisfac-
tory purity (Table 1).
Párkányi, L.; Kálmán, A. J. Chem. Soc. Perkin Trans.1
1993, 139. (b) Paravelo, P.; Varasi, M. Synth. Commun.
1992, 22, 1939. (c) Dannahardt, G.; Kiefer, W.; Lambrecht,
G. Eur. J. Med. Chem. 1995, 30, 839. (d) Bräuner-Osborne,
H.; Nielsen, B.; Krogsgaard-Larsen, P. J. Eur. Pharmacol.
1998, 350, 311.
3-Hydroxy-5-trichloromethyl-4,5-dihydroisoxazole (8a)
A solution of hydroxylamine hydrochloride (0.15 g, 2.2 mmol) in
H2O (10 mL) was added to a stirred solution of 3a or 3b (2 mmol)
in pyridine (0.17 g, 2.2 mmol) at r.t. The mixture was stirred for 24
h at 30 °C. The solvent was evaporated in a rotary evaporator and
the residue was extracted with Et2O (15 mL). The organic layer was
washed with 0.5 N HCl and H2O (2 × 10 mL), the organic layer was
dried (MgSO4), and the solvent was removed by rotary evaporator.
The product obtained was purified by recrystallization from hex-
ane–EtOAc (1:1) (Table 1).
(3) (a) Moser, H.; Boehner, B.; Foery, W. European Patent
Appl. EP 268554, 1988; Chem Abstr. 1988, 110, 23879.
(b) Okada, I.; Yoshida, K.; Sekine, M. Japan Kokai Tokkyo
Koho, JP 02292263, 1990; Chem. Abstr. 1990, 114, 185497.
(c) Sohn, E.; Handle, R.; Mildenberger, H.; Buerstell, H.;
Bauer, K.; Bieringer, H. German Patent 3633840, 1988;
Chem. Abstr. 1988, 110, 8202.
(4) (a) Pushkevich, K. I.; Saloutin, V. I.; Postovskii, I. Russ.
Chem. Rev. 1981, 50, 180. (b) Lyga, J. W.; Patera, R. M. J.
Heterocycl. Chem. 1990, 27, 919. (c) Claire, P. P. K.; Coe,
P. L.; Jones, C. J.; McCleverty, J. A. J. Fluorine Chem.
1991, 51, 283. (d) Bumgardner, C. L.; Sloop, J. C. J.
Fluorine Chem. 1992, 56, 141. (e) Song, L.; Chu, Q.; Zhu,
S. J. Fluorine Chem. 2001, 107, 107.
(5) (a) Song, L.; Chu, Q.; Zhu, S. J. Fluorine Chem. 2001, 111,
201. (b) Singh, S. P.; Kumar, D.; Jones, B. G.; Threadgill,
M. D. J. Fluorine Chem. 1999, 94, 199.
(6) (a) Braibante, M. E. F.; Clar, G.; Martins, M. A. P. J.
Heterocycl. Chem. 1993, 30, 1159. (b) Bonacorso, H. G.;
Wastowski, A. D.; Zanatta, N.; Martins, M. A. P. Synth.
Commun 2000, 30, 1457.
3-Trichoromethyl-5-ethoxy-1H-pyrazoles 4a,b
A CCl4 solution of 2a (0.52 g, 2 mmol) was added dropwise to a
cooled stirred solution (at 0 °C) of anhyd hydrazine or methylhydra-
zine (2.2 mmol). The reaction mixture was stirred for 12 h at r.t. Af-
ter this time, H2O (10 mL) was added and the organic phase was
extracted with CHCl3 (15 mL). The organic layer was washed with
H2O (3 × 15 mL), dried (MgSO4) and the solvent was removed un-
der reduced pressure. The residue was purified by column chroma-
tography (Merck silica gel 230–400 mesh) with hexane–CHCl3
(8:2) as eluent (Table 1).
3-Ethoxy-1H-pyrazole-5-carboxylic Acid (5a)
(7) (a) Colla, A.; Martins, M. A. P.; Clar, G.; Krimmer, S.;
Fischer, P. Synthesis 1991, 483. (b) Martins, M. A. P.;
Siqueira, G. M.; Bastos, G. P.; Bonacorso, H. G.; Zanatta, N.
J. Heterocycl. Chem. 1996, 33, 1619.
A 20% solution HCl (10 mL) was added to 4a (0.46 g, 2 mmol) and
the mixture was stirred at 40 °C for 12 h. The solvent was evaporat-
ed and the crude product was kept under vacuum. The product was
isolated with satisfactory purity (Table 1).
(8) (a) Flores, A. F. C.; Brondani, S.; Zanatta, N.; Rosa, A.;
Martins, M. A. P. Tetrahedron Lett. 2002, 43, 8701.
(b) Martins, M. A. P.; Bastos, G. P.; Bonacorso, H. G.;
Zanatta, N.; Flores, A. F. C.; Siqueira, G. M. Tetrahedron
Lett. 1999, 40, 4309. (c) Bonacorso, H. G.; Martins, M. A.
P.; Bittencourt, S. R. T.; Lourega, R. V.; Zanatta, N.; Flores,
A. F. C. J. Fluorine Chem. 1999, 99, 177. (d) Martins, M.
A. P.; Zoch, A. N.; Flores, A. F. C.; Clar, G.; Zanatta, N.;
Bonacorso, H. G. J. Heterocycl. Chem. 1995, 32, 739.
(e) Siqueira, G. M.; Flores, A. F. C.; Clar, G.; Zanatta, N.;
Martins, M. A. P. Química Nova 1994, 17, 24; Chem. Abstr.
1995, 122: 187063. (f) Flores, A. F. C.; Siqueira, G. M.;
Freitag, R.; Zanatta, N.; Martins, M. A. P. Química Nova
1994, 17, 298; Chem. Abstr. 1994, 121, 230377.
3-Ethoxycarbonyl-5-hydroxy-1H-pyrazoles 7a–c
Compound 3a or 3b (2 mmol) was added to a stirred solution of hy-
drazine (methyl-or phenylhydrazine) hydrochloride (2.2 mmol) in
EtOH (15 mL) at r.t. The mixture was refluxed for 24 h. The solvent
was evaporated and to the residue was added H2O (10 mL) and the
organic phase was extracted with CH2Cl2 (15 mL). The organic lay-
er was dried (Na2SO4) and the solvent was removed under reduced
pressure. The residue was purified by column chromatography
(Merck silica gel 230–400 mesh) using CHCl3 as eluent (Table 1).
Acknowledgment
(9) (a) Martins, M. A. P.; Flores, A. F. C.; Freitag, R.; Zanatta,
N. J. Heterocycl. Chem. 1995, 32, 731. (b) Martins, M. A.
P.; Flores, A. F. C.; Freitag, R. A.; Zanatta, N. J. Heterocycl.
Chem. 1996, 33, 1223. (c) Martins, M. A. P.; Flores, A. F.
C.; Bastos, G. P.; Zanatta, N.; Bonacorso, H. G. J.
Heterocycl. Chem. 1999, 36, 837. (d) Martins, M. A. P.;
Neto, M.; Sinhorin, A. P.; Bastos, G. P.; Zimmermann, N. E.
K.; Rosa, A.; Bonacorso, H. G.; Zanatta, N. Synth. Commun.
2002, 32, 425.
(10) (a) Martins, M. A. P.; Sinhorin, A. P.; Zimmermann, N. E.
K.; Zanatta, N.; Bonacorso, H. G.; Bastos, G. P. Synthesis
2001, 1959. (b) Martins, M. A. P.; Sinhorin, A. P.; Rosa, A.;
Flores, A. F. C.; Wastowski, A. D.; Pereira, C. M. P.; Flores,
D. C.; Beck, P.; Freitag, R. A.; Brondani, S.; Cunico, W.;
Bonacorso, H. G.; Zanatta, N. Synthesis 2002, 2353.
(c) Martins, M. A. P.; Beck, P.; Cunico, W.; Pereira, C. M.
P.; Sinhorin, A. P.; Blanco, R. F.; Peres, R.; Bonacorso, H.
G.; Zanatta, N. Tetrahedron Lett. 2002, 43, 7005.
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq/PADCT-II/ FINEP, and Fundação
de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS)
for financial support. Fellowships from CNPq, CAPES and FA-
PERGS are also acknowledged.
References
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(d) Buntaim, J. G.; Hatton, L. R.; Hawkins, D.; Pearson, C.
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Synthesis 2003, No. 15, 2353–2357 © Thieme Stuttgart · New York