Regioselective synthesis of 1-aryl-4-bromo-5-trifluoromethylpyrazoles

Article abstract of DOI:10.1007/s11172-006-0233-z

A novel regioselective route to 1-aryl-4-bromo-5-trifluoromethylpyrazoles involves reactions of arylhydrazines with 3-bromo-4-ethoxy-1,1,1-trifluorobut-3- en-2-one.

Full text of DOI:10.1007/s11172-006-0233-z

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Russian Chemical Bulletin, International Edition, Vol. 55, No. 1, pp. 172—173, January, 2006
Regioselective synthesis of 1ꢀarylꢀ4ꢀbromoꢀ5ꢀtrifluoromethylpyrazoles
V. G. Nenajdenko,ꢀ A. L. Reznichenko, and E. S. Balenkova
Department of Chemistry, M. V. Lomonosov Moscow State University,
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Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 932 8846. Eꢀmail: nen@acylium.chem.msu.ru
A novel regioselective route to 1ꢀarylꢀ4ꢀbromoꢀ5ꢀtrifluoromethylpyrazoles involves reacꢀ
tions of arylhydrazines with 3ꢀbromoꢀ4ꢀethoxyꢀ1,1,1ꢀtrifluorobutꢀ3ꢀenꢀ2ꢀone.
Key words: pyrazoles, arylhydrazines, heterocyclization, organofluorine compounds, enones.
The unique stereoelectronic and biological properties
tion of enone 1 with hydrazine hydrate afforded Nꢀunꢀ
substituted 4ꢀbromoꢀ3ꢀtrifluoromethylpyrazole (2g).
of the trifluoromethyl group make it topical to develop
efficient methods for the synthesis of heterocyclic comꢀ
pounds containing this group. The most promising route
to such compounds involves polyfunctional fluoroꢀconꢀ
taining building blocks, e.g., α,βꢀunsaturated trifluoroꢀ
methyl ketones, which have two electrophilic sites and
Scheme 1
thus can be employed for the synthesis of various CF ꢀconꢀ
3
1
taining heterocyclic systems.
Earlier,2
—5
α,βꢀunsaturated trifluoromethyl ketones
have been used to obtain CF ꢀcontaining pyrazoles.
3
A topical problem in the chemistry of pyrazoles is the
regioselective synthesis of Nꢀsubstituted derivatives, which
often form as a mixture of regioisomers. The present study
is devoted to the synthesis of 1ꢀarylꢀ4ꢀbromoꢀ5ꢀtrifluoroꢀ
methylpyrazoles, which are promising intermediates for
further functionalization due to the presence of the broꢀ
mine atom. It has been recently demonstrated that
3
ꢀbromoꢀ4ꢀethoxyꢀ1,1,1ꢀtrifluorobutꢀ3ꢀenꢀ2ꢀone (1) acts
2
R
Yield (%)
2
R
Yield (%)
as a 1,2ꢀbielectrophile in the synthesis of trifluoroacetylꢀ
imidazopyridine. We assumed that enone 1 can also serve
as a 1,3ꢀbielectrophile in reactions with arylhydrazines.
It should be noted that enone 1 is a polyfunctional
compound and its heterocyclization can theoretically yield
two regioisomeric pyrazoles. However, we found that the
6
a
b
c
d
Ph
65
e
f
g
3ꢀCF3C6H4
3,4ꢀ(OCH CH O)C H
55
63
64
4ꢀMeOC H4 61
4ꢀMeC H4
3ꢀClC H4
6
2
2
6 3
61
52
H
6
6
The regiochemistry of the heterocyclization observed
reaction of enone 1 with phenylhydrazine gives the known
conforms with data on the reactivities of CF ꢀcontaining
alkoxy enones. The first step involves replacement (adꢀ
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7
1
4
ꢀbromoꢀ1ꢀphenylꢀ5ꢀtrifluoromethylpyrazole (2a) as the
sole product in 65% yield (Scheme 1). We studied this
reaction in various solvents (ethanol, methanol, acetoniꢀ
trile, DMF, and acetic acid). The highest yield of the
target product was achieved in acetic acid. According to
GCꢀMS data for reaction mixtures, the solvent nature
does not affect the reaction pathway: in all the cases, the
alternative regioisomer was not formed. Under the optiꢀ
mized conditions, we carried out reactions of enone 1
with other arylhydrazines (see Scheme 1) and obtained
the corresponding 1ꢀarylꢀ4ꢀbromoꢀ5ꢀtrifluoromethylꢀ
pyrazoles 2a—f in satisfactory to good yields. The reacꢀ
dition—elimination) of the ethoxy group; arylhydrazine is
attached by its most nucleophilic terminal N atom. This
is followed by closure of the target heterocycle (see
Scheme 1).
In the conclusion, we developed a novel, simple and
efficient method for the synthesis of 1ꢀarylꢀ4ꢀbromoꢀ5ꢀ
trifluoromethylpyrazoles. The combination of the Br atom
and the CF group makes these compounds promising for
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8
further transformations by means of crossꢀcoupling, nuꢀ
cleophilic substitution, and transmetalation, which open
up routes to novel CF ꢀcontaining heterocyclic systems.
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Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 167—168, January, 2006.
066ꢀ5285/06/5501ꢀ0172 © 2006 Springer Science+Business Media, Inc.
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ꢀArylꢀ4ꢀbromoꢀ5ꢀtrifluoromethylpyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 1, January, 2006
173
Experimental
270 Hz); 126.5; 129.1; 129.9; 130.3 (q, JC,F = 38 Hz); 131.9 (q,
JC,F = 33 Hz); 139.7; 142.4.
1
ꢀ(1,4ꢀBenzodioxanꢀ6ꢀyl)ꢀ4ꢀbromoꢀ5ꢀtrifluoromethylꢀ1Hꢀ
1H and 13C NMR spectra were recorded on a Varian
VXRꢀ400 spectrometer (400 and 100 MHz, respectively) in
pyrazole (2f). White crystals, m.p. 73 °C, Rf 0.42 (hexꢀ
ane—CH Cl2 (1 : 2)). Found (%): C, 41.37; H, 2.17.
C H BrF N O . Calculated (%): C, 41.29; H, 2.31. H NMR,
δ: 4.27 (s, 4 H); 6.85—6.94 (m, 3 H); 7.64 (s, 1 H). C NMR, δ:
4.15; 64.24; 96.4; 115.4; 117.3; 119.1; 119.3 (q, JC,F = 270 Hz);
30.1 (q, JC,F = 37 Hz); 132.5; 141.3; 143.3; 144.8.
4
2
CDCl3 with Me Si as the internal standard. GCꢀMS spectra
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1
12
8
3
2
2
were recorded on a Finnigan SSQ 7000 mass spectrometer conꢀ
nected to a Varian 3400 GC gas chromatograph. TLC analysis
was carried out on Merck 60 F254 plates. Silica gel (63—200 mesh,
Merck) was used for column chromatography. 3ꢀBromoꢀ4ꢀ
ethoxyꢀ1,1,1ꢀtrifluorobutꢀ3ꢀenꢀ2ꢀone (1) was prepared accordꢀ
13
6
1
ꢀBromoꢀ3ꢀtrifluoromethylpyrazole (2g). Hydrazine hydrate
(
2.5 mL, 5 mmol) was added dropwise to a stirred solution of
9
ing to a known procedure.
enone 1 (5 mmol) in ethanol (20 mL). The reaction mixture was
refluxed for 30 min, cooled, and concentrated in vacuo. The
residue was purified by column chromatography with CH Cl as
the eluent to give pyrazole 2g as yellow crystals, m.p. 108 °C
cf. Ref. 10: m.p. 112 °C), R 0.2 (CH Cl ). Found (%): C, 21.97;
H, 1.06. C H BrF N . Calculated (%): C, 22.35; H, 0.94.
H NMR, δ: 7.73 (s, 1 H); 13.14 (br.s, 1 H). C NMR, δ: 92.2;
20.8 (q, JC,F = 270 Hz); 132.1; 140.6 (q, JC,F = 36 Hz).
1
ꢀArylꢀ4ꢀbromoꢀ5ꢀtrifluoromethylpyrazoles 2a—g (general
procedure). An arylhydrazine (1 mmol) was added to a stirred
solution of enone 1 (1 mmol) in AcOH (5 mL). Stirring was
continued at ~20 °C until the reaction was completed (12—24 h;
TLC monitoring). Then the solvent was removed in vacuo and
the product was isolated by column chromatography with hexꢀ
ane—CH Cl as the eluent.
2
2
(
f
2
2
4
2
3
2
1
13
2
2
1
4
ꢀBromoꢀ1ꢀphenylꢀ5ꢀtrifluoromethylꢀ1Hꢀpyrazole (2a).
1
A yellow oil, R 0.42 (hexane—CH Cl (1 : 2)). H NMR, δ:
f
2
2
This work was financially supported by the Russian
Science Support Foundation.
7
.39—7.43 (m, 2 H); 7.46—7.50 (m, 3 H); 7.70 (s, 1 H).
1
3
C NMR, δ: 96.8; 119.4 (q, JC,F = 270 Hz); 125.9; 129.1; 129.7;
1
1
30.1 (q, JC,F = 30 Hz); 139.4; 141.7. The H NMR spectrum
4
agrees with the known data.
References
4
ꢀBromoꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀtrifluoromethylꢀ1Hꢀ
pyrazole (2b). White crystals, m.p. 55 °C, Rf 0.42 (hexꢀ
1. V. G. Nenajdenko, A. V. Sanin, and E. S. Balenkova, Usp.
Khim., 1999, 68, 483 [Russ. Chem. Rev., 1999, 68, 437 (Engl.
Transl.)].
ane—CH Cl2 (1 : 2)). Found (%): C, 41.01; H, 2.39.
2
1
C H BrF N O. Calculated (%): C, 41.15; H, 2.51. H NMR,
1
1
8
3
2
δ: 3.84 (s, 3 H); 6.96, 7.32 (both d, 2 H each, J = 9.0 Hz); 7.66
2
. M. Braibante, G. Clar, and M. Martins, J. Heterocycl. Chem.,
1993, 30, 1159.
13
(
s, 1 H). C NMR, δ: 55.5; 96.4; 119.4 (q, JC,F = 270 Hz);
27.3; 130.2 (q, JC,F = 30 Hz); 132.2; 141.4; 160.4.
ꢀBromoꢀ1ꢀ(4ꢀmethylphenyl)ꢀ5ꢀtrifluoromethylꢀ1Hꢀpyrazole
2c). White crystals, m.p. 64 °C, R 0.42 (hexane—CH Cl
1
3. A. Touzot, M. Soufyane, H. Berber, L. Toupet, and
C. Mirand, J. Fluorine Chem., 2004, 125, 1299.
4. M. Martins, C. Pereira, N. Zimmermann, W. Cunico,
S. Moura, P. Beck, N. Zanatta, and H. Bonacorso, J. Fluoꢀ
rine Chem., 2003, 123, 261.
4
(
f
2
2
(
1 : 2)). Found (%): C, 43.17; H, 2.57. C H BrF N . Calcuꢀ
11 8 3 2
1
lated (%): C, 43.30; H, 2.64. H NMR, δ: 2.42 (s, 3 H);
13
7
1
1
.24—7.30 (m, 4 H); 7.68 (s, 1 H). C NMR, δ: 21.2; 96.6;
19.4 (q, JC,F = 270 Hz); 125.7; 129.6; 130.2 (q, JC,F = 30 Hz);
36.9; 140.0; 141.5.
5
. J. Pavlik, T. Ayudhya, and S. Tantayanon, J. Heterocycl.
Chem., 2003, 40, 1087.
6
. L. M. Kacharova, I. I. Gerus, and A. D. Kacharov, J. Fluoꢀ
rine Chem., 2002, 117, 193.
4
ꢀBromoꢀ1ꢀ(3ꢀchlorophenyl)ꢀ5ꢀtrifluoromethylꢀ1Hꢀpyrazole
(
2d). A yellow oil, R 0.42 (hexane—CH Cl (1 : 2)). Found (%):
f
2
2
7. M. Schlosser, J.ꢀN. Volle, F. Leroux, and K. Schenk, Eur.
J. Org. Chem., 2002, 17, 2913.
C, 36.68; H, 1.42. C H BrClF N . Calculated (%): C, 36.90;
1
0
5
3
2
1
H, 1.55. H NMR, δ: 7.31—7.49 (m, 4 H); 7.71 (s, 1 H).
3C NMR, δ: 97.5; 119.3 (q, JC,F = 270 Hz); 124.1; 126.3;
8
. J. P. Chupp, J. Heterocycl. Chem., 1994, 31, 1377.
1
9. I. I. Gerus, L. M. Kacharova, and C. I. Vdovenko, Synthesis,
2001, 431.
0. J. Athedron and R. Fields, J. Chem. Soc. C, 1968, 1507.
1
30.06; 130.11; 130.2 (q, JC,F = 30 Hz); 134.9; 140.2; 142.2.
ꢀBromoꢀ5ꢀtrifluoromethylꢀ1ꢀ[3ꢀ(trifluoromethyl)phenyl]ꢀ
Hꢀpyrazole (2e). A yellow oil, R 0.42 (hexane—CH Cl (1 : 2)).
4
1
1
f
2
2
Found (%): C, 36.49; H, 1.30. C H BrF N . Calculated (%):
1
1
5
6
2
1
C, 36.79; H, 1.40. H NMR, δ: 7.64—7.68 (m, 2 H); 7.75—7.79
m, 3 H). C NMR, δ: 97.8; 119.3, 123.2 (both q, JC,F
Received November 18, 2005;
in revised form December 8, 2005
13
(
=