Comparative study of the regioselectivity and reaction media for the synthesis of 1-tert-butyl-3(5)-trifluoromethyl-1H-pyrazoles

Article abstract of DOI:10.1002/ejoc.201201111

A study is presented for the synthesis of a series of 1-tert-butyl-3(5)- (trifluoromethyl)-1H-pyrazoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3- alken-2-ones [CF₃C(O)CH=C(R¹)(OR), where R = Et and R ¹ = H or R = Me and R¹ = Me, Ph, 4-Me-C₆H ₄, 4-MeO-C₆H₄, 4-F-C₆H₄, 4-Cl-C₆H₄, 4-Br-C₆H₄, 4-I-C ₆H₄, fur-2-yl, thien-2-yl, or naphth-2-yl] with tert-butylhydrazine hydrochloride. When [BMIM][BF₄] (1-butyl-3-methylimidazolium tetrafluoroborate) and pyridine were used as the reaction media, we obtained a mixture of 1-tert-butyl-3(5)- trifluoromethylpyrazoles. The formation of 5-trifluoromethyl-1-tert-butyl-1H- pyrazoles with high regioselectivity occurred when the reaction was carried out with NaOH in EtOH. The formation of 1-tert-butyl-3-trifluoromethyl-1H-pyrazoles occurred, after hydrolysis of the 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones in H₂O and H₂SO₄, followed by cyclization in [BMIM][BF₄] and pyridine.

Full text of DOI:10.1002/ejoc.201201111

FULL PAPER
DOI: 10.1002/ejoc.201201111
Comparative Study of the Regioselectivity and Reaction Media for the
Synthesis of 1-tert-Butyl-3(5)-trifluoromethyl-1H-pyrazoles
Marcos A. P. Martins,*[a] Mara R. B. Marzari,[a] Clarissa P. Frizzo,[a] Marcileia Zanatta,[a]
Lilian Buriol,[a] Valquiria P. Andrade,[a] Nilo Zanatta,[a] and Helio G. Bonacorso[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Fluorinated substituents / Ionic liquids / Enones / Regioselectivity
A study is presented for the synthesis of a series of 1-tert-
butyl-3(5)-(trifluoromethyl)-1H-pyrazoles from the reaction
of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF3C(O)CH=C-
(R1)(OR), where R = Et and R1 = H or R = Me and R1 = Me,
Ph, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-
C6H4, 4-I-C6H4, fur-2-yl, thien-2-yl, or naphth-2-yl] with tert-
butylhydrazine hydrochloride. When [BMIM][BF4] (1-butyl-
3-methylimidazolium tetrafluoroborate) and pyridine were
used as the reaction media, we obtained a mixture of 1-tert-
butyl-3(5)-trifluoromethylpyrazoles. The formation of 5-tri-
fluoromethyl-1-tert-butyl-1H-pyrazoles with high regioselec-
tivity occurred when the reaction was carried out with NaOH
in EtOH. The formation of 1-tert-butyl-3-trifluoro-
methyl-1H-pyrazoles occurred, after hydrolysis of the 4-alk-
oxy-1,1,1-trifluoro-3-alken-2-ones in H2O and H2SO4, fol-
lowed by cyclization in [BMIM][BF4] and pyridine.
halo-3-alken-2-ones, β-enaminones, and β-enamino ketones
with hydrazines.[12–18] In general, we have observed that the
regioselectivity of the reaction depends somewhat on the
hydrazine, but mainly on the reactivity of the 1,3-dielectro-
philic compound. The reaction of 4-alkoxy-1,1,1-trihalo-3-
alken-2-ones with methyl and phenyl hydrazines generally
results in a mixture of isomers.[19–21] On the other hand, the
reaction between tert-butylhydrazine hydrochloride and β-
enamino ketones in ethanol is highly regioselective and fur-
nishes 1-tert-butyl-4,5-disubstituted-1H-pyrazoles.[22] Simi-
larly, the reaction between tert-butylhydrazine hydrochlo-
ride and β-enaminones using an ionic liquid results in the
exclusive formation of 1-tert-butyl-5-substituted-1H-pyr-
azoles.[23] Thus, the problem of regioselectivity in the for-
mation of pyrazoles is evident when 4-alkoxy-1,1,1-tri-
fluoro-3-alken-2-ones are used as the 1,3-dielectrophile.
These 1,3-dielectrophiles are important precursors to the tri-
fluoromethylated pyrazoles, however, the availability of di-
versely substituted 1,3-diketones is limited. In this context,
we decided to study the regioselectivity in the formation of
pyrazoles by studying the reaction of 4-alkoxy-1,1,1-tri-
fluoro-3-alken-2-ones with tert-butylhydrazine hydrochlo-
ride under neutral conditions and with basic and acidic ad-
ditions to highlight the dependence of acidic or basic reac-
tion media on the regioselectivity of this reaction.
Introduction
The pyrazole nucleus has pronounced pharmacological
applications for analgesic and anti-inflammatory drugs.[1]
The incorporation of fluorine into a drug allows the simul-
taneous modulation of electronic, lipophilic, and steric pa-
rameters, all of which can critically influence both the phar-
macodynamic and pharmacokinetic properties of drugs.[2–4]
Celecoxib is the most recognized example of a drug that
contains a trifluoromethylated pyrazole moiety.[5]
The reaction between trifluoromethylated 1,3-dielectro-
philic compounds and hydrazines constitutes the main syn-
thetic approach to the trifluoromethylated pyrazole ring.
The synthesis of 3(5)-trifluoromethyl-1H-pyrazole from a
fluorinated 1,3-dicarbonyl compound has been extensively
studied, including regioselectivity studies in neutral media
with the addition of acid[6–10] and fluorinated solvents.[11]
Kinetic investigations of these condensation reactions with
the addition of acid showed that the regioselectivity in the
synthesis of pyrazole is influenced by a combination of ste-
ric effects, reactant ratio, and acidity.[10] In general, authors
observed that the 1,5 regioisomer (CF3 group at the 5-posi-
tion) is formed by maintaining a pH Ͼ 1.7, whereas more
acidic conditions led to larger quantities of the 1,3 re-
gioisomer.[6–11]
Our research group has extensively studied the reactions
of 1,3-dielectrophilic compounds such as 4-alkoxy-1,1,1-tri-
[a] Núcleo de Química de Heterociclos (NUQUIMHE), Depart-
ment of Chemistry, Federal University of Santa Maria,
97105-900, Santa Maria, RS, Brazil
Results and Discussion
To evaluate the reactivity of 4-alkoxy-1,1,1-trifluoro-3-
alken-2-ones 1a–1c with tert-butylhydrazine hydrochloride
2, a series of experiments were performed. The 4-alkoxy-
1,1,1-trifluoro-3-alken-2-ones used in the optimization of
Fax: +55-55-3220-8756
E-mail: mmartins@base.ufsm.br
Homepage: http://lattes.cnpq.br/6457412713967642
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201111.
7112
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Synthesis of 1-tert-Butyl-3(5)-trifluoromethyl-1H-pyrazoles
the reaction were chosen according to the substituent at the Table 1. Optimization of the reaction conditions for the synthesis
of 1-tert-butyl-1H-pyrazoles.
4-position. Hydrogen represents a substituent that does not
have any electronic effects on the structure (i.e., 1a), methyl
represents a group with an electron-donating effect (i.e., 1b),
and phenyl represents a group with an electron-donating
or -withdrawing effect (i.e., 1c), as shown in Figure 1.
Ethanol
[BMIM][BF4]
Product Molar ratio Yield[a] Product Molar ratio[b]
Yield[a]
[%]
Figure 1. Enones used in the optimization of the reaction.
3/4
[%]
3/4
1a
(3a + 4a) + byproducts
3a + 4a
3b + 4b
3c + 4c
75:25
66:34
15:85
44
58
85
1b 3b + 4c
1c 3c + 4c
24:76
36:64
56
65
Previously, we performed the reaction between tert-butyl-
hydrazine hydrochloride and β-enamino ketones or β-en-
aminones in different solvents[22,23] and determined that it
was worth evaluating the solvent used in the reaction.
Therefore, we started our investigation with the reaction of
4-alkoxy-1,1,1-trifluoro-3-alken-2-ones 1a–1c and tert-bu-
tylhydrazine hydrochloride 2 (at a molar ratio of 1:1.5,
respectively) using ethanol or the ionic liquid 1-butyl-3-
methyl imidazolium tetrafluoroborate ([BMIM][BF4]) as
the solvent. Initially, we performed the reaction between
1a–1c and 2 in the presence of pyridine at room tempera-
ture (25 °C) for 15 h. However, in both solvents, the starting
material was not totally converted into the desired products.
The next reaction was carried out at 78 °C (boiling point of
the ethanol) for 15 h using ethanol or the ionic liquid (see
Table 1). At this temperature, we observed the complete
conversion of the reactants into the pyrazoles (see Table 1).
We also performed the reaction in the absence of pyridine
and observed the loss of the tert-butyl group, which led to
an undesired product (1H-pyrazole). Pyridine is probably
needed to neutralize the hydrochloride present in the tert-
butylhydrazine hydrochloride.[13] Under these conditions,
[a] Yield of the mixture of isomers 3 and 4. [b] Molar ratio 3/4 was
obtained from the integration of the signals of the tert-butyl group
in the H NMR spectra.
1
of aryl and heteroaryl enones towards tert-butylhydrazine
hydrochloride was similar to the trifluoromethylated 1,3-di-
ketones, as both led to the formation of a mixture of 1,3
and 1,5 isomers.[2–4,11]
Table 2. Synthesis of 1-tert-butyl-1H-pyrazoles in [BMIM][BF4].
Enone
R1
Molar ratio 3/4[a]
% Yield[b]
the reactions of 1a–1c furnished a mixture of 1,3 and 1,5 1c
Ph
15:85
43:57
44:56
30:70
36:64
39:61
40:60
25:75
57:43
47:53
85
72
72
81
93
93
81
70
75
84
1d
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-I-C6H4
fur-2-yl
isomers, where the trifluoromethyl group is attached to C-
3 or C-5, respectively, on the pyrazole ring. In particular,
1a led to the formation of byproducts when ethanol was
1e
1f
1g
used as the solvent (see Table 1, Entry 1). From the experi-
ments described in Table 1, we observed that the reactions
performed in the ionic liquid resulted in higher yields. We
also noted that 1c (see Table 1, Entries 3 and 6) showed
better performance in comparison to 1a and 1b.
After optimizing the reaction conditions, we extended
the scope to the syntheses of new 1-tert-butyl-1H-pyrazoles.
Aryl and heteroaryl 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones
1c–1l were treated with 2 in the presence of [BMIM][BF4]
1h
1i
1j
1k
1l
thien-2-yl
naphth-2-yl
[a] Molar ratio 3/4 was obtained from the integration of the signals
1
in the H NMR spectra. [b] Yield of the mixture of isomers 3 and
4.
Isomers 3c, 3f–3i and 4c, 4f–4i were separated by wash-
and pyridine to furnish products 3c–3l and 4c–4l in good ing with cold hexane. The solid isomer 3c was submitted to
to excellent yields (70–93%), as shown in Table 2. To con- X-ray crystal structure analysis, and the crystallographic
firm the importance of the ionic liquid, we carried out the data revealed that it was the 1,3 isomer, as shown in Fig-
reactions in ethanol under the same conditions. The yields ure 2. From this, the isomers were characterized by analyz-
1
of the products 3c/4c (65%), 3d/4d (55%), 3g/4g (75%), and ing the H and 13C NMR spectra and mass spectrometric
1
3l/4l (75%) were lower than those obtained in fragmentation. The H NMR spectroscopic data of the 1,3
[BMIM][BF4], and formation of the byproduct (1H-pyr- isomer showed a chemical shift of the tert-butyl group from
azole) was observed. Thus, in neutral media, the reactivity δ = 1.47 to 1.54 ppm, whereas the spectroscopic data of the
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. A. P. Martins et al.
FULL PAPER
1,5 isomer showed a chemical shift for the same group from Table 3. Addition of PTSA in the synthesis of 1-tert-butyl-3(5)-tri-
fluoromethyl-1H-pyrazoles.
1.69 to 1.71 ppm. In addition, the chemical shift for H-4 in
each of the isomers was different, with a range of 6.37–
6.59 ppm for the 1,3 isomer and a range of 6.87–6.98 ppm
for the 1,5 isomer. The 13C NMR chemical shift of the tert-
butyl group was in the range of 29.7–30.9 ppm for the 1,3
isomer, whereas the spectra for the 1,5 isomer showed a
chemical shift of 29.8–29.9 ppm for the same group. Inter-
esting magnetic resonance behavior was observed for 4c–4l
(1,5 isomer). The multiplicity of the signal for the methyl
carbon in the tert-butyl group appeared as a quartet, be-
Entry
Solvent
PTSA Molar ra- % Yield % Yield
cause of a through-space 13C–19F coupling with J =
2 Hz.[24–27] The mass spectra of all of the compounds were
characterized by the presence of the [M]+ ion. The loss of
the tert-butyl group resulted in the most stable fragment,
which underwent a loss of one fluorine atom and then one
N2 molecule, thus generating less stable fragments. Another
low stability fragment formed by the loss of the tert-butyl
group and trifluoromethyl group was also observed. The
spectral differences between the 1,3 and the 1,5 isomer were
due to the abundance of fragments. In the majority of com-
pounds, the most abundant fragments were observed for the
1,5 isomers.
tio
3c[a]
5c[a]
1
2
3
4
5
EtOH
EtOH
[BMIM][BF4]
[BMIM][BF4] 0.25
[HMIM][HSO4] –
1
0.25
1
50:50
83:17
90:10
75:25
50:50
46
75
59
49
31
46
15
6
16
31
[a] Yield of isomers 3c and 5c in the mixture.
with the addition of the acid (see Table 3). The addition of
acid induced the formation of the 1H-pyrazole byproduct,
however, exclusive formation of 1,3 isomer was observed.
From the experiments performed with the acid, we found
that even very small amounts of acid led to the formation
of 1H-pyrazole. In an attempt to avoid the use of an acid
catalyst, we decided to employ the ionic liquid 3-methylimi-
dazolium hydrogen sulfate ([HMIM][HSO4]) as the solvent/
catalyst. It is known that this protic ionic liquid (PIL) has
an inherent Brönsted acidic nature, and thus it could per-
form the dual role in this reaction.[29,30] The reaction was
performed using 1 mmol of [HMIM][HSO4]. A mixture of
products 3c/5c was obtained, which showed a lower effi-
ciency in obtaining 3c in comparison to the reaction with
[BMIM][BF4] in the presence of PTSA. The formation of
the 1H-pyrazole was expected, as it was also observed when
the reaction was performed in the absence of pyridine (to
neutralize the hydrazine hydrochloride).
Thus, we proposed a mechanism for the formation of the
1H-pyrazole in acidic media (see Scheme 1). Its formation
can be explained by an initial protonation at N-2. After
this protonation step, electron delocalization in the pyrazole
occurs. As the molecule is charged, it is susceptible to an
elimination reaction. The E1 elimination takes place, and
the 1H-pyrazole and tert-butyl carbocation are formed. The
carbocation probably undergoes an attack by a nucleophilic
Figure 2. ORTEP of 1-(1,1-dimethylethyl)-5-phenyl-3-trifluorome-
thyl-1H-pyrazole (3c).[28] Displacement ellipsoids are drawn at the
40% probability level. H atoms are represented by circles of arbi-
trary radii.
To achieve the conditions for the regioselective syntheses species present in the reaction media and then is eliminated
of 1-tert-butyl-1H-pyrazoles, we tested the addition of 4- as a byproduct of the reaction.
toluenesulfonic acid (PTSA) to the reaction mixture. Reac-
In acidic media, it is known that 1j and 1k undergo hy-
tions were performed in either [BMIM][BF4] or ethanol drolysis.[31] Thus, we decided to obtain the product in two
Scheme 1. Mechanism for the formation of 1H-pyrazole in acidic media.
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Eur. J. Org. Chem. 2012, 7112–7119

Synthesis of 1-tert-Butyl-3(5)-trifluoromethyl-1H-pyrazoles
steps: (i) the acid hydrolysis of 1c–1l and (ii) a cycloconden- Table 5. Synthesis of 1-tert-butyl-5-trifluoromethyl-1H-pyrazoles.
sation reaction. Under these conditions, the desirable prod-
ucts
1-tert-butyl-3-trifluoromethyl-1H-pyrazoles
were
formed in high regioselectivity and good yields (65–82%),
as depicted in Table 4. These results are in accordance with
those reported by other authors, who describe the forma-
tion of the 1,3 isomers from the reaction between trifluoro-
methylated 1,3-diketones and methyl or phenyl hydrazine
with the addition of acid.[6–10]
Entry
Enone
R
% Yield 4[a]
1
2
3
4
5
6
7
8
9
1c
1d
1e
1f
1g
1h
1i
Ph
76
65
50
68
65
78
66
56
66
81
Table 4. Synthesis of 1-tert-butyl-3-trifluoromethyl-1H-pyrazoles.
4-Me-C6H4
4-OMe-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-I-C6H4
fur-2-yl
1j
1k
1l
thien-2-yl
naphth-2-yl
10
[a] Yield of isolated product.
Enone
R
% Yield 6[a]
% Yield 3[a]
1c
1d
1e
1f
1g
1h
1i
Ph
54
77
70
55
70
91
80
85
66
74
75
82
65
81
82
74
74
77
80
75
4-Me-C6H4
4-OMe-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-I-C6H4
fur-2-yl
Our study using 4-alkoxy-1,1,1-trifluoro-3-alken-2-one
furnished similar results to those found for trifluoromethyl-
ated 1,3-diketones under neutral conditions or with the ad-
dition of acid or base. The PTSA addition led to formation
of a 1,3 regioisomer, indicating the possible hydrolysis of 4-
alkoxy-1,1,1-trifluoro-3-alken-2-one to form the 1,3-dike-
tone. The hydrolysis of 4-alkoxy-1,1,1-trifluoro-3-alken-2-
one went to completion when using aqueous sulfuric acid,
confirming that under the addition of acid, the 1,3-diketone
1j
1k
1l
thien-2-yl
naphth-2-yl
[a] Yield of isolated product.
As the addition of acid allowed the exclusive formation was likely to be the dielectrophilic reactant. The hydrolysis
of the 1,3 isomer, we assumed that in reactions with the of 4-alkoxy-1,1,1-trifluoro-3-alken-2-one also explains the
trifluoromethylated 1,3-diketones, basic media could permit exclusive formation of the 1,3 regioisomer, which is formed
the formation of the 1,5 isomer in high regioselectivity.[6,10] under acidic conditions by the addition of acid.[6–10] The
However, reactions performed with a molar excess amount advantage of the hydrolysis of 4-alkoxy-1,1,1-trifluoro-3-
of pyridine (3 equiv.) were not efficient enough to convert alken-2-one is in the creation of trifluoromethylated 1,3-di-
the reactants into the expected pyrazoles with high regiose- ketones that are not available by other sources. Trifluorome-
lectivity in either [BMIM][BF4] or EtOH as the solvent. On thylated 1,3-diketones form an equilibrium with their enol
the other hand, the addition of NaOH with an equimolar forms. Thus, the most electrophilic carbon is the one at-
amount of hydrazine in both [BMIM][BF4] and EtOH led tached to the trifluoromethyl group, which has its LUMO
to the formation of products. The reaction carried out in energy reduced by protonation from the addition of acid.
[BMIM][BF4] resulted in a mixture of the 1,3 and 1,5 iso-
On the other hand, the hydrolysis reaction is avoided
mers, and the reaction performed in EtOH furnished the 1- with the addition of NaOH, and the β-carbon of 4-alkoxy-
tert-butyl-5-trifluoromethyl-1H-pyrazoles with high re- 1,1,1-trifluoro-3-alken-2-one, which is more reactive, suffers
gioselectivity. Therefore, reactions performed in the pres- attack by the tert-butyl hydrazine hydrochloride (NH2).
ence of NaOH and ethanol led to the corresponding 1-tert- Thus, the 1,5 regioisomer is formed in high regioselectivity,
butyl-5-trifluoromethyl-1H-pyrazoles 4c–4l in good yields different from the 1,3-diketone.
(50–81%), as shown in Table 5. These results are in accord-
Finally, these observations support the result found when
ance with those reported by other authors[10] who describe 4-alkoxy-1,1,1-trifluoro-3-alken-2-one was treated with tert-
the formation of the 1,5 isomer from the reaction of trifluo- butyl hydrazine hydrochloride in the presence of pyridine
romethylated 1,3-diketones and methyl- or phenylhydrazine and [BMIM][BF4]. A part of 4-alkoxy-1,1,1-trifluoro-3-
using a pH Ͼ 1.7. On the other hand, they are opposite to alken-2-one underwent hydrolysis and led to formation of
the results described by Singh et al.[6] who isolated the 1,3 the 1,3 regioisomer, but the other part was not hydrolyzed
isomer in acidic, basic, and neutral conditions, when treat- (stabilized by pyridine/[BMIM][BF4]) and led to the forma-
ing 1-(4-methoxyphenyl)hydrazine with trifluoromethylated tion of the 1,5 regioisomer. These results are depicted in
1,3-diketones.
Scheme 2.
Eur. J. Org. Chem. 2012, 7112–7119
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M. A. P. Martins et al.
FULL PAPER
Scheme 2. Summary of results described in this paper.
Synthesis of the β-Diketones: β-Diketones 5c–5j were obtained from
the hydrolysis reaction of enones 1c–1j in accordance with the pro-
cedure described in the literature.[31]
Conclusions
This work presents the synthesis of a series of new 1-tert-
butyl-3(5)-trifluoromethyl-1H-pyrazoles with high regiose-
lectivity. The most important aspect is that the 1,3 isomer
is formed with high regioselectivity from β-diketones (or
enols), after the hydrolysis of 4-alkoxy-1,1,1-trifluoro-3-
alken-2-ones. In addition, the presence of a base in the reac-
tion media leads 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones to
form 1,5 isomers with high regioselectivity. When mixtures
of isomers are isolated, they can be obtained individually
by washing with hexane. These results are highly innovative,
when one considers the use of 4-alkoxy-1,1,1-trifluoro-3-
alken-2-ones in the regioselective syntheses of 1-alkyl-1H-
pyrazoles. Structures with hydrazine features (especially
those displaying steric factors) may be affecting this regiose-
lectivity. Studies are in progress in our laboratories and will
be published hereafter.
Synthesis of the Mixture of 1-(1,1-Dimethylethyl)-3(5)-trifluorome-
thyl-1H-pyrazoles: An enone (1a–1l, 1 mmol), hydrazine
2
(1.5 mmol), pyridine (1.5 mmol), and [BMIM][BF4] (0.5 mmol) or
EtOH (5 mL) were placed in a round-bottomed flask. The mixture
was magnetically stirred at 78 °C for 15 h. When the reaction was
performed in EtOH, the mixture was evaporated under reduced
pressure. Chloroform (5 mL) was then added, and the reaction mix-
ture was washed with water (3ϫ5 mL). The combined organic
phases were dried with anhydrous Na2SO4, and the solvent was
evaporated under reduced pressure. The pyrazole mixtures were ob-
tained in pure form without further purification. The mixtures of
pyrazoles 3c/4c and 3f/4f–3i/4i were washed with hexane and then
separated.
Synthesis of the 1-(1,1-Dimethylethyl)-5-trifluoromethyl-1H-pyr-
azoles: An enone (1a–1l, 1 mmol), hydrazine 2 (1.5 mmol), NaOH
(1.5 mmol), and EtOH (5 mL) were placed in a round-bottomed
flask. The mixture was magnetically stirred at 78 °C for 15 h. After
completion of the reaction time, the EtOH was evaporated under
reduced pressure. Chloroform (5 mL) was then added, and the reac-
tion mixture was washed with water (3ϫ5 mL). The combined or-
ganic phases were dried with anhydrous Na2SO4, and the solvent
was evaporated under reduced pressure. The 1,5 isomer of the pyr-
azole was obtained in pure form without further purification.
Experimental Section
General Methods: Unless otherwise indicated, all of the common
reagents and solvents were used as obtained from commercial sup-
pliers without further purification. The H and 13C NMR spectro-
1
scopic data were recorded with a Bruker DPX 400 (1H NMR at
400.13 MHz and 13C NMR at 100.62 MHz) in CDCl3/TMS solu-
tions at 298 K, and the chemical shifts (δ values) are given in ppm.
Mass spectra were registered with a HP 5973 MSD connected to a
HP 6890 GC and interfaced by a Pentium PC. The GC was
equipped with a split-splitless injector, crosslinked to a HP-5 capil-
lary column (30 m, 0.32 mm i.d.), and helium was used as the car-
rier gas. The melting points were measured with a Microquímica
MQAPF 301. Elemental analyses were performed with a Perkin–
Elmer CHN 2400 elemental analyzer, and the results agreed favor-
ably with the calculated values.
Synthesis of the 1-(1,1-Dimethylethyl)-3-trifluoromethyl-1H-pyr-
azoles: A 1,3-dicarbonyl compound (6c–6j, 1 mmol), hydrazine 2
(1.5 mmol), pyridine (1.5 mmol), and [BMIM][BF4] (0.5 mmol)
were placed in a round-bottomed flask. The mixture was magneti-
cally stirred at 78 °C for 15 h. Chloroform (5 mL) was then added,
and the reaction mixture was washed with water (3ϫ5 mL). The
combined organic phases were dried with anhydrous Na2SO4, and
the solvent was evaporated under reduced pressure. The 1,3 isomer
of the pyrazole was obtained in pure form without further purifica-
tion.
1-(1,1-Dimethylethyl)-5-phenyl-3-trifluoromethyl-1H-pyrazole (3c):
M.p. 87–89 °C. 1H NMR (200 MHz, CDCl3): δ = 1.47 (s, 9 H,
tBu), 6.38 (s, 4-H), 7.31–7.44 (m, 5 H, Ar) ppm. 13C NMR
(100 MHz, CDCl3): δ = 30.1 (tBu), 62.7 (C), 107.3 (q, 3JC,F = 2 Hz,
Synthesis of Enones: Enones 1a–1l were obtained from the acyl-
ation reaction of the enol ether or acetal with trifluoroacetic anhy-
dride in accordance with the methodology developed in our labora-
tory.[32]
1
C-4), 121.7 (q, JC,F = 268 Hz, CF3), 125.4, 127.9, 128.6, 132.5
7116
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 7112–7119

Synthesis of 1-tert-Butyl-3(5)-trifluoromethyl-1H-pyrazoles
2
(Ar), 139.2 (q, JC,F = 38 Hz, C-3), 144.0 (C-5) ppm. MS (EI,
4-H), 6.45 (dd, 1 H, Ar), 6.65 (d, 1 H, Ar), 7.45 (d, 1 H, Ar) ppm.
70 eV): m/z (%) = 268 (36) [M]+, 212 (100), 193 (40), 164 (49), 143
13C NMR (100 MHz, CDCl3): δ = 29.7 (tBu), 62.5 (C), 108.9 (q,
(35). C14H15F3N2 (268.28): calcd. C 62.68, H 5.64, N 10.44; found 3JC,F = 2 Hz, C-4), 121.4 (q, JC,F = 267 Hz, CF3), 106.1, 111.2,
1
2
C 62.21, H 5.67, N 10.45.
142.0, 143.1 (C-2Ј, C-3Ј, C-4Ј, C-5Ј), 139.2 (q, JC,F = 38 Hz, C-3),
133.3 (C-5) ppm. MS (EI, 70 eV): m/z (%) = 258 (6) [M]+, 202
(100), 183 (5), 154 (7). C12H13F3N2O (258.24): calcd. C 55.81, H
5.07, N 10.85; found C 54.43, H 5.06, N 8.66.
1-(1,1-Dimethylethyl)-5-(4-methylphenyl)-3-trifluoromethyl-1H-
pyrazole (3d): 1H NMR (200 MHz, CDCl3): δ = 1.46 (s, 9 H, tBu),
2.41 (s, 3 H, CH3), 6.35 (s, 4-H), 7.25–7.70 (m, 4 H, Ar) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.2 (Me), 30.9 (tBu), 62.6 (C), 107.4
(q, 3JC,F = 2 Hz, C-4), 121.7 (q, 1JC,F = 268 Hz, CF3), 125.4, 128.6,
1-(1,1-Dimethylethyl)-5-thien-2-yl-3-trifluoromethyl-1H-pyrazole
1
(3k): H NMR (200 MHz, CDCl3): δ = 1.54 (s, 9 H, tBu), 6.86 (s,
2
129.7, 138.9 (Ar), 139.1 (q, JC,F = 39 Hz, C-3), 144.1 (C-5) ppm.
4-H), 7.02–7.11 (m, 1 H, Ar), 7.27 (d, 1 H, Ar), 7.30 (d, 1 H,
MS (EI, 70 eV): m/z (%) = 282 (23) [M]+, 226 (100), 207 (17), 177
(8), 157 (12). C15H17F3N2 (282.31): calcd. C 63.82, H 6.07, N 9.92;
found C 64.66, H 6.05, N 9.29.
Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 30.5 (tBu), 63.0 (C),
3
109.6 (q, JC,F = 2 Hz, C-4), 121.4 (q, 1JC,F = 268 Hz, CF3), 123.8,
124.7, 127.7, 131.5 (C-2Ј, C-3Ј, C-4Ј, C-5Ј), 139.6 (q, 2JC,F = 38 Hz,
C-3), 135.6 (C-5) ppm. MS (EI, 70 eV): m/z (%) = 274 (5) [M]+,
218 (100), 199 (3), 170 (9), 149 (2). C12H13F3N2S (274.30): calcd.
C 52.54, H 4.78, N 10.21; found C 52.25, H 4.64, N 9.82.
1-(1,1-Dimethylethyl)-5-(4-methoxyphenyl)-3-trifluoromethyl-1H-
1
pyrazole (3e): H NMR (200 MHz, CDCl3): δ = 1.47 (s, 9 H, tBu),
3.83 (s, 3 H, CH3), 6.50 (s, 4-H), 7.25–7.70 (m, 4 H, Ar) ppm. 13C
NMR (100 MHz, CDCl3): δ = 30.9 (tBu), 55.2 (OMe), 62.5 (C),
1-(1,1-Dimethylethyl)-5-(naphth-2-yl)-3-trifluoromethyl-1H-pyrazole
3
107.4 (q, JC,F = 2 Hz, C-4), 121.7 (q, 1JC,F = 268 Hz, CF3), 114.0,
1
(3l): H NMR (200 MHz, CDCl3): δ = 1.49 (s, 9 H, tBu), 6.45 (s,
2
4-H), 7.40–8.21 (m, 7 H, Ar) ppm. 13C NMR (100 MHz, CDCl3):
126.7, 130.5, 159.5 (Ar), 139.0 (q, JC,F = 37 Hz, C-3), 143.8 (C-
5) ppm. MS (EI, 70 eV): m/z (%) = 298 (25) [M]+, 242 (100), 227
(63), 223 (10). C15H17F3N2O (298.31): calcd. C 60.40, H 5.74, N
9.39; found C 60.6, H 5.76, N 8.81.
1
δ = 30.9 (tBu), 62.7 (C), 107.6–107.7 (m, C-4), 121.8 (q, JC,F
=
267 Hz, CF3), 125.9, 126.2, 127.7, 127.7, 128.1, 128.3, 129.7, 133.0,
2
133.1, 133.5 (Ar), 139.3 (q, JC,F = 38 Hz, C-3), 143.9 (C-5) ppm.
C18H17F3N2 (318.34): calcd. C 67.91, H 5.38, N 8.80; found C
67.93, H 5.28, N 8.51.
1-(1,1-Dimethylethyl)-5-(4-fluorophenyl)-3-trifluoromethyl-1H-
pyrazole (3f): M.p. 96–97 °C. 1H NMR (200 MHz, CDCl3): δ =
1.46 (s, 9 H, tBu), 6.38 (s, 4-H), 7.06–7.36 (m, 4 H, Ar) ppm. 13C
1-(1,1-Dimethylethyl)-3-phenyl-5-trifluoromethyl-1H-pyrazole (4c):
1H NMR (200 MHz, CDCl3): δ = 1.71 (s, 9 H, tBu), 6.98 (s, 4-H),
7.31–7.32 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ =
3
NMR (100 MHz, CDCl3): δ = 30.9 (tBu), 62.7 (C), 107.6 (q, JC,F
1
2
= 2 Hz, C-4), 121.5 (q, JC,F = 268 Hz, CF3), 115.2 (d, JC,F
=
21 Hz, Ar), 128.6 (d, 4JC,F = 3 Hz, Ar), 132.3 (d, 3JC,F = 8 Hz, Ar),
5
3
29.9 (q, JC,F = 2 Hz, tBu), 63.1 (C), 107.4 (q, JC,F = 4 Hz, C-4),
1
2
1
163.0 (d, JC,F = 248 Hz, Ar), 139.3 (q, JC,F = 38 Hz, C-3), 142.7
(C-5) ppm. MS (EI, 70 eV): m/z (%) = 286 (12) [M]+, 230 (100),
211 (17), 182 (22), 161 (13). C14H14F4N2 (286.27): calcd. C 58.74,
H 4.93, N 9.79; found C 58.59, H 4.94, N 9.77.
120.5 (q, JC,F = 268 Hz, CF3), 127.9, 128.9, 130.4, 132.7 (Ar),
2
132.2 (q, JC,F = 38 Hz, C-5), 147.8 (C-3) ppm. MS (EI, 70 eV):
m/z (%) = 268 (97) [M]+, 212 (100), 193 (36), 164 (74), 143 (57).
C14H15F3N2 (268.28): calcd. C 62.68, H 5.64, N 10.44; found C
62.21, H 5.67, N 10.45.
5-(4-Chlorophenyl)-1-(1,1-dimethylethyl)-3-trifluoromethyl-1H-
1
pyrazole (3g): M.p. 139–141 °C. H NMR (200 MHz, CDCl3): δ =
1-(1,1-Dimethylethyl)-3-(4-methylphenyl)-5-trifluoromethyl-1H-
pyrazole (4d): 1H NMR (200 MHz, CDCl3): δ = 1.70 (s, 9 H, tBu),
2.36 (s, 3 H, CH3), 6.94 (s, 4-H), 7.25–7.70 (m, 4 H, Ar) ppm. 13C
1.47 (s, 9 H, tBu), 6.37 (s, 4-H), 7.20–7.64 (m, 4 H, Ar) ppm. 13C
3
NMR (100 MHz, CDCl3): δ = 30.9 (tBu), 62.8 (C), 107.5 (q, JC,F
= 1.4 Hz, C-4), 121.5 (q, 1JC,F = 268 Hz, CF3), 121.9, 127.0, 131.5,
131.7 (Ar), 139.4 (q, 2JC,F = 38 Hz, C-3), 142.6 (C-5) ppm. MS (EI,
70 eV): m/z (%) = 302 (23) [M]+, 248 (100), 227 (23), 198 (24), 177
(15). C14H14ClF3N2 (302.73): calcd. C 55.55, H 4.66, N 9.25; found
C 55.26, H 4.70, N 9.13.
5
NMR (100 MHz, CDCl3): δ = 21.2 (Me), 29.9 (q, JC,F = 2 Hz,
3
1
tBu), 63.0 (C), 107.3 (q, JC,F = 4 Hz, C-4), 120.5 (q, JC,F
=
=
2
268 Hz, CF3), 129.3, 129.7, 130.2, 137.7 (Ar), 132.1 (q, JC,F
39 Hz, C-5), 147.9 (C-3) ppm. MS (EI, 70 eV): m/z (%) = 282 (52)
[M]+, 226 (100), 206 (20), 177 (11), 157 (16). C15H17F3N2 (282.31):
calcd. C 63.82, H 6.07, N 9.92; found C 64.66, H 6.05, N 9.29.
5-(4-Bromophenyl)-1-(1,1-dimethylethyl)-3-trifluoromethyl-1H-
1
pyrazole (3h): M.p. 141–143 °C. H NMR (200 MHz, CDCl3): δ =
1-(1,1-Dimethylethyl)-3-(4-methoxyphenyl)-5-trifluoromethyl-1H-
1.47 (s, 9 H, tBu), 6.37 (s, 4-H), 7.20–7.64 (m, 4 H, Ar) ppm. 13C
1
pyrazole (4e): H NMR (200 MHz, CDCl3): δ = 1.68 (s, 9 H, tBu),
3
NMR (100 MHz, CDCl3): δ = 30.9 (tBu), 62.8 (C), 107.5 (q, JC,F
3.85 (s, 3 H, CH3), 6.35 (s, 4-H), 7.25–7.70 (m, 4 H, Ar) ppm. 13C
1
= 2 Hz, C-4), 121.5 (q, JC,F = 267 Hz, CF3), 126.7, 126.9, 128.7,
5
NMR (100 MHz, CDCl3): δ = 29.9 (q, JC,F = 2 Hz, tBu), 55.2
131.7 (Ar), 139.3 (q, 2JC,F = 37 Hz, C-3), 142.7 (C-5) ppm. MS (EI,
70 eV): m/z (%) = 346 (7) [M]+, 290 (100), 273 (4), 242 (2), 221 (2).
C14H14BrF3N2 (347.18): calcd. C 48.43, H 4.06, N 8.07; found C
48.37, H 4.08, N 7.94.
3
1
(OMe), 62.9 (C), 106.9 (q, JC,F = 4 Hz, C-4), 120.4 (q, JC,F
=
=
2
268 Hz, CF3), 113.3, 129.9, 131.7, 160.0 (Ar), 132.1 (q, JC,F
39 Hz, C-5), 147.6 (C-3) ppm. MS (EI, 70 eV): m/z (%) = 298 (42)
[M]+, 242 (100), 223 (6), 227 (77). C15H17F3N2O (298.31): calcd. C
60.40, H 5.74, N 9.39; found C 60.6, H 5.76, N 8.81.
1-(1,1-Dimethylethyl)-5-(4-iodophenyl)-3-trifluoromethyl-1H-
1
pyrazole (3i): M.p. 139–141 °C. H NMR (200 MHz, CDCl3): δ =
1-(1,1-Dimethylethyl)-3-(4-fluorophenyl)-5-trifluoromethyl-1H-
1.47 (s, 9 H, tBu), 6.37 (s, 4-H), 7.12 (d, 2 H, Ar), 7.70–7.78 (m, 2
1
pyrazole (4f): H NMR (200 MHz, CDCl3): δ = 1.69 (s, 9 H, tBu),
H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 30.9 (tBu), 62.8
6.93 (s, 4-H), 7.04–7.80 (m, 4 H, Ar) ppm. 13C NMR (100 MHz,
3
1
(C), 93.4 (Ar), 107.4 (q, JC,F = 2 Hz, C-4), 121.5 (q, JC,F
=
5
3
CDCl3): δ = 29.9 (q, JC,F = 2 Hz, tBu), 63.2 (C), 107.6 (q, JC,F
2
267 Hz, CF3), 127.2, 132.2, 137.2 (Ar), 139.3 (q, JC,F = 39 Hz, C-
3), 142.7 (C-5) ppm. MS (EI, 70 eV): m/z (%) = 394 (12) [M]+, 338
(100), 319 (6), 211 (6), 191 (28). C14H14IF3N2 (394.17): calcd. C
42.66, H 3.58, N 7.11; found C 42.39, H 3.47, N 6.81.
1
2
= 2 Hz, C-4), 120.4 (q, JC,F = 268 Hz, CF3), 115.5 (d, JC,F
=
22 Hz, Ar), 127.2 (d, 3JC,F = 8 Hz, Ar), 128.8 (d, 4JC,F = 3 Hz, Ar),
1
2
162.7 (d, JC,F = 248 Hz, Ar), 132.4 (q, JC,F = 38 Hz, C-5), 147.0
(C-3) ppm. MS (EI, 70 eV): m/z (%) = 286 (71) [M]+, 230 (100),
1-(1,1-Dimethylethyl)-5-(fur-2-yl)-3-trifluoromethyl-1H-pyrazole 211 (32), 182 (76), 161 (44). C14H14F4N2 (286.27): calcd. C 58.74,
1
(3j): H NMR (200 MHz, CDCl3): δ = 1.57 (s, 9 H, tBu), 6.49 (s, H 4.93, N 9.79; found C 58.59, H 4.94, N 9.77.
Eur. J. Org. Chem. 2012, 7112–7119
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7117

M. A. P. Martins et al.
FULL PAPER
3-(4-Chlorophenyl)-1-(1,1-dimethylethyl)-5-trifluoromethyl-1H-
578426/2008-0 and 471519/2009-0), the Fundação de Amparo à
pyrazole (4g): 1H NMR (200 MHz, CDCl3): δ = 1.70 (s, 9 H, tBu), Pesquisa do Estado do Rio Grande do Sul (FAPERGS/CNPq-
6.95 (s, 4-H), 7.26–7.38 (m, 4 H, Ar) ppm. 13C NMR (100 MHz,
PRONEX Edital No. 008/2009 and Proc. No. 10/0037-8), and the
CDCl3): δ = 29.9 (q, JC,F = 2 Hz, tBu), 63.4 (C), 107.4 (q, JC,F Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
5
3
1
= 4 Hz, C-4), 120.3 (q, JC,F = 268 Hz, CF3), 123.4, 131.3, 131.6,
132.0 (Ar), 132.5 (q, 2JC,F = 38 Hz, C-5), 146.7 (C-3) ppm. MS (EI,
70 eV): m/z (%) = 302 (35) [M]+, 248 (100), 227 (12), 198 (20), 177
(14). C14H14ClF3N2 (302.73): calcd. C 55.55, H 4.66, N 9.25; found
C 55.26, H 4.70, N 9.13.
(CAPES/PROEX) for financial support. The fellowships from
CNPq (to M. A. P. M., M. R. B. M., M. Z., N. Z., V. P. A., and
H. G. B.) and CAPES (to C. P. F. and L. B.) are also acknowledged.
[1] L. Yet, Pyrazoles, in: Comprehensive Heterocyclic Chemistry III
(Eds.: A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven,
R. J. K. Taylor), Pergamon, Oxford, UK, 2008, vol. 4, pp. 1–
141.
[2] B. E. Smart, J. Fluorine Chem. 2001, 109, 3–11.
[3] F. M. D. Ismail, J. Fluorine Chem. 2002, 118, 27–33.
[4] K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881–
1886.
[5] M. Williams, E. A. Kowaluk, S. P. Arneric, J. Med. Chem.
1999, 42, 1481–1500.
[6] S. K. Singh, M. S. Reddy, S. Shivaramakrishna, D. Kavitha, R.
Vasudev, J. M. Babu, A. Sivalakshmidevi, Y. K. Rao, Tetrahe-
dron Lett. 2004, 45, 7679–7682.
3-(4-Bromophenyl)-1-(1,1-dimethylethyl)-5-trifluoromethyl-1H-
pyrazole (4h): 1H NMR (200 MHz, CDCl3): δ = 1.69 (s, 9 H, tBu),
6.95 (s, 4-H), 7.48–7.56 (m, 4 H, Ar) ppm. 13C NMR (100 MHz,
5
3
CDCl3): δ = 29.9 (q, JC,F = 2 Hz, tBu), 63.4 (C), 107.4 (q, JC,F
1
= 4 Hz, C-4), 120.3 (q, JC,F = 268 Hz, CF3), 128.3, 129.4, 131.4,
133.6 (Ar), 131.1 (q, 2JC,F = 38 Hz, C-5), 146.7 (C-3) ppm. MS (EI,
70 eV): m/z (%) = 346 (10) [M]+, 290 (100), 271 (2), 242 (2), 221
(2). C14H14BrF3N2 (347.18): calcd. C 48.43, H 4.06, N 8.07; found
C 48.37, H 4.08, N 7.94.
3-(4-Iodophenyl)-1-(1,1-dimethylethyl)-5-trifluoromethyl-1H-
1
pyrazole (4i): Oil. H NMR (200 MHz, CDCl3): δ = 1.70 (s, 9 H,
tBu), 6.96 (s, 4-H), 7.55 (d, 2 H, Ar), 7.70–7.78 (m, 2 H, Ar) ppm.
[7] P. S. Humphries, J. M. Finefield, Tetrahedron Lett. 2006, 47,
13C NMR (100 MHz, CDCl3): δ = 29.9 (tBu), 63.4 (C), 91.5 (Ar),
2443–2446.
3
107.3 (q, JC,F = 4 Hz, C-4), 120.3 (q, 1JC,F = 267 Hz, CF3), 132.0,
[8] S. W. Djuric, N. Y. BaMaung, A. Basha, H. Liu, J. R. Luly,
D. J. Madar, R. J. Sciotti, N. P. Tu, F. L. Wagenaar, P. E. Wied-
eman, X. Zhou, S. Ballaron, J. Bauch, Y.-W. Chen, X. G.
Chiou, T. Fey, D. Gauvin, E. Gubbins, G. C. Hsieh, K. C.
Marsh, K. W. Mollison, M. Pong, T. K. Shaughnessy, M. P.
Sheets, M. Smith, J. M. Trevillyan, U. Warrior, C. D. Wegner,
G. W. Carter, J. Med. Chem. 2000, 43, 2975–2981.
[9] T. Norris, R. Colon-Cruz, D. H. B. Ripin, Org. Biomol. Chem.
2005, 3, 1844–1849.
2
132.1 (Ar), 132.5 (q, JC,F = 39 Hz, C-3), 137.6, 146.7 (C-5) ppm.
MS (EI, 70 eV): m/z (%) = 394 (11) [M]+, 338 (100), 319 (3), 211
(4), 191 (18). C14H14IF3N2 (394.17): calcd. C 42.66, H 3.58, N 7.11;
found C 42.39, H 3.47, N 6.81.
1-(1,1-Dimethylethyl)-3-(fur-2-yl)-5-trifluoromethyl-1H-pyrazole
1
(4j): H NMR (200 MHz, CDCl3): δ = 1.73 (s, 9 H, tBu), 6.94 (s,
4-H), 6.48–6.59 (m, 2 H, Ar), 7.55 (m, 1 H, Ar) ppm. 13C NMR
(100 MHz, CDCl3): δ = 29.8 (q, 5JC,F = 2 Hz, tBu), 63.3 (C), 107.5
(q, 3JC,F = 4 Hz, C-4), 120.3 (q, 1JC,F = 268 Hz, CF3), 111.3, 112.2,
[10]
[11]
[12]
[13]
[14]
J. C. Sloop, B. Lechner, G. Washington, C. L. Bumgardner,
W. D. Loehle, W. Creasy, Int. J. Chem. Kinet. 2008, 40, 370–
383.
S. Fustero, R. Román, J. F. Sanz-Cervera, A. Simón-Fuentes,
A. A. Cuñat, S. Villa Nova, M. Murguía, J. Org. Chem. 2008,
73, 3523–3529.
H. G. Bonacorso, L. M. F. Porte, C. A. Cechinel, G. R. Paim,
E. D. Deon, N. Zanatta, M. A. P. Martins, Tetrahedron Lett.
2009, 50, 1392–1394.
H. G. Bonacorso, R. P. Vezzosi, I. R. Rodrigues, R. L. Drek-
ener, L. M. F. Porte, A. F. C. Flores, N. Zanatta, M. A. P. Mar-
tins, J. Braz. Chem. Soc. 2009, 20, 1370–1378.
2
142.3, 147.9 (C-2Ј, C-3Ј, C-4Ј, C-5Ј), 139.2 (q, JC,F = 38 Hz, C-5),
140.8 (C-3) ppm. MS (EI, 70 eV): m/z (%) = 258 (11) [M]+, 202
(100), 183 (5), 154 (6). C12H13F3N2O (258.24): calcd. C 55.81, H
5.07, N 10.85; found C 54.43, H 5.06, N 8.66.
1-(1,1-Dimethylethyl)-3-(thien-2-yl)-5-trifluoromethyl-1H-pyrazole
1
(4k): H NMR (200 MHz, CDCl3): δ = 1.69 (s, 9 H, tBu), 6.91 (s,
4-H), 6.48–6.59 (m, 2 H, Ar), 7.55 (m, 1 H, Ar) ppm. 13C NMR
(100 MHz, CDCl3): δ = 29.8 (q, 5JC,F = 2 Hz, tBu), 63.2 (C), 107.4
(q, 3JC,F = 4 Hz, C-4), 120.2 (q, 1JC,F = 269 Hz, CF3), 126.7, 127.3,
L. Buriol, C. P. Frizzo, M. R. B. Marzari, D. N. Moreira,
L. D. T. Prola, N. Zanatta, H. G. Bonacorso, M. A. P. Martins,
J. Braz. Chem. Soc. 2010, 21, 1037–1044.
2
130.4, 135.9 (C-2Ј, C-3Ј, C-4Ј, C-5Ј), 139.6 (q, JC,F = 38 Hz, C-5),
143.4 (C-3) ppm. MS (EI, 70 eV): m/z (%) = 274 (22) [M]+, 218
(100), 199 (6), 170 (20), 149 (5). C12H13F3N2S (274.30): calcd. C
52.54, H 4.78, N 10.21; found C 52.25, H 4.64, N 9.82.
[15]
[16]
S. Moura, A. F. C. Flores, F. R. Paula, E. Pinto, P. Machado,
M. A. P. Martins, Lett. Org. Chem. 2008, 5, 91–97.
M. A. P. Martins, C. M. P. Pereira, S. Moura, C. P. Frizzo, P.
Beck, N. Zanatta, H. G. Bonacorso, A. F. C. Flores, J. Hetero-
cycl. Chem. 2007, 44, 1195–1199.
1-(1,1-Dimethylethyl)-3-(naphth-2-yl)-5-trifluoromethyl-1H-pyrazole
1
(4l): H NMR (200 MHz, CDCl3): δ = 1.74 (s, 9 H, tBu), 7.12 (s,
4-H), 7.40–8.21 (m, 7 H, Ar) ppm. 13C NMR (100 MHz, CDCl3):
[17]
M. A. P. Martins, C. M. P. Pereira, P. Beck, P. Machado, S.
Moura, M. V. M. Teixeira, H. G. Bonacorso, N. Zanatta, Tet-
rahedron Lett. 2003, 44, 6669–6672.
1
δ = 29.9 (tBu), 63.2 (C), 107.6–107.7 (m, C-4), 120.5 (q, JC,F
=
268 Hz, CF3), 123.7, 124.1, 126.8, 126.9, 127.5, 127.7, 128.0, 129.9,
2
129.9, 132.4 (Ar), 132.2 (q, JC,F = 39 Hz, C-5), 147.8 (C-3) ppm. [18]
C18H17F3N2 (318.34): calcd. C 67.91, H 5.38, N 8.80; found C
67.93, H 5.28, N 8.51.
A. F. C. Flores, M. A. P. Martins, A. Rosa, D. C. Flores, N.
Zanatta, H. G. Bonacorso, Synth. Commun. 2002, 32, 1585–
1594.
M. A. P. Martins, R. A. Freitag, A. Rosa, A. F. C. Flores, N.
Zanatta, H. G. Bonacorso, J. Heterocycl. Chem. 1999, 36, 217–
219.
[19]
Supporting Information (see footnote on the first page of this arti-
1
cle): Mass spectra and H and 13C NMR spectra of 3c–3l and 4c–
4l.
[20]
[21]
J. W. Pavlik, T. I. Na Ayudhya, S. Tantayanon, J. Heterocycl.
Chem. 2003, 40, 1087–1089.
M. A. P. Martins, G. P. Bastos, A. P. Sinhorin, N. E. K. Zim-
mermann, A. Rosa, S. Brondani, D. Emmerich, H. G. Bona-
corso, N. Zanatta, J. Fluorine Chem. 2003, 123, 249–253.
F. A. Rosa, P. Machado, P. S. Vargas, H. G. Bonacorso, N.
Zanatta, M. A. P. Martins, Synlett 2008, 1673–1678.
Acknowledgments
The authors are grateful to the Conselho Nacional de Desenvolvi-
mento Científico e Tecnológico (CNPq/Universal Proc. Nos.
[22]
7118
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 7112–7119

Synthesis of 1-tert-Butyl-3(5)-trifluoromethyl-1H-pyrazoles
[23] C. P. Frizzo, M. R. B. Marzari, L. Buriol, D. N. Moreira, F. A.
Rosa, P. S. Vargas, N. Zanatta, H. G. Bonacorso, M. A. P. Mar-
tins, Catal. Commun. 2009, 10, 1967–1970.
[30]
[31]
M. A. P. Martins, C. P. Frizzo, D. N. Moreira, N. Zanatta,
H. G. Bonacorso, Chem. Rev. 2008, 108, 2015–2050.
A. F. C. Flores, S. Brondani, N. Zanatta, A. Rosa, M. A. P.
Martins, Tetrahedron Lett. 2002, 43, 8701–8705.
[24] F. R. Jerome, K. L. Servis, J. Am. Chem. Soc. 1972, 94, 5896–
5897.
[32] a) M. A. P. Martins, E. A. Guarda, C. P. Frizzo, D. N. Moreira,
M. R. B. Marzari, N. Zanatta, H. G. Bonacorso, Catal. Lett.
2009, 130, 93–99; b) M. A. P. Martins, E. A. Guarda, C. P.
Frizzo, E. Scapin, P. Beck, A. C. da Costa, N. Zanatta, H. G.
Bonacorso, J. Mol. Catal. A 2007, 266, 100–103; c) M. A. P.
Martins, W. Cunico, C. M. P. Pereira, A. F. C. Flores, H. G.
Bonacorso, N. Zanatta, Curr. Org. Synth. 2004, 1, 391–403; d)
S. V. Druzhinin, E. S. Balenkova, V. G. Nenajdenko, Tetrahe-
dron 2007, 63, 7753–7808.
[25] P. Szczecinski, M. Maminski, J. Chem. Res. Synop. 2001, 88–
89.
[26] J. W. Lyga, R. N. Henrie, G. A. Meier, W. Creekmore, R. M.
Patera, Magn. Reson. Chem. 1993, 31, 323–328.
[27] I. D. Rae, J. A. Weigold, R. H. Contreras, R. R. Biekosfsky,
Magn. Reson. Chem. 1993, 31, 836–840.
[28] CCDC-721171 (for 3c) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: August 15, 2012
Published Online: November 6, 2012
[29] T. L. Greaves, C. J. Drummond, Chem. Rev. 2008, 108, 206–
237.
Eur. J. Org. Chem. 2012, 7112–7119
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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