New strategy for the regioselective synthesis of 1-phenyl-3- trifluoromethyl-1H-pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2013.05.103

A regioselective synthesis of 3-trifluoromethyl-1-phenyl-1H-pyrazoles (1,3-isomers) as well as their 1,5-isomers (5-trifluoromethyl-1-phenyl-1H- pyrazoles), is described. The 1,3-isomers were obtained from the reaction of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with arylhydrazones followed by deprotective hydrolysis while the 1,5-isomer was obtained by direct cyclocondensation of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with phenylhydrazine. An unequivocal assignment of the 1,3- and 1,5-isomers of the pyrazole products is given.

Full text of DOI:10.1016/j.tetlet.2013.05.103

Accepted Manuscript
New strategy for the regioselective synthesis of 1-Phenyl-3-trifluorometh‐
yl-1H-pyrazoles
Nilo Zanatta, Simone S. Amaral, Josiane M. dos Santos, Andréia M. P. W. da
Silva, Juliana M. F. M. Schneider, Liana da S.Fernandes, Helio G. Bonacorso,
Marcos A. P. Martins
PII:
S0040-4039(13)00882-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.103
TETL 43003
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 April 2013
21 May 2013
23 May 2013
Please cite this article as: Zanatta, N., Amaral, S.S., dos Santos, J.M., P. W. da Silva, A.M., F. M. Schneider, J.M.,
S.Fernandes, L.d., Bonacorso, H.G., P. Martins, M.A., New strategy for the regioselective synthesis of 1-Phenyl-3-
trifluoromethyl-1H-pyrazoles, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.103
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New strategy for the regioselective synthesis of
1-Phenyl-3-trifluoromethyl-1H-pyrazoles
Nilo Zanatta, Simone S. Amaral, Josiane M. dos Santos, Andréia M. P. W. da Silva, Juliana M. F. M. Schneider,
Liana da S. Fernandes, Helio G. Bonacorso, Marcos A. P. Martins
R1
R2
H
N
Ar
R1
OR3
N
R1
R2
Ph
PhNHNH2
R2
N
O
F3C
N
N
CF3
"Classical
Approach"
"Innovative
Approach"
F3C
Ph
N
Ph
(1,5-Isomer)
(1,3-Isomer)

1
Tetrahedron Letters
journal homepage: www.elsevier.com
New strategy for the regioselective synthesis of 1-Phenyl-3-trifluoromethyl-1H-
pyrazoles
Nilo Zanatta,* Simone S. Amaral, Josiane M. dos Santos, Andréia M. P. W. da Silva, Juliana M. F. M.
Schneider, Liana da S. Fernandes, Helio G. Bonacorso, Marcos A. P. Martins
a Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900, Santa Maria, Brazil, Fax:
+55 55 3220 8756. *Email: zanatta@base.ufsm.br
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A regioselective synthesis of 3-trifluoromethyl-1-phenyl-1H-pyrazoles (1,3-isomers) as well as their
1,5-isomers (5-trifluoromethyl-1-phenyl-1H-pyrazoles), is described. The 1,3-isomers were obtained
from the reaction of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with arylhydrazones followed by
deprotective hydrolysis while the 1,5-isomer was obtained by direct cyclocondensatio of 4-alkoxy-
1,1,1-trifluoroalk-3-en-2-ones with phenylhydrazine. An unequivocal assignment of the 1,3- and 1,5-
isomers of the pyrazole products is given.
Available online
Keywords:
pyrazoles
2009 Elsevier Ltd. All rights reserved.
trifluoromethylpyrazoles
trifluoromethyl enones
regioselective synthesis
phenylhydrazones
Pyrazoles are an interesting class of heteroaromatic ring
system because they exhibit important biological activities1
that find extensive application in the agriculture,2
microbiology,3 and medicine4 fields. Additionally, it is well
known that the insertion of fluorine and fluorinated groups
into organic molecules is often associated with positive
changes in their physical, chemical and biological
proprieties.1c,5 Therefore, the development of efficient and
regioselective methods for the synthesis of pyrazoles
bearing fluorinated groups in their structures are of great
interest.
In previous papers, we have demonstrated that the direct
cyclocondensation between trifluoromethylated enones and
phenylhydrazine is highly regioselective furnishing 1-
substituted-5-trifluoromethyl-1H-pyrazoles
(1,5-isomer,
Figure 1) as the only product.8 In our estimation, the
synthesis of 1-substituted-3-trifluoromethyl-1H-pyrazoles
(1,3-isomer, Figure 1) from these precursors under classical
reaction conditions is quite unusual, having occurred in only
two different occasions in the course of our investigations.9
The high selectivity observed in those reactions can be
ascribed to the well defined reactivity of the enones
(compounds 1–7, Scheme 1) which is mainly induced by the
electron “push-pull” effect of the carbonyl (-acceptor) and
the 4-alkoxy or 4-amino groups (-donor), as reported
previously.10
The most general method employed in the preparation of
trifuoromethylpyrazoles is the [3+2] cyclocondensation
reaction between a trifluoromethylated CCC building block
and a NN building block.6 Among the starting materials
available for the 3-atom fragment, trifluoromethylated 1,3-
diketones have been widely employed and their use is
considered a general approach to the synthesis of these
heterocycles. However, despite excellent yields and
widespread application, this method suffers from poor
regioselectivity and frequently affords a mixture of isomeric
pyrazoles (Figure 1).6,7
Thus, as part of our research program aimed to develop
novel synthetic strategies leading to the regioselective
heterocyclization of 4-alkoxy-1,1,1-trifluoro-3-alken-2-
ones, we now wish to report the synthesis of a series of 1-
phenyl-3-trifluoromethyl-1H-pyrazoles 16-22 (Scheme 1)
under regiochemical control. Additionally, in order to
achieve a concise characterization of the products, we have
also synthesized the 1-phenyl-5-trifluoromethyl-1H-
pyrazole isomers 23-29 (Scheme 1) for comparing GC-MS
and 1H and 13C NMR data.
R1
R2
F3C
R1
R2
F3C
R = Alkyl, Aryl, Heteroaryl
R1 = H, Alkyl, Aryl
R2 = H, Alkyl, Aryl, Heteroaryl
N
The
synthesis
of
the
desired
1-phenyl-3-
N
R
N
R
N
trifluoromethylpyrazoles (16-22) was envisioned using a
two-step procedure that involves: (a) the reaction of
trifluoromethylated enones with hydrazones derived from
phenylhydrazine, and (b) hydrazone acidic deprotection.
This synthetic approach is believed to proceed by a Michael
addition-elimination of the hydrazones to the enones
1,3-Isomer
1,5-Isomer
Figure 1. Structure of 1,3- and 1,5-pyrazole regioisomers.

2
followed by the deprotective hydrolysis of the hydrazone
azomethine linkage, and subsequent intramolecular
nucleophilic heterocyclization (Scheme 1). In fact, we were
actually able to isolate and characterize some enaminone
intermediates (9-15a-e) suggesting that this reaction
mechanism is probably plausible.
9, the crystal structure of compound 9d was determined by
single-crystal X-ray diffraction. Crystals suitable for X-ray
diffraction were obtained by slow evaporation of
chloroform solutions of compound 9d.13 Crystallographic
analysis revealed that both C–C double bond and
benzyliminic moiety exhibit an (E)–configuration. In the
course of our investigations, we observed that enaminone
intermediates 10-15a-e spontaneously decomposed to the
H
Ph
N
N
8a-e
Ar
corresponding pyrazole after isolation. Therefore,
complete characterization was unpractical.
a
R2
OR
R1
R2
Ph
N
F3C
O
N
Ar
CHCl3, r.t., 4h
Acid hydrolysis of the azomethine linkage of enaminones
9a-e afforded the 3-trifluoromethyl-1-phenyl-1H-pyrazole
1614 as the only product in good yields (entries 1-5, Table
1). Reactions were carried out by stirring a solution of
selected enaminones 9a-e with hydrochloric acid in
acetonitrile at room temperature for one hour (Method A,
Table 1). The best hydrolysis condition was achieved when
two equivalents of concentrated hydrochloric acid was
employed. Aqueous solutions of hydrochloric acid and basic
reaction conditions were also tested, but did not furnish a
complete conversion to the pyrazole.
CF3
1-7
O
R1
9-15a-e
92-98%
PhNHNH2
Hydrolysis
R1
R2
R1
N
R2
F3C
N
N
F3C
Ph
N
Ph
(1,5-Isomer)
(1,3-Isomer)
Pyrazole 1714 was isolated after stirring enone 2 with
hydrazones 8a–e in chloroform for 24 hours at room
temperature followed by the addition of two equivalents of
hydrochloric acid, and stirring for an additional hour
(Method B, Table 1). Unfortunately, these reactions always
afforded a small amount of the 1,5- pyrazole regioisomer,
compound 24 (entries 6-10 Table 1).
16-22
23-29
Compds.
1, 9, 16, 23
2, 10, 17, 24
R
Et
Et
R1
H
H
R2 Compd. 8
Ar
C6H5
a
b
c
d
H
Me
2-HOC6H4
4-MeOC6H4
4-O2NC6H4
4-HOC6H4
3 11 18 25
,
,
,
,
,
,
,
Me C6H5
H
H
H
H
H
4 12 19 2
,
6
Me 4-Me-C6H4
Me 4-MeO-C6H4
Me 4-F-C6H4
Me 2-Furyl
e
5 13 20 27
,
6, 14, 21, 28
7, 15, 22, 29
It was also not possible to isolate enaminone 11a-e because
the pyrazole 1814 was directly obtained after stirring the
reaction in chloroform under reflux for 24 hours (Method C,
Table 1). Apparently, the hydrolysis of the intermediate was
accomplished simply by heating the solution, thus, the
addition of hydrochloric acid was not required for the
cyclization step.
Scheme 1. Synthetic strategies leading to 1-phenyl-3(5)-
trifluoromethyl-1H-pyrazoles from 4-alkoxy-1,1,1-trifluoro-3-alken-2-
ones.
The reactions between enaminones and dinucleophiles
addressing to heterocycles have been extensively
reported.8d,11 In these reactions, however, the amino group is
frequently eliminated as the ring closure takes place and, as
a result, this group does not take part of the final
heterocycle structure. Thus, the use of hydrazone reagents
for the regioselective synthesis of pyrazoles remains
underexplored.12
Finally, pyrazoles 19-22 were obtained with high
regioselectivity from hydrazone 8a using the same method
as compound 17 (entries 16-19, Method B, Table 1).
The results shown in Table 1 imply that the presence of
different groups attached to the benzylidene portion of
hydrazones 8a–e do not indicate a great influence on the
reaction yields and times, but it may have a small effect on
the regioisomer proportion. The ratio of isomers was
determined by integration of the GC–MS total ion
chromatograms (Table 1).
Scheme 2 outlines the synthesis of novel enaminones 9a–e
from the Michael addition-elimination reaction of
hydrazones (8a–e) to 4-alkoxy-1,1,1-trifluoro-3-alken-2-
ones. These reactions were monitored by thin-layer
chromatography by following the disappearance of the
enone.
To further confirm the correct isomer assignment, direct
cyclization of enones 1–7 with phenylhydrazine was carried
out to obtain preferentially 5-trifluoromethyl-1-phenyl-1H-
pyrazoles (1,5-isomer). Table
2 shows the reaction
H
N
H
C
H
OEt
H
Ph
H
conditions, yields and proportion of 1,3– and 1,5–isomers.
The results state that the direct cyclization of enones 1-7
with phenylhydrazine furnished the 1,5-isomer of pyrazoles
with high regioselectivity, as expected.15 In addition, by
having both isomers in hands, it was easy to establish
CHCl3
r.t., 4 h
H
N
H
N
N
Ar
+
O
Ar
92-98%
CF3
O
CF3
1
8a-e
9a-e
1
unequivocally the H and 13C NMR and GC–MS spectral
Compds
a
b
c
d
e
data of each regioisomer. In particular, GC-MS was very
useful for assigning the 1,3- and 1,5-isomers of pyrazoles
since each one eluted from the capillary column in different
retention times allowing a simple and direct comparison.
This trend was the simplest, fastest, and reliable information
for assigning the correct structure of the title compounds.
8, 9
C6H5 2-OHC6H4 4-OMeC6H4 4-NO2C6H4 4-OHC6H4
Scheme 2.
The structures of the enaminones 9a–e were examined by
1H and 13C NMR and mass spectra. High resolution mass
spectra and/or elemental analysis were registered to confirm
the purity of compounds. Additionally, in order to
unequivocally assign the stereochemistry of the enaminones

3
PAPER
Table 1: Reaction conditions and yields for the synthesis of 1-phenyl-3-trifluoromethyl-1H-pyrazoles (16–22)
Entry
Enone
R
R1
R2
Hydrazone
Ar
Method
Yield
(%)b
87
Pyrazole
Isomer
1,3:1,5c
100:0
100:0
100:0
100:0
100:0
87:13
85:15
83:17
90:10
94 : 6
100:0
100:0
100:0
100:0
100:0
100:0
88:12
97:3
1
2
1
1
1
1
1
2
2
2
2
2
3
3
3
3
3
4
5
6
7
Et
Et
H
H
H
8a
8b
8c
8d
8e
8a
8b
8c
8d
8e
8a
8b
8c
8d
8e
8a
8a
8a
8a
C6H5
2-OH-C6H4
4-OMe-C6H4
4-NO2-C6H4
4-OH-C6H4
C6H5
A
A
A
A
A
B
B
B
B
B
C
C
C
C
C
B
B
B
B
16
16
H
76
3
Et
H
H
82
16
4
Et
H
H
H
91
16
5
Et
H
63
16
6
Et
H
Me
Me
Me
Me
Me
H
84
17 + 24
17 + 24
17 + 24
17 + 24
17 + 24
18
7
Et
H
2-OH-C6H4
4-OMe-C6H4
4-NO2-C6H4
4-OH-C6H4
C6H5
76
8
Et
H
82
9
Et
H
72
10
11
12
13
14
15
16
17
18
19
Et
H
74
Me
Me
Me
Me
Me
Me
Me
Me
Me
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeC6H4
4-MeOC6H4
4-FC6H4
2-Furyl
87
H
2-OH-C6H4
4-OMe-C6H4
4-NO2-C6H4
4-OH-C6H4
C6H5
56
18
H
60
18
H
40
18
H
63
18
H
78
19
H
C6H5
76
20 + 27
21 + 28
22
H
C6H5
81
H
C6H5
75
100:0
a
Reaction Conditions: Method A: 1) CHCl3, r.t., 4 h. 2) MeCN, HCl, 2.0 equiv., r.t., 1 h; Method B: 1) CHCl3, r.t., 24 h. 2) HCl, 2.0 equiv., r.t., 1 h;
Method C: CHCl3, reflux, 24h. b Yields of isolated compounds. c Isomeric proportion calculated from the GC/MS total ion chromatogram.
The structure assignment of the pyrazole isomers was also
supported by the study done by Laurent et al., which described
the synthesis of both 1,5-diphenyl-3(5)-trifluoromethyl-1H-
pyrazoles 18 and 25 from the reaction of β-chloro-β-
trifluoromethylenone and phenylhydrazine.16 1H and 13C NMR
chemical shifts of their compounds are in agreement with the
data collected from our pyrazoles. Data from our previous study
was also helpful for the confirmation of the 5-trifluormethyl-1-
phenyl-1H-pyrazoles.15
approach”) to provide an unequivocal assignment of the
obtained products. Thus, by combining the method developed in
this study with the direct cyclocondensation of enones one can
obtain both 1,3- and 1,5-isomers of pyrazole under regioselective
control.
Acknowledgments
The authors thank the Conselho Nacional de Desenvolvimento
Table 2: Proportion of 1,3– versus 1,5–isomers of N-phenyl pyrazoles from
the direct condensation between enones 1–4 and phenylhydrazine (“classical
approach”).
Científico
e
Tecnológico (CNPq, Universal Grant No.
473512/2009-2) and the Fundação de Amparo à Pesquisa do
Estado do Rio Grande do Sul (FAPERGS Grant No. 11/1608-8,
PRONEX, Grant No. 10/0037–8) for financial support and
fellowships from CNPq (S. S. Amaral, J. M. Santos, and L. S.
Fernandes) and fellowship from CAPES (J. F. M. Schneider) are
also acknowledged.
Enone
R
R1
R2
Yield
(%)a
90
Pyrazole
Isomerb
(1,3 : 1,5)
12:88
2:98
1
2
3
4
5
6
7
Et
Et
H
H
H
Me
H
16 +23
17 +24
18+25
19+26
20+27
21+28
22+29
79
Me C6H5
87
1:99
Me 4-MeC6H5
Me 4-MeOC6H5
Me 4-FC6H5
Me 2-Furyl
H
90
0:100
0:100
1:99
References and Notes
H
94
(1) (a) Knaus, E. E.; Uddin, M. J.; Rao, P. N. P. Bioorg. Med. Chem. 2003,
11, 5273. (b) Yonetoku, Y.; Kubota, H.; Okamoto, Y.; Ishikawa, J.;
Takeuchi, M.; Ohta, M.; Tsukamoto, S. Bioorg. Med. Chem. Lett.
2006, 14, 5370. (c) Fustero, S.; Román, R.; Sanz–Cervera, J. F.;
Simón–Fuentes, A.; Bueno, J.; Villanova, S. J. Org. Chem. 2008, 73,
8545, and references cited therein.
H
95
H
78
0:100
a
b
Yields of isolated compounds. Reaction conditions: PhNHNH2, MeCN,
reflux, 24 H.
(2) (a) Fang, J.–X.; Dai, H.; Li, Y.–Q.; Du, D.; Qin, X.; Zhang, X.; Yu,
H.–B. J. Agric. Food Chem. 2008, 56, 10805. (b) Hamaguchi, H.;
Kajihara, O.; Katoh, M. J. Pestic. Sci. 1995, 20, 173.
In conclusion, this work described a regioselective synthesis of 1-
phenyl-3-trifluoromethyl-1H-pyrazoles from 4-alkoxy-1,1,1-
trifluoro-3-alken-2-ones using a simple and efficient one pot
method. The desired trifluoromethylpyrazoles were easily
prepared in a two-step procedure that involved the reaction of
enones with hydrazones derived from phenyl hydrazine and
commercially available aldehydes, followed by deprotective
hydrolysis of the hydrazone azomethine linkage, and subsequent
intramolecular nucleophilic heterocyclization. Additionally, a
series of novel (E)-4-(N'-benzylidene-N-phenyl-hydrazino)-1,1,1-
trifluoro-but-3-en-2-ones was obtained in good to excellent
yields. A series of 1,5–pyrazole isomers was synthesized from
the direct cyclization of enones and phenylhydrazine (“classical
(3) Da Silva, P. E. A.; Ramosa, D. F.; Bonacorso, H. G.; De La Iglesia, A.
I.; Oliveira, M. R.; Coelho, T.; Navarini, J.; Morbidoni, H. R.; Zanatta,
N.; Martins, M. A. P. Int. J. Antimicrob. Agents 2008, 32, 139.
(4) (a) Peat, A. J.; Townsend, C.; McKay, M. C.; Garrido, D.; Terry, C.
M.; Wilson, J. L. R.; Thomson, S. A. Biorg. Med. Chem. Lett. 2004,
14, 813. (b) Milano, J.; Oliveira, S. M.; Rossato, M. F.; Sauzem, P. D.;
Machado, P.; Beck, P.; Zanatta, N.; Martins, M. A. P.; Mello, C. F.;
Rubin, M. A.; Ferreira, J.; Bonacorso, H. G. Eur. J. Pharmacol. 2008,
581, 86.
(5) (a) De Arriba, A. F.; L. Gómez–Carajús, A.; Cavalcanti, F.; Almansa,
C.; García–Rafanell, J.; Forn, J. Eur. J. Pharmacol. 1996, 318, 341. (b)
Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.

4
Tetrahedron
1
(6)
(a) Nenajdenko, V. G.; Druzhinin, S. V.; Balenkova, E. S.
3-Trifluoromethyl-1-phenyl-4-methyl-1H-pyrazole (17): yellow oil; H
Tetrahedron 2007, 63, 7753. (b) Eicher, T.; Hauptmann S. The
Chemistry of Heterocycles – Structure, Reactions, Synthesis, and
Applications, Willey–VHC, Weinheim, 2003, 179.
NMR (200 MHz, CDCl3) δ 7.71 (s, 1H, H–5), 7.63 (d, J = 7.8 Hz, 2H,
Ph), 7.43 (t, J = 7.9 Hz, 2H, Ph), 7.30 (t, J = 7.4 Hz, 1H, Ph), 2.22 (s,
2
3H, Me); 13C NMR (100 MHz, CDCl3) δ 142.0 (q, JCF = 36.7 Hz, C–
1
(7) (a) Singh, S. K.; Reddy, G.; Rao, K. S.; Lohray, B. B.; Misra, P.;
Rajjak, S. A.; Rao, Y. K.; Venkateswarlu, A. Bioorg. Med. Chem. Lett.
2004, 14, 499. (b) Singh, S. K.; Rao, Y. K.; Vobbalareddy, S.;
Shivaramakrishna, S.; Krishnamraju, A.; Rajjak, S. A.; Casturi, S. R.;
Akhila, V. Bioorg. Med. Chem. Lett. 2004, 14, 1683.
3), 139.3, 129.4 (Ph), 127.6 (C–5), 127. 2 (Ph), 121.9 (q, JCF = 269.2
Hz, CF3), 117.1 (C–4), 8.1 (Me); MS-EI (m/z): 226 (100, M+), 207
(74), 157 (82), 130 (89), 104 (77), 96 (23), 77 (98), 69 (62), 51 (97);
HRMS–ESI: MH+, calcd for C11H10F3N2, 227.0796; found 227.0786.
1
3-Trifluoromethyl-1,5-diphenyl-1H-pyrazole (18): yellow oil; H NMR
(8) (a) Braibante, M. E. F.; Clar, G.; Martins, M. A. P. J. Heterocycl.
Chem. 1993, 30, 1159. (b) Flores, A. F. C.; Brondani, S.; Zanatta, N.;
Rosa, A.; Martins, M. A. P. Tetrahedron Lett. 2002, 43, 8701. (c)
Flores, A. F. C.; Brondani, S.; Pizutti, L.; Martins, M. A. P.; Zanatta,
N.; Bonacorso, H. G. Synthesis 2005, 2744. (d) Martins, M. A. P.;
Cunico, W.; Brondani, S.; Peres, R. L.; Zimmermann, N. E. K.; Rosa,
A.; Fiss, G. F.; Zanatta, N.; Bonacorso, H. G. Synthesis 2006, 1485. (e)
Bonacorso, H. G.; L. Porte, M. F.; Cechinel, C. A.; Paim, G. R.; Deon,
E. D.; Zanatta, N.; Martins, M. A. P. Tetrahedron Lett. 2009, 50, 1392.
(9) (a) Martins, M. A. P.; Bastos, G. P.; Sinhrin, A. P.; Zimmermann, N.
E. K.; Rosa, A.; Brondani, S.; Emmerich, D.; Bonacorso, H. G.;
Zanatta, N. J. Fluorine Chem. 2003, 123, 249. (b) Martins, M. A. P.;
Pereira, C. M. P.; Zimmermann, N. E. K.; Cunico, W.; Moura, S.;
Beck, P.; Zanatta, N.; Bonacorso, H. G. J. Fluorine Chem. 2003, 123,
261.
(200 MHz, CDCl3) δ 7.24–7.12 (m, 10H, Ph), 6.66 (s, 1H, H–4); 13C
2
NMR (100 MHz, CDCl3) δ 144.6 (Ph), 143.2 (q, JCF = 38.8 Hz, C–3),
1
139.2 (Ph), 129.2–128.4 (Ph, C–5), 125.4 (Ph), 121.3 (q, JCF = 268.6
Hz, CF3), 105.5 (C–4); MS-EI (m/z): 288 (100, M+), 267 (28), 219 (4),
134 (19), 116 (6), 89 (12), 77 (35), 51 (5). HRMS–ESI: MH+ calcd for
C16H12F3N2, 289.0952; Found: 289.0947.
3-Trifluoromethyl-1-phenyl-5-(4-methylphenyl)-1H-pyrazole
(19):
yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.35-7.33 (m, 3H, Ph), 7.31-
7.29 (m, 2H, Ph), 7.10 (m, 4H, Ph), 6.71 (s, 1H, H-4), 2.33 (s. 3H,
2
Me); 13C NMR (100 MHz, CDCl3) δ 144.7 (C-5), 143.1 (q, JCF
=38.78Hz, C-3), 139.4 (Ph), 139.0 (Ph), 129.3 (Ph), 129.0 (Ph), 128.6
2
(Ph), 128.3 (Ph), 126.2 (Ph), 125.5 (Ph), 121.1 (q, JCF = 269.3Hz,
CF3), 105.2 (C-4), 21.2 (Me); MS-EI (m/z): 302 (100, M+), 281 (33),
269 (13), 233 (5), 140 (5), 77 (5). HRMS–ESI: MNa+ calcd for
C17H13F3N2Na, 325.0929; Found: 325.1000.
(10) For an explanation of the “push-pull” effect on 4-alkoxy or 4-amino
groups of compounds 1-7 and 9-15 respectively, and its influence on
the E and Z configurations, see the following references (a) Zanatta,
N.; Schneider, J. M. F. M.; Schneider, P. H.; Wouters, A. D.;
Bonacorso, H. G.; Martins, M. A. P.; Wessjohann, L. A. J. Org. Chem.
2006, 71, 6996. (b) Zanatta, N.; Wouters, A. D.; Fantinel, L.; Da Silva,
F. M.; Barichello, R.; Da Silva, P. E. A.; Ramos, D. F.; Bonacorso, H.
G.; Martins, M. A. P. Synlett 2009, 775.
(11) (a) Pinto, D. J. P.; Orwat, M. J.; Wang, S.; Fevig, J. M.; Quan, M. L.;
Amparo, E.; Cacciola, J.; Rossi, K. A.; Alexander, R. S.; Smallwood,
A. M.; Luettgen, J. M.; Liang, L.; Aungst, B. J.; Wright, M. R.; Knabb,
R. M.; Wong, P. C.; Wexler, R. R.; Lam, P. Y. S. J. Med. Chem. 2001,
44, 566. (b) Bonacorso, H. G.; Lourega, R. V.; Wastowski, A. D.;
Flores, A. F. C.; Zanatta, N.; Martins, M. A. P. Tetrahedron Lett. 2002,
43, 9315. (b) Saloutin, V. I.; Bugart, Y. V.; Fokin, A. S.; Kuzueva, O.
G.; Chupakhin, O. N. J. Fluorine Chem. 1998, 92, 101. (c) Filippone,
P.; Attanasi, O. A.; De Crescentini, L.; Favi, G.; Mantellini, F.
Synthesis 2002, 1546.
3-Trifluoromethyl-1-phenyl-5-(4-methoxyphenyl)-1H-pyrazole
(20):
1
brown oil; H NMR (400 MHz, CDCl3) δ 7.85 (d, 2H, J = 8.55 Hz,
Ph), 7.36-7.33 (m, 3H, Ph), 7.32- 7.29 (m, 2H, Ph), 6.82 (d, 2H, J =
8.80Hz, Ph), 6.68 (s, 1H, H-4), 3.79 (s, 3H, OMe); 13C NMR (100
1
MHz, CDCl3) δ 160.1 (Ph) , 144.5 (C-5), 143.1 (q, JCF = 38.5 Hz, C-
3), 139.5 (Ph), 130.1 (Ph), 129.0 (Ph), 128.3 (Ph), 125.5 (Ph), 121.5
2
(Ph), 120.8 (q, JCF =268.5Hz , CF3) 114.1 (Ph), 104.9 (C-4), 55.23
(OMe); MS-EI (m/z): 318 (100, M+), 303 (20), 275 (7), 205 (7), 77
(17). HRMS–ESI: MH+ calcd for C17H14F3N2O, 319.1058; Found:
319.1056.
3-Trifluoromethyl-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole
(21):
brown oil 1H NMR (400 MHz, CDCl3) δ 7.35-7.34 (m, 2H, Ph), 7.29-
7.27 (m, 2H, Ph), 7.20 -7.17 (m, 3H, Ph), 6.99 (m, 2H, Ph), 6.70 (s,
1H, H-4); 13C NMR (100 MHz, CDCl3) δ 161.7 (Ph), 143.6 (C-5),
2
143.2 (q, JCF = 38.1 Hz, C-3), 139.0 (Ph), 130.7 (d, J = 8.1 Hz, Ph),
1
130.1 (Ph), 129.2 (Ph), 128.6 (Ph), 125.5 (Ph), 121.2 (q, JCF = 269.3
Hz, CF3), 115.8 (d, J = 22.0 Hz, Ph), 105.5 (C-4); MS-EI (m/z): 306
(100, M+), 285 (46), 237 (6), 77 (9). HRMS–ESI: MH+ calcd for
C16H11F4N2, 307.0858; Found: 307.0856.
(12) (a) Hojo, M.; Kamitori, Y.; Masuda, R.; Kawamura, Y.; Kawasaki, K.;
Ida, J. Tetrahedron Lett. 1990, 8, 1183. (b) Saloutin, V. I.; Bugart, Y.
V.; Fokin, A. S.; Kuzueva, O. G.; Chupakhin, O. N. J. Fluorine Chem.
1998, 92, 101. (c) Filippone, P.; Attanasi, O. A.; De Crescentini, L.;
Favi, G.; Mantellini, F. Synthesis 2002, 1546. (d) Bonacorso, H. G.;
Correa, M. S.; Porte, L. M. F.; Pittaluga, E. P., Zanatta, N.; Martins, M.
A. P. Tetrahedron Lett. 2012, 53, 5488.
3-Trifluoromethyl-1-phenyl-5-(2-furyl)-1H-pyrazole (22): brown oil 1H
NMR (400 MHz, CDCl3) δ 7.48-7.47 (m, 3H, Ph), 7.43-7.40 (m, 2H,
Ph), 7.41-7.39 (m, 1H, furyl), 6.89 (s, 1H, H-4), 6.32 (dd, J = 3.42 Hz,
1,66 Hz, 1H, furyl), 6.97 (d, 1H, J = 3.42 Hz, furyl). 13C NMR (100
2
MHz, CDCl3) δ 143.2 (C-furyl), 143.1 (q, JCF = 38.4Hz, C-3), 139.4
(furyl), 136.2 (Ph), 130.2 (C-5), 129.4 (Ph), 129.2 (Ph), 126.1 (Ph),
121.7 (q, 1JCF = 269,3 Hz, CF3), 111.4 (C-furyl), 109.8 (C-furyl), 103.8
(C-4); MS-EI (m/z): 278 (100, M+), 249 (12), 224 (8), 77 (4). HRMS–
ESI: MH+ calcd for C14H9F3N2ONa, 301.0565; Found: 301.0560.
(15) Buriol, L; Frizzo, C. P.; Prola, L. D. T.; Moreira, D. N.; Marzari, M. R.
B.; Scapin, E.; Zanatta, N.; Bonacorso, H. G.; Martins, M. A. P. Catal.
Lett. 2011, 141, 1130.
(16) (a) Sloop, J. C.; Bumgardner, C. L.; Ioehle, W. D. J. Fluorine Chem.
2002, 118, 135. (b) Laurent, A.; Diab, J.; Le Dréan, I. J. Fluorine
Chem. 1997, 84, 145.
(13) CCDC No. 773176 for 6d contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033).
(14) 3-Trifluoromethyl-1-phenyl-1H-pyrazole (16): yellow oil; 1H NMR
(200 MHz, CDCl3) δ 7.86 (d, J = 2.4 Hz, 1H, H–5), 7.64–7.59 (m, 2H,
Ph), 7.43–7.26 (m, 3H, Ph), 6.63 (d, J = 2.4 Hz, 1H, H–4); 13C NMR
(100 MHz, CDCl3) δ 143.9 (q, 2JCF = 38.4 Hz, C–3), 139.4, 129.6 (Ph),
1
128.3 (C–5), 127.7 (Ph), 121.2 (q, JCF = 275.3 Hz, CF3), 119.9 (Ph),
105.9 (C–4); MS-EI (m/z): 212 (100, M+), 193 (18), 143 (26), 116 (30),
96 (5), 77 (90), 69 (39), 51 (78). HRMS–ESI: MH+, calcd for
C10H8F3N2, 213.0639; Found: 213.0630.
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