Synthesis of new 1,1′-carbonyl-bis[3-aryl(heteroaryl)-5- (trihalomethyl)-1H-pyrazoles] and trifluoromethyl derivatives through ring-opening reactions

Article abstract of DOI:10.1002/jhet.427

(Chemical Equation Presented) Two new series of 1,1-carbonyl-bis[3- aryl(heteroaryl)-5-trihalomethyl-1H-pyrazoles], where aryl = C₆H ₅, 4-CH₃C₆H₄, 4-FC6H4, 4-OCH ₃C₆H₄, 4-NO₂C₆H ₄, 4,4′-BiPh, 1-naphthyl, and heteroaryl = 2-thienyl and 2-furyl have been synthesized, in a one-pot methodology, from the reaction of 4-methoxy-4-aryl(heteroaryl)-1,1,1-trihalobut-3-en-2-ones with 1,3-diaminoguanidine monohydrochloride. The heterocycles were obtained regioselectively in good yields (62-86%) and in a short reaction time. Ring-opening reactions with 1,2-dinuleophiles and the synthesis of ethyl carboxylate derivative from a pyrazolycarbohydrazide is also reported.

Full text of DOI:10.1002/jhet.427

September 2010
Synthesis of New 1,10-Carbonyl-bis[3-aryl(heteroaryl)-5-
(trihalomethyl)-1H-pyrazoles] and Trifluoromethyl Derivatives
through Ring-Opening Reactions
1073
Helio G. Bonacorso,* Cleber A. Cechinel, Liliane M. F. Porte,
Jussara Navarini, Susiane Cavinatto, Ronan C. Sehnem, Demetrius B. Martins,
Nilo Zanatta, and Marcos A. P. Martins
´
´
´
Nucleo de Quımica de Heterociclos (NUQUIMHE), Departamento de Quımica,
Universidade Federal de Santa Maria, 97.105-900, Santa Maria, RS, Brazil
*E-mail: heliogb@base.ufsm.br
Received December 16, 2009
DOI 10.1002/jhet.427
Published online 13 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
Two new series of 1,10-carbonyl-bis[3-aryl(heteroaryl)-5-trihalomethyl-1H-pyrazoles], where aryl ¼
C6H5, 4-CH3C6H4, 4-FC6H4, 4-OCH3C6H4, 4-NO2C6H4, 4,40-BiPh, 1-naphthyl, and heteroaryl ¼ 2-
thienyl and 2-furyl have been synthesized, in a one-pot methodology, from the reaction of 4-methoxy-4-
aryl(heteroaryl)-1,1,1-trihalobut-3-en-2-ones with 1,3-diaminoguanidine monohydrochloride. The hetero-
cycles were obtained regioselectively in good yields (62–86%) and in a short reaction time. Ring-open-
ing reactions with 1,2-dinuleophiles and the synthesis of ethyl carboxylate derivative from a
pyrazolycarbohydrazide is also reported.
J. Heterocyclic Chem., 47, 1073 (2010).
INTRODUCTION
common in the literature. For instance, new synthetic
routes to obtain these compounds and studies on their
potential as pharmaceuticals and agrochemicals have
been relatively little explored [10–12].
1,10-Carbonyl-bispyrazoles have been most commonly
synthesized by substitution reaction involving phosgene
and other derivatives with pyrazoles [13–19]. However,
this synthetic procedure is efficient only when the start-
ing materials are symmetric substituted or nonsubstituted
pyrazoles, because nonsymmetric 3- or 5-substituted
pyrazoles may exist in two tautomeric structures in solu-
tion and their N1-substitution reactions lead undoubtedly
to three possible carbonyl-bispyrazoles isomers.
The linked pyrazole ring represents an interesting
block for synthesis strategies as well as studies on their
biological and chemical properties. Moreover, pyrazoles
are a class of heterocyclic compounds with many deriv-
atives, and of note, the fluorinated pyrazoles have been
demonstrated to play key pharmacophore functions in
many pharmaceutical and agrochemical fields [1,2].
The introduction of fluorine(s) into heterocyclic rings
is still limited and the trifluoromethyl substituted a,b-
unsaturated ketones represent a practical way to access
such compounds [3–11]. In recent years, the synthesis
of trifluoromethyl pyrazoles has drawn much attention
and the literature has reported a series of specific 5-CF3
substituted pyrazoles. The main synthetic methods to
prepare such compounds involve CCC and NN atom
fragments in cyclization reactions of substituted hydra-
zines or derivatives thereof with 4-alkoxy-1,1,1-tri-
fluoro-3-alken-2-ones [3–9].
Soliman and Darwish [13] have reported that substi-
tuted 3,5-dimethyl-1H-pyrazoles reacted with ethyl
chloroformate, in the presence of anhydrous potassium
carbonate, giving bis-(3,5-dimethyl-1H-pyrazole)metha-
none, in good yields, as a possible hypoglycemic agent.
However, a very limited scope is observed when the
bis-pyrazole synthesized by this procedure has only
methyl substituents at the position 3 and 5 of both pyr-
azole rings.
This [3þ2] cyclization approach has been shown to
be an efficient method to prepare such compounds,
where the pyrazole ring is linked to another pyrazole.
On the other hand, carbonyl-bispyrazoles are not so
More recently, Higgs and Carrano [20] reported the
synthesis of carbonyl-bispyrazoles prepared by the
C
V
2010 HeteroCorporation

1074
H. G. Bonacorso, C. A. Cechinel, L. M. F. Porte, J. Navarini, S. Cavinatto, R. C. Sehnem, D. B.
Martins, N. Zanatta, and M. A. P. Martins
Vol 47
Scheme 1. Synthetic route to prepare bis-pyrazoles 3. Reagents and conditions: (i) 1,3-diaminoguanidine. HCl (1.0 equiv), EtOH/H2O, 90ꢀC,
4–5 h.
reaction of 3,5-substituted 1H-pyrazoles (R and R1 ¼ H,
CH3, i-Pr) with phosgene, using triethylamine in anhy-
drous THF as solvent. In this procedure, symmetric car-
bonyl-bispyrazoles (R ¼ R1 ¼ H or CH3) were
obtained, except when R ¼ H and R1 ¼ i-Pr. In the pre-
vious example, a mixture of isomeric bis-pyrazoles was
not obtained due to a steric hindrance between the i-
propyl substituents.
describe firstly the full regioselective synthesis and
characterization of a new series of 1,10-carbonyl-bis(3-
substituted-5-trifluoromethyl-1H-pyrazoles) (3) from the
reaction of trifluoromethyl vinyl ketones (1) with 1,3-
diaminoguanidine monohydrochloride (Scheme 1).
In principle, b-alkoxyvinyl trihalomethyl ketones (1a–
i and 8a–f) are prepared by trihaloacetylation reaction
of acetals derived from ketones, according to the previ-
ously described procedures [5,26–28].
Recently, we have reported the one-step and regiose-
lective procedure for the synthesis of a novel series of
1,10-carbonyl-bis[3-alkyl(aryl/heteroaryl)-5-trifluoromethyl-
5-hydroxy-4,5-dihydro-1H-pyrazoles] [21] from the
cyclocondensation reactions of 4-alkoxy-4-aryl(heter-
oaryl)-1,1,1-trifluoroalk-3-en-2-ones with carbohydrazide.
Subsequently, as an example, 1,10-carbonyl-bis(5-trifluoro-
methyl-5-hydroxy-3-phenyl-4,5-dihydro-1H-pyrazole) was
subjected to dehydration reactions, using acetic acid/etha-
nol [22,23], at reflux for 4 h or sulfuric acid/ethanol [24]
at reflux for 4 h. In both the cases, the aromatic 1H-pyr-
azole was obtained with the simultaneous removal of the
carbonyl function. Because of the relative elimination dif-
ficulty, the presence of trifluoromethyl, and the carbonyl
groups at positions 5 and 1 of the pyrazole, respectively,
another synthetic procedure was performed. After a
review of the literature and in an attempt to obtain the ar-
omatic bis-pyrazole, we chose thionyl chloride/pyridine
[24,25] as the dehydration agent. Again, the isolation of
1H-pyrazole was observed with the cleavage of both
C(O)AN bonds.
1,10-carbonyl-bis(3-substituted-5-trifluoromethyl-1H-
pyrazoles) (3a–i) were obtained from the reaction of
two equivalents of 4-methoxy-1,1,1-trifluorobut-3-en-2-
ones (1a–i) and one equivalent of 1,3-diaminoguanidine
monohydrochloride, in a one-pot reaction and in 62 to
86% yields. All reactions were carried out in ethanol/
water (20:1), monitored by TLC, and the optimal reac-
tion time and temperature were 4–5 h at 90ꢀC. After
this time, the compounds (3a–i) were isolated by
extraction with chloroform/water (1.5:1). The organic
layer was dried and evaporated under reduced pressure.
The products (3a–i) were purified by recrystallization
from iso-propyl ether, to give pure yellow solids.
According to our previous experience, trifluoromethyl
vinyl ketones 1a–i readily react with substituted hydra-
zines to give only 5-CF3 substituted pyrazoles [3–9]. In
this study, we found that 1,3-diaminoguanidine monohy-
drochloride reacted specifically as a bis-1,2-dinucleo-
phile with enones 1a–i and 8a–f to give bis-pyrazoles
linked through a carbonyl carbon. As for the reaction
mechanism, firstly, the cyclization of enones 1a–i takes
place furnishing 1,10-carbonyl-bis(4,5-dihydro-pyrazole)
intermediates linked through an imino group. These
intermediates undergo in situ water elimination and
hydrolysis of the imino group to give the respective bis-
pyrazoles 3a–i. The evidence of this mechanism is given
RESULTS AND DISCUSSION
As an alternative strategy for the synthesis of trifluor-
omethylated aromatic bis-pyrazoles, in this study we
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of New 1,10-Carbonyl-bis[3-aryl(heteroaryl)-5-(trihalomethyl)-
1H-pyrazoles] and Trifluoromethyl Derivatives through Ring-Opening Reactions
1075
3) and 86.7 ppm (C-4). The C-5 exhibit signals at
around 169.3 and appear as a characteristic quartet with
2J ¼ 28 Hz, because they are attached to a CF3 group.
The CF3 group shows a typical quartet at an average of
118.2 ppm, with JC-F ¼ 291 Hz. The 13C chemical shifts
of the other aromatic carbons present a signal in the
range of 113.2–147.3 ppm. The carbonyl carbon inter-
facing the two pyrazole rings shows signals in the range
of 185.6 ppm.
Subsequently, aiming to obtain examples of heterocy-
clic derivatives, the reaction of carbohydrazide 4 with a
1,3-diketone (2,4-pentanedione) was performed. In this
case, the well-known ester 5 [30] was isolated in 63%
yield, instead the desired nonsymmetrical bis-pyrazole,
showing an interesting and promising employment
of pyrazolyl carbohydrazides such as 4 (Scheme 2).
Compound 4 was obtained when the reaction of pure car-
bohydrazide [(NH2NH)2CO] and 4-methoxy-4-phenyl-
1,1,1-trifluorobut-3-en-2-one was carried out at a molar
ratio 1:1, in ethanol, according to the literature [21].
Finally, the new ketone 3b was subjected to reactions
with phenylhydrazine [31] and hydroxylamine hydro-
chloride [32] to verify the possibility of an induced
ring-opening reaction followed by recyclization with
these two dinucleophiles (Scheme 3).
Figure 1. ORTEP plot of the intermediate 2a. Thermal ellipsoids are
shown at the 50% probability level. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
by the isolation of the intermediate 2a, the only interme-
diate that was isolated and whose was structure con-
firmed by single-crystal x-ray diffraction (Fig. 1) [29].
The optimal condition to isolate product 3a together
with a trace of the intermediate 2a was when the reac-
tion was carried out in ethanol/water, at 90ꢀC for 3 h.
The structures of 3a–i and 9a–f were deduced from
their NMR spectra (1H and 13C) and by comparison
with NMR data of other pyrazoles formerly synthesized
in our laboratory [5–9].
Although 3b is not the best precursor to synthesize
pyrazole 6 and isoxazoline 7, these well-known hetero-
cycles were easily isolated in good yields (77–89%)
from this type of reaction.
In addition to the interest inherent in the chemical
attributes of these novel trifluoromethylated condensa-
tion products 3, it seemed appropriate to evaluate the
cyclization reactions involving now the b-alkoxyvinyl
trichloromethyl ketones 8a–f and 1,3-diaminoguanidine
monohydrochloride (Scheme 4).
The symmetrical carbonyl heterocycles 3a–i show a
symmetrical pattern with one set of signals for the
hydrogens and carbons of the 3-substituted pyrazole
1
Scheme 3. Preparation of pyrazole 6 and isoxazole 7 from ketone 3b.
Reagents and conditions: (i) NH2NHPh, EtOH, reflux,
NH2OHꢁHCl, Py, H2O, 45ꢀC, 24 h (R ¼ 4-Tolyl).
rings. The compounds 3a–i show the H NMR chemical
4 h; (ii)
shifts in DMSO-d6 for the H-4 as a sharp singlet in the
range of 5.85–6.41 ppm. The signals for the other aro-
matic hydrogens are in the range of 6.53–8.23 ppm.
The compounds 3a–i present the typical 13C chemical
shifts of pyrazole rings at an average of 148.1 ppm (C-
Scheme 2. Synthesis of nonsymmetrical ketone 5. Reagents and condi-
tions: (i) 2,4-pentanedione, EtOH, reflux, 20 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1076
H. G. Bonacorso, C. A. Cechinel, L. M. F. Porte, J. Navarini, S. Cavinatto, R. C. Sehnem, D. B.
Martins, N. Zanatta, and M. A. P. Martins
Vol 47
Scheme 4. Synthetic route to prepare bis-pyrazoles 9. Reagents and
conditions: (i) 1,3-diaminoguanidine. HCl (1.0 equiv), EtOH/H2O,
90ꢀC, 4–5 h.
minoguanidine monohydrochloride in a one-pot method
leading to high yields (62–86%). In addition, the reac-
tion was proven to be regioselective because only the
1,10-carbonyl-bis(5-trihalomethyl-1H-pyrazole)
isomer
was isolated. Moreover, we think that alkylcarboxylate
heterocycles such as 5 and many other ring-opening
reactions can be induced in this new heterocyclic system
using several dinucleophiles.
EXPERIMENTAL
Unless otherwise indicated all common reagents and sol-
vents were used from commercial suppliers without further pu-
rification. All melting points were determined using open
capillaries on an Electrothermal Mel-Temp 3.0 apparatus. 1H
and 13C NMR spectra were acquired on a Bruker DPX 200
spectrometer (1H at 200.13 MHz and 13C at 50.32 MHz), 5
mm sample tubes, 298 K, digital resolution 6 0.01 ppm, in
DMSO-d6 for 3, 5, 9 and in CDCl3 for 6 and 7, using TMS as
internal reference. Mass spectra were registered in 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, auto-
sampler, cross-linked HP-5 capillary column (30 m, 0.32 mm
of internal diameter), and He was used as the carrier gas.
Synthetic procedures. General procedure for the prepa-
ration of 1,10-carbonyl-bis[3-aryl(heteroaryl)-5-(trihalo-
methyl)-1H-pyrazoles] (3a–i, 9a–f). A stirred mixture of
4-methoxy-1,1,1-trifluorobut-3-en-2-ones (1a–i) or 4-methoxy-
1,1,1-trichlorobut-3-en-2-ones (8a–f) (2.0 mmol) and 1,3-dia-
minoguanidine monohydrochloride (1.0 mmol), diluted in etha-
nol (20 mL) and water (1 mL) was heated in an oil bath for
4–5 h at 90ꢀC. After cooling, water (10 mL) was added to the
reaction and the product extracted with chloroform (2 ꢂ 15
mL). The organic layer was dried (Na2CO3) and evaporated
under reduced pressure. The solid residues were recrystallized
from iso-propyl ether to give white solids.
We reported now the results of reactions of ketones 8
with 1,3-diaminoguanidine monohydrochloride which
were expected to deliver 1,10-carbonyl-bis(5-trichloro-
methyl-1H-pyrazoles) 9a–f bearing an carbonyl moiety
on the newly formed bis-trichoromethyl substituted het-
erocyclic system. We carried out the reactions of 4-
methoxy-1,1,1-trichlorobut-3-en-2-ones 8 with 1,3-dia-
minoguanidine monohydrochloride, in 2:1 molar ratio,
respectively, and in ethanol/water (20:1) as solvent.
When the mixtures were heated at 90ꢀC, after stirring
for 4–5 h, the TLC showed that the reactions proceeded
smoothly and gave the products 9 in 62–80% yields
(Scheme 4). The derivatives 9 were all stable, white
crystalline solids, which showed no significant signs of
decomposition after being stored for many months under
refrigeration and were unaffected by the recrystallization
method.
NMR spectroscopic studies alone allow convincing
structural assignments for this heterocyclic system and
consequently unequivocal determination of structures of
9. The symmetrical carbonyl heterocycles 9a–f show a
symmetrical pattern with one set of signals for the
hydrogens and carbons of the 3-substituted pyrazole
1,10-Carbonyl-bis(3-phenyl-5-trifluoromethyl-1H-pyrazole)
(3a). This compound was obtained as a yellow solid, yield
75%, Mp. 211–212ꢀC. 1H NMR (DMSO-d6) d ¼ 7.75–7.79
(m, 4H, aromatic-H), 7.38–7.42 (m, 6H, aromatic-H), 5.94 (s,
2H, H-4). 13C NMR (DMSO-d6) d ¼ 186.1 (C¼¼O), 169.3 (C-
5, J ¼ 28), 141.7 (C-3), 130.2; 128.1; 126.8; 126.6 (aromatic-
C); 118.2 (q, CF3, J ¼ 291), 87.3 (C-4).
1
rings. The compounds 9a–f show the H NMR chemical
shifts in DMSO-d6 for the H-4 as a sharp singlet in the
range of 6.21–6.98 ppm. The signals for the other aro-
matic hydrogens are in the range of 7.21–8.30 ppm.
The compounds 9a–f present the typical 13C chemical
shifts of pyrazole rings in average of 175.0 ppm (C-3)
and 85.6 ppm (C-4). The carbonyl carbon bonding the
two pyrazole rings shows signals in the range of 182.8
ppm. The two CCl3 groups show a typical singlet in
average of d 98.9 ppm. All the signals are consistent
1,10-Carbonyl-bis[3-(4-tolyl)-5-trifluoromethyl-1H-pyrazole]
(3b). This compound was obtained as a yellow solid, yield
1
80%, Mp. 241–243ꢀC. H NMR (DMSO-d6) d ¼ 7.69 (d, 4H,
Ar); 7.21 (d, 4H, Ar); 5.91 (s, 2H, H-4); 2.32 (s, 3H, Me). 13C
2
NMR (DMSO-d6) d ¼ 185.6 (C¼¼O); 169.3 (q, J ¼ 28, C-5),
152.9 (C-3), 128.7, 128.5, 126.7, 126.5 (6C, Ar), 122.1 (q, 1J
¼ 291, CF3), 86.8 (C-4), 20.7 (Me).
1,10-Carbonyl-bis[3-(4-fluorophenyl)-5-trifluoromethyl-1H-
pyrazole] (3c). This compound was obtained as a yellow solid,
1
yield 79%, Mp. 179–181ꢀC. H NMR (DMSO-d6) d ¼ 7.85 (t,
1
with H and 13C NMR chemical shifts of the pyrazoline
4H, Ar), 7.20 (t, 4H, Ar), 5.91 (s, 2H, H-4). 13C NMR
moieties for these symmetrical systems.
2
(DMSO-d6) d ¼ 184.5 (C¼¼O), 169.3 (q, J ¼ 28, C-5), 138.1
In conclusion, we have developed a useful, simple,
and convenient procedure to obtain new 1,10-carbonyl-
bis[3-aryl(heteroaryl)-5-trihalomethyl-1H-pyrazoles] (3,
9), starting from the cyclocondensation reactions with
b-alkoxyvinyl trihalomethyl ketones (1, 8) and 1,3-dia-
(C-3), 129.1, 129, 114.9, 114.7 (6C, Ar), 118.1 (q, 1J ¼ 291,
CF3), 86.9 (C-4).
1,10-Carbonyl-bis[3-(4-methoxyphenyl)-5-trifluoro-methyl-
1H-pyrazole] (3d). This compound was obtained as a yellow
solid, yield 81%, Mp. 242–244ꢀC. 1H NMR (DMSO-d6) d ¼
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of New 1,10-Carbonyl-bis[3-aryl(heteroaryl)-5-(trihalomethyl)-
1H-pyrazoles] and Trifluoromethyl Derivatives through Ring-Opening Reactions
1077
1,10-Carbonyl-bis[3-(4-bromophenyl)-5-trichoromethyl-1H-
pyrazole] (9d). This compound was obtained as a white solid,
yield 64%, Mp. 142–144ꢀC. 1H NMR (DMSO-d6) d ¼ 7.72
(d, 4H, Ar), 7.60 (d, 4H, Ar), 6.3 (s, 2H, H-4). 13C NMR
(DMSO-d6) d ¼ 184.1 (C¼¼O), 175.3 (C-3), 140.9 (C-5),
131.7, 131.0, 130.0, 128.5 (6C, Ar), 100.3 (CCl3), 83.2 (C-4).
1,10-Carbonyl-bis[3-(4-nitrophenyl)-5-trichoromethyl-1H-
pyrazole] (9e). This compound was obtained as a white solid,
yield 73%, Mp. 191–193ꢀC. 1H NMR (DMSO-d6) d ¼ 8.30
(d, 4H, Ar), 7.71 (d, 4H, Ar), 6.32 (s, 2H, H-4). 13C NMR
(DMSO-d6) d ¼ 178.7 (C¼¼O), 174.9 (C-3), 148.2 (C-5),
140.5, 129.8, 123.8, 123.2 (4C, Ar), 97.0 (CCl3), 91.8 (C-4).
1,10-Carbonyl-bis[3-(thien-2-yl)-5-trichoromethyl-1H-pyr-
azole] (9f). This compound was obtained as a white solid,
yield 68%, Mp. 183–185ꢀC. 1H NMR (DMSO-d6) d ¼ 7.61
(d, 2H, Thienyl), 7.50 (d, 2H, Thienyl), 7.08 (d, 2H, Thienyl)
6.29 (s, 2H, H-4). 13C NMR (DMSO-d6) d ¼ 179 (C¼¼O),
174.7 (C-3), 149.6 (C-5), 129.4, 128.7, 127.8, 126.3 (4C,
Thienyl), 100.4 (CCl3), 82.9 (C-4).
7.76 (d, 4H, Ar), 6.93 (d, 4H, Ar), 5.90 (s, 2H, H-4), 3.78 (s,
3H, OMe). 13C NMR (DMSO-d6) d ¼ 173.4 (C¼¼O), 168.5 (q,
2J ¼ 28, C-5), 160.9 (C-3), 134.1, 128.5, 128.3, 113.2 (4C,
1
Ar), 119.3 (q, J ¼ 291, CF3), 86.5 (C-4), 55.1 (OMe).
1,10-Carbonyl-bis[3-(4-nitrophenyl)-5-trifluoromethyl-1H-
pyrazole] (3e). This compound was obtained as a yellow
solid, yield 62%, Mp. 258–260ꢀC. 1H NMR (DMSO-d6) d ¼
8.23 (d, 4H, Ar), 7.99 (d, 4H, Ar), 5.94 (s, 2H, H-4). 13C
2
NMR (DMSO-d6) d ¼ 183.1 (C¼¼O), 170.2 (q, J ¼ 28, C-5),
148.1 (C-3), 147.3, 127.8, 123.5, 123.3 (4C, Ar), 118.3 (q,
1J ¼ 292, CF3), 87.7 (C-4).
1,10-Carbonyl-bis[3-(4,40-biphenyl)-5-trifluoromethyl-1H-
pyrazole] (3f). This compound was obtained as a yellow
solid, yield 83%, Mp. 170–172ꢀC. 1H NMR (DMSO-d6) d ¼
8.02 (s, 4H, Ar), 7.71–7.76 (m, 8H, Ar), 7.45 (d, 6H, Ar), 6.41
(s, 2H, H-4). 13C NMR (DMSO-d6) d ¼ 187.3 (C¼¼O), 170.5
(q, 2J ¼ 31, C-5), 143.2 (C-3), 138.9, 137.7, 137.4, 128.8,
1
127.9, 127.7, 126.6, 126.5 (8C, Ar), 119.2 (q, J ¼ 287, CF3),
89.2 (C-4).
1,10-Carbonyl-bis[3-(1-naphthyl)-5-trifluoromethyl-1H-
pyrazole] (3g). This compound was obtained as a yellow
solid, yield 74%, Mp. 186–188ꢀC. 1H NMR (DMSO-d6) d ¼
7.98–8.07 (m, 4H, Ar), 7.70–7.75 (m, 2H, Ar), 7.43–7.60 (m,
8H, Ar), 6.37 (s, 2H, H-4). 13C NMR (DMSO-d6) d ¼ 177.5
(C¼¼O), 176.5 (q, 2J ¼ 33, C-5), 132.8 (C-3), 132.4, 129.8,
129.6, 128.2, 127.5, 126.8, 126.1, 126, 125.1, 123.7 (10C, Ar),
General procedure for the synthesis of ethyl 5-(trifluoro-
methyl)-3-phenyl-5-hydroxy-4,5-dihydro-1H-pyrazole-1-car-
boxylate (5). A solution of 5-trifluoromethyl-3-(phenyl)-5-
hydroxy-4,5-dihydro-1H-pyrazolylcarbohydrazide (4) (1 mmol)
and 2,4-pentanedione (1 mmol), in ethanol as solvent (4 mL)
was stirred under reflux for 20 h. After the reaction time,
the solvent was removed under reduced pressure. The solid
residue was recrystallized from ethanol and isolated in high
purity.
1
115.7 (q, J ¼ 293, CF3), 94.4 (C-4).
1,10-Carbonyl-bis[3-(thien-2-yl)-5-trifluoromethyl-1H-pyr-
azole] (3h). This compound was obtained as a yellow solid,
yield 86%, Mp. 237–239ꢀC. 1H NMR (DMSO-d6) d ¼ 7.63
(d, 2H, Thienyl), 7.56 (d, 2H, Thienyl), 7.08 (d, 2H, Thienyl),
5.89 (s, 2H, H-4). 13C NMR (DMSO-d6) d ¼ 178.9 (C¼¼O),
Ethyl
dro-1H-pyrazole-1-carboxylate (5). This compound was
5-(trifluoromethyl)-3-phenyl-5-hydroxy-4,5-dihy-
1
obtained as a white solid, yield 63%, Mp. 127–129ꢀC [30]. H
NMR (DMSO-d6) d ¼ 8.08 (s, 1H, OH), 7.76–7.74 (m, 2H,
Ar), 7.47 (s, 3H, Ar), 4.23 (q, 2H, CH2, J ¼ 7), 3.86 (d, 1H,
H-4a, J ¼ 19), 3.55 (d, 1H, H-4b, J ¼ 19), 1.26 (t, 3H, CH3,
J ¼ 7). 13C NMR (DMSO-d6) d ¼ 151.08 (C¼¼O), 150.79
(C-3), 130.17, 130.09, 128.46, 126.2 (Ar), 123.4 (q, CF3, J ¼
285), 91,2 (q, J ¼ 41), C-5), 61.4 (C-4), 44.4 (CH2), 13.9
(CH3). GC-MS (EI, 70 eV): m/z (%) ¼ 302 (Mþ, 19), 212
(46), 189 (42), 161 (100), 77 (72).
General procedure for the synthesis of 3-(4-methyl-
phenyl)-5-(trifluoromethyl)-1H-1-phenylpyrazole (6). A stirred
solution of ketone (3b) (2 mmol) with phenylhydrazine (2
mmol) in 15 mL of dry ethanol was stirred at 80ꢀC during 4
h. After the reaction time, the solvent was removed under
reduced pressure, and the product 6 was dried under reduced
pressure, and isolated in high purity.
2
168.9 (q, J ¼ 28, C-5), 149 (C-3), 129.7, 127.8, 126.9, 126.7
1
(4C, Thienyl), 118.7 (q, J ¼ 291, CF3), 86.7 (C-4).
1,10-Carbonyl-bis[3-(fur-2-yl)-5-trifluoromethyl-1H-pyraz-
ole] (3i). This compound was obtained as a yellow solid, yield
1
67%, Mp. 259–261ꢀC. H NMR (DMSO-d6) d ¼ 7.69 (s, 2H,
Furyl), 6.90 (d, 2H, Furyl), 6.53–6.54 (m, 2H, Furyl), 5.85 (s,
2H, H-4). 13C NMR (DMSO-d6) d ¼ 175.8 (C¼¼O), 169.4 (q,
2J ¼ 28, C-5), 155.3 (C-3), 144, 143.8, 111.7, 111.6 (4C, Fu-
1
ryl), 118.9 (q, J ¼ 291, CF3), 86.8 (C-4).
1,10-Carbonyl-bis(3-phenyl-5-trichloromethyl-1H-pyrazole)
(9a). This compound was obtained as a white solid, yield
80%, Mp. 150–152ꢀC. 1H NMR (DMSO-d6) d ¼ 7.43–7.53
(m, 2H, Ar), 7.42–7.48 (m, 8H, Ar), 6.21 (s, 2H, H-4). 13C
NMR (DMSO-d6) d ¼ 185.6 (C¼¼O), 175.2 (C-3), 141.8 (C-
5), 130.1, 128.6, 128.1, 126.4 (4C, Ar), 100.4 (CCl3), 83.4
(C-4).
3-(4-Methylphenyl)-5-(trifluoromethyl)-1H-1-phenylpyra-
zole (6). This compound was obtained as an oil, yield 77%.
1H NMR (CDCl3) d ¼ 7.34 (s, 5H, Ar), 7.11 (s, 4H, Ar), 6.72
(s, 1H, H-4), 2.34 (s, 3H, CH3). GC-MS (EI, 70 eV): m/z (%)
¼ 302 (Mþ, 100), 281 (19), 233 (5), 77 (10).
1,10-Carbonyl-bis(3-tolyl-5-trichloromethyl-1H-pyrazole)
(9b). This compound was obtained as a white solid, yield
1
62%, Mp. 204–206ꢀC. H NMR (DMSO-d6) d ¼ 7.68 (d, 4H,
Ar), 7.21 (d, 4H, Ar), 6.36 (s, 2H, H-4), 2.33 (s, 6H, Me). 13C
NMR (DMSO-d6) d ¼ 185.8 (C¼¼O), 174.6 (C-3), 139.6 (C-
5), 129.1, 128.6, 128.2, 126.5 (4C, Ar), 100.8 (CCl3), 82.9
(C-4), 20.9 (Me).
General procedure for the synthesis of 5-hydroxy-3-(4-
methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (7). To
a stirred solution of ketone (3b) (2 mmol) in pyridine (2
mmol), was added a solution of hydroxylamine hydrochloride
(2 mmol) in H2O (1 mL). The mixture was stirred at 45ꢀC for
24 h. After 24 h, water (25 mL) was added and extracted with
diethyl ether (3 ꢂ 15 mL). The organic layer was dried with
Na2CO3, filtered and evaporated under reduced pressure. The
solid was recrystallized from diethyl ether and obtained in
high purity.
1,10-Carbonyl-bis[3-(4-chlorophenyl)-5-trichoromethyl-1H-
pyrazole] (9c). This compound was obtained as a white solid,
yield 76%, Mp. 168–169ꢀC. 1H NMR (DMSO-d6) d ¼ 7.77
(d, 4H, Ar), 7,44 (d, 4H, Ar), 6.98 (s, 2H, H-4). 13C NMR
(DMSO-d6) d ¼ 184.1 (C¼¼O), 177.9 (C-3), 138.4 (C-5),
130.7, 130.4, 129.1, 129.0 (6C, Ar), 94.6 (CCl3), 89.5 (C-4).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1078
H. G. Bonacorso, C. A. Cechinel, L. M. F. Porte, J. Navarini, S. Cavinatto, R. C. Sehnem, D. B.
Martins, N. Zanatta, and M. A. P. Martins
Vol 47
[12] Angerman, A.; Franke, H.; Geisler, J.; Johann, G.; Rees, R.
Schering AG, U.S. Pat. 4,008,200 (1991).
5-Hydroxy-3-(4-methylphenyl)-5-(trifluoromethyl)-4,5-dihy-
droisoxazole (7). This compound was obtained as a yellow
solid, yield 89%, Mp. 62–63ꢀC. 1H NMR (CDCl3) d ¼ 7.53
(d, 2H, Ar, J ¼ 8), 7.23 (d, 2H, Ar, J ¼ 8), 3.66 (d, 1H, H-4a,
J ¼ 18), 3.47 (d, 1H, H-4b, J ¼ 18), 2.39 (s, 3H, CH3). GC-
MS (EI, 70 eV): m/z (%) ¼ 245 (Mþ, 100), 176 (30), 133
(21), 91 (53).
[13] Soliman, R.; Darwish, S. A. S. J Med Chem 1983, 11,
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´
[16] Esteves-Souza, A.; Echevarrıa, A.; Vencato, I.; Jimeno,
Acknowledgment. The authors thank the financial support from
M. L.; Elguero, J. Tetrahedron 2001, 57, 6147.
´
´
Conselho Nacional de Desenvolvimento Cientıfico e Tecnolo-
gico—CNPq (Proc. 303.296/2008-9). Fellowships from CAPES
and CNPq are also acknowledged.
[17] Byers, P. K.; Canty, A. J.; Honeyman, R. T.; Gardinier,
J. R.; Reger, D. L. Inorg Synth 2004, 34, 30.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet