New succinyl-spaced pyrazoles: Regioselective synthesis of 1,4-bis[5-(trichloromethyl)-1H-pyrazol-1-yl]butane-1,4-diones

Article abstract of DOI:10.1002/jhet.523

The facile and convenient access by a conventional procedure in ethanol as solvent to a new series of succinyl-spaced pyrazoles including 1,4-bis[5-(trichloromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl]butane-1, 4-diones (64-82%) and the respective dehy

Full text of DOI:10.1002/jhet.523

January 2011
New Succinyl-spaced Pyrazoles: Regioselective Synthesis of
1,4-Bis[5-(trichloromethyl)-1H-pyrazol-1-yl]butane-1,4-diones
113
Helio G. Bonacorso,* Cleber A. Cechinel, Gisele R. Paim,
Marcos A. P. Martins, Nilo Zanatta, and Alex F. C. Flores
´
´
´
Nucleo de Quımica de Heterociclos (NUQUIMHE), Departamento de Quımica, Universidade
Federal de Santa Maria, Santa Maria 97.105-900, RS, Brazil
*E-mail: heliogb@base.ufsm.br
Received February 24, 2010
DOI 10.1002/jhet.523
Published online 9 September 2010 in Wiley Online Library (wileyonlinelibrary.com).
The facile and convenient access by a conventional procedure in ethanol as solvent to a new series of
succinyl-spaced pyrazoles including 1,4-bis[5-(trichloromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-
yl]butane-1,4-diones (64–82%) and the respective dehydrated derivatives as 1,4-bis[5-(trichloromethyl)-
1H-pyrazol-1-yl]butane-1,4-diones in 57–82% yields, from the regioselective cyclocondensation reactions
of 4-substituted 4-methoxy-1,1,1-trichloroalk-3-en-2-ones with succinic acid dihydrazide, where the 4-sub-
stituents are Me, Ph, 4-FC6H4, 4-ClC6H4, 4-NO2C6H4, 2-furyl, and 2-thienyl, is reported.
J. Heterocyclic Chem., 48, 113 (2011).
INTRODUCTION
geminated-trihalosubstituted heterocycles but also alkyl-
and carbonyl-linked bis-heterocycles [15–20].
Recently, there has been great interest in the synthesis
of trifluoromethyl-substituted heteroaromatic compounds
due, in part, to the unique biological properties exhibited
by fluorine [1]. On the other hand, trichloromethylated
heterocycles are relatively rare but promising templates
for biological activity. For example, trichloromethyl-
substituted benzodiazepines, quinazolines, and pyrimi-
dines have exhibited activity as acetyl cholinesterase
and ATPDase inhibitors, anxiolytics, cyclin-dependent
kinase (CDKs) inhibitors in cell cycle proteins and ATP
and ADP hydrolysis inhibitors in synaptosomes from rat
cerebral cortex. Particularly, 3-aryl-5-trichloromethyl-5-
hydroxy-4,5-dihydro-1H-pyrazoles presented anti-inflam-
matory and analgesic activity [2].
Moreover, specifically, bis-pyrazolyl systems contain-
ing acyl spacer groups are rare in the literature and new
synthetic routes to obtain these compounds and studies
of their potential for pharmaceuticals and agrochemicals
such as herbicidal agents have been relatively little
explored [16–23].
A review of the literature disclosed few publications
on the construction of a succinyl spacer bis-(3,5-substi-
tuted 1H-pyrazoles) system. In 1961, according to a US
patent, Wright [16] reported the systematic synthesis
and a biological activity study of a series of bis-(4-nitro-
pyrazol-1-yl) spacer compounds, where the linker moi-
ety was an aliphatic hydrocarbon chain [A(CH2)nA]
containing 1–12 carbon atoms, saturated or unsaturated,
and substituted by one or more lower alkyl (not more
than four carbon atoms) or hydroxyl groups. In the same
patent, diacyl group spacers [ACOA (CH2)nACOA]
with n being an integer from 1 to 12 or an ether group
of the formula [A(CH2)xAOA(CH2)yA], where x and y
were identical or different integers from 1 to 10, or
even a divalent cycloalkyl group such as 1,4-cyclohexy-
lene were synthesized and biologically tested. These
new bis-pyrazolyl compounds showed useful activity as
antiprotozoal agents, especially in the treatment of trich-
omoniasis (e.g., that caused by T. vaginalis). The 1,7
di-(4-nitropyrazol-1-yl)n-heptane and their respective
Among several classes of N-heterocycles, the 2-pyra-
zolines have been used as antitumor [3], antibacterial,
antifungal, antiviral, antiparasitic, antitubercular, and in-
secticidal agents [4–11]. Some of these compounds also
showed anti-inflammatory, antidiabetic, anesthetic, and
analgesic properties [12–14].
In the course of our ongoing interest in new heterocy-
clic scaffolds, we have explored the application of
4-alkoxy-4-(alkyl/aryl/heteroaryl)-1,1,1-trichloroalk-3-en-
2-ones 1 in the synthesis of novel or uncommon low-
molecular weight heterocyclic compounds [15] and have
reported not only the synthesis of single-, linked-, or
C
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114
H. G. Bonacorso, C. A. Cechinel, G. R. Paim, M. A. P. Martins, N. Zanatta, and A. F. C. Flores
Vol 48
Scheme 1. Synthetic route to 1,4-bis(5-(trichloromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)butane-1,4-diones (2).
n-pentane analog were of outstanding activity and low
toxicity. Specifically, only 1,10-succinylbis(3,5-dimethyl-
4-nitropyrazole) and the nonsubstituted 1,10-succinyl bis-
(4-nitropyrazole) were prepared using the appropriate
1H-pyrazole and succinyl chloride. In 2005, Shi et al.
[17] reported the synthesis of N,N0-butanedioylbis(5-fer-
rocenyl-3-methyl-1H-pyrazole) from the reaction of fer-
rocenoylacetone and succinic acid dihydrazide. In the
same year, Al-Talib et al. [18] reported that the reaction
of oxalic-, malonic-, and succinic acid dihydrazide with
2,4-pentanedione gave smoothly the corresponding oxa-
lyl-, malonyl-, and succinyl-N,N0-bis(3,5-dimethyl-1H-
pyrazole). It is also important to mention that aroyl
and heteroaroyl spacer bis-pyrazoles have been synthe-
sized using 1,3-dicarbonyl compounds or derivatives
thereof and, for example, isophthalic acid dihydrazide
[19] or 1,3,4-thiadiazole-2,5-dithioglycolic acid dihy-
drazide [20], respectively.
sation reactions of 4-substituted 4-methoxy-1,1,1-trichlor-
oalk-3-en-2-ones (1) with succinic acid dihydrazide in
ethanol as solvent under conventional reaction conditions
(Scheme 1), and, as an example, the dehydrated bis-pyr-
azole system, 1,4-bis(5-(trichloromethyl)-1H-pyrazol-1-
yl)butane-1,4-diones (3) from the dehydration reactions
of 2 using thionyl chloride and pyridine in benzene media
is also presented (Scheme 2).
In this work, we initially carried out the reaction of
4-methoxy-4-(4-fluorophenyl)-1,1,1-trichlorobut-3-en-2-
one (1c) with succinic acid dihydrazide in 2:1 molar
ratio, respectively, in ethanol/water (20:1) as solvent at
room temperature.
RESULTS AND DISCUSSION
Since the 1970s, research groups have reported the
systematic synthesis of 4-substituted 4-methoxy-1,1,1-
trihaloalk-3-en-2-ones (1) from the trihaloacetylation
reaction of the respective enolethers or acetals with tri-
fluoroacetic anhydride or trichloroacetyl chloride,
respectively [1,15]. In this article, 4-methoxy-1,1,1-tri-
chloropent-3-en-2-one (1a) was prepared according to
ref. [24]; 4-aryl-4-methoxy-1,1,1-trichlorobut-3-en-2-
ones (1b–e) were synthesized from the reaction of the
respective acetophenone dimethyl acetals with trichlor-
oacetyl chloride [25] and 4-heteroaryl-4-methoxy-1,1,1-
Until now, no molecules containing an alkanoyl moi-
ety, such as a succinyl bridge, bonding two identical or
different trichloromethylated heterocycles have been
synthesized.
In this context and in an attempt to develop synthetic
methods to obtain acyl spacer heterocycles and new tri-
chloromethyl-substituted molecules, we herein report a
regioselective methodology for the preparation of a series
of 1,4-bis(5-(trichloromethyl)-5-hydroxy-4,5-dihydro-1H-
pyrazol-1-yl)butane-1,4-diones (2) from the cycloconden-
Scheme 2. Synthetic route to 1,4-bis(5-(trichloromethyl)-1H-pyrazol-1-yl)butane-1,4-diones (3).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
New Succinyl-Spaced Pyrazoles: Regioselective Synthesis of
1,4-Bis[5-(trichloromethyl)-1H-pyrazol-1-yl]butane-1,4-diones
115
trichlorobut-3-en-2-ones (1f–g) were obtained following
the procedure from the literature [26].
NMR spectra exhibited only one set of peaks, despite
the fact that two stereogenic carbons were present in
each molecule. The succinyl derivatives 2 also presented
the typical 13C-NMR chemical shifts for both pyrazoline
rings at d 153.8 ppm (C3), d 47.1 ppm (C4), 101.1 ppm
(CCl3), and 98.3 ppm (C5). The two carbonyl and ethyl-
ene carbons showed NMR signals in the range of d 172.9
and 29.3 ppm, respectively. All the signals are consistent
According to the literature [16], 1,10-succinylbis(3,5-
dimethyl-4-nitropyrazole) and the nonsubstituted 1,10-
succinylbis(4-nitropyrazole) were prepared using the
appropriate 1H-pyrazole and succinyl chloride in the
presence of anhydrous sodium carbonate, when the reac-
tions were carried out in dry acetone as solvent for 20 h
at 20ꢀC but no yields were reported.
1
with H- and 13C-NMR chemical shifts for the pyrazoline
However, this reaction, monitored by TLC, did not take
place and the starting reagents were recovered. Subse-
quently, when the mixture was heated to reflux, after stir-
ring for 4 h, TLC showed that the reaction proceeded
smoothly and gave the product 2c in 64% yield (Scheme 1).
The most satisfactory results for the synthesis of other
compounds 2a–g were obtained using the above
described reaction condition, and these compounds were
isolated as stable solids by recrystallization from etha-
nol/water (20:1 v/v).
and succinyl moieties of this symmetric system.
The dehydrated compounds 3, being symmetric
systems, presented one set of signals in both 1H- and
13C-NMR spectra and, in comparison with 2, now
showed typical chemical shifts for the pyrazole ring for
both H-4 on average at 7.92 ppm as singlet peaks.
The 13C{1H}-NMR spectra exhibited chemical shifts,
in DMSO-d6, for both pyrazole ring carbons on average
at 154.4 (C3), 92.1 (C4), 103.1 (CCl3), and 141.9 ppm
(C5). Both carbonyl and ethylene carbons showed sig-
nals in the range of d 169.4 and 32.5 ppm, respectively.
In conclusion, 4-alkoxy-4-(alkyl/aryl/heteroaryl)-1,1,1-
trichloroalk-3-en-2-ones 1 have been shown to react
with succinic acid dihydrazide under conventional and
mild conditions to produce, in a one-step reaction, new
succinyl spacer bis-(3,5-substituted 2-pyrazolines and
1H-pyrazoles), namely, 1,4-bis(5-(trichloromethyl)-5-
hydroxy-4,5-dihydro-1H-pyrazol-1-yl)butane-1,4-diones
2 (64–82%). The efficient dehydration reaction used
for the heterocycles 2 to afford the 1,4-bis(5-(trichloro-
methyl)-1H-pyrazol-1-yl)butane-1,4-diones 3 (57–72%)
was also demonstrated.
Subsequently, after a review of the literature, attempt-
ing to obtain aromatic pyrazoles for further biological
assays, we chose thionyl chloride/pyridine as the de-
hydrating agent and report here the conditions required
to accomplish the dehydration of two representative
examples of compounds 2, which present a hydroxyl
and a trichloromethyl group, a phenyl (for 2b), a 4-fluo-
rophenyl (for 2c) or a 4-nitrophenyl (for 2e), and a suc-
cinyl 2-pyrazoline attached directly to the C-5, C-3, and
N-1 atom of each pyrazoline ring, respectively (Scheme
2). Due to the relative difficulty to carry out the dehy-
dration reaction, because of the presence of the trichlor-
omethyl substituent and the carbonyl function at posi-
tions 5 and 1 of these two bis-succinyl-pyrazolines, 2b,
2c, and 2e were dehydrated to give the respective 3-
aryl-substituted 1,4-bis(5-(trichloromethyl)-1H-pyrazol-
1-yl)butane-1,4-diones 3b, 3c, and 3e in 57–72% yields,
only by stirring the mixtures of 3, thionyl chloride, and
pyridine at 80ꢀC for about 1 h in benzene as solvent
(Scheme 2), according to procedures similar to those
described in the literature [27].
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, and digital resolution 6 0.01 ppm
in DMSO-d6 for 2 and 3 using TMS as internal reference.
Infrared spectra were recorded from 4000 to 650 cmꢁ1 using a
Perkin-Elmer Model Spectrum One FTIR spectrometer with 16
scans and 4 cmꢁ1. This instrument is equipped with a univer-
sal ATR sampling accessory supplied with a top plate ZnSe
crystal. For ATR data acquisition, 5.0 6 0.3 mg of solid sam-
ple was placed onto the crystal and its spectrum was recorded.
Data were handled using Matlab software 6.1 version (The
Math Works, Natick, MA). The CHN elemental analyses were
performed on a Perkin-Elmer 2400 CHN elemental analyzer
(Sa˜o Paulo University, USP/Brazil).
The structures of 1,4-bis[5-(trichloromethyl)-5-
hydroxy-4,5-dihydro-1H-pyrazol-1-yl]butane-1,4-diones
(2a–g) were deduced from NMR experiments and by
comparison with NMR data of other 2-pyrazolines for-
merly synthesized in our laboratory [15,28].
Compounds 2 showed 1H-NMR chemical shifts in
DMSO-d6 for the hydroxy protons in the range of d
7.62 ppm and the four methylene protons (H4) were
observed as a typical AB system, as two doublets, in
which one of them was on average at d 3.89 and the
other at d 3.66 ppm, with a geminal coupling constant
of 19–20 Hz. Because of the symmetry of compounds 2,
the four ethylene protons (succinyl moiety) appeared as
one singlet peak on average at 3.13 ppm. The 13C{1H}-
Synthetic procedures. General procedure for the prepa-
ration of 1,4-bis[5-(trichloromethyl)-5-hydroxy-4,5-dihydro-
1H-pyrazol-1-yl]butane-1,4-diones (2a–g). A solution of
4-substituted 4-methoxy-1,1,1-trichloroalk-3-en-2-ones (1a–g)
Journal of Heterocyclic Chemistry
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H. G. Bonacorso, C. A. Cechinel, G. R. Paim, M. A. P. Martins, N. Zanatta, and A. F. C. Flores
Vol 48
(10 mmol), succinic acid dihydrazide (5 mmol), ethanol (20
mL), and distilled water (1 mL) was stirred at 80ꢀC for 4 h.
After the reaction time, the solvent was evaporated to half by
rotatory evaporator under reduced pressure. After cooling
(ꢂ8ꢀC) for 1–2 days, the compounds 2a–g were obtained pure
directly by filtration, washed with cold ethanol, and dried
under vacuum apparatus.
1,4-Bis[5-(trichloromethyl)-3-(2-furyl)-5-hydroxy-4,5-dihydro-
1H-pyrazol-1-yl]butane-1,4-dione (2f). This compound was
obtained as
a
white solid, yield 80%, Mp 223–225ꢀC.
1H-NMR (DMSO-d6) d ¼ 7.57–7.58 (m, 2H, 2 Fur), 7.46 (s,
2H, 2OH), 6.85–6.87 (m, 2H, 2Fur), 6.53–6.55 (m, 2H, 2Fur),
3.89 (d, J ¼ 18, 2H, 2H-4), 3.59 (d, J ¼ 18, 2H, 2H-4), 3.22
(s, 4H, 2CH2). 13C-NMR (DMSO-d6) d ¼ 172.1 (2C¼¼O),
144.9 (4C, 2Fur), 142.0 (2C-3), 115.0, 112.2 (4C, 2Fur), 103.2
(2CCl3), 101.4 (2C-5), 46.4 (2C-4), 29.8 (2CH2). ATR-IR (m,
cmꢁ1): 3193, 1650, 766. Anal. Calc. for C20H16Cl6N4O6
(617.92): C, 38.68; H, 2.60; N, 9.02%. Found C, 38.51; H,
3.01; N, 8.73%.
1,4-Bis[5-(trichloromethyl)-5-hydroxy-3-methyl-4,5-dihydro-
1H-pyrazol-1-yl]butane-1,4-dione (2a). This compound was
obtained as
a
white solid, yield 64%, Mp 170–171ꢀC.
1H-NMR (DMSO-d6) d ¼ 7.72 (s, 2H, 2OH), 3.50 (d, J ¼ 19,
2H, 2H-4), 3.32 (d, J ¼ 19, 2H, 2H-4), 2.87 (s, 4H, 2CH2),
2.02 (s, 6H, 2CH3). 13C-NMR (DMSO-d6) d ¼ 173.9 (2C¼¼O),
156.4 (2C-3), 103.4 (2CCl3), 100.9 (2C-5), 49.7 (2C-4), 27.3
(2CH2), 26.2 (2CH3). ATR-IR (m, cmꢁ1): 3211, 1647, 772.
Anal. Calc. for C14H16Cl6N4O4 (513.93): C, 32.52; H, 3.12; N,
10.84%. Found C, 32.92; H, 3.48; N, 11.14%.
1,4-Bis[5-(trichloromethyl)-5-hydroxy-3-(2-thienyl)-4,5-dihydro-
1H-pyrazol-1-yl]butane-1,4-dione (2g). This compound was
obtained as
a
white solid, yield 78%, Mp 208–210ꢀC.
1H-NMR (DMSO-d6) d ¼ 7.79–7.81 (m, 2H, 2Thien), 7.48 (s,
2H, 2OH), 7.45–7.50 (m, 4H, 2Thien), 3.97 (d, J ¼ 19,2H,
2H-4), 3.77 (d, J ¼ 19, 2H, 2H-4), 3.11 (s, 4H, 2CH2).
13C-NMR (DMSO-d6) d ¼ 171.8 (2C¼¼O), 159.6 (2C-3),
149.4, 127.5, 125.4, 124.5 (8C, 2Th), 104.7 (2CCl3), 101.4
(2C-5), 47.1 (2C-4), 30.2 (2CH2). ATR-IR (m, cmꢁ1): 3183,
1645, 737. Anal. Calc. for C20H16Cl6N4O4S2 (649.87): C,
36.77; H, 2.47; N, 8.58%. Found C, 36.70; H, 2.88; N, 8.42%.
General procedure for the synthesis of 1,4-bis[5-(trichlor-
omethyl)-1H-pyrazol-1-yl]butane-1,4-diones (3b–c, 3e). A
solution of bis-pyrazoline butane-1,4-diones (2b–c, 2e) (2.8
mmol) and pyridine (37.1 mmol, 3 mL) in 50 mL of benzene
was cooled to 0ꢀC and thionyl chloride (16.8 mmol, 1.22 mL)
diluted in 25 mL of benzene was added dropwise over 10 min.
The solution was stirred for an additional 30 min, during
which time the temperature was allowed to rise to 20ꢀC. The
mixture was then heated under reflux (bath temperature 80ꢀC)
for 1 h and then filtered to remove the pyridine hydrochloride
at room temperature. The solution was extracted twice with
benzene (2 ꢃ 50 mL) and dried over sodium sulfate. Evapora-
tion of the solvent under reduced pressure by rotatory evapora-
tor left 3b–c, 3e as solid products, which were purified by
recrystallization from aqueous ethanol.
1,4-Bis[5-(trichloromethyl)-5-hydroxy-3-phenyl-4,5-dihydro-
1H-pyrazol-1-yl]butane-1,4-dione (2b). This compound was
obtained as a white solid, yield 73%, Mp 214–216ꢀC. 1H-
NMR (DMSO-d6) d ¼ 7.92 (s, 2H, 2OH), 7.81–7.83 (m, 4H,
2Ar), 7.48–7.50 (m, 6H, 2Ar), 3.97 (d, J ¼ 18, 2H, 2H-4),
3.78 (d, J ¼ 18, 2H, 2H-4), 3.11 (s, 4H, 2CH2). 13C-NMR
(DMSO-d6) d ¼ 175.5 (2C¼¼O), 155.1 (2C-3), 131.1, 130.2,
128.8, 126.8 (8C, 2Ar), 103.7 (2CCl3), 102.1 (2C-5), 46.7 (2C-
4), 30.1 (2CH2). ATR-IR (m, cmꢁ1): 3366, 1672, 757. Anal.
Calc. for C24H20Cl6N4O4 (637.96): C, 44.96; H, 3.14; N,
8.74%. Found C, 44.63; H, 2.89; N, 8.94%.
1,4-Bis[5-(trichloromethyl)-3-(4-fluorophenyl)-5-hydroxy-4,5-
dihydro-1H-pyrazol-1-yl]butane-1,4-dione (2c). This compound
was obtained as a white solid, yield 64%, Mp 188–190ꢀC.
1H-NMR (DMSO-d6) d ¼ 7.71–7.78 (m, 4H, 2Ar), 7.27 (s, 2H,
2OH), 7.09–7.17 (m, 4H, 2Ar), 3.92 (d, J ¼ 18, 2H, 2H-4),
3.70 (d, J ¼ 18, 2H, 2H-4), 3.26 (s, 4H, 2CH2). 13C-NMR
(DMSO-d6) d ¼ 172.3 (2C¼¼O), 163.4 (d, J ¼ 249, 2C-F, 2Ar),
152.6 (2C-3), 128.9, 126.5, 115.7 (6C, 2Ar), 103.3 (2CCl3),
101.7 (2C-5), 46.7 (2C-4), 29.6 (2CH2). ATR-IR (m, cmꢁ1):
3371, 1645, 772. Anal. Calc. for C24H18Cl6F2N4O4 (673.94): C,
42.57; H, 2.68; N, 8.27%. Found C, 42.98; H, 2.41; N, 7.82%.
1,4-Bis[5-(trichloromethyl)-3-(4-chlorophenyl)-5-hydroxy-4,5-
dihydro-1H-pyrazol-1-yl]butane-1,4-dione (2d). This compound
was obtained as a white solid, yield 82%, Mp 244–246ꢀC.
1H-NMR (DMSO-d6) d ¼ 7.43 (s, 2H, 2OH), 7.65–7.70 (m,
4H, 2Ar), 7.39–7.43 (m, 4H, 2Ar), 3.91 (d, J ¼ 18, 2H, 2H-4),
3.62 (d, J ¼ 18, 2H, 2H-4), 3.25 (s, 4H, 2CH2). 13C-NMR
(DMSO-d6) d ¼ 173.1 (2C¼¼O), 159.7 (2C-3), 132.3, 128.6,
128.5, 126.5 (8C, 2Ar), 86.7 (2CCl3), 78.9 (2C-5), 46.5 (2C-
4), 28.6 (2CH2). ATR-IR (m, cmꢁ1): 3319, 1694, 774. Anal.
Calc. for C24H18Cl8N4O4 (705.88): C, 40.60; H, 2.56; N,
7.89%. Found C, 40.53; H, 2.83; N, 7.94%.
1,4-Bis[5-(trichloromethyl)-3-phenyl-1H-pyrazol-1-yl]butane-
1,4-dione (3b). This compound was obtained as a white solid,
1
yield 57%, Mp 190–191ꢀC. H-NMR (DMSO-d6): d 8.04–8.07
(m, 4H, 2Ar), 7.85 (s, 2H, 2H-4), 7.50–7.53 (m, 5H, 2Ar),
3.76 (s, 4H, 2CH2). 13C-NMR (DMSO-d6): d 173.3 (2C¼¼O),
154.1 (2C-3), 144.1 (2C-5), 128.8, 128.6, 128.5, 125.3 (8C,
2Ar), 104.9 (2CCl3), 100.3 (2C-4), 28.6 (2CH2). ATR-IR (m,
cmꢁ1): 1760, 761. Anal. Calc. for C24H16Cl6N4O2 (601.94): C,
47.64; H, 2.67; N, 9.26%. Found C, 47.96; H, 2.38; N, 9.46%.
1,4-Bis[5-(trichloromethyl)-3-(4-fluorophenyl)-1H-pyrazol-1-
yl]butane-1,4-dione (3c). This compound was obtained as a
1
white solid, yield 63%, Mp 189–190ꢀC. H-NMR (DMSO-d6):
1,4-Bis[5-(trichloromethyl)-5-hydroxy-3-(4-nitrophenyl)-4,5-
dihydro-1H-pyrazol-1-yl]butane-1,4-dione (2e). This com-
pound was obtained as a white solid, yield 66%, Mp 245–
247ꢀC. 1H-NMR (DMSO-d6) d ¼ 8.10 (s, 2H, 2OH), 8.28–
8.33 (m, 4H, 2Ar), 8.06–8.10 (m, 4H, 2Ar), 4.09 (d, J ¼ 18,
2H, 2H-4), 3.82 (d, J ¼ 18, 2H, 2H-4), 3.14 (s, 4H, 2CH2).
13C-NMR (DMSO-d6) d ¼ 171.9 (2C¼¼O), 151.6 (2C-3),
148.2, 135.9, 127.7, 123.9 (8C, 2Ar), 103.1 (2CCl3), 102.2
(2C-5), 46.6 (2C-4), 29.9 (2CH2). ATR-IR (m, cmꢁ1): 3332,
1699, 779. Anal. Calc. for C24H18Cl6N4O8 (727.93): C, 39.42;
H, 2.48; N, 11.49%. Found C, 39.54; H, 2.94; N, 11.45%.
d 7.87 (s, 2H, 2H-4), 7.34–7.39 (m, 8H, 2Ar), 3.74 (s, 4H,
2CH2). 13C-NMR (DMSO-d6): d 162.1 (2C¼¼O), 155.3 (2C-3),
145.0 (2C-5), 127.7, 127.6, 116.4, 116.2 (8C, 2Ar), 101.3
(2CCl3), 89.9 (2C-4), 38.3 (2CH2). ATR-IR (m, cmꢁ1): 1750,
763. Anal. Calc. for C24H14Cl6F2N4O2 (637.92): C, 44.96; H,
2.20; N, 8.74%. Found C, 44.99; H, 2.04; N, 8.51%.
1,4-Bis[5-(trichloromethyl)-3-(4-nitrophenyl)-1H-pyrazol-1-
yl]butane-1,4-dione (3e). This compound was obtained as a
yellow solid, yield 72%, Mp 131–133ꢀC. 1H-NMR (DMSO-
d6): d 8.35–8.36 (m, 4H, 2Ar), 8.04 (s, 2H, 2H-4), 7.36 (s, 4H,
2Ar), 3.81 (s, 4H, 2CH2). 13C-NMR (DMSO-d6): d 169.9
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
New Succinyl-Spaced Pyrazoles: Regioselective Synthesis of
1,4-Bis[5-(trichloromethyl)-1H-pyrazol-1-yl]butane-1,4-diones
117
[10] Holla, B. S.; Akaberali, P. M.; Shivanada, M. K. Farmaco
2000, 55, 256.
(2C¼¼O), 153.9 (2C-3), 136.6 (C-5), 135.4, 128.3, 127.0, 126.3
(8C, 2Ar), 103.1 (2CCl3), 86.1 (2C-4), 30.8 (2CH2). ATR-IR
(m, cmꢁ1): 1756, 771. Anal. Calc. for C24H14Cl6N6O6
(691.91): C, 41.47; H, 2.03; N, 12.09%. Found C, 41.17; H,
2.16; N, 11.83%.
[11] Palaska, E.; Aytemir, M.; Tayfun, I.; Erol, K.; Dilek, E. Eur
J Med Chem Chim Ther 2001, 36, 539.
[12] Regaila, H. A.; El-Bayonk, A. K.; Hammad, M. Egypt J
Chem 1979, 20, 197.
[13] Krishna, R.; Pande, B. R.; Bharthwal, S. P.; Parmar, S. S.
Eur J Med Chem 1980, 15, 567.
Acknowledgments. The authors are thankful for the financial
´
support from Conselho Nacional de Desenvolvimento Cientıfico
e Tecnologico – CNPq (Proc. Nr. 303296/2008-9). Fellowships
[14] Husain, M. I.; Shukla, S. Ind J Chem B 1986, 25, 983.
[15] Martins, M. A. P.; Cunico, W.; Pereira, C. M. P.; Sinhorin,
A. P.; Flores, A. F. C.; Bonacorso, H. G.; Zanatta, N. Curr Org Chem
2004, 1, 391; and references therein.
´
´
from Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de Nıvel
Superior—CAPES (Cechinel, C. A. and Paim, G. R.) are also
acknowledged.
[16] Wright, D. E. May & Baker Ltd, US Patent 2,979,512, 1961.
[17] Shi, Y.-C.; Sui, C.-X.; Cheng, H.-J. Acta Cryst E 2005, 61,
m1563.
REFERENCES AND NOTES
[18] Al-Talib, M.; Tashtoush, H.; Al-Ghoul, A.; Ziemer, B.;
Koert, U. J Heterocycl Chem 2005, 42, 287.
[1] (a) Welch, J. T. Tetrahedron 1987, 43, 3123; (b) Park, B.
K.; Kitterringham, N. R.; O’Neill, P. M. Annu Rev Pharmacol Toxicol
2001, 41, 443; (c) Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V.
G. Tetrahedron 2007, 63, 7753; (d) Nenajdenko, V. G.; Sanin, A. V.;
Balenkova, E. S. Molecules 1997, 2, 186.
[19] Moore, J. A.; Mehta, P. G. Macromolecules 1995, 28, 444.
[20] Rutavichyus, A.; Valyulene, S.; Kuodis, Z. Chem Hetero-
cycl Compd 1997, 33, 118.
[21] Denisova, A. B.; Sosnovskikh, V. Y.; Dehaen, W.; Toppet,
S.; Meervelt, L. V.; Bakulev, V. A. J Fluorine Chem 2002, 115, 183.
[22] Hanamoto, T.; Hakoshima, Y.; Egashira, M. Tetrahedron
Lett 2004, 45, 7573.
[2] Souza, F. R.; Fighera, M. R.; Lima, T. T. F.; Bastiani,
J.; Barcellos, I. B.; Almeida, C. E.; Oliveira, M. R.; Bonacorso, H.
G.; Flores, A. E.; Mello, C. F. Pharmacol Biochem Behav 2001, 68,
525.
[23] Angerman, A.; Franke, H.; Geisler, J.; Johann, G.; Rees, R.;
Schering AG, US Patent 4,008,200, 1991.
[3] Taylor, E. C.; Patel, H.; Kumar, H. Tetrahedron 1992, 48,
8089.
[24] Martins, M. A. P.; Colla, A.; Clar, G.; Fischer, P.;
Krimmer, S. Synthesis 1991, 483.
[4] Roelfvan, S. G.; Arnold, C.; Wellnga, K. J Agric Food
Chem 1979, 84, 406.
[25] Martins, M. A. P.; Siqueira, G. M.; Flores, A. F. C.; Clar,
G.; Zanatta, N. Quim Nova 1994, 17, 24.
[5] Kedar, R. M.; Vidhale, N. N.; Chincholkar, M. M. Orient J
Chem 1997, 13, 143.
[26] Flores, A. F. C.; Brondani, S.; Rosa, A.; Zanatta, N.;
Martins, M. A. P. Tetrahedron Lett 2002, 43, 8701.
[27] Padwa, A. J Org Chem 1965, 30, 1274.
[6] Singh, A.; Rathod, S.; Berad, B. N.; Patil, S. D.; Dosh, A.
G. Orient J Chem 2000, 16, 315.
[7] Katri, H. Z.; Vunii, S. A. J Ind Chem Soc 1981, 58, 1968.
[8] Das, N. B.; Mittra, A. S. Ind J Chem B 1978, 16, 638.
[9] Azarifar, D.; Shaebanzadeh, M. Molecules 2002, 7, 885.
[28] Bonacorso, H. G.; Oliveira, M. R.; Wentz, A. P.; Wastow-
ski, A. D.; Oliveira, A. B.; Hoerner, M.; Zanatta, N.; Martins, M. A.
P. Tetrahedron 1999, 55, 345.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet