New pyrazolyl-nicotinic acids, methyl esters, and 1,3,4-oxadiazolyl- pyrazolyl-pyridine tricyclic scaffold derivatives from 6-hydrazinylnicotinic acid hydrazide hydrate

Article abstract of DOI:10.1002/jhet.2110

This paper describes an efficient approach for the synthesis of a new series of 6-[3-alkyl(aryl/heteroaryl)-5-trifluoromethyl-1H-pyrazol-1-yl] nicotinic acids (where alkyl = CH₃; aryl = Ph, 4-OCH₃Ph, 4,4′-BiPh; and heteroaryl = 2-Furyl) from the hydrolysis reaction of alkyl(aryl/heteroaryl)substituted 2-(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H- pyrazol-1-yl)-5-(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-1-carbonylpyrazol-1- yl)pyridines, under basic conditions and at 70-95% yields. In a subsequent step, the esterification reaction of pyrazolyl-nicotinic acids done in thionyl chloride and methanol led to the isolation of a series of methyl 6-[alkyl(aryl/heteroaryl)-5-trifluoromethyl-1H-pyrazol-1-yl] nicotinates as stable hydrochloride salts at 64-84% yields, which could be easily converted to hydrazides to give new oxadiazolyl-pyrazolyl-pyridine tricyclic scaffolds at good yields from a [4 + 1] cyclocondensation reaction with 1,1,1-triethoxyethane and 1-(triethoxymethyl)benzene as the reagent/solvent.

Full text of DOI:10.1002/jhet.2110

July 2014
New Pyrazolyl-Nicotinic Acids, Methyl Esters, and 1,3,4-Oxadiazolyl-
pyrazolyl-pyridine Tricyclic Scaffold Derivatives from 6-
Hydrazinylnicotinic Acid Hydrazide Hydrate
1171
*
H. G. Bonacorso, G. R. Paim, L. M. F. Porte, E. P. Pittaluga, S. Cavinatto, A. R. Meyer, M. A. P. Martins,
and N. Zanatta
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria,
97105-900, Santa Maria, Rio Grande do Sul, Brazil
*
E-mail:heliogb@base.ufsm.br
Received December 18, 2012
DOI 10.1002/jhet.2110
Published online 16 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
O
N
R
N
N
R
NHNH2
N
Z
N
N
N
F3C
R
N
OH
H2NHN
N
CF3
CF3
OH
(16 examples)
R = Me, Ph, 4-OMeC6H4, 4,4'-BiPh, 2-Furyl
Z = CO2H, CO2CH3, CONHNH2, (1,3,4-Oxadiazol-2-yl)
This paper describes an efficient approach for the synthesis of a new series of 6-[3-alkyl(aryl/
heteroaryl)-5-trifluoromethyl-1H-pyrazol-1-yl]nicotinic acids (where alkyl = CH3; aryl = Ph, 4-OCH3Ph,
4,4′-BiPh; and heteroaryl = 2-Furyl) from the hydrolysis reaction of alkyl(aryl/heteroaryl)substituted 2-
(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-5-(5-trifluoromethyl-5-hydroxy-4,5-dihydro-
1H-1-carbonylpyrazol-1-yl)pyridines, under basic conditions and at 70–95% yields. In a subsequent step,
the esterification reaction of pyrazolyl-nicotinic acids done in thionyl chloride and methanol led to the iso-
lation of a series of methyl 6-[alkyl(aryl/heteroaryl)-5-trifluoromethyl-1H-pyrazol-1-yl] nicotinates as sta-
ble hydrochloride salts at 64–84% yields, which could be easily converted to hydrazides to give new
oxadiazolyl-pyrazolyl-pyridine tricyclic scaffolds at good yields from a [4 + 1] cyclocondensation reaction
with 1,1,1-triethoxyethane and 1-(triethoxymethyl)benzene as the reagent/solvent.
J. Heterocyclic Chem., 51, 1171 (2014).
INTRODUCTION
heterocycles displaying a broad spectrum of biological
activities (Fig. 1), such as 5-HT-receptor antagonists [12],
benzodiazepine[13] and muscarinic receptor agonists [14],
and tyrosinase inhibitors [15]. Many substituted 1,3,4-
oxadiazoles have also shown antibacterial [16–18],
antimicobacterial [19], antifungal [20,21], anti-inflammatory
[22,23], analgesic [24], anticonvulsivant [25,26],
antihypoglycemic [27], and insecticidal properties [28].
Compounds containing oxadiazole moieties have been
described as possessing anticancer [29] or muscle relaxant
activity [30] and have been used as fluorescent whiteners
[31]. To the best of our knowledge, the synthesis of non-
symmetrical 2,5-disubstituted 1,3,4-oxadiazoles has mainly
been done by dehydration of diacylhydrazines or oxidative
cyclization of aldehyde N-acylhydrazones, but many other
reagents and reaction conditions have been reported to
achieve their obtainment [32].
On the other hand, halogenated heterocyclic have an
important role, not only as synthetic and chemical interme-
diates but also as pharmacological agents [33], especially
when this halogen is the fluorine atom [34a]. The replace-
ment of hydrogen atoms with fluorine substituents in
organic substrates is of great interest in synthetic chemistry be-
cause of the strong electronegativity of fluorine and small
steric footprint of fluorine atoms [34b]. More specifically,
Nicotinic acid (niacin, pyridine-3-carboxilic acid, and
vitamin B3) is most commonly associated with its nutri-
tional role as a vitamin, and its absence leads to pellagra.
In addition, it is the precursor to the various forms of the
nicotinamide adenine dinucleotide coenzyme [1,2] and is
one of the oldest drugs used to treat dyslipidemia. Long term
studies have demonstrated that nicotinic acid therapy
reduces mortality from coronary heart disease [3,4].
Nicotinic acid is also the foundation for a plethora of
commercial compounds, from antibacterial and anticancer
drugs in the pharmaceutical industry, to charge control
agents in photocopier toner [5].
Pyrazoles [6a] are important compounds that have many
derivatives with anti-hyperglycemic, analgesic, anti-inflam-
matory, anti-pyretic, antibacterial, hypoglycemic and seda-
tive-hypnotic properties [6b–e]. The synthesis of pyrazole
derivatives has been extensively explored by our research
group through the cyclocondensation reaction of 4-alkoxy-
1,1,1-trihalo-3-alken-2-ones and different hydrazines, and
thus contemplating their biological activities as analgesic
and anti-inflammatory [7], antimycobacterial [8], antimicro-
bial [9], antinociceptive [10], and antioxidant agents [11].
Among five-membered aromatic heterocycles, 1,3,4-
oxadiazoles are another important class of aromatic
© 2013 HeteroCorporation

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H. G. Bonacorso, G. R. Paim, L. M. F. Porte, E. P. Pittaluga, S. Cavinatto,
A. R. Meyer, M. A. P. Martins, and N. Zanatta
Vol 51
N
N
N
N
N
N
S
O
O
O
N
N
N
Cl
Br
H3 C
N
Cl
CF3
Enzyme inhibitor
Cytotoxic agent
Analgesic Activity
Figure 1. Heterocycles containing pyrazole, 1,3,4-oxadiazole, and pyridine moieties.
the influence of the trifluoromethyl substituent on physiologi-
cal activity is due mainly to the increased lipophilicity of the
molecules, causing greater cell permeability [35].
RESULTS AND DISCUSSION
In 2009, we described that the cyclocondensation reactions
of 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-
ones (2) with 6-hydrazinylnicotinic acid hydrazide hydrate
(1) regioselectively furnished a new trifluoromethylated
system, namely 2-(1H-pyrazolyl)-5-(1H-1-carbonylpyrazol-
1-yl)pyridines (3), at good yields (Fig. 2) [46a]. However,
these reaction conditions do not lead to a chemoselective
cyclization at the most reactive center (hydrazine moiety).
Recently, in an attempt to demonstrate the reactivity differen-
tiation between the two dinucleophilic centers in hydrazide
hydrate 1, we performed a reaction involving 1 and 1,1,1-tri
ethoxyethane (4), which was also used as the reaction solvent.
The hydrazine and the hydrazide moieties showed similar
reactivity and only conducted to the not yet known structure
of 3-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-[1,2,4]triazolo
[4,3-a]pyridine (5) at 82% yield by a double [4 + 1]
cyclocondensation reaction [46b]. On the basis of the
literature data, we also performed several tests to differentiate
the two nucleophilic centers of 1. The most satisfactory results
were obtained from the reaction of 1 with aryl aldehydes (6),
which allowed to isolate a new series of 6-(methyli
denehydrazinyl)nicotinohydrazides (7) [46b].
Conversely, it is widely known that acidic conditions can
promote the hydrolysis of the C(O)-N function with the
respective elimination of the carbamoyl group in some
pyrazoles [46c–e].
The Japanese patent, published in 2005 by Kajino et al. [43],
reported that 6-(1H-pyrazol-1-yl)nicotinic acid can be
synthesized by a basic hydrolysis reaction of the ester methyl
6-(1H-pyrazol-1-yl)nicotinate using 1 M aqueous sodium
hydroxide solution in methanol as the solvent at 60°C for
2.5 h. Previously, the respective ester was obtained at 64%
yield when sodium hydride was added to a suspension of
1H-pyrazole in DMF, and after 5 h, methyl 6-chloronicotinate
Although there have been many reports on the synthesis
and pharmacological attributes of nicotinic acid [4,36–42],
a review of the literature revealed that only one patent
reported the synthesis of nicotinic acid derivatives that
present structural similarities to 6-pyrazolyl-nicotinic
acids, that is, a pyrazolyl ring attached to the 6-position
of the pyridine ring. However, it is important to mention
that trifluoromethyl-substituted pyrazoles or pyridines
were not included in this Japanese patent [43].
According to the literature data reviewed previously, it
seems important to us to expand the reaction scope of the com-
pounds of 3 in order to develop easier and more efficient
methods for obtaining molecules with further biological and
commercial interest, for example, new pyrazolyl-substituted
nicotinic acid derivatives, esters, and triheterocyclic systems
such as 1,3,4-oxadiazolyl-pyrazolyl-pyridines.
Herein, we would like to report a simple method for the
synthesis of a new series of 6-[3-alkyl(aryl/heteroaryl)-5-
trifluoromethyl-1H-pyrazol-1-yl]nicotinic acids (8) [44]
derived from the hydrolysis reaction of 2-(5-trifluoromethyl-
5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-5-(5-trifluorometh
yl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl-1-carbonyl) pyr-
idines (3) (Scheme 1) [45]. Subsequently, the esterification
reaction of pyrazolyl-nicotinic acids (8), which allows the
isolation of a series of methyl 6-[alkyl(aryl/heteroaryl)-5-tri
fluoromethyl-1H-pyrazol-1-yl]nicotinate hydrochloride de-
rivatives (9), is also presented (Scheme 2). Finally, we dem-
onstrate that the compounds of 9 can easily be converted to
hydrazides (10) by treatment with hydrazine hydrate to give
(at good yields) a new oxadiazole-pyrazole-pyridine tricyclic
scaffold (11) from the [4 + 1] cyclocondensation reaction of
the respective hydrazides with 1,1,1-triethoxyethane (4a)
and 1-(triethoxymethyl)benzene (4b) as the solvent/reagent.
Scheme 1. Reagents and conditions: (i) NaOH 10%, EtOH/H2O, reflux, 20 h; (ii) SOCl2, MeOH, RT, 24 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Pyrazolyl-Nicotinic Acids and Derivatives
1173
Scheme 2. Reagents and conditions: (i) NH2NH2.H2O, EtOH, reflux, 20 h; (ii) R1C(OEt)3, 110°C, 16 h.
O
O
O
2
6
N
N
R
NHNH2
N
N
NHNH2
N
Ref. 44a
N
H
Ar
Ref. 44b
R
N
N
F3C
O
H2NHN
N
CF3
OH
1
HO
7
3
MeC(OEt)3
Ref. 44b
O
4
OR1
O
Me
N
Ar
H
F3C
R
N
N
N
6
2
N
5
Me
Figure 2. Synthetic derivatives of 6-hydrazinonicotinic acid hydrazide (1).
was also added to the mixture. After stirring for an additional
27 h, 6-(1H-pyrazolyl)nicotinic acid was isolated.
(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones (2a–e) with
6-hydrazinylnicotinic acid hydrazide hydrate 1 in ethanol
as the solvent at 78°C for 4 h (78–97%), as described in
the literature [46]. Thus, we attempted to perform the
hydrolysis of the amide bond of some compounds of 3
using a procedure similar to that described by Bavetsias
et al. [51], employing Fe(NO3)3.9H2O in methanol for
24 h at 40–50°C. However, this procedure, as well as more
drastic acidic conditions described elsewhere, which
employ concentrated HCl in ethanol and heat the mixture
under reflux for 20 h [52], were unsuccessful. Subse-
quently, the C(O)-N bond hydrolysis was performed
successfully under alkaline conditions, that is, 2.5 M
NaOH aqueous solution in ethanol (7:3 v/v) at 100°C for
20 h [50], which furnished the nicotinic acid derivatives
8a–e at a high degree of purity and at 70–95% yields. All
compounds of 8 precipitated in the reaction course during
the neutralization process using 37% HCl aqueous solution
and were isolated by a simple filtration. It is important to
mention that the alkaline condition allowed us to not only
perform the expected hydrolysis reaction at position 5 but
also the unexpected dehydration reaction at the 2-pyrazoline
attached to position 2 of the pyridine ring, in a one-step
procedure (Scheme 1).
In 1998, we reported the regioselective synthesis of 5-triflu
oromethyl-4,5-dihydro-1H-pyrazoles by the cyclocondensa-
tion of ketones 2 with thiosemicarbazide, at excellent yields
[47]. However, in an attempt to perform the dehydration of
these 2-pyrazolines under acidic conditions, a degradation oc-
curred (hydrolysis), and only 3(4)-alkyl- and 3-arylsubstituted
5-trifluoromethyl-1H-pyrazoles were furnished, without the
presence of the thiocarbamoyl group attached to the N-1 atom
of the pyrazole ring. Seven years later, we also reported the
synthesis of 1-(isonicotinoyl)-3-phenyl-5-hydroxy-5-trifluor
omethyl-4,5-dihydro-1H-pyrazole [45]. In agreement with
the literature [48], this 2-pyrazoline was extremely resistant
to dehydration reactions with chloroform/P2O5 under reflux
for 48 h or with acetic acid under reflux for 4 h.
In 2008, we reported that not only the C(O)-N bond of 1-cy
anoacetyl-4,5-dihydropyrazoles [49] but also that of 2-acety
laminopyrimidines [50] can be cleaved under acidic and basic
reaction conditions.
Because it is known that numerous nicotinic acid
derivatives exhibit interesting properties and applications
[4,36–42], we then attempted to obtain new pyrazolyl-nic-
otinic acids 8a–e by hydrolyzing the C(O)-N linkage at
position 5 of the pyridines 3a–e. The best reaction condi-
tions, in addition to selected physical and spectral data,
are presented in the experimental part. As mentioned previ-
ously, the heterocyclic precursors 3a–e were synthesized
by the cyclocondensation reactions of 4-alkoxy-4-alkyl
After that, compounds 8a–e underwent further esterifica-
tion reactions using thionyl chloride in methanol as the
solvent/reagent. The reactions were monitored by TLC; the
optimal temperature and reaction time were RT for 24 h,
according to methods described elsewhere [37,53]. Methyl
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H. G. Bonacorso, G. R. Paim, L. M. F. Porte, E. P. Pittaluga, S. Cavinatto,
A. R. Meyer, M. A. P. Martins, and N. Zanatta
Vol 51
esters 9a and 9c–e began to precipitate after 1–2 h of the
reaction course and were also isolated by a simple filtration
at 64–84% yields and at a high purity grade, except for 9b,
which had to be purified by recrystallization from acetone
(Scheme 1). In attempting to introduce another class of
nitrogenated azoles into the pyrazolyl-pyridine system, two
examples of the compounds of 9 were elected to react firstly
with hydrazine hydrate under reflux of ethanol to give the
hydrazides of 10a–b. These hydrazides were submitted to
a cyclocondensation reaction with R1C(OEt)3 (4), where
R1 = methyl (4a) and phenyl (4b), leading to the isolation
of four examples of oxadiazolyl-pyrazolyl-pyridines (11),
at moderate yields (Scheme 2).
J= 9 Hz. Compounds 8a–e also present the typical 13C-NMR
chemical shifts of the pyrazole ring in the range of δ
148.8–152.8 ppm(C-3B) and δ 109.3–114.5 ppm (C-4B).
Because of the presence of the CF3 group, the C-5B presents
a characteristic quartet in the range of δ 132.4–134.4 ppm
with 2JCF = 40Hz. Also, the CF3 group shows a typical quar-
1
tet in the range of δ 119.3–121.9 ppm with JCF = 268 Hz,
and the carbonyl carbon of the acid moiety shows an NMR
signal in the range of δ 164.9–166.7 ppm. The pyridine ring
carbons appear in the range of δ 111.7–116.5 ppm (C-5A),
125.6–126.9 ppm (C-3A), 140.1–141.9 ppm (C-4A), 145.5–
151.9 ppm (C-2A), and 152.5–160.1 ppm (C-6A).
Methyl esters 9a–e show similar NMR chemical shifts in
comparison with compounds 8a–e, and present signals for
the methoxy group, a feature of the ester, in the region of δ
3.92–3.98 ppm (1H-NMR) and δ 52 ppm (13C-NMR).
Complementarily, we performed X-ray diffraction mea-
surements for a monocrystal of compound 9b (Fig. 3).
The crystallographic data showed that because of the
possible steric effect from the phenyl and pyridine rings,
the trifluoromethyl group occupies a position on the same
side as the pyridine nitrogen. Crystallographic data
reported in this paper for compound 9b have been given
to the Cambridge Crystallographic Data Center (CCDC
753328) [54].
As the reaction property, the orthoesters were used simul-
taneously as solvent and reagent and compounds of 11
precipitated steadily during the reaction time at 110°C. The
new oxadiazoles 11 are purified to a high degree by reaction
cooling, filtration under reduced pressure, washing with cold
ethanol, and storage in a desiccator over P2O5. The structures
of 6-[3-alkyl(aryl/heteroaryl)-5-trifluoromethyl-1H-pyrazol-
1-yl]nicotinic acids (8a–e) were deduced from NMR experi-
ments and by comparison with NMR data from other
pyrazoles formerly synthesized in our laboratory [46].
1
Initially, the compounds of 3 showed H-NMR chemical
shifts for the diastereotopic methylene protons (H-4a, H-4b)
characteristic of a pyrazoline system as doublets, at δ 3.73
and 3.35 ppm, with a geminal coupling constant in the range
of 2J 18 Hz [46]. After the dehydration reaction, the
compounds of 8 showed 1H-NMR chemical shifts in
acetone-d6 or DMSO-d6 for the pyrazole H-4 as a characteris-
tic singlet, in the range of δ 6.96–7.92 ppm. The pyridine
protons appear in the range of δ 8.97–9.03 ppm (H-2A),
8.50–8.55 ppm (H-4A), and 8.05–8.17 ppm (H-5A), with
1
Relative to the pyrazolyl-pyridine system, the H and
13C-NMR spectra registered in DMSO-d6 for compounds
9, 10, and 11, show signals with small variations in
comparison to the compounds of 2. Substantial variations
in the chemical shifts are observed for position 5 of
the pyridine due to the insertion of different substituents,
namely, –COOMe (9), –CONHNH2 (10), and an oxadiazole
ring (11).
Figure 3. A perspective view of methyl 6-(3-phenyl-5-trifluoromethyl-1H-pyrazol-1-yl) nicotinate (9b) with atoms labeled (CCDC 753328). Displace-
ment ellipsoids are drawn at the 50% probability level. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
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July 2014
Pyrazolyl-Nicotinic Acids and Derivatives
1175
the carrier gas. Mass spectra were registered in an Agilent 6460 Tri-
ple Quad LC/MS (Agilent Technologies, Inc., Wilmington, DE)
connected to a 1200 series LC and equipped with a solvent degasser,
binary pump, column oven, and autosampler. The CHN elemental
analyses were performed on a Perkin-Elmer 2400 CHN elemental
analyzer (University of São Paulo, Brazil), the high resolution mass
spectrometry was performed in an Agilent-QTOF 6530 spectrometer
(UFSM, Brazil) and Micro TOF Bruker Daltonic (University of São
Paulo, Brazil). The diffraction measurements were done by graphite-
monochromatized Mo Kα radiation with λ = 0.71073 Å on a Bruker
SMART CCD diffractometer [55]. The structure of 3b was solved
with direct methods using the SHELXS-97 program [56], and
refined on F2 by full-matrix least-squares using the SHELXL-97
package [57]. The absorption correction was performed by Gaussian
methods [58]. Anisotropic displacement parameters for non-
hydrogen atoms were applied. The hydrogen atoms were placed at
calculated positions with 0.96 Å (methyl CH3) and 0.93 Å (aromatic
CH) using a riding model. The hydrogen isotropic thermal parame-
ters were kept equal to Uiso(H) = χUeq (carrier C atom), with
χ = 1.5 for methyl groups and χ = 1.2 for others. The valence angles
C–C–H and H–C–H of methyl groups were set to 109.5º, and the H
atoms were allowed to rotate around the C–C bond. The molecular
graph was prepared using ORTEP-3 for Windows [59].
The 6-(5-trifluoromethyl-1H-pyrazol-1-yl)nicotinohydrazi
des (10) presents important features observed in the H-
1
NMR spectra: broad singlets at an average of δ 10 ppm
(NH) and δ 4.6 ppm (NH2). In comparison to the esters of 9,
the 13C-NMR spectra of 10 show a characteristic signal at
an average of δ 163 ppm relative to the C═O. Oxadiazolyl-
pyrazolyl-pyridines 11aa and 11ba (R1═Me) exhibit the typ-
ical singlet for the methyl group in the region of δ 2.6–2.1 ppm
(1H-NMR) in relation to the oxadiazole substituent. In addi-
tion, signals of NH and NH2 are absent near δ 10 and δ
4.6 ppm, respectively, a characteristic of 10. Compounds
11ab and 11bb (R═R1═Ph) show the typical signal range
for phenyl protons at δ ~8.1 ppm as a doublet with J=7 Hz
and a multiplet in the range of δ 7.6–7.4 ppm. 13C-NMR
spectra also showed important features, for example, the
absence of the signal of the C═O, which appeared in the
range of δ 163 ppm for the hydrazides 10. Triheterocycles
11 present two signals appearing in the region relative to
the oxadiazole carbons C-2C and C-5C in the range of
164 and 162 ppm, respectively.
Furthermore, it should be noted that these compounds
were not isolated as crystalline solids but rather in powder
form, which prevented further study by X-ray diffraction.
General procedure for the synthesis of 6-[3-alkyl(aryl/heteroaryl)-
5-trifluoromethyl-1H-pyrazol-1-yl]nicotinic acids (8a–e). To a stirred
solution of pyrazolyl-pyridines 3a–e (2 mmol) in a mixture of ethanol:
water (7:3 v/v) (10 mL) kept at RT (20–25°C), was added in one
portion 2.5 M aqueous NaOH solution (5 mL). The mixture was then
refluxed for 20 h. After cooling (<5°C), the reaction was neutralized
with 37% HCl. The solids 8a–e were collected by filtration, washed
with ice-water (20 mL), and dried under reduced pressure in a P2O5-
containing desiccator.
CONCLUSIONS
In summary, we have developed a simple new convenient
and one-pot procedure to obtain novel trifluoromethyl-
substituted pyrazolyl-nicotinic acids (8). Methyl pyrazoly
lnicotinate hydrochloride derivatives (9) were subsequently
prepared with ease at good yields and high purity. To demon-
strate the applicability of the esters of 9, new hydrazides (10)
and their oxadiazolyl-pyrazolyl-pyridines (11) were produced
as a new triheterocyclic scaffold at moderate yields. The struc-
tures of the acids of 8 were checked by the synthesis of the
esters of 9. The structure of the esters of 9 was determined
by NMR and X-ray diffraction, and the triheterocycles of 11
by NMR.
6-(5-Trifluoromethyl-3-methyl-1H-pyrazol-1-yl)nicotinic acid (8a).
White solid, yield: 70%; mp 192–194°C. 1H-NMR (acetone-d6): δ 9.03
(s, 1H, 2A); 8.52–8.54 (m, 1H, 4A); 8.05 (d, 1H, 5A, J=9Hz); 6.96
(s, 1H, 4B); 2.37 (s, 3H, CH3).
13C-NMR (acetone-d6): δ 166.7 (CO); 155.4 (C-6A); 152.6
2
(C-3B); 151.2 (C-2A); 141.9 (C-4A); 134.4 (q, JC–F = 40 Hz,
1
C-5B); 126.9 (C-3A); 121.9 (q, JC–F = 267 Hz, CF3); 116.5
(C-5A); 114.5 (C-4B); 14.4 (CH3). MS (ESI) m/z: [(M + H)+,
272.1]. Anal. Calcd for C11H8F3N3O2 (271.19): C, 48.72; H,
2.97; N, 15.49%. Found: C, 48.33; H, 2.59; N, 15.24%.
6-(5-Trifluoromethyl-3-phenyl-1H-pyrazol-1-yl)nicotinic acid
(8b). White solid; yield 95%; mp 215–217°C. 1H-NMR
(DMSO-d6): δ 8.98 (s, 1H, 2A); 8.51–8.53 (m, 1H, 4A); 8.13
(d, 1H, 5A, J = 9 Hz); 8.01–8.03 (m, 2H, Ph); 7.8 (s, 1H, 4B);
7.45–7.53 (m, 3H, Ph). 13C-NMR (DMSO-d6): δ 165.0 (CO);
152.6 (C-6A); 151.9 (C-3B); 148.8 (C-2A); 140.1 (C-4A);
EXPERIMENTAL
Unless otherwise indicated, all common reagents and solvents
were used as obtained from commercial suppliers without further pu-
rification. The melting points were determined using coverslips on a
Microquímica MQAPF – 302 apparatus and are uncorrected. 1H and
13C-NMR spectra were acquired on a Bruker DPX 200 (1H at
200.13 MHz) and Bruker DPX 400 (1H at 400.13 MHz and 13C at
100.61 MHz) spectrometer (Bruker Co., Germany), 5 mm sample
tubes, 298 K, digital resolution 0.01 ppm, in CDCl3, DMSO-d6 or
acetone- d6, and using TMS as an internal reference. Mass spectra
were registered in an 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 internal diameter), and helium was used as
2
132.6 (q, JC–F = 40 Hz, C-5B); 130.3 (Ph); 129.0 (Ph); 128.6
1
(Ph); 125.8 (Ph); 125.6 (C-3A); 119.4 (q, JC–F = 268 Hz,
CF3); 115.3 (C-5A); 110.0 (C-4B). MS (ESI) m/z: [(M + H)+,
334.1] Anal. Calcd for C16H10F3N3O2 (333.26): C, 57.66;
H, 3.02; N, 12.61%. Found: C, 57.43; H, 3.37; N, 12.22%.
6-[5-Trifluoromethyl-3-(4-methoxyphenyl)-1H-pyrazol-1-yl]nico
tinic acid (8c). Yellow solid; yield 83%; mp 226–228°C. 1H-NMR
(DMSO-d6): δ 8.97 (s, 1H, 2A); 8.50–8.52 (m, 1H, 4A); 8.12 (d, 1H,
5A, J= 9 Hz); 7.96 (d, 2H, Ph, J= 9 Hz); 7.77 (s, 1H, 4B); 7.06 (d, 2H,
Ph, J= 9 Hz); 3.82 (s, 3H, OCH3). 13C-NMR (DMSO-d6): δ 165.4
(CO); 160.1 (C-6A2); 152.8 (C-3B); 151.9 (C-2A); 149.0 (Ph); 140.3
(C-4A); 132.5 (q, JC–F =40Hz, C-5B); 127.3 (Ph); 125.6 (C-3A);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1176
H. G. Bonacorso, G. R. Paim, L. M. F. Porte, E. P. Pittaluga, S. Cavinatto,
A. R. Meyer, M. A. P. Martins, and N. Zanatta
Vol 51
123.0 (Ph); 119.7 (q, 1JC–F = 267 Hz, CF3); 115.1 (C-5A); 114.3 (Ph);
110.0 (C-4B). MS (ESI) m/z: [(M + H)+,364.1] Anal. Calcd for
C17H12F3N3O3 (363.29): C, 56.20; H, 3.33; N, 11.57%. Found:
C, 55.87; H, 3.14; N, 11.28%.
3.83 (s, 3H, OCH3-B). 13C-NMR (DMSO-d6): δ 165.3 (CO); 160.1
(C-6A); 152.7 (C-3B); 151.9 (C-2A); 148.9 (C-4A); 140.3 (Ph);
2
132.4 (q, JC–F =40Hz, C-5B); 127.3 (Ph); 125.6 (C-3A); 122.9
1
(Ph); 119.6 (q, JC–F = 268 Hz, CF3); 115.1 (C-5A); 114.2 (Ph);
6-[3-(4,4′-Biphenyl)-5-trifluoromethyl-1H-pyrazol-1-yl]nicotinic
acid (8d). Yellow solid; yield 87%; mp 244–246°C. 1H-NMR
(DMSO-d6): δ 8.99 (s,1H, 2A); 8.52–8.55 (m, 1H, 4A); 8.17 (d, 1H,
5A, J= 9 Hz); 8.13 (d, 2H, BiPh, J= 8 Hz); 7.92 (s, 1H, 4B); 7.82
(d, 2H, BiPh, J= 8 Hz); 7.75–7.76 (m, 2H, BiPh); 7.48–7.52
(m, 3H, BiPh). 13C-NMR (DMSO-d6): δ 164.9 (CO); 152.5 (C-6A);
151.5 (C-3B); 148.7 (C-2A); 140.7 (C-4A); 140.0 (BiPh); 139.19
(BiPh), 132.6 (q, 2JC–F =40Hz, C-5B); 129.3 (BiPh); 128.6 (BiPh);
127.3 (BiPh); 126.7 (BiPh); 126.2 (BiPh); 125.8 (C-3A); 119.3
(q, 1JC–F = 267 Hz, CF3); 115.2 (C-5A); 110.0 (C-4B). MS (ESI) m/
z: [(M + H)+,410] Anal. Calcd for C22H14F3N3O2 (409.36):
C, 64.55; H, 3.45; N, 10.26%. Found: C, 64.41; H, 3.66; N, 9.88%.
6-[5-Trifluoromethyl-3-(fur-2-yl)-1H-pyrazol-1-yl]nicotinic acid
110.0 (C-4B); 55.1 (OCH3); 52.4 (OCH3-ester). MS: m/z (%) = 377
(M+, 100); 362 (14); 46 (5); 207 (33); 173 (11). Anal. Calcd for
C18H15Cl F3N3O3 (413.78): C, 52.25; H, 3.65; N, 10.16%. Found:
C, 52.44; H, 3.24; N, 10.06%.
Methyl 6-[3-(4,4′-biphenyl)-5-trifluoromethyl-1H–pyrazol-1-
yl]nicotinate hydrochloride (9d). Yellow solid; yield 57%; mp
242–244°C. 1H-NMR (CDCl3): δ 9.11 (s, 1H, 2A); 8.45–8.47
(m, 1H, 4A); 8.12 (d, 1H, 5A, J = 9 Hz); 7.97 (d, 2H, BiPh,
J = 8 Hz); 7.70 (d, 2H, BiPh, J = 8 Hz); 7.64–7.65 (m, 3H,
BiPh + 4B) 7.45–7.47 (m, 2H, BiPh); 7.37–7.39 (m, 1H, BiPh); 3.98
(s, 3H, OCH3). 13C-NMR (DMSO-d6): 165.2 (CO); 152.7 (C-6A);
151.7 (C-3B); 148.9 (C-2A); 140.9 (BiPh); 140.3 (C-4A); 139.2
2
(BiPh); 132.8 (q, JC–F =40Hz, C-5B); 129.5 (C-3A); 129.5 (BiPh);
(8e). Brown solid; yield 76%; mp 205–207°C. 1H-NMR (DMSO-d6):
δ 8.97 (s, 1H, 2A); 8.51–8.53 (m, 1H, 4A); 8.07 (d, 1H, 5A, J=9Hz);
7.86–7.87 (m, 1H, furyl); 7.64 (s, 1H, 4B); 7.12–7.13 (m, 1H, furyl);
6.68–6.69 (m, 1H, furyl). 13C-NMR (DMSO-d6): δ 165.0 (CO);
152.5 (C-6A); 148.8 (C-3B); 145.5 (C-2A); 144.3 (furyl); 143.9
(furyl); 140.3 (C-4A); 132.4 (q, 2JC–F =41Hz, C-5B); 126.0 (C-3A);
128.8 (BiPh); 127.6 (BiPh); 127.0 (BiPh); 126.5 (BiPh); 126.4
1
(BiPh); 126.0 (BiPh); 119.5 (q, JC–F = 268 Hz, CF3); 115.5 (C-5A);
110.4 (C-4B); 52.4 (OCH3). MS: m/z (%) = 423 (M+, 100); 392 (5);
317 (9); 196 (31); 153 (11). Anal. Calcd for C23H17Cl F3N3O2 (459.85):
C, 60.07; H, 3.73; N, 9.14%. Found: C, 60.37; H, 3.43; N, 8.75%.
Methyl 6-[5-trifluoromethyl-3-(fur-2-yl)-1H-pyrazol-1-yl]nicotinate
1
hydrochloride (9e). Brown solid; yield 72%; mp 151–152°C. 1H-
NMR (CDCl3): δ 9.10 (s, 1H, 2A); 8.42–8.47 (m, 1H, 4A); 8.05
(d, 1H, 5A, J= 9 Hz); 7.54 (m, 1H, furyl); 7.14 (s, 1H, 4B); 6.85–6.87
(m, 1H, furyl); 6.52–6.54 (m, 1H, furyl); 6.52–6.54 (m, 1H, furyl); 3.97
(s, 3H, OCH3). 13C-NMR (CDCl3): δ 165.0 (CO); 153.5 (C-6A); 149.6
(C-3B); 146.5 (C-2A); 144.9 (furyl); 143.2 (furyl); 139.7 (C-4A); 133.9
119.3 (q, JC–F = 268 Hz, CF3); 115.4 (furyl); 111.7 (C-5A); 109.7
(furyl); 109.3 (C-4B). MS (ESI) m/z: [(M + H)+, 324] Anal. Calcd
for C14H8F3N3O3 (323.22): C, 52.02; H, 2.49; N, 13.00%. Found:
C, 51.74; H, 3.66; N, 12.75%.
General procedure for the synthesis of methyl 6-[3-alkyl(aryl/
heteroaryl)-5-trifluoromethyl-1H-pyrazol-1-yl]nicotinate hydroc
2
1
(q, JC–F =40, C-5B); 124.8 (C-3A); 119.4 (q, JC–F = 268 Hz, CF3);
115.0 (furyl); 111.6 (C-5A); 109.5 (furyl); 108.3 (C-4B); 52.4 (OCH3).
MS: m/z (%) = 337 (M+, 100); 306 (19); 283 (17); 153 (31); 136 (11).
Anal. Calcd for C15H11ClF3N3O3 (373.71): C, 48.21; H, 2.97;
N, 11.24%. Found: C, 48.21; H, 2.63; N, 11.13%.
hlorides (9a–e). Pyrazolyl-nicotinic acids 8 (1 mmol) were added
to a stirred solution of methanol (10 mL) and SOCl2 (15 mmol).
After stirring the reaction mixture at RT for 24 h, the solids 9a–e
were isolated by filtration, washed with cold methanol and in the
case of 9b purified by recrystallization from acetone.
General procedure for the synthesis of 6-[3-alkyl(aryl)-5-trifluo
romethyl-1H-pyrazol-1-yl]nicotinohydrazides (10a–b). Methyl
nicotinate hydrochlorides 9a–b (1 mmol) were added to a stirred
solution of ethanol (5 mL) and 24% aqueous solution of hydrazine
hydrate (1 mL). After stirring the reaction mixture at reflux
temperature for 20 h, the solids 10a–b were isolated by filtration,
washed with cold ethanol, and dried under reduced pressure in a
P2O5-containing desiccator.
Methyl 6-(5-trifluoromethyl-3-methyl-1H-pyrazol-1-yl)nicotinate
hydrochloride (9a). White solid; yield 61%; mp 110–112°C. H-
1
NMR (CDCl3): δ 9.08 (s, 1H, 2A); 8.38–8.43 (m, 1H, 4A); 7.93
(d, 1H, 5A, J= 9 Hz); 6.71 (s, 1H, 4B); 3.96 (s, 3H, OCH3); 2.38
(s, 3H, CH3). 13C-NMR (CDCl3): δ 165.3 (CO); 152.7 (C-6A);
2
150.5 (C-3B); 148.9 (C-2A); 140.2 (C-4A); 131.5 (q, JC–F =40Hz,
1
C-5B); 125.4 (C-3A); 119.6 (q, JC–F = 267 Hz, CF3); 114.9 (C-5A);
112.9(C-4B); 52.4 (OCH3); 13.0 (CH3). MS: m/z (%) = 285 (M+,
100); 254 (90); 216 (23); 149 (14). Anal. Calcd for C12H11Cl
F3N3O2 (321.68): C, 44.80; H, 3.45; N, 13.06%. Found: C, 45.19;
H, 3.07; N, 13.44%.
6-(5-Trifluoromethyl-3-methyl-1H-pyrazol-1-yl) nicotinohydrazide
(10a). White solid; yield 70%; mp 154–156°C. 1H-NMR (DMSO-d6):
δ 9.98 (s, 1H, NH); 8.87 (s, 1H, 2A); 8.39 (dd, 1H, 4A, J= 8 Hz); 7.92
(d, 1H, 5A, J= 9 Hz); 7.04 (s, 1H, 4B); 4.58 (s, 2H, NH2); 2.34
(s, 3H, CH3). 13C-NMR (DMSO-d6): δ 163.3 (CO); 151.7 (C-6A);
Methyl 6-(5-trifluoromethyl-3-phenyl-1H-pyrazol-1-yl)nicotinate
1
hydrochloride (9b). White solid; yield 74%; mp 179–181°C. H-
2
150.2 (C-3B); 146.5 (C-2A); 138.1 (C-4A); 131.5 (q, JC–F =40Hz,
NMR (CDCl3): δ 9.09 (s, 1H, 2A); 8.41–8.44 (m, 1H, 4A); 8.07
(d, 1H, 5A, J=9Hz); 7.87–7.89 (m, 2H, Ph); 7.39–7.47 (m, 3H, Ph);
7.2 (s, 1H, 4B); 3.96 (s, 3H, OCH3). 13C-NMR (CDCl3): δ 165.0
(CO); 153.9 (C-6A); 152.6 (C-3B); 149.7 (C-2A); 139.6 (C-4A);
1
C-5B); 127.9 (C-3A); 119.7 (q, JC–F = 268 Hz, CF3); 115.1 (C-5A);
3
112.3 (q, JC–F =3, C-4B); 12.9 (CH3). HRMS (ESI): m/z calcd for
C11H10F3N5O: 286.0915(M + H), found: 286.0987.
2
6-(5-Trifluoromethyl-3-phenyl-1H-pyrazol-1-yl) nicotinohydrazide
134.3 (q, JC–F =42Hz, C-5B); 131.3 (Ph); 129.1 (Ph); 128.8 (Ph);
1
126.1 (Ph); 124.8 (C-3A); 119.9 (q, JC–F =267Hz, CF3); 114.9 (C-
(10b). White solid; yield 62%; mp 218–219°C. 1H-NMR (DMSO-d6):
δ 10.06 (s, 1H, NH); 8.93 (s, 1H, 2A); 8.47 (dd, 1H, 4A, J=8Hz); 8.11
(d, 1H, 5A, J=9Hz); 8.02–8.04 (m, 2H, Ph); 7.82 (s, 1H, 4B); 7.44–7.54
(m, 3H, Ph); 4.60 (s, 2H, NH2). 13C-NMR (DMSO-d6): δ 163.1 (CO);
151.8 (C-6A); 151.73 (C-3B); 146.5 (C-2A); 138.2 (C-4A); 132.5
(q, 2JC–F =40Hz, C-5B); 130.5 (Ph); 129.1 (Ph); 128.8 (Ph); 128.3 (C-
5A); 109.7 (C-4B); 52.3 (OCH3). MS: m/z (%) = 347 (M+, 100); 316
(23); 287 (5); 77 (5). Anal. Calcd for C17H13Cl F3N3O2 (383.75): C,
53.21; H, 3.41; N, 10.95%. Found: C, 53.18; H, 3.53; N, 10.59%.
Methyl 6-[5-trifluoromethyl-3-(4-methoxyphenyl)-1H-pyrazol-1-
yl]nicotinate hydrochloride (9c). Yellow solid; yield 84%; mp
1
1
202–204°C. H-NMR (DMSO-d6): δ 8.97 (s, 1H, 2A); 8.48–8.53
3A); 125.7 (Ph); 119.6 (q, JC–F = 267 Hz, CF3); 115.5 (C-5A); 109.8
3
(m, 1H, 4A); 8.11 (d, 1H, 5A, J= 8 Hz); 7.96 (d, 2H, Ph, J=9Hz);
(q, JC–F =3, C-4B). HRMS (ESI): m/z calcd for C16H12F3N5O:
7.76 (s, 1H, 4B); 7.06 (d, 2H, Ph, J= 8 Hz); 3.92 (s, 3H, OCH3);
348.1072 (M + H), found: 348.1064.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Pyrazolyl-Nicotinic Acids and Derivatives
1177
1
General procedure for the synthesis of 5-[5-Methyl(phenyl)-
1,3,4-oxadiazol-2-yl]-2-(3-alquil(aril)-5-trifluoromethyl-1H-pyrazo
l-1-yl) pyridine (11aa, 11ab, 11ba, 11bb). mixture of
pyrazolylnicotino hydrazides 10 (1 mmol) and 1,1,1-triethoxyethane
(4a) or 1-(triethoxymethyl)benzene (4b) (6mmol) was stirred for
16 h at 110°C. After the reaction time, the solids were isolated by
filtration, washed with cold ethanol, and drying in desiccators under
reduced pressure over P2O5, furnished 11 in high degree of
purity (HRMS).
123.5 (Ph); 119.1 (Ph); 120.5 (q, JC–F = 268 Hz, CF3); 115.6
3
(C-3A); 109.8 (q, JC–F = 3 Hz, C-4B). MS: m/z (%) (EI) = 433
A
(M+, 100); 376 (14); 316 (31); 105 (35); 77 (19). HRMS
(ESI): m/z calcd for C23H14F3N5O 434.1228 (M + H), found
434.1222.
Acknowledgments. The authors thank the Coordination for
Improvement of Higher Education Personnel (CAPES) for
fellowships and the National Council for Scientific and
Technological Development (CNPq) for financial support
(Process no. 303.013/2011-7 and 470.788/2010-0-Universal).
5-(5-Methyl-1,3,4-oxadiazol-2-yl)-2-(3-methyl-5-trifluoromethyl-
1H-pyrazol-1-yl) pyridine (11aa). Yellow solid; yield 52%; mp
1
147–149°C. H-NMR (DMSO-d6): δ 9.00 (d, 1H, 6A, J = 2 Hz);
8.53 (dd, 1H, 4A, J = 8 Hz); 8.05 (d, 1H, 3A, J = 8 Hz); 7.08 (s,
1H, 4B); 2.62 (s, 3H, CH3-C); 2.36 (s, 3H, CH3-B). 13C-NMR
(DMSO-d6): δ 164.3 (C-2C); 161.4 (C-5C); 151.8 (C-2A); 150.5
REFERENCES AND NOTES
2
(C-3B); 145.4 (C-6A); 137.1 (C-4A); 131.5 (q, JC–F = 40 Hz, C-
5B); 118.92 (C-5A); 119.6 (q, 1JC–F = 268 Hz, CF3); 115.7 (C-3A);
[1] Carlson, L. A. J Intern Med 2005, 258, 94.
[2] Hudson, M. R.; Allis, D. G.; Hudson, B. S. Chem Phys Lett
2009, 473, 81.
3
112.7 (q, JC–F = 3 Hz, C-4B); 12.9 (CH3-B); 10.4 (CH3-C). 19 F-
NMR (C6H5F): À55.96 (CF3). MS: m/z (%) (EI) = 309 (M+, 100);
254 (44); 184 (11); 149 (7). HRMS (ESI): m/z calcd for
C13H10F3N5O 310.0915 (M + H), found 310.0908.
[3] (a) Altschul, R.; Hoffer, A. Arch Biochem 1955, 54, 558;
(b) Schmidt, D.; Smenton, A.; Raghavan, S.; Carballo-Jane, E.; Lubell, S.;
Ciecko, T.; Holt, T. G.; Wolff, M.; Taggart, A.; Wilsie, L.; Krsmanovic, M.;
Ren, N.; Blom, D.; Cheng, K.; McCann, P. E.; Waters, M. G.; Tata, J.;
Colletti, S. Bioorg Med Chem Lett 2009, 19, 4768.
[4] (a) Elvehjem, C. A.; Teply, L. J Chem Rev 1943, 33, 185;
(b) Boatman, P. D.; Richman, J. G.; Semple, G. J Med Chem 2008, 51, 7653.
[5] Everts, S. Chem Eng News 2008, 86, 15.
[6] (a) Elguero, J. In Comprehensive Heterocyclic Chemistry II;
Katristzky, A. R.; Rees, C. W.; Scriven, E. F., Eds.; Pergamon: Oxford,
1996; Vol 3, pp 1–75; (b) Fati, K.; Karci, F. Dyes Pigments 2008, 76, 97;
(c) Burke, A.; Smyth, E. M.; Gerald, G. A. Analgesic- Antipyretic Agents.
In Goodman and Gilman’s The Pharmacological Basis of Therapeutics
(11th Edn.); Laurence, L. B., John, S. L., Keith, L. P., eds.; McGraw Hill:
New York, USA, 2005, pp 684–685; (d) Park, P. Y.; Lee, M. J.; Kim, J. N.
Tetrahedron Lett 2005, 46, 8799; (e) Bonacorso, H. G.; Porte, L. M. F.;
Cechinel, C. A.; Paim, G. R.; Deon, E. D.; Zanatta, N.; Martins, M. A.
P. Tetrahedron Lett 2009, 50, 1392.
[7] (a) Martins, M. A. P.; Sauzem, P. D.; Machado, P.; Rubin, M. A.;
Sant’anna, G. S.; Faber, H. B.; Souza, A. H.; Mello, C. F.; Beck, P.;
Burrow, R. A.; Bonacorso, H. G.; Zanatta, N. Eur J Med Chem
2008, 43, 1237; (b) Martins, M. A. P.; Machado, P.; Rosa, F. A.;
Rossatto, M.; Sauzem, P. D.; Silva, R. M. S.; Rubin, M. A.;
Ferreira, J.; Bonacorso, H. G.; Zanatta, N. Arkivoc 2007, xvi, 281.
[8] Silva, P. E. A.; Ramosa, D. F.; Bonacorso, H. G.; 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.
[9] (a) Bonacorso, H. G.; Pittaluga, E. P.; Alves, S. H.; Schaffer, L. F.;
Cavinatto, S.; Porte, L. M. F.; Paim, G. R.; Martins, M. A. P.; Zanatta, N.
Arkivoc 2012, viii, 62; (b) Zanatta, N.; Alves, S. H.; Coelho, H. S.;
Borchhardt, D. M.; Machado, P.; Flores, K. M.; Silva, F. M.; Spader, T. B.;
Santurio, J. M.; Bonacorso, H. G.; Martins, M. A. P. Bioorg Med Chem
2007, 15, 1947.
[10] 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.
[11] Bonacorso, H. G.; Cavinatto, S.; Campos, P. T.; Porte, L. M. F.;
Navarini, J.; Paim, G. R.; Martins, M. A. P.; Zanatta, N.; Stüker, C. Z. J
Fluorine Chem 2012, 135, 303.
[12] Swain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Saunders, J.;
Seward, E. M.; Stevenson, G.; Beer, M.; Stanton, J.; Watling,
K. J Med Chem 1991, 34, 140.
[13] (a) Orlek, B. S.; Blaney, F. E.; Brown, F.; Clark, M. S. G.;
Hadley, M. S.; Hatcher, J.; Riley, G. J.; Rosenberg, H. E.; Wadsworth, H. J.;
Wyman, P. J Med Chem 1991, 34, 2726; (b) Saunders, J.; Cassidy, M.;
Freedman, S. B.; Harley, E. A.; Iversen, L. L.; Kneen, C.; MacLeod, A. M.;
Merchant, K. J.; Snow, R. J.; Baker, R. J Med Chem 1990, 33, 1128.
[14] Tully, W. R.; Gardner, C. R.; Gillespie, R. J.; Westwood, R. J Med
Chem 1991, 34, 2060.
5-(5-Phenyl-1,3,4-oxadiazol-2-yl)-2-(3-methyl-5-trifluoromethyl-
1H-pyrazol-1-yl) pyridine (11ab).
White solid; yield 56%; mp
166–168°C. 1H-NMR (DMSO-d6): δ 9.15 (s, 1H, 6A); 8.65
(dd, 1H, 4A, J= 8 Hz); 8.14 (d, 2H, Ph, J= 7 Hz); 8.05 (d, 1H, 3A,
J= 8 Hz); 7.65–7.60 (m, 3H, Ph); 7.04 (s, 1H, 4B); 2.34 (s, 3H,
CH3). 13C-NMR (DMSO-d6): δ 164.4 (C-2C); 161.79 (C-5C); 152.0
2
(C-2A); 150.6 (C-3B); 145.9 (C-6A); 137.4 (C-4A); 131.2 (q, JC–
F =40Hz, C-5B); 132.1(Ph); 129.0 (Ph); 128.7 (Ph); 126.7 (Ph);
1
128.4 (C-5A); 119.6 (q, JC–F = 268 Hz, CF3); 115.7 (C-3A); 112.8
3
(q, JC–F =3, C-4B); 12.9 (CH3). 13C-NMR (CDCl3): δ 165.1 (C-
2C); 162.1 (C-5C); 152.9 (C-2A); 150.6 (C-3B); 146.2 (C-6A); 136.6
2
(C-4A); 133.2 (q, JC–F =40Hz, C-5B); 132.0 (Ph); 129.4 (Ph);
1
129.1(Ph); 127.0 (Ph); 128.2 (C-5A); 119.8 (q, JC–F = 268 Hz,
CF3); 115.4 (C-3A); 112.5 (q, 3JC–F =3Hz, C-4B); 13.4 (CH3). MS:
m/z (%) (EI) = 371 (M+, 100); 254 (31); 105 (28); 77 (14). HRMS
(ESI): m/z calcd for C18H12F3N5O 372.1072 (M + H), found
372.1087.
5-(5-Methyl-1,3,4-oxadiazol-2-yl)-2-(5-trifluoromethyl-3-phenyl-1H-p
yrazol-1-yl)pyridine (11ba). Yellow solid; yield 60%; mp 208–210°C.
1H-NMR (DMSO-d6): δ 8.94 (s, 1H, 6A); 8.45 (dd, 1H, 4A, J=8Hz);
8.10 (d, 1H, 3A, J= 8 Hz); 8.02 (d, 2H, Ph, J= 7 Hz); 7.78 (s, 1H, 4B);
7.53–7.45 (m, 3H, Ph); 2.1 (s, 3H, CH3-C). 13C-NMR (DMSO-d6): δ
164.3 (C-2C); 163.16 (C-5C); 151.8 (C-2A); 151.7 (C-3B); 146.5 (C-6A);
2
138.2 (C-4A); 132.5 (q, JC–F=40Hz, C-5B); 130.5 (Ph); 129.0 (Ph);
1
128.7 (Ph); 128.3 (C-5A3); 125.7 (Ph); 119.6 (q, JC–F=268Hz, CF3);
115.6 (C-3A); 109.8 (q, JC–F=3Hz, C-4B); 10.3 (CH3). MS: m/z (%)
(EI) = 371 (M+, 100); 316 (27); 207 (34); 103 (9); 77 (9). HRMS (ESI):
m/z calcd for C18H12F3N5O 372.1072 (M + H), found 372.1085.
5-(5-Phenyl-1,3,4-oxadiazol-2-yl)-2-(3-phenyl-5-trifluoromethyl-1
H-pyrazol-1-yl) pyridine (11bb). Yellow solid; yield 66%; mp
204–206°C. 1H-NMR (DMSO-d6): δ 9.26 (s, 1H, 6A); 8.76
(dd, 1H, 4A, J = 8 Hz); 8.26 (d, 1H, 3A, J = 8 Hz); 8.19 (d, 2H,
Ph, J = 7 Hz); 8.04 (d, 2H, Ph, J = 7 Hz); 7.83 (s, 1H, 4B);
7.67–7.65 (m, 3H, Ph); 7.54–7.46 (m, 3H, Ph). 1H-NMR
(CDCl3): δ 9.21 (s, 1H, 6A); 8.59 (dd, 1H, 4A, J = 8 Hz); 8.20
(d, 1H, 3A, J = 8 Hz); 8.16 (d, 2H, Ph, J = 7 Hz); 7.90 (d, 2H,
Ph, J = 7 Hz); 7.59–7.54 (m, 3H, Ph); 7.49–7.42 (m, 3H, Ph);
7.24 (s, 1H, 4B). 13C-NMR (CDCl3): δ 165.1 (C-2C); 162.1
(C-5C); 153.0 (C-2A); 152.6 (C-3B); 146.2 (C-6A); 136.7 (C-
2
4A); 134.1 (q, JC–F = 40 Hz, C-5B); 132.1(Ph); 131.1 (Ph);
129.3 (C-5A); 129.2 (Ph); 128.9 (Ph); 127.1 (Ph); 126.0 (Ph);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1178
H. G. Bonacorso, G. R. Paim, L. M. F. Porte, E. P. Pittaluga, S. Cavinatto,
A. R. Meyer, M. A. P. Martins, and N. Zanatta
Vol 51
[15] Khan, M. T. H.; Choudhary, M. I.; Khan, K. M.; Rani,
[39] Spicer, J. A.; Rewcastle, G. W.; Kaufman, M. D.; Black,
S. L.; Plummer, M. S.; Denny, W. A.; Quin, J. III; Shahripour,
A. B.; Barret, S. D.; Whitehead, C. E.; Milbank, J. B. J.; Ohren,
J. F.; Gowan, R. C.; Omer, C.; Camp, H. S.; Esmaeil, N.; Moore,
K.; Sebolt-Leopold, J. S.; Pryzbranowski, S.; Merriman, R. L.; Ortwine,
D. F.; Warmus, J. S.; Flamme, C. M.; Pavlovsky, A. G.; Tecle, H. J Med
Chem 2007, 50, 5090.
M.; Ahman, A.-u. Bioorg Med Chem 2005, 13, 3385.
[16] (a) Gaonkar, S. L.; Rai, K. M. L.; Prabhuswamy, B. Eur J Med
Chem 2006, 41, 841; (b) Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur J
Med Chem 2000, 35, 267.
[17] Laddi, U. V.; Desai, S. R.; Bennur, R. S.; Bennur, S. C. Indian
J Heterocycl Chem 2002, 11, 319.
[40] Bardelang, D.; Camerel, F.; Hotze, A. C. G.; Kariuki, B.; Paik,
B.; Schmutz, M.; Ziessel, R.; Hannon, M. J. Chem Eur J 2007, 13, 9277.
[41] Reddy, P. M.; Shanker, K.; Rohini, R.; Sarangapani,
M.; Ravinder, V. Spectrochim. Acta Part A 2008, 70, 1231.
[42] Ott, L.; Heyl, A.; Clausen, N.; Vogel, H.; Michalik, G.; Lonza,
A. G. PCT/EP 2008/003186, WO 2008/128744 A1, 2008.
[43] Kajino, M.; Hird, N.; Tarui, N.; Banno, H.; Kawano,
Y.; Inatomi, N. Takeda Pharmaceutical Company Limited, Int.
C07D471/04, JP Pat. 008558, 2005.
[44] (a) Bonacorso, H. G.; Paim, G. R.; Martins, M. A. P.; Zanatta,
N. BR Patent deposited on National Institute for Industrial Property - INPI
(PI1105804-8) in agreement to Federal University of Santa Maria, 2011;
(b) Paim, G. R. PhD. Thesis, Federal University of Santa Maria, 2012.
[45] Bonacorsso, H. G.; Oliveira, M. R.; Costa, M. B.; Silva, L. B.;
Wastowski, A. D.; Zanatta, N.; Martins, M. A. P. J Heterocycl Chem
2005, 42, 631.
[46] (a) Bonacorso, H. G.; Paim, G. R.; Guerra, C. Z.; Sehnem,
R. C.; Cechinel, C. A.; Porte, L. M. F.; Martins, M. A. P.; Zanatta, N. J Braz
Chem Soc 2009, 20, 509; (b) Bonacorso, H. G.; Paim, G. R.; Porte, L. M. F.;
Pittaluga, E. P.; Martins, M. A. P.; Zanatta, N. Arkivoc 2012, viii, 214; (c)
Bonacorso, H. G.; Wastowski, A. D.; Zanatta, N.; Martins, M. A. P.; Naue,
J. A. J Fluorine Chem 1998, 92, 23; (d) Bonacorso, H. G.; Wastowski,
A. D.; Zanatta, N.; Martins, M. A. P. Synth Commun 2000, 30, 1457;
(e) Bonacorso, H. G.; Correa, M. S.; Porte, L. M. F.; Pittaluga, E. P.; Zanatta,
N.; Martins, M. A. P. Tetrahedron Lett 2012, 53, 5488.
[47] Bonacorso, H. G.; Wastowski, A. D.; Zanatta, N.; Martins,
M. A. P.; Naue, J. A. J Fluorine Chem 1998, 92, 23.
[48] Sing, S. P.; Kumar, D.; Batra, H.; Naithani, R.; Rozas,
I.; Elguero, J. Can J Chem 2000, 78, 1109.
[49] Martins, M. A. P.; Moreira, D. N.; Frizzo, C. P.; Longhi,
K.; Zanatta, N.; Bonacorso, H. G. J Braz Chem Soc 2008, 19, 1361.
[50] Bonacorso, H. G.; Ferla, A.; Cechinel, C. A.; Zanatta, N.; Martins,
M. A. P. J Heterocycl Chem 2008, 45, 483.
[51] Bavetsias, V.; Henderson, E. A.; McDonald, E. Tetrahedron
Lett 2004, 45, 5643.
[18] Sahin, G.; Palaska, E.; Ekizoglu, M.; Ozalp, M. Farmaco 2002,
57, 539.
[19] Macaev, F.; Rusu, G.; Pogrebnoi, S.; Gudima, A.; Stingaci, E.;
Vlad, L.; Shvets, N.; Kandemirli, F.; Dimoglo, A.; Reynolds, R. Bioorg
Med Chem 2005, 13, 4842.
[20] Zou, X.; Zhang, Z.; Jin, G. J Chem Res Synopses 2002, 5, 228.
[21] Zou, X. J.; Lai, L. H.; Jin, G. Y.; Zhang, Z. X. J Agric Food
Chem 2002, 50, 3757.
[22] Burbuliene, M. M.; Jakubkiene, V.; Mekuskiene, G.; Udrenaite,
E.; Smicius, R.; Vainilavicius, P. Il Farmaco 2004, 59, 747.
[23] Palaska, E.; Sahin, G.; Kelicen, P.; Durlu, N. T.; Altinok,
G. Farmaco 2002, 57, 101.
[24] Amir, M.; Shikha, K. Eur J Med Chem 2004, 39, 535.
[25] Zarghi, A.; Tabatabai, S. A.; Faizi, M.; Ahadian, A.; Navabi,
P.; Zanganeh, V.; Shafiee, A. Bioorg Med Chem Lett 2005, 15, 1863.
[26] Almasirad, A.; Tabatabai, S. A.; Faizi, A.; Kebriaeezadeh,
N.; Mehrabi, A.; Dalvandi, A.; Shafiee, A. Bioorg Med Chem Lett
2004, 14, 6057.
[27] Husain, M. I.; Kumar, A.; Srivastava, R. C. Curr Sci 1986,
55, 644.
[28] Zheng, X.; Li, Z.; Wang, Y.; Chen, W.; Huang, O.; Liu,
C.; Song, C. J Fluorine Chem 2003, 123, 163.
[29] Bhatt, J. J.; Shah, B. R.; Shah, H. P.; Trivedi, P. B.; Undavia,
N. K.; Desai, N. C. J Indian Chem 1994, 33B, 189.
[30] Hill, J. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, UK, 1984; Vol 6,
pp 427–446.
[31] Meyer, H. R. Chem Abstr 1976, 85, 125807 (Swiss Pat. 1976,
577, 536).
[32] (a) Weaver, G. W. In Science of Synthesis; Storr, R. C.; Gilchrist,
T. L., Eds.; Thieme: Stuttgart, 2004; Vol 13, pp 219–251; (b) Hill, J. In Com-
prehensive Heterocyclic Chemistry II; Storr, R. C., Ed.; Pergamon: Oxford,
1996; Vol 4, pp 267–287 and 905–1006; (c) Dobrotã, C.; Paraschivescu,
C. C.; Dumitru, I.; Matache, M.; Baciu, I.; Rutã, L. L. Tetrahedron Lett
2009, 50, 1886 and references therein.
[33] (a) Janin, Y. L. Chem Rev 2012, 112, 3924; (b) Lednicer,
D.; Mitscher, L. A. Organic Chemistry of Drugs Synthesis, A Wiley-
Interscience Publication; John Wiley & Sons: New York, 1997; (c) Arriba,
A. F.; Gómez-Casajús, L. A.; Cavalcanti, F.; Almansa, C.; García-
Rafanell, J. Eur J Pharmacol 1996, 318, 341.
[34] (a) Park, B. K.; Kitterringham, N. R.; O’Neill, P. M. Annu Rev
Pharmacol Toxicol 2001, 41, 443; (b) Nyffleler, P. T.; Durón, S. G.; Burkart,
M. D.; Vincent, S. P.; Wong, C. H. Angew Chem Int Ed 2005, 44, 192.
[35] Balenkova, E.; Druzhinin, S.; Nenajdenko, V. Tetrahedron
2007, 63, 7753.
[36] Westaway, S. M.; Thompson, M.; Rami, H. K.; Stemp,
G.; Trouw, L. S.; Mitchell, D. J.; Seal, J. T.; Medhurst, S. J.; Lappin,
S. C.; Biggs, J.; Wright, J.; Arpino, S.; Jerman, J. C.; Cryan, J. E.; Holland,
V.; Winborn, K. Y.; Coleman, T.; Stevens, A. J.; Davis, J. B.; Gunthorpe,
M. J. Bioorg Med Chem Lett 2008, 18, 5609.
[52] Akama, T.; Shida, Y.; Sugaya, T.; Ishida, H.; Gomi, K.; Kasai,
M. J Med Chem 1996, 39, 3461.
[53] Hosangadi, B. D.; Dave, R. Tetrahedron Lett 1996, 37, 6375.
[54] Crystallographic data for compound 3b, reported in this paper,
have been deposited with the Cambridge Crystallographic Data Center
(CCDC 753328). Copies of the data can be obtained, free of
the charge, on application to CCDC 12 Union Road, Cambridge
CB2 1EZ, UK (Fax +44-1223-336033 or e-mail deposit@ccdc.
cam.ac.uk).
[55] Bruker, APEX2 (Version 2.1), COSMO (Version 1.56), BIS
(Version 2.0.1.9), SAINT (Version 7.3A) and SADABS (Version 2004/
1) and XPREP 9Version 2005/4), Bruker AXS Inc., Madison, Wisconsin,
USA, 2006.
[56] Sheldrick, G. M. SHELXS-97, program for crystal structure
solution, University of Göttingen, Germany, 1997.
[57] Sheldrick, G. M. SHELXL-97, program for crystal structure
refinement, University of Göttingen, Germany, 1997.
[58] Coppens, P.; Leiserowitz, L.; Rabinovich, D. Acta Crystallogr
1965, 18, 1035.
[37] Boovanahalli, S. K.; Jin, X.; Jin, Y.; Kim, J. H.; Dat, N. T.; Hong,
Y. S.; Lee, J. H.; Jung, S. H.; Lee, K.; Lee, J. J. Bioorg Med Chem Lett 2007,
17, 6305.
[38] Suksrichavalit, T.; Prachayasittikul, S.; Nantasenamat, C.; Ayudhya,
C. I. N.; Prachayasittikul, V. Eur J Med Chem 2009, 44, 3259.
[59] Farrugia, L. J. J Appl Crystallogr 1997, 30, 565.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet