Preparations of 4-substituted 3-carboxypyrazoles

Article abstract of DOI:10.1002/jhet.1654

The scopes of three synthetic methods reported for the preparation of an array of 3-pyrazolecarboxylates featuring substituents on position 4 were investigated. The first one is based on the potassium permanganate oxidation of methylpyrazoles. The second starts with the condensation between DMF dimethylacetal and ethyl pyruvate and is followed by the addition of hydrazine hydrochloride. The last one makes use of the cycloaddition of diazomethane on acrylate esters followed by a bromine-based oxidative rearrangement into 4-substituted 3-pyrazole esters.

Full text of DOI:10.1002/jhet.1654

Month 2013
Preparations of 4-Substituted 3-Carboxypyrazoles
Yves L. Janina,b
*
aInstitut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France
bCNRS, UMR 3523, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France
*
E-mail: yves.janin@pasteur.fr
Received December 13, 2011
DOI 10.1002/jhet.1654
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
The scopes of three synthetic methods reported for the preparation of an array of 3-pyrazolecarboxylates
featuring substituents on position 4 were investigated. The first one is based on the potassium permanganate
oxidation of methylpyrazoles. The second starts with the condensation between DMF dimethylacetal and
ethyl pyruvate and is followed by the addition of hydrazine hydrochloride. The last one makes use of the
cycloaddition of diazomethane on acrylate esters followed by a bromine-based oxidative rearrangement into
4-substituted 3-pyrazole esters.
J. Heterocyclic Chem., 00, 00 (2013).
In the course of our work [1–7] on the design of chemical
libraries with a potential against infectious disease, we were
led to synthesize 3-pyrazolecarboxylic acid derivatives
preferably lacking a substituent on carbon 5. From the
available synthetic methods reported [8–10], three different
approaches were used. The controlled oxidation of
3-methylpyrazoles derivatives 1a–e into acids 2a–e using
potassium permanganate was first investigated [11–15]
(Scheme 1). It appeared that this method is limited by some
decarboxylation taking place in refluxing water. Moreover,
the lack of solubility of potential reaction substrates, at RT,
often prevented less stringent methyl oxidation. Further
purification by recrystallization of the rather water-soluble
acids was often found necessary and thus led to pure
compounds 2a–e in yields no higher than 16%.
We then investigated the recently reported preparation
of ethyl-3-pyrazolecarboxylate from ethylpyruvate [16].
From the reaction between DMF dimethylacetal and the
two pyruvate derivatives 3a–b, followed by addition of
hydrazine hydrochloride on the resulting Mannich bases
4a–b, we could extend this original method and prepare
esters 5a–b (Scheme 2). The quite low yields obtained
are due to the occurrence of many unidentified side
compounds. From the benzyl-bearing substrate 3a, we
could isolate in 18% yield and fully characterize the furan
derivative 6. This side compound, which results from a
dimerization of compound 3a under the reaction condi-
tions, illustrates the difficulties we encountered with this
synthetic method. A related preparation of such furan
derivative has actually been reported [17]. From esters
5a–b, an acidic hydrolysis led to sizable amount (75%)
of the target acids 7c but much smaller (5%) amount of
the diacid 7d.
Far more pyrazole derivatives were made by the well-
described cycloaddition of diazomethane on a,b-unsaturated
esters [18–20]. From the acrylates 8a–k, this cycloaddition
led to the intermediates 9a–k. No attempts were made to
isolate these compounds, and the following oxidative rear-
rangement into 4-substituted 3-pyrazole esters 10a–k was
achieved with bromine. As described in the experimental
part, the commercially unavailable a,b-unsaturated esters
were prepared by acid-catalyzed esterification of the avail-
able acids or by using the greatly optimized condensation
of malonic acid monoethylester on aldehydes [21]. To mini-
mize the handling of the carcinogenic as well as explosive
diazomethane, we used a comparatively safer one-pot proto-
col starting from the also carcinogenic N-methylnitrosourea
[22]. A noteworthy phase-separation step, based on the
freezing of the aqueous phase, led fairly safely to a dry ether
solution of diazomethane, which was immediately used
without any other purification. The hydrolysis of the
resulting esters 10a–k in boiling hydrochloric acid provided
acids 11a–k in acceptable overall yield (from 20 to 35%)
(Scheme 3).
In conclusion, this work allowed the preparation of
many known as well as previously undescribed 4-subtituted
3-carboxypyrazoles. By far, the last method, based on the
diazomethane cycloaddition on acrylates, provided the most
© 2013 HeteroCorporation

Y. L. Janin
Vol 000
diverse set of compounds. However, the inherent hazards of
this approach point at the fact that the optimization or the
design of alternative synthetic accesses could be of interest,
especially if a large scale production is required.
Note concerning the 13C NMR data: In some cases, an equilib-
rium existing between the two forms of the pyrazole nucleus and/
or the carboxyester group conformation prevented the determination
of the carbons 2 and 5 13C NMR signals value as they were spread
on a too large frequency band and probably overlapped in some
cases. Quite often these two signals were observed as a large
peak with a width of as much as 4 ppm. If a higher concentration
of the sample was used for NMR experiments, two almost complete
set of signals were then observed in 1H as well as 13C NMR spectra,
and their respective proportion varied according to the solvent
used. This phenomenon is likely to be due to some kind of self-
organization taking place via intermolecular interactions.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on a Bruker
spectrometer at 400 and 100MHz, respectively. Shifts (d) are given
in parts per million with respect to the TMS signal, and coupling
constants (J) are given in Hertz. Column chromatography were
performed over Merck silica gel 60 (0.035–0.070 mm), using
a solvent pump operating at a pressure between 2 and 7 bar
(25–50mL/mn) and an automated collecting system driven by a
UV detector set to 254 nm, unless stated otherwise. Melting points
were measured on a Koffler apparatus. Mass spectra were obtained
on an Agilent 1100 series LC/MSD system using an atmospheric
ESI system, a C18 column, a gradient of water, and either acetoni-
trile containing 0.07% of formic acid or, more often, methanol
containing 0.07% of ammonium formate.
Scheme 3. i: CH2N2, Et2O. ii: Br2. iii: hydrochloric acid, reflux.
R
R
i
ii
OEt
R
N
OEt
N
O
O
8a-k
9a-k
Scheme 1. i: KMnO4, H2O, 25ꢀC, or reflux.
R
R1
N
R2
R1
N
R2
i
iii
OEt
OH
OH
N
N
N
N
H
N
H
N
H
O
O
H
O
10a-k
11a-k
1a-e
2a-e
f: R = CH2iPr
g: R = npentyl
h: R = phenyl
i: R = 2-pyridyl
j: R = 3-pyridyl
k: R = 4-pyridyl
a: R1, R2 = H, H
b: R1, R2 = H, Cl
c: R1, R2 = H, Br
d: R1, R2 = Me, H
e: R1, R2 = Me, Cl
a: R = CH3
b: R = CF3
c: R = Et
d: R = Pr
e: R = iPr
Scheme 2. i: DMF dimethylacetal. ii: NH2NH2, HCl. iii: hydrochloric acid, reflux.
N
R1
R1
R1
i
ii
a: R1= CH2C6H5
R2 = Et
OR2
OR2
N
OR2
O
N
b: R1 = CH2CO2Me
R2 = Me
O
H
O
O
O
3a-b
4a-b
5a-b
iii
O
R1
O
O
c: R1= CH2C6H5
d: R1 = CH2CO2H
OH
N
N
H
O
O
HO
6
7c-d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 Investigation of Three Available Methods for 4-Subtituted 3-Carboxypyrazoles Preparation
Preparation of acids 2a–e. The 3-methyl pyrazoles 1a–e
(0.003 mol) were dispersed in water (30 mL), and potassium
permanganate (1.4 g; 0.009 mol.) was added. The resulting
suspension was stirred at RT or refluxed for the requisite time
as described in the succeeding sections. The manganese oxide
was filtered, and the filtrate was made acid using concentrated
acid hydrochloric acid 2N. The resulting precipitate was filtered,
washed with cold water, and further purified as described in
the following.
(s(br), 1H). 13C (DMSO-d6): 15.0; 27.2; 30.4; 60.6 (br); 123.5
(br); 126.6; 129.08; 129.13; 130.3 (br); 141.9. LC/MS:
m/z = 231 (M + H)+.
3-Benzyl-4-hydroxy-5-oxo-2-phenethyl-2,5-dihydrofuran-2-
carboxylic acid ethyl ester (6). This compound was obtained in a
18% yield after the corresponding chromatographic fraction (silica
gel elution with cyclohexane/ethyl acetate 4:1) was further
purified by recrystallization in cyclohexane. mp = 120ꢀC. 1H
(CDCl3): 1.69 (t, 3H, J = 7.1 Hz); 2.15 (m, 1H); 2.39 (m, 1H);
2.48 (m, 2H); 3.7 (s, 2H); 3.96 (q, 2H, J = 7.1 Hz); 6.25 (s, 1H);
7.19 (m, 2H); 7.28 (m, 8H). 13C (CDCl3): 14.2; 29.5; 30.4; 36.3;
62.9; 87.5; 126.6; 127.4; 128.8; 128.83; 129.14; 129.4; 131.4;
136.5; 139.5; 140.6; 168.3; 169.5. LC/MS: m/z = 384 (M + NH4)+.
4-(Carboxymethyl)-1H-pyrazole-3-carboxylic acid dimethyl
ester (5b). This compound was obtained in a 13% yield after
the corresponding chromatographic fraction (silica gel elution
with dichloromethane/methanol 98:2) was further purified by
recrystallization in a toluene/cyclohexane mixture. mp = 120ꢀC
1H-Pyrazole-3-carboxylic acid (2a).
This compound was
obtained in a 10% yield after 4 h at reflux. The precipitate was
purified by a recrystallization in acetic acid. mp = 212ꢀC
(lit. [15] = 213–215ꢀC). 1H (MeOD): 5.01 (s (br), 2H); 6.83
(d, 1H, J = 1.5 Hz); 7.70 (d, 1H, J = 1.5 Hz). 13C (MeOD):
109.4; 134.1; 143.1; 165.1. LC/MS: m/z = 113 (M + H)+.
4-Chloro-1H-pyrazole-3-carboxylic acid (2b). From 4-chloro-
3-methylpyrazole (made by the chlorination of 3-methyl-1
H-pyrazole with NCS and still containing succinimide), this
compound was obtained in a 10% yield after 4 h at reflux. The
precipitate was purified by a recrystallization in acetic acid.
mp = 250ꢀC (lit. [15] = 244–245ꢀC). 1H (MeOD): 4.95 (s (br),
2H); 7.73. 13C (MeOD): 114.7; 135.0 (br); 163.0. LC/MS: m/
z = 145/ 147 (M À H)À.
1
(lit. [26] = 139–140ꢀC). H (MeOD): 3.70 (s, 3H); 3.83 (s, 2H);
3.87 (s, 3H); 7.55 and 7.72 (2s, 1H overall). 13C (MeOD): 31.0;
52.4; 52.8; 118.1; 131.9; 142.5; 164.9; 174.1. LC/MS:
m/z = 199 (M + H)+.
Hydrolysis of esters 5a–b.
The corresponding ester was
4-Bromo-1H-pyrazole-3-carboxylic acid (2c). From 4-bromo-
3-methylpyrazole [23], this compound was obtained in a 12% yield
after 4h at reflux. The precipitate was purified by a recrystallization
dispersed in 35% hydrochloric acid (10mL for 0.5 g) and refluxed
for 3 h. The resulting solution was concentrated to dryness and the
residue further purified as described in what follows.
4-Benzyl-1H-pyrazole-3-carboxylic acid (7a). This compound
was obtained in a 75% yield after dispersion in boiling water.
mp= 235ꢀC. 1H (DMSO-d6): 4.04 (s, 2H); 7.19 (m, 5H); 7.47
(s, 1H). 13C (DMSO-d6): 30.3; 124.0; 126.6; 129.1; 129.2; 136.0;
142.0; 163.5. LC/MS: m/z = 203 (M+ H)+.
4-(Carboxymethyl)-1H-pyrazole-3-carboxylic acid (7b). This
compound was obtained in a 5% yield after a recrystallization in
water. mp > 250ꢀC (dec.) [lit. [26]=241–243ꢀC (dec.)]. 1H
(DMSO-d6): 3.66 (s, 2H); 7.62 (s, 1H); 12.8 (s (br), 1H). 13C
(DMSO-d6): 30.5; 117.8; 135.8; 163.5; 173.2. LC/MS: m/z =171
(M+ H)+; weak signal.
1
in acetic acid. mp= 260ꢀC (lit. [15]= 250–251ꢀC). H (MeOD):
4.96 (s (br), 2H); 7.76 (s, 1H). 13C (MeOD): 98.1; 138 (br); 163.1.
LC/MS: m/z = 189/191 (MÀ H)À.
5-Methyl-1H-pyrazole-3-carboxylic acid (2d). This compound
was obtained in a 16% yield after 4 days of reaction at RT. The
precipitate was purified by a recrystallization in hydrochloric acid
0.2N and two supplementary recrystallizations, which were
necessary to fully remove the traces of the corresponding diacid
also occurring in the reaction. mp= 245ꢀC (lit. [24] = 241–243ꢀC).
1H (DMSO-d6): 2.24 (s, 3H); 6.45 (s, 2H); 12.87 (s (br), 1H). 13
C
(DMSO-d6): 11.9; 107.6; 142.2; 143.8; 163.7. LC/MS: m/z = 125
(M À H)À.
Preparation of the a,b-unsaturated ethyl esters 8g and 8j–k
4-Chloro-5-methyl-1H-pyrazole-3-carboxylic acid (2e). From
4-chloro-3,5-dimethylpyrazole (made by the chlorination of 3,5-
dimethyl-1H-pyrazole with N-chlorosuccinimide and still containing
succinimide), this compound was obtained in a 7% yield after
3 weeks of reaction at RT. The precipitate was purified by
by esterification.
The a,b-unsaturated acid (0.007mol) was
dissolved in ethanol (100 mL), and concentrated (95%) sulfuric
acid (1.5 mL in the case of pyridinyl acrylic acids or 10 drops in
the case of alkylacrylic acid) was added. This was heated to reflux
for 36 h, concentrated, diluted in water, and extracted with
dichloromethane. The organic phase was washed with 1N sodium
hydroxide and water, and dried over sodium sulfate. The resulting
esters were used directly in the cycloaddition step.
1
recrystallization in acetic acid. mp = 260ꢀC (lit. [25] = 259ꢀC). H
(MeOD): 2.28 (s, 3H); 4.97 (s (br), 2H). 13C (MeOD): 10.0; 112.7;
137.4; 143.3; 163.3. LC/MS: m/z= 161/163 (M + H)+; weak signal.
Preparation of esters 2a–e. To the pyruvates 3a–b (0.01
mol), dissolved in dichloromethane (100 mL), was added DMF
dimethyl acetal (1.33 mL; 0.01 mol). This was stirred at 25ꢀC
for 2 h and concentrated to dryness without heating. The residue
was dissolved in ethanol (or methanol according to the ester
used) (100 mL), and hydrazine hydrochloride was added (0.68 g;
0.01 mol). This was heated to reflux for 8 h and concentrated to
dryness. The residue was then purified as described in the
succeeding sections.
Preparation of the a,b-unsaturated esters 8c and 8i by
condensation of malonic acid monoethylester.
Following
the reported procedure [21], the corresponding aldehyde
(0.018 mol), malonic acid monoethylester (3.3 mL; 0.028 mol),
4-dimethylaminopyridine (0.22 g, 0.0018 mol), and piperidine
(0.15 mL; 0.0018 mol; just for the preparation of the pyridyl
acrylate) were dissolved in dry DMF (100 mL, dried over 4-Å
molecular sieves). The solution was stirred at RT for 24 h. In
the case of the nonvolatile pyridyl acrylate, the solution was
concentrated to dryness, and the residue was dissolved in ethyl
acetate and washed with 1N sodium hydrogenocarbonate twice
and water five times. The organic layer was dried over sodium
sulfate and concentrated to dryness. In the case of the ethyl
acrylate, the solution was diluted in ether (500 mL) and washed
with 1N ammonium chloride twice, 1N sodium hydrogenocarbonate
4-Benzyl-1H-pyrazole-3-carboxylic acid ethyl ester (5a). This
compound was obtained in a 12% yield after the corresponding
chromatographic fraction (silica gel elution with cyclohexane/
ethyl acetate 4:1) was further purified by recrystallization in
cyclohexane. mp = 129ꢀC. 1H (DMSO-d6): 1.24 (t, 3H,
J = 6.9 Hz); 4.03 (s, 2H); 4.19 (m, 2H); 7.20 (m, 5H); 7.60
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. L. Janin
Vol 000
of signals 0.88 (t, 3H, J = 7.3 Hz); 1.30 (m, 3H); 1.53 (m, 2H);
2.63 (m, 2H); 4.30 (m, 2H); 7.47 and 7.65 (2s, 1H overall); 13.19
and 13.6 (s (br) 1H overall). 13C (DMSO-d6): two sets of signals
14.5; 14.6; 14.95; 15.04; 24.12; 24.16; 26.46; 26.78; 60.42; 61.16;
124.4; 125.97; 129.2; 129.4; 130.1; 140.6; 140.9; 160.4; 163.6.
LC/MS: m/z = 183 (M + H)+.
twice, and water thrice before drying it over sodium sulfate and a
cautious concentration to dryness. The resulting esters were used
in the next step without further purification.
Preparation of the pyrazole esters 10a–k. CAUTION: due
precautions must be taken when working with the carcinogenic
diazomethane or N-methyl-N-nitrosourea. Any residue of N-
methyl-N-nitrosourea can be neutralized with a 1:1 solution of
acetone and sodium hydroxide 1N; any solution of diazomethane
can be quenched with acetic acid. Under a well-ventilated hood, in
a 250-mL Erlenmeyer “free of defaults and devoid of a ground
glass joint”, potassium hydroxide (3.8g, 0.057mol) was dissolved
in water (45 mL). After cooling to 0ꢀC, diethyl ether (45 mL) was
added followed by N-methyl-N-nitrosourea (2 g; 0.019 mol;
contains acetic acid as a stabilizer). The biphasic suspension was
well stirred at 0ꢀC for 10 min. The stirring of the resulting yellow
biphasic solution was stopped, and after it settled, the bottom layer
was frozen at À78ꢀC using an acetone and dry ice bath. The cold
yellow top layer was quickly filtered using a large cotton-plugged
(“not glass wool”) funnel, and the filtrate was allowed to drop
directly into a cooled (0ꢀC) solution of the a,b-unsaturated ethyl
ester (0.0096 mol; in three instances, a methyl ester was used) in
diethyl ether (45mL). This was stirred overnight while allowing
the temperature to rise to 25ꢀC, and bromine (0.5mL; 0.0096 mol)
was then added. The solution was stirred for 10min, washed
successively with 1N solutions of sodium sulfite, sodium
carbonate, and water, dried over sodium sulfate, and concentrated
to dryness. Note: in few cases described in the succeeding
sections, dichloromethane was used to improve the extraction of
the reaction product. The resulting residues were then purified as
described in the following.
4-Isopropyl-1H-pyrazole-3-carboxylic acid methyl ester (10e).
This compound was obtained as a solid in a 20% yield, from
the corresponding methyl acrylate, after purification by
a
chromatography over silica gel (dichloromethane/ethanol 98:2).
1
mp= 96ꢀC). H (DMSO-d6): 1.27 (d, 6H, J = 6.9 Hz); 3.45 (sept,
1H, J = 6.9 Hz); 3.96 (s, 3H); 7.56 (s, 1H). 13C (DMSO-d6): 24.0;
24.5; 52.1; 131.2 (br); 132.9; 162.7. LC/MS: m/z = 169 (M+ H)+.
4-Isobutyl-1H-pyrazole-3-carboxylic acid methyl ester (10f).
This compound was obtained as a solid in a 50% yield, from
the corresponding methyl acrylate, after purification by a
chromatography over silica gel (dichloromethane/ethanol from
99:1 to 98:2). mp = 80ꢀC. 1H (DMSO-d6): two sets of signals
0.84 (d, 6H, J = 6.8 Hz); 1.79 (sept, 1H, J = 6.8 Hz); 2.55
(m, 2H); 3.76 and 3.82 (2s, 1H overall); 7.45 and 7.65 (2s, 1H
overall). 13C (DMSO-d6): two sets of signals 23.01; 23.03;
29.6; 29.8; 33.2; 33.5; 51.8; 52.4; 123.3; 125.1; 130.0; 130.2;
140.7; 141.5; 160.8; 164.1. LC/MS: m/z = 183 (M + H)+.
4-Pentyl-1H-pyrazole-3-carboxylic acid ethyl ester (10g). This
compound was obtained as a solid in a 47% yield after purification
by a chromatography over silica gel (dichloromethane/ethanol
98:2). mp = 107ꢀC. 1H (DMSO-d6): two sets of signals 0.86
(t, 3H, J = 6.5 Hz); 1.28 (m, 7H); 1.52 (m, 2H); 2.63 (t, 2H,
J = 7.3 Hz); 4.28 (m, 2H); 7.46 and 7.65 (2s (br), 1H overall). 13C
(DMSO-d6): two sets of signals 14.76; 14.79; 15.0; 22.7; 24.6;
30.6; 31.87; 31.9; 60.4; 61.1; 124.6; 126.2; 129.2; 129.4; 130.1;
140.6; 140.9; 160.4; 163.6. LC/MS: m/z = 211 (M + H)+.
4-Phenyl-1H-pyrazole-3-carboxylic acid methyl ester (10h).
This compound was obtained as a solid in a 25% yield, from the
corresponding methyl cinnamate, by filtration of the material
precipitating at the interface between the water and ether layers in
the course of the extraction step. mp = 191ꢀC (lit. [23]= 185ꢀC).
1H (DMSO-d6): 3.76 (s, 3H); 7.29 (m, 1H); 7.37 (m, 2H); 7.50
(m, 2H); 7.95 (s, 1H). 13C (MeOD): 52.5; 127.2; 128.7; 129.4;
130.7; 133.7; 135.7; 163.7. LC/MS: m/z = 203 (M + H)+.
4-Methyl-1H-pyrazole-3-carboxylic acid ethyl ester (10a). This
compound was obtained in a 25% yield after an extraction of the
aqueous phase first with ether then with dichloromethane. The
residue, resulting from the concentration to dryness of these
organic phases, was then dispersed in boiling cyclohexane before
filtering it at RT. mp = 156ꢀC (lit. [27] = 156–157ꢀC). 1H
(MeOD): two sets of signals 1.39 (t, 3H, J = 7.1 Hz); 2.29 (s, 3H);
4.36 (q, 2H, J = 7.1Hz); 7.41 and 7.53 (2s, 1H overall). 13C
(MeOD): two sets of signals 9.9; 10.2; 61.9; 62.0; 121.0; 122.5;
130.8; 142.4; 165.0. LC/MS: m/z = 155 (M+ H)+.
4-(Pyridin-2-yl)-1H-pyrazole-3-carboxylic acid ethyl ester (10i).
This compound was obtained as a solid in a 12% yield after
purification by a chromatography over silica gel (dichloromethane/
4-(Trifluoromethyl)-1H-pyrazole-3-carboxylic acid ethyl ester
(10b). This compound was obtained in a 35% yield after an
extraction of the aqueous phase first with ether then with
dichloromethane The residue, resulting from the concentration to
dryness of these organic phases, was then recrystallized in
1
cyclohexane 95:5). mp= 134ꢀC. H (MeOD): 1.29 (m, 3H); 4.33
(m, 2H); 7.36 (m, 1H); 7.79 (s (br), 1H); 7.86 (m, 1H); 7.92
(s (br), 1H); 8.55 (m, 1H). 13C (MeOD): 15.1; 62.9 (br); 124.4;
126.2 (br); 126.9; 132.6; 138.8; 138.9; 143 (br); 150.4; 153.3. LC/
MS: m/z = 218 (M+ H)+.
1
cyclohexane. mp= 163ꢀC. H (MeOD): 1.39 (t, 3H, J = 7.1 Hz);
4.40 (q, 2H, J = 7.1 Hz); 8.16 (s (br), 1H). 13C (MeOD): 14.9;
63.0; 115.4 (q, J = 32Hz); 123.0 (q, J = 264 Hz); 132.9 (br); 142.3
(br); 163.0 (br). LC/MS: m/z = 209 (M + H)+ and 226 (M+ NH4)+.
4-(Pyridin-3-yl)-1H-pyrazole-3-carboxylic acid ethyl ester (10j).
This compound was obtained as a solid in a 20% yield after
purification by a chromatography over silica gel (dichloromethane/
ethanol from 98:2 to 95:5) followed by washing the solid obtained
in boiling cyclohexane. mp= 135ꢀC. 1H (MeOD): two sets of
signals 1.21 (m, 3H); 4.13 (m, 2H); 7.47 (m, 1H); 7.83 and 7.99
(2s (br), 2H overall); 8.44 (m, 1H); 8.67 and 8.75 (2s (br), 1H
overall). 13C (MeOD): two sets of signals 14.8; 62.4; 62.5; 123.0;
125.05; 130.9; 131.7; 139.4; 141.8 (br); 148.8; 150.7. LC/MS:
m/z = 218 (M + H)+.
4-Ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (10c). This
compound was obtained as a solid in a 30% yield after purification
by a chromatography over silica gel (dichloromethane/ethanol
1
98:2). mp = 102ꢀC (lit. [19] = 102ꢀC). H (DMSO-d6): two sets of
signals 1.13 (m, 3H); 1.28 (m, 3H); 2.66 (m, 2H); 4.25 (m, 2H);
7.49 (s, 1/3H) 7.65 (s, 2/3H). 13C (DMSO-d6): two sets of signals
15.0; 15.6; 17.9; 18.1; 60.4; 61.1; 126.3; 127.7; 128.9; 129.9;
140.3; 140.5; 160.4; 163.6. LC/MS: m/z = 169 (M+ H)+.
4-Propyl-1H-pyrazole-3-carboxylic acid ethyl ester (10d). This
compound was obtained as a solid in a 44% yield after purification
by a chromatography over silica gel (dichloromethane/ethanol
4-(Pyridin-4-yl)-1H-pyrazole-3-carboxylic acid ethyl ester (10k).
This compound was obtained as a solid in a 20% yield after
purification by a chromatography over silica gel (dichloromethane/
ethanol from 98:2 to 95:5) followed by a recrystallization in
1
98:2). mp = 77ꢀC (lit. [19] = 81–82ꢀC). H (DMSO-d6): two sets
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 Investigation of Three Available Methods for 4-Subtituted 3-Carboxypyrazoles Preparation
toluene. mp= 191ꢀC. 1H (DMSO-d6): two set of signals 1.24 (t, 3H,
J = 7.0Hz); 4.26 (q, 2H, J =7.0 Hz); 7.54 (m, 2H); 8.19 (s (br), 1H).
13C (DMSO-d6): 14.8; 61.3; 124.3; 131.4; 140.6 (br); 150.1. LC/
MS: m/z = 218 (M+ H)+.
4-(Pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (11j). This
compound was obtained as a solid in a 94% yield after
dispersion in ether. mp > 260ꢀC (lit. [29] = 250–251ꢀC). 1H
(DMSO-d6): 7.95 (dd, 1H, J = 5.5 and 8.1 Hz); 8.20 (m, 1H);
8.76 (dd, 1H, J = 1.2 and 5.5 Hz); 9.08 (d, 1H, J = 1.9 Hz). 13C
(DMSO-d6): 118.6; 127.1; 132.4; 136.0; 140.9; 142.4; 145.5;
163.1. LC/MS: m/z = 190 (M + H)+.
4-(Pyridin-4-yl)-1H-pyrazole-3-carboxylic acid (11k). This
compound was obtained as a solid in a 94% yield after dispersion
in ether. mp > 260ꢀC (lit. [29] = 255–256ꢀC). 1H (DMSO-d6):
8.28 (d, 2H, J = 6.8 Hz); 8.49 (s (br), 1H); 8.86 (d, 2H,
J = 6.8 Hz). 13C (DMSO-d6): 119.6; 126.3; 136.2; 141.9; 149.9;
164.4 (br). LC/MS: m/z = 190 (M + H)+.
Hydrolysis of esters 10a–k.
The corresponding ester was
dispersed in 35% hydrochloric acid (10 mL for 0.5 g) and refluxed
for 3 h. The resulting solution was concentrated to dryness and the
residue further purified as described in the following.
4-Methyl-1H-pyrazole-3-carboxylic acid (11a). This compound
was obtained as a solid in 93% yield after dispersion in ether.
mp = 210ꢀC (lit. [27]=218–220ꢀC).. 1H (DMSO-d6): 2.18 (s, 3H);
7.51 (s, 1H). 13C (DMSO-d6): 10.2; 119.8; 135.7; 136.5; 163.5.
LC/MS: m/z = 155 (M+ H)+.
4-(Trifluoromethyl)-1H-pyrazole-3-carboxylic acid (11b). This
compound was obtained as a solid in a 77% yield after dispersion
in water. mp= 236ꢀC (dec.). 1H (DMSO-d6): 8.37 (s(br), 1H);
13.05 (s (br), 1H); 13.98 (s (br), 1H). 13C (DMSO-d6): 113.2
(q, J =37Hz); 123.0 (q, J = 264 Hz); 133.7 (br); 141.3 (br); 161.9
(br). LC/MS: m/z = 179 (M À H)À.
REFERENCES AND NOTES
[1] Salanouve, E.; Retailleau, P.; Janin, Y. L. Tetrahedron 2012,
68, 2135.
[2] Guillou, S.; Bonhomme, F. J.; Ermolenko, M. S.; Janin, Y. L.
Tetrahedron 2011, 67, 8451.
[3] Guillou, S.; Bonhomme, F. J.; Chahine, D.; Nesme, O.; Janin,
Y. L. Tetrahedron 2010, 66, 2654.
[4] Guillou, S.; Janin, Y. L. Chem Eur J 2010, 16, 4669.
[5] Guillou, S.; Bonhomme, F. J.; Janin, Y. L. Tetrahedron 2009,
65, 2660.
4-Ethyl-1H-pyrazole-3-carboxylic acid (11c). This compound
was obtained as a solid in a 75% yield after recrystallization in
1
water. mp = 206ꢀC (lit. [19] = 214–215ꢀC). H (DMSO-d6): 1.13
(t, 3H, J = 7.5Hz); 2.66 (q, 2H, J = 7.5 Hz); 7.54 (s, 1H); 13.0
(s (br), 1H). 13C (DMSO-d6): 15.8; 18.0; 126.8; 129.0 (br); 165.5.
LC/MS: m/z = 141 (M+ H)+.
4-Propyl-1H-pyrazole-3-carboxylic acid (11d). This compound
was obtained as a solid in a 98% yield after recrystallization in
[6] Guillou, S.; Nesme, O.; Ermolenko, M. S.; Janin, Y. L.
Tetrahedron 2009, 65, 3529.
[7] Guillou, S.; Bonhomme, F. J.; Janin, Y. L. Synthesis 2008, 3504.
[8] Fusco, R. Pyrazoles. In Pyrazoles, Pyrazolines, Pyrazolidines,
Indazoles and Condensed Rings; Wiley, R. H., Ed.; John Wiley & Sons:
New York, 1967; Vol 22, pp 1–174.
[9] Stanovik, E.; Svete, J. Product Class 1: Pyrazoles. In Science
of Synthesis; Neier, R., Ed.; Georg Thieme Verlag: Berlin, 2002;
Vol 12, pp 15–225.
[10] Janin, Y. L. Mini Rev Org Chem 2010, 7, 314.
[11] Musante, C. Gazz Chim Ital 1945, 75, 121.
[12] Meltzer, R. I.; Lewis, A. D.; McMillan, F. H.; Genzer, J. D.;
Leonard, F.; King, J. A. J Am Pharm Assoc 1953, 42, 594.
[13] Moore, J. A.; Medeiros, R. W. J Am Chem Soc 1959, 81, 6026.
[14] Grandberg, I. I.; Nikitina, S. B.; Moskalenko, V. A.; Minkin,
V. I. Chem Heterocycl Compd (Engl Transl) 1967, 837 (Khim. Geterotsikl.
Soedin. 1967, 1076–1082). See Chem. Abstr. 69: 52067.
[15] Manaev, Y. A.; Andreeva, M. A.; Perevalov, V. P.; Stepanov,
B. I.; Dubrovskaya, V. A.; Seraya, V. I. J Gen Chem USSR (EnglTransl)
1982, 52, 2291. See Chem. Abstr. 98: 71993.
[16] Hanzlowsky, A.; Jelencic, B.; Recnik, S.; Svete, J.; Golobic,
A.; Stanovnik, B. J Heterocyclic Chem 2003, 40, 487.
[17] Stach, H.; Huggenberg, W.; Hesse, M. Helv Chim Acta 1987,
70, 369.
[18] v Auwers, K.; Cauer, E. Justus Liebigs Ann Chem 1929, 470,
284. See Chem. Abstr. 23: 3704.
1
water. mp = 214ꢀC (lit. [19] = 214–245ꢀC). H (DMSO-d6): 0.88
(t, 3H, J = 7.3Hz); 1.54 (m, 2H); 2.62 (t, 2H, J =7.4 Hz); 7.52
(s, 1H). 13C (DMSO-d6): 14.6; 24.0; 26.5; 125.0; 135.0 (br);
163.5. LC/MS: m/z = 155 (M+ H)+.
4-Isopropyl-1H-pyrazole-3-carboxylic acid (11e). This compound
was obtained as a solid in a 71% yield after recrystallization in
water. mp = 201ꢀC. 1H (DMSO-d6): 1.16 (d, 6H, J = 6.9Hz); 3.32
(sept, 1H, J = 6.9 Hz); 7.57 (s, 1H). 13C (DMSO-d6): 24.3; 24.5;
123.6; 132.3; 145.8; 163.5. LC/MS: m/z = 155 (M+ H)+.
4-Isobutyl-1H-pyrazole-3-carboxylic acid (11f). This compound
was obtained as a solid in a 70% yield after dispersion in boiling
water. mp = 195ꢀC. 1H (DMSO-d6): 0.84 (d, 6H, J = 6.6Hz); 1.79
(m, 1H); 2.54 (d, 2H, J = 7.0 Hz); 7.50 (s, 1H). 13C (DMSO-d6):
23.0; 29.7; 33.4; 123.9; 136.1 (br); 163.4. LC/MS: m/z = 169
(M + H)+.
4-Pentyl-1H-pyrazole-3-carboxylic acid (11g). This compound
was obtained as a solid in a 93% yield after dispersion in boiling
1
water. mp= 165ꢀC. H (DMSO-d6): 0.85 (t, 3H, J = 6.8 Hz); 1.28
(m, 4H); 1.53 (m, 2H); 2.64 (t, 2H, J = 7.5Hz); 7.52 (s, 1H). 13C
(DMSO-d6): 14.7; 22.7; 24.4; 30.5; 31.8; 125.2; 135.0; 163.5. LC/
MS: m/z = 183 (M+ H)+.
[19] Alberti, C.; Zerbi, G. Pharmaco Ed Sci 1961, 16, 527.
[20] Elguero, J.; Guiraud, G.; Jacquier, R. Bull Soc Chim Fr 1966, 619.
[21] List, B.; Doehring, A.; Hechavarria Fonseca, M. T.; Job,
A.; Rios Torres, R. Tetrahedron 2006, 62, 476.
[22] Arndt, F. Org Synth Coll Vol 1943, 2, 165.
[23] Elguero, J.; Jacquier, R. Bull Soc Chim Fr 1966, 2832.
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[25] Musante, C.; Mugnaini, E. Gazz Chim Ital 1947, 77, 182.
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1958, 48, 140.
[27] v Auwers, K.; Koenig, F. Justus Liebigs Ann Chem 1932, 496, 27.
[28] von Pechmann, H.; Burkard, E. Ber Dtsch Chem Ges 1901, 33,
3594.
[29] Cativiela, C.; Diaz de Villegas, M. D.; Mayoral, J. A.;
Avenoza, A.; Roy, M. A. J Heterocyclic Chem 1988, 25, 851.
4-Phenyl-1H-pyrazole-3-carboxylic acid (11h). This compound
was obtained as a solid in a 75% yield after recrystallization in
water. mp > 260ꢀC (lit. [28] = 251–253ꢀC (dec.)). 1H (DMSO-d6):
7.28 (m, 1H); 7.36 (m, 2H); 7.55 (m, 2H); 7.87 (s, 1H); 13.3
(s (br), 2H). 13C (MeOD): 127.1; 128.6; 129.4; 130.7; 133.7;
136.3 (br); 164.4. LC/MS: m/z = 189 (M +H)+.
4-(Pyridin-2-yl)-1H-pyrazole-3-carboxylic acid (11i). This
compound was obtained as a solid in a 74% yield after a
recrystallization in water. mp> 200ꢀC (dec.). 1H (DMSO-d6):
7.55 (m, 1H); 8.23 (m, 2H); 8.54 (s (br), 1H); 8.62 (m, 1H); 14.14
(s (br), 1H). 13C (DMSO-d6): 118.5; 122.6; 123.9; 135.6 (br);
140.3 (br); 140.3 (br); 141.9; 145.6; 149.3; 161.0 (br). LC/MS:
m/z = 190 (M + H)+.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet