Polyfunctional pyrazoles 6.* Convenient method for the synthesis of 1-aryl-1H-pyrazole-3,4-dicarboxylic acids

Article abstract of DOI:10.1007/s10593-010-0491-4

A preparatively convenient method was developed for the synthesis of 1-aryl-1H-pyrazole-3,4-di-carboxylic acids based on the alkaline hydrolysis and oxidation of 1-aryl-4-formyl-1H-pyrazole-3-carboxylic esters with hydrogen peroxide in an aqueous medium.

Full text of DOI:10.1007/s10593-010-0491-4

Chemistry of Heterocyclic Compounds, Vol. 46, No. 2, 2010
POLYFUNCTIONAL PYRAZOLES
6.* CONVENIENT METHOD FOR THE SYNTHESIS OF
1-ARYL-1H-PYRAZOLE-3,4-DICARBOXYLIC ACIDS
M. K. Bratenko1**, M. M. Barus1, and M. V. Vovk2
A preparatively convenient method was developed for the synthesis of 1-aryl-1H-pyrazole-3,4-di-
carboxylic acids based on the alkaline hydrolysis and oxidation of 1-aryl-4-formyl-1H-pyrazole-
3-carboxylic esters with hydrogen peroxide in an aqueous medium.
Keywords: pyrazole-3,4-dicarboxylic acids, 4-formylpyrazole-3-carboxylic esters, aqueous medium,
hydrolysis, oxidation.
Pyrazole-3,4-dicarboxylic acids and their derivatives are used as the main subjects for the production of
a series of pharmacologically important condensed pyrazole systems [2] and heterocyclic assemblies with
clearly defined electroluminescent effects [3] and also exhibit a wide range of biological activity. In particular,
certain amides of pyrazole-3,4-dicarboxylic acids are characterized by high sedative and anti-inflammatory
activity [4]. The esters of the acids have been tested as bactericidal [5, 6] and antineoplastic [7] agents.
O
O
O
O
AlkO
H
HO
OH
NaOH, H2O2
N
N
N
N
Ar
Ar
1 a–k
2 a–f
1 af Alk = Me, a Ar = Ph, b Ar = 4-BrC6H4, c Ar = 2-MeC6H4, d Ar = 4-MeC6H4,
e Ar = 4-MeO(O)CC6H4, f Ar = 2-naphthyl, gk Alk = Et, g Ar = Ph, h Ar = 4-BrC6H4,
i Ar = 2-MeC6H4, j Ar = 4-MeC6H4, k Ar = 2-naphthyl; 2 a Ar = Ph, b Ar = 4-BrC6H4,
c Ar = 2-MeC6H4, d Ar = 4-MeC6H4, e Ar = 4-HO(O)CC6H4, f Ar = 2-naphthyl
_______
*For Communication 5 see [1].
** To whom correspondence should be addressed, e-mail: bratenko@inbox.ru.
1Bukovinian State Medical University, Chernovtsy 58000, Ukraine.
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine; e-mail:
mvovk@i.com.ua.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 243-247, February, 2010. Original
article submitted January 20, 2009.
196
0009-3122/10/4602-0196©2010 Springer Science+Business Media, Inc.

Several methods used for the production of pyrazole-3,4-dicarboxylic acids have certain preparative
disadvantages. Thus, the use of alkaline hydrolysis of the corresponding diesters is restricted by their relatively
poor availability [8-10]. The synthetic significance of the method involving oxidation of 3,4-dimethyl-1-phenyl-
pyrazole with potassium permanganate is reduced by the formation of 4-methyl-1-phenylpyrazole-3-carboxylic
acid as side product [11]. The oxidation of ethyl 4-formyl-5-methyl-1-phenylpyrazole-3-carboxylate with silver
oxide has only found use for analytical purposes [12]. Thus, the problem of an effective method for the
production of pyrazole-3,4-dicarboxylic acids remains urgent.
We have developed a preparatively convenient approach to their synthesis based on the use of the
accessible alkyl esters of 1-aryl-4-formylpyrazole-3-carboxylic acids 1a-k [1, 13]. It was found that compounds
1a-k, irrespective of the nature of the alkyl substituent, are easily converted into 1-arylpyrazole-3,4-di-
carboxylic acids 2a-f with almost quantitative yields when treated successively with an aqueous solution of
NaOH at 40-50°C and with 30% hydrogen peroxide at room temperature. Here in the case of compound 1e `
of the ester group of the aryl substituent and the formation of the tricarboxylic acid 2e are also
observed.
TABLE 1. The Characteristics of the Synthesized Compounds 2a-f
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %*
М+
mp, °С
С
Н
N
a
b
2a
2b
2с
2d
2е
2f
С11Н8N2О4
57.07
56.90
42.66
42.47
58.79
58.54
58.41
58.54
52.34
52.18
63.69
63.83
3.58
3.47
2.35
2.27
4.22
4.09
4.17
4.04
3.04
2.92
3.69
3.57
12.19
12.06
9.18
9.00
11.30
11.38
11.25
11.38
10.29
10.14
10.05
9.92
232.8
311.6
246.9
257.2
277.0
283.1
235-237
250-252
225-227
235-237
280
97
95
93
98
98
94
95
98
96
96
—
97
С11Н7ВrN2О4
С12Н10N2О4
С12Н10N2О4
С12Н8N2О6
С15Н10N2О4
265-267
_______
*Compounds 2a-f were obtained from the esters 1a-f (a) and 1g-k (b)
respectively.
TABLE 2. The Spectral Characteristics of Compounds 2a-f
Com-
pound
IR spectrum, , cm–1
1Н NMR spectrum, , ppm (J, Hz)*
С=О
О–Н
2а
2b
2с
2d
1720
2550-2900
7.40 (1Н, t, J = 7.0, Н Аr); 7.52 (2Н, d, J = 7.5, Н Аr);
7.94 (2Н, d, J = 7.5, Н Аr); 9.09 (1Н, s, Н-5)
1720
1725
1720
2570-2940
2560-2920
2580-2890
7.70 (2Н, d, J = 9.5, Н Аr); 7.94 (2Н, d, J = 9.5, Н Аr);
9.14 (1Н, s, Н-5)
2.19 (3Н, s, СН3); 7.37-7.43 (4Н, m, Н Аr);
8.66 (1Н, s, Н-5)
2.40 (3Н, s, СН3); 7.33 (2Н, d, J = 8.5, Н Аr);
7.83 (2Н, d, J = 8.5, Н Аr); 9.04 (1Н, s, Н-5)
2е
1715
1720
2560-2900
2565-2920
8.09 (4Н, s, Н Аr); 9.22 (1Н, s, Н-5)
2f
7.52-7.58 (2Н, m, Н Аr); 7.94–8.16 (4Н, m, Н Аr);
8.52 (1Н, s, Н Аr); 9.25 (1Н, s, Н-5)
_______
*The signals of the protons of the carboxyl groups of the acids 2a-f are in
exchange with the protons of the water contained in the DMSO-d6.
197

TABLE 3. The 13C NMR Spectra of Compounds 2a-f
Com-
pound
Chemical shifts, , ppm
С(3)
С(4)
С(5)
С(О)ОН
С Аr
СН3
2а
2b
2с
145.15
116.77
133.26
133.31
136.94
163.28
163.44
120.64, 121.50
132.53, 137.08
—
145.15
144.23
116.75
115.51
163.28
163.48
120.63, 121.45
132.37, 137.70
—
163.43
163.82
126.15, 126.86,
129.48, 131.27,
133.14, 138.40
17.33
2d
144.52
145.66
116.55
117.30
133.08
133.42
163.43
163.78
119.42, 130.06,
136.26, 137.63
20.50
—
2е
163.32
163.55
166.50
119.19, 129.98,
130.84, 141.50
2f
144.96
116.84
133.58
163.52
163.85
117.29, 118.20,
126.76, 127.37,
127.81, 128.14,
129.74, 132.05,
132.91, 135.94
—
We note that hydrogen peroxide in the absence of other reagents has been used extremely rarely for the
conversion of an aldehyde group into a carboxyl group. Only examples of the oxidation of aromatic aldehydes to
carboxylic acids in an alkaline medium [14] and also of aromatic and certain heteroaromatic aldehydes in acidic
media [15, 16] are known.
An advantage of our proposed method for the synthesis of the acids 2a-f is also realization of the two-
stage hydrolysis and subsequent oxidation of the esters 1a-k in a one-pot regime without isolation of the
intermediate 1-aryl-4-formylpyrazole-3-carboxylic acids [1].
The composition of the synthesized pyrazoledicarboxylic acids 2a-f agrees with the data from elemental
analysis and mass spectra (Table 1), and the structure was proved by the IR and 1H (Table 2) and 13C (Table 3)
NMR spectra.
EXPERIMENTAL
The IR spectra were recorded in tablets with KBr on a UR-20 instrument. The 1H and 13C NMR spectra
were obtained in DMSO-d6 on a Bruker Avance DRX-500 spectrometer (500 and 125 MHz respectively) with
TMS as internal standard. The chromato-mass spectra of compounds 2a-f were obtained on an Aligent
1100/DAD/HSD/VLG 119562 instrument. Compounds 1a-k were synthesized by the method in [1].
Compound 1d. Yield 78%; mp 100-101°C (mp 98°C [13]).
Compound 1h. Yield 82%; mp 155-156°C (EtOH). IR spectrum, ν, cm−1: 1680, 1740 (С=О). 1H NMR
spectrum, δ, ppm (J, Hz): 1.38 (3Н, t, J = 7.0, СН3); 4.21 (2Н, d, J = 7.0, СН2); 7.69 (2Н, d, J = 8.4, Н Аr); 7.92
(2Н, d, J = 8.4, Н Аr); 9.08 (1Н, s, Н-5); 10.24 (1Н, s, СН=О). Found, %: С 48.07; Н 3.57; N 8.51.
С13Н11ВrN2О3. Calculated, %: С 48.32; Н 3.43; N 8.67.
1
Compound 1i. Yield 71%; mp 108-109°C (EtOH). IR spectrum, ν, cm−1: 1685, 1740 (С=О). H NMR
spectrum, δ, ppm (J, Hz): 1.40 (3Н, t, J = 7.0, СН3); 2.25 (3Н, s, СН3); 4.41 (2Н, q, J = 7.0, СН2); 7.38-7.50
(4Н, m, Н Аr); 8.74 (1Н, s, Н-5); 10.34 (1Н, s, СН=О). Found, %: С 62.33; Н 5.55; N 10.69. С14Н14N2О3.
Calculated, %: С 65.11; Н 5.46; N 10.85.
1
Compound 1j. Yield 75%; mp 116-117°C (EtOH). IR spectrum, ν, cm−1: 1685, 1735 (С=О). H NMR
spectrum, δ, ppm (J, Hz): 1.41 (3Н, t, J = 7.0, СН3); 2.40 (3Н, s, СН3); 4.24 (2Н, d, J = 7.0, СН2);
198

7.34 (2Н, d, J = 8.5, Н Аr); 7.85 (2Н, d, J = 8.5, Н Аr); 9.15 (1Н, s, Н-5); 10.31 (1Н, s, СН=О). Found, %:
С 64.89; Н 5.56; N 10.71. С14Н14N2О3. Calculated, %: С 65.11; Н 5.46; N 10.85.
Compound 1k. Yield 67%; mp 171-172°C (EtOH). IR spectrum, ν, cm−1: 1690, 1730 (С=О). 1H NMR
spectrum, δ, ppm (J, Hz): 1.44 (3Н, t, J = 7.0, СН3); 4.46 (2Н, d, J = 7.0, СН2); 7.57-7.63 (2Н, m, Н Аr); 7.97-
8.15 (4Н, m, Н Аr); 8.55 (1Н, s, Н Аr); 9.34 (1Н, s, Н-5); 10.35 (1Н, s, СН=О). Found, %: С 69.16; Н 4.93; N
9.68. С17Н14N2О3. Calculated, %: С 69.38; Н 4.79; N 9.55.
1-Aryl-1H-pyrazole-3,4-dicarboxylic Acids 2a-f. A suspension of the alkyl ester 1a-k (1 mmol) and
NaOH (2 g, 5 mmol) in water (50 ml) was heated at 40-50°C with stirring until completely dissolved (~30 min).
The reaction mixture was cooled to room temperature, 2 ml of 30% hydrogen peroxide was added, and the
mixture was stirred for 2 h and acidified to pH 2 with dilute hydrochloric acid. The precipitate was filtered off,
dried, and recrystallized from acetic acid.
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