Polyfunctional pyrazoles 5*. preparative synthesis of 1-aryl-4-formylpyrazole- 3-carboxylic acids

Article abstract of DOI:10.1007/s10593-010-0451-z

Treatment of methyl pyruvate N-arylhydrazones with the Vilsmeier-Haack reagent gave methyl 1-aryl-4-formylpyrazole-3-carboxylates, basic hydrolysis of which yielded the corresponding acids.

Full text of DOI:10.1007/s10593-010-0451-z

Chemistry of Heterocyclic Compounds, Vol. 45, No. 12, 2009
POLYFUNCTIONAL PYRAZOLES
5*. PREPARATIVE SYNTHESIS OF
1-ARYL-4-FORMYLPYRAZOLE-
3-CARBOXYLIC ACIDS
M. K. Bratenko1**, M. M. Barus1, and M. V. Vovk2
Treatment of methyl pyruvate N-arylhydrazones with the Vilsmeier-Haack reagent gave methyl 1-aryl-
4-formylpyrazole-3-carboxylates, basic hydrolysis of which yielded the corresponding acids.
Keywords: methyl pyruvate N-arylhydrazones, 1-aryl-4-formylpyrazole-3-carboxylic acids, Vilsmeier-
Haack reaction.
Polyfunctional pyrazole-3-carboxylic acids are of interest for chemical and biological investigation. In
particular, esters and amides of 4-halo(nitro)-1-glucosylpyrazole-3-carboxylic acid show clear antiviral and
antitumor activity [2]. Fungicidal activity has been observed in 1-(2,4-dinitrophenyl)-4-formylpyrazole-
3-carboxylate [3] which have also been used in the synthesis of the potential calcium channel blockers 4-(3-
carboxypyrazol-4-yl)-1,4-dihydropyridines [4]. 1-Aryl-5-chloro-4-formylpyrazole-3-carboxylic acids are
important intermediates in the preparation of 2,6-dihydropyrazolo[3,4-d]pyridazin-7-ones as novel antagonists
of the cannabinoid receptor 1 (CB1-R) [5]. As a whole, the synthetic potential of 4-formylpyrazole-3-carboxylic
acid and its derivatives remains unexplored to this time and this is due, to a large degree, to the absence of
convenient preparative methods.
The synthesis of a series of 5-substituted 4-formylpyrazole-3-carboxylic acids via formylation of the
corresponding 3-ethoxycarbonylpyrazol-5-ones [6] and also by reduction of 4-[oxo(phenyl)acetyl]-1,5-diphenyl-
pyrazole-3-carboxylic acid [7, 8] has been reported. The method discussed in [3, 4] of a Vilsmeier-Haack
preparation of 4-formylpyrazole-3-carboxylic acid is limited to examples using only the 4-nitro- and
2,4-dinitrophenylhydrazones of alkyl pyruvate and, because of the marked acceptor properties of the aryl
substituents, its universality cannot be judged. It should also be noted that the N-arylhydrazones of pyruvates are
generally obtained from acids least stable on storage with subsequent esterification of the carboxyl group [9-11].
_______
* For Communication 4 see [1].
** To whom correspondence should be addressed, e-mail: chornous@inbox.ru.
1Bukovinian State Medical University, Chernivtsy 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. 12, pp. 1817-1822, December, 2009.
Original article submitted January 16, 2009.
1464
0009-3122/09/4512-1464©2009 Springer Science+Business Media, Inc.

In this study we have carried out an improved method for synthesizing pyruvic acid N-arylhydrazones. It
was found that the stable and cheap sodium salt could be used in place of the acid and this readily reacts with the
arylhydrazine hydrochlorides 1a-f in aqueous solution to give the hydrazones 2a-f. Without further purification the
latter were treated with a solution of HCl in methanol to form the methyl pyruvate hydrazones 3a-f.
Under Vilsmeier-Haack conditions compounds 3a-f are cyclized to the methyl 1-aryl-4-formylpyrazole-
3-carboxylates 4a-f. By analogy with methyl ketone hydrazones [12] it is likely that initial attack by the Vilsmeier-
Haack reagent occurs at the most nucleophilic nitrogen atom of the hydrazones 3a-f with a subsequent
C-formylation of the methyl group to form the pyrazole ring functionalized by an N,N-dimethyliminium group.
O
O
Me
Me
OH
OMe
MeCOCOONa
MeOH
HCl
HCl
ArNHNH2·
N
N
NH
Ar
NH
1a–f
Ar
3a–f
2a–f
O
O
CHO
CHO
MeO
HO
DMF/POCl3
NaOH
N
N
N
N
Ar
4a–f
Ar
5a–f
1–5 a Ar = Ph, b Ar = C6H4Br-p, c Ar = C6H4Me-o, d Ar = C6H4Me-p,
f Ar = 2-C10H7; 1–4 e Ar = C6H4COOMe-p, 5 e Ar = C6H4COOH-p
TABLE 1. Characteristics of Compounds 4a-f, 5a-f
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp,°С
Yield, %
C
H
N
4а
4b
4c
4d
4e
4f
C12H10N2O3
C12H9BrN2O3
C13H12N2O3
C13H12N2O3
C14H12N2O5
C16H12N2O3
C11H8N2O3
C11H7BrN2O3
C12H10N2O3
C12H10N2O3
C12H8N2O5
C15H10N2O3
62.38
62.61
46.35
46.63
64.17
63.93
64.01
63.93
58.55
58.33
68.29
68.57
61.40
61.11
44.56
44.77
62.88
62.61
62.49
62.61
55.62
55.39
67.42
67.67
4.28
4.38
3.03
2.93
4.79
4.95
5.12
4.95
4.34
4.20
4.46
4.32
3.88
3.73
2.51
2.39
4.25
4.38
4.45
4.38
3.08
3.10
3.89
3.79
12.02
12.17
8.89
9.06
11.66
11.47
11.22
11.47
9.87
9.72
10.11
9.99
12.77
12.96
9.64
9.49
11.99
12.17
12.41
12.17
10.95
10.77
10.70
10.52
136-137
181-182
121-122
137-138
220-222
151-152
182-184
245-247
171-172
230-232
268-270
215-216
78
81
74
76
80
75
91
96
84
88
92
85
5a
5b
5c
5d
5e
5f
1465

TABLE 2. Spectroscopic Characteristics of Compounds 4a-f, 5a-f
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm (J, Hz)*
НС=О
С=О
О–Н
4a
4b
4c
4d
4e
4f
1680
1865
1690
1685
1680
1685
1675
1745
3.94 (3Н, s, СН3О); 7.41-7.43 (1Н, m, Н Ar);
7.52-7.54 (2Н, m, Н Ar); 7.96 (2Н, d, J = 8.0, Н Ar);
9.20 (1Н, s, Н-5); 10.29 (1Н, s, СН=О)
1740
1735
1745
1745
1740
1695
3.95 (3Н, s, СН3О); 7.71 (2Н, d, J = 8.4, Н Ar);
7.96 (2Н, d, J = 8.4, Н Ar); 9.27 (1Н, s, Н-5);
10.29 (1Н, s, СН=О)
2.22 (3Н, s, СН3); 3.92 (3Н, s, СН3О);
7.37-7.45 (4Н, m, Н Ar), 8.72 (1Н, s, Н-5),
10.30 (1Н, s, СН=О)
2.37 (3Н, s, СН3); 3.94 (3Н, s, СН3О);
7.31 (2Н, d, J = 6.0, Н Ar); 7.83 (2Н, d, J = 6.0, Н Ar);
9.13 (1Н, s, Н-5); 10.28 (1Н, s, СН=О)
3.88 (3Н, s, СН3О); 3.95 (3Н, s, СН3О);
8.12 (2Н, d, J = 5.9, Н Ar); 8.16 (2Н, d, J = 5.9, Н Ar);
9.35 (1Н, s, Н-5); 10.28 (1Н, s, СН=О)
3.97 (3Н, s, СН3О); 7.52-7.54 (2Н, m, Н Ar);
7.96-8.13 (4Н, m, Н Ar); 8.54 (1Н, s, Н Ar);
9.34 (1Н, s, Н-5); 10.32 (1Н, s, СН=О)
5a
2540-285
7.40-7.43 (1Н, m, Н Ar); 7.51-7.55 (2Н, m, Н Ar);
7.96 (2Н, d, J = 7.5, Н Ar); 9.15 (1Н, s, Н-5);
10.33 (1Н, s, СН=О)
5b
5c
5d
1680
1680
1680
1700
1705
1700
2560-2880 7.73 (2Н, d, J = 8.5, Н Ar); 7.91 (2Н, d, J = 8.5, Н Ar);
9.14 (1Н, s, Н-5); 10.29 (1Н, s, СН=О)
2550-2850 2.20 (3Н, s, СН3); 7.32-7.44 (4Н, m, Н Ar);
8.86 (1Н s, Н-5); 10.24 (1Н, s, СН=О)
2540-2870 2.37 (3Н, s, СН3); 7.32 (2Н, d, J = 8.0, Н Ar);
7.83 (2Н, d, J = 8.0, Н Ar); 9.08 (1Н, s, Н-5);
10.32 (1Н, s, СН=О)
5e
5f
1685
1675
1705
1705
2570-2860 8.10 (2Н, d, J = 6.0, Н Ar), 8.16 (2Н, d, J = 6.0, Н Ar);
9.31 (1Н, s, Н-5); 10.25 (1Н, s, СН=О)
2540-2890 7.52-7.56 (2Н, m, Н Ar); 7.95-8.13 (4Н, m, Н Ar),
8.53 (1Н, s, Н Ar); 9.28 (1Н, s, Н-5);
10.36 (1Н, s, СН=О)
_______
* Signals for the carboxylic group protons of acids 5a-f were not observed
due to exchange with water present in the DMSO-d6.
Hydrolysis of the latter gives the target aldehydes 4a-f in 74-81% yields. It should also be noticed that, in contrast
to the 4-nitro- and 2,4-dinitrophenylhydrazones of the alkyl pyruvates [4], compounds 3a-f can be used with a 2.5
fold rather than 8 fold excess of POCl3 and reaction time is shortened from 4 to 2 h.
Since a carboxyl function is more acceptable than an ester for subsequent modification the esters 4a-f
were converted using basic hydrolysis to the acids 5a-f in close to quantitative yields. Moreover, in the case of
compound 4e the aryl substituent ester group is also hydrolyzed to form the diacid 5e.
The composition of esters 4a-f and acids 5a-f was in agreement with the results of elemental analysis
(Table 1) and the structure with IR and 1H NMR spectroscopic data (Table 2). The IR spectra of compounds 4, 5
show aldehyde absorption bands in the range 1675-1680 cm-1. The ester C=O bond of esters 4 absorbs at
1735-1745 cm-1 and the carboxyl group of acids 5 at 1695-1705 cm-1. The broad absorption band for the OH
1
group in the range 2540-2890 cm-1 suggests a dimer structure for acids 5a-f in the solid state. The H NMR
spectra of compounds 4 and 5 show an aldehyde proton at 10.24-10.36 ppm and an H-5 pyrazole proton at
9.08-9.35 ppm. An exclusion is found in compounds 4c and 5c in which these protons are seen at 8.72 and 8.86
ppm respectively due to the shielding effect of the methyl group in the o-position of the phenyl substituent.
1466

EXPERIMENTAL
1
IR spectra were recorded on a UR-20 instrument for KBr tablets. H NMR spectra were obtained on a
Bruker Avance DRX-500 instrument (500 MHz) using DMSO-d6 and with TMS as internal standard.
Methyl 2-(Arylhydrazono)propionates 3a-f (General Method). A solution of the hydrazine
hydrochloride 1a-f (0.1 mol) in water (30 ml) was added with vigorous stirring to a solution of sodium pyruvate
(11.0 g, 0.1 mol) in water (50 ml) followed by a solution of 2N HCl (25 ml) and then stirred for a further 0.5 h.
The precipitated hydrazones 2a-f were filtered off, dried, and added to methanol (50 ml) saturated with
hydrogen chloride. The reaction mixture was refluxed for 2 h, cooled, poured into iced water (100 ml), and the
precipitate formed was filtered off, washed with water (2×40 ml), dried, and crystallized from methanol.
Methyl 2-(Phenylhydrazono)propionate (3a). Yield 69%; mp 97-98ºC (mp 98ºC [13]).
Methyl 2-(4-Bromophenylhydrazono)propionate (3b). Yield 78%; mp 126-127ºC. IR spectrum, ν,
cm-1: 1695 (C=O), 3320-3500 (N–H). 1H NMR spectrum, δ, ppm (J, Hz): 2.05 (3H, s, CH3); 3.73 (3H, s, CH3O);
7.20 (2H, d, J = 8.5, H Ar); 7.36 (2H, d, J = 8.5, H Ar); 9.86 (1H, s, NH). Found, %: C 44.03; H 4.29; N 10.24.
C10H11BrN2O2. Calculated, %: C 44.30; H 4.09; N 10.33.
Methyl 2-(2-Methylphenylhydrazono)propionate (3c). Yield 70%; mp 71-72ºC. IR spectrum, ν, cm-1:
1
1690 (C=O), 3340-3520 (N–H). H NMR spectrum, δ, ppm (J, Hz): 2.13 (3H, s, CH3); 2.21 (3H, s, CH3); 3.79
(3H, s, CH3O); 6.81 (1H, t, = 7.0, H Ar); 7.09-7.15 (2H, m, H Ar); 7.42 (1H, d, J = 7.5, H Ar); 12.04 (1H, s,
NH). Found, %: C 64.19; H 6.91; N 13.75. C11H14N2O2. Calculated, %: C 64.06; H 6.84; N 13.58.
Methyl 2-(4-Methyphenylhydrazono)propionate (3d). Yield 75%; mp 136-137ºC. IR spectrum, ν,
cm-1: 1695 (C=O), 3330-3520 (N–H). 1H NMR spectrum, δ, ppm (J, Hz): 2.04 (3H, s, CH3); 2.24 (3H, s, CH3);
3.72 (3H, s, CH3O); 7.03 (2H, d, J = 7.0, H Ar); 7.15 (2H, d, J = 7.0, H Ar); 9.65 (1H, s, NH). Found, %:
C 64.29; H 6.91; N 13.75. C11H14N2O2. Calculated, %: C 64.06; H 6.84; N 13.58.
Methyl 2-(4-Methoxycarbonylhydrazono)propionate (3e). Yield 82%; mp 164-165ºC (mp 166ºC
[14]).
Methyl 2-(2-Naphthylhydrazono)propionate (3f). Yield 72%; mp 121-122ºC (mp 90-91ºC (syn form),
136-137ºC (anti form [15]). IR spectrum, ν, cm-1: 1695 (C=O), 3310-3490 (NH). 1H NMR spectrum, δ, ppm (J,
Hz): 2.12 (3H, s, CH3); 3.77 (3H, s, CH3O); 7.27 (1H, t, J = 7.0, H Ar); 7.39 (1H, t, J = 7.0, H Ar); 7.57-7.76
(5H, m, H Ar); 9.99 (1H, s, NH). Found, %: C 69.44; H 6.01; N 11.69. C14H14N2O2. Calculated, %: C 69.41;
H 5.82; N 11.56.
Methyl 1-Aryl-4-formylpyrazole-3-carboxylates 4a-f. POCl3 (38.0 g, 0.25 mol) was added with
stirring to DMF (50 ml) cooled to 0ºC at such a rate that the temperature of the reaction mixture did not exceed
10ºC. The hydrazone 3a-f (0.1 mol) was added portionwise after 0.5 h and following its solution the cooling was
ceased and the reaction mixture temperature spontaneously rose to 50-60ºC. The product was stirred for 2 h at
65-70ºC, cooled, poured into iced water (300 ml), and the precipitate was filtered off, washed with water, dried,
and crystallized from methanol.
1-Aryl-4-formylpyrazole-3-carboxylic Acids 5a-f. A solution of NaOH (4 g, 0.01 mol) in water
(20 ml) was added with stirring to a suspension of the methyl ester 4a-f (0.005 mol) in ethanol (20 ml) and water
(60 ml). After homogenization of the reaction mixture (~ 30 min) it was filtered, acidified with dilute
hydrochloric acid to pH 2, and the precipitate formed was filtered off, washed with water, dried, and crystallized
from a mixture of acetic acid and water (1:2).
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