4-Functionally substituted 3-heterylpyrazoles: III. 3-aryl(heteryl)pyrazole-4-carboxylic acids and their derivatives

Article abstract of DOI:10.1023/A:1012490120976

3-Aryl(heteryl)-4-formylpyrazoles were cleanly oxidized by potassium permanganate in water-pyridine medium to afford in high yield 3-aryl(heteryl)pyrazole-4-carboxylic acids, that were further converted into the corresponding chlorides and amides.

Full text of DOI:10.1023/A:1012490120976

Russian Journal of Organic Chemistry, Vol. 37, No. 4, 2001, pp. 552 555. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 4, 2001,
pp. 587 590.
Original Russian Text Copyright
2001 by Bratenko, Chornous, Vovk.
4-Functionally Substituted 3-Heterylpyrazoles: III.*
3-Aryl(heteryl)pyrazole-4-carboxylic Acids and Their
Derivatives
M. K. Bratenko1, V. A. Chornous1, and M. V. Vovk2
1Bukovinskaya State Medical Academy Chernovtsy, 58000 Ukraine
2Institute of Organic Chemistry, Ukrainian Academy of Sciences, Kiev, 02094 Ukraine
Received March 16, 1999
Abstract 3-Aryl(heteryl)-4-formylpyrazoles were cleanly oxidized by potassium permanganate in water-
pyridine medium to afford in high yield 3-aryl(heteryl)pyrazole-4-carboxylic acids, that were further
converted into the corresponding chlorides and amides.
In the series of functionally substituted pyrazoles
are important 4-pyrazolecarboxylic acids. On their
capability to decarboxylate at elevated temperature is
based an extensively used preparation method for
pyrazoles unsubstituted in 4 position [2 4]. Besides
some derivatives of 4-pyrazolecarboxylic acids, e.g.
amides, possess pronounced farmaceutical activity
[5, 6]. The main described method of preparation for
4-pyrazolecarboxylic acids is the alkaline hydrolysis
of the corresponding esters [4, 7, 8] or acid hydro-
lysis of their amides [2]. The oxidation of 4-pyrazole-
carbaldehydes apart from singular examples [3, 9] up
till now have not found application in the synthesis of
the pyrazole-substituted carboxylic acids. Yet for
preparation of 1,3-disubstituted 4-pyrazolecarboxylic
acids oxidation of the corresponding aldehydes can
be a promising approach taking into account the
preparative accessibility of the latter [10 14]. The
oxidation with potassium permanganate was studied
by an example of 3-aryl(heteryl)-1-phenyl-4-formyl-
pyrazoles Ia h.
Scheme.
I, II, R1
=
Ph (a), 4-FC6H4 (b), 4-ClC6H4 (c),
4-BrC6H4 (d), 4-EtC6H4 (e), 4-PhC6H4 (f), 3-pyridyl
(g), 2-thienyl (h); III, R1 = Ph (a), 4-FC6H4 (b),
4-ClC6H4 (c), 4-BrC6H4 (d), 4-EtC6H4 (e), 2-thienyl
(f); IV, R1 = Ph, R2 = H, R3 = 3-Et2NSO2C6H4 (a);
R2,R3 = 1-CH2-2-C2H4C6H4 (b); R1 = 4-FC6H4, R2 =
H, R3
=
3,5-Cl2C6H3 (c); R2,R3
=
2,2 -
C6H4CH2CH2C6H4 (d); R1 = 4-ClC6H4, R2 = H, R3 =
2-tetrahydrofurylmethyl (g); R2,R3 = (CH2CH2)2NPh
(f); R1 = 2-thienyl, R2 = H, R3 = 3-morpholinosulfon-
ylphenyl (g); R2,R3 = 2,2 -C6H4CH2CH2C6H4 (h).
We found that aldehydes Ia h treated with potas-
sium permanganate in 50% aqueous pyridine at 18
20 C afford 4-pyrazolecarboxylic acids in high yield
(71 94%) (see the Scheme).
evidences the dimeric character of the acids syn-
thesized [15]. In the H NMR spectra the protons of
Acids II (Table 1) are high-melting colorless or
1
light yellow substances. Their structure was confirm-
1
aromatic and heteroaromatic substituents in positions
1 and 3 of the pyrazole ring are clearly seen as sets
of multiplet signals in the region 7.17 8.35 ppm, and
the singlet of the proton in position 5 (8.85 9.08 ppm)
is shifted downfield by about 0.5 ppm compared to
the corresponding singlet in the spectra of 4-formyl-
pyrazoles [14].
ed by H NMR and IR spectra. In particular, the
presence in their IR spectra recorded from solid
samples of characteristic wide absorption bands in
1
the 2500 3100 cm
region corresponds to OH
groups participating in hydrogen bonds, together
with the absorption bands of the stretching vibrations
1
of C=O groups in 1700 1710 cm
region
1070-4280/01/3704-0552$25.00 2001 MAIK Nauka/Interperiodica

4-FUNCTIONALLY SUBSTITUTED 3-HETERYLPYRAZOLES: III.
553
1
Table 1. Yields, melting points, IR and H NMR spectra, and elemental analyses of 4-pyrazolecarboxylic acids IIa h
1
IR spectrum, cm
Compd.
no.
Yield,
%
mp,
C
1H NMR spectrum, , ppma
(C=O)
(OH)
IIa
IIb
IIc
IId
IIe
94
89
86
90
82
204 205b
229 230
240 242
249 250
200 202
1710
1705
1710
1705
1700
2550 3050 7.21 7.65 m (10H, H arom), 8.87 s (1H, C5H)
2600 3000 7.40 8.03 m (9H, H arom), 8.96 s (1H, C5H)
2600 3100 7.30 7.71 m (9H, H arom), 9.03 s (1H, C5H)
2600 3000 7.34 7.78 m (9H, H arom), 8.85 s (1H, C5H)
2500 3100 1.30 t (3H, CH3), 2.55 q (2H, CH2), 7.18 7.59 m
(9H, H arom), 8.94 s (1H, C5H)
IIf
IIg
IIh
74
84
71
198 199
236 238
180 171
1710
1710
1700
2550 3050 7.28 7.84 m (14H, H arom), 8.88 s (1H, C5H)
2600 3000 7.39 8.35 m (9H, H arom), 8.93 s (1H, C5H)
2600 3050 7.17 8.12 m (8H, H arom), 9.08 s (1H, C5H)
Found, %
Calculated, %
Formula
Compd. no.
C
H
N
C
H
N
IIa
IIb
IIc
IId
IIe
IIf
73.09
67.65
64.61
56.33
73.54
77.42
67.66
62.52
4.80
4.07
3.89
3.03
5.67
4.97
4.49
3.99
10.50
9.30
9.63
8.42
10.00
8.07
C16H12N2O2
C16H11FN2O2
C16H11ClN2O2
C16H11BrN2O2
C18H16N2O2
C22H16N2O2
C15H11N3O2
C14H10N2O2S
72.71
68.09
64.32
55.98
73.95
77.63
67.93
62.21
4.55
3.90
3.69
3.21
5.51
4.74
4.18
3.73
10.61
9.43
9.40
8.16
9.58
8.23
15.84
10.36
IIg
IIh
15.67
10.19
a
The protons of COOH group and of water present in the solvent due to fast exchange appear as a broad signal in the region
3.30 3.50 ppm.
mp 206 C [2].
b
In order to obtain new derivatives of 4-pyrazole-
1-Phenyl-3-(4-ethylphenyl)-4-pyrazolecarb-
aldehyde Ie was obtained by a procedure from [13].
Yield 78%, mp 113 115 C (from ethanol). IR spec-
trum, , cm : 1700 [ (C=O)]. H NMR spectrum
(CDCl3), , ppm: 1.13 t (3H, CH3), 3.12 q (2H,
CH2), 7.25 7.74 m (9H, H arom), 8.56 s (1H, C5H),
10.05 s (1H, HC=O). Found, %: C 77.93; H 5.63;
N 10.03. C18H16N2O. Calculated, %: C 78.26; H
5.79; N 10.14.
carboxylic acids, in particular, those possessing bio-
logical activity, we converted compounds IIa e, h by
treating with thionyl chloride into 4-pyrazolecarbonyl
chlorides IIIa f in close to quantitative yield. The
constants of compounds IIIa f are listed in Table 2.
1
1
We established that 4-pyrazolecarbonyl chlorides
IIIa c, f were less reactive than typical aroyl
chlorides, and they acylate primary and secondary
aliphatic and aromatic amines by heating in toluene
for 3 h affording amides IVa h (Table 3).
3-Aryl(heteryl)-1-phenylpyrazole-4-carboxylic
acids IIa h. To a suspension of 0.05 mol of aldehyde
Ia h in 50 ml of 50% aqueous pyridine at stirring
and cooling with tap water was added within 1 h by
small portions 7.9 g (0.05 mol) of potassium per-
manganate maintaining the temperature of the reac-
tion mixture at 20 22 C. The mixture was stirred till
the violet color disappeared, the manganese dioxide
precipitate was filtered off, washed with 5% water
solution of sodium hydroxide, and to the filtrate was
added diluted hydrochloric acid. The separated pre-
EXPERIMENTAL
IR spectra were recorded on spectrometer UR-20
1
from KBr pellets. H NMR spectra were registered in
DMSO-d6 solutions on spectrometer Varian-Gemini
(300 MHz), internal reference TMS.
Aldehydes used in the study were synthesized by
the following methods: Ia, b, d f [13], Ic [12], Ig
[16]. Ih [14].
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 4 2001

554
BRATENKO et al.
Table 2. Yields, melting points, and elemental analyses of 4-pyrazolecarbonyl chlorides IIIa f
Found, %
Calculated, %
Compd.
no.
Yield,
%
mp,
C
Formula
Cl
N
Cl
N
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
95
90
88
91
81
85
99 100
140 141
124 125
126 127
184 188b
162 164
12.74
11.96
22.51
32.14a
11.09
12.68
10.20
9.04
8.88
8.03
9.36
10.49
C16H11ClN2O
C16H10ClFN2O
C16H10Cl2N2O
C16H11BrClN2O
C18H15ClN2O
C14H9ClN2OS
12.56
11.79
22.36
31.90a
11.41
13.00
9.91
9.32
8.83
7.75
9.02
10.27
a
b
Overall content of Cl and Br.
Table 3. Yields, melting points, 1H NMR spectra, and elemental analyses of 4-pyrazolecarboxamides IVa h
1H NMR spectrum, , ppm
bp at 0.02 mm Hg.
Compd. no. Yield, % mp,
C
IVa
IVb
69
68
200
121
1.06 t (6H, CH3), 3.17 q (4H, CH2), 7.42 8.18 m (14H, H arom), 9.14 s (1H, C5H),
0.47 s (1H, NH)
2.61 2.87 m (2H, CH2), 3.54 3.95 m (2H, CH2), 4.62 4.81 m (2H, CH2), 7.16
7.97 m (14H, H arom), 8.84 s (1H, C5H)
IVc
IVd
IVe
80
75
71
183 184 7.27 7.92 m (12H, H arom), 9.13 s (1H, C5H), 9.71 s (1H, NH)
234
139
2.90 m (2H, CH2), 3.33 m (2H, CH2), 7.25 7.86 m (17H, H arom), 8.27 s (1H, C5H)
1.57 1.82 m (6H, CH2), 3.65 3.96 m (3H, CH, CH2), 7.36 7.89 m (9H, H arom),
8.23 s (1H, NH), 8.93 s (1H, C5H)
IVf
IVg
68
82
159 160 2.95 3.97 m (8H, CH2), 6.80 7.96 m (14H, H arom), 8.85 s (1H, C5H)
188
2.92 m (4H, CH2), 3.65 m (4H, CH2), 7.14 8.15 m (12H, H arom), 9.17 s (1H,
C5H), 10.52 s (1H, NH)
IVh
78
204 205 2.83 m (2H, CH2), 3.64 m (2H, CH2), 8.21 s (1H, C5H), 7.21 7.77 m (16H, H arom)
Found, %
H
Calculated, %
H
Compd. no.
Formula
C
N
C
N
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
66.02
80.01
62.20
78.60
66.30
70.80
58.55
75.50
5.59
5.50
3.49
5.05
4.73
5.35
4.70
5.15
11.63
10.80
9.64
C26H26N4O3S
C25H21N3O
65.82
79.15
61.97
78.43
66.05
70.51
58.30
75.17
5.49
5.54
3.29
4.79
5.28
5.20
4.45
4.70
11.81
11.08
9.86
C22H14Cl2FN3O
C30H22FN3O
C21H20ClN3O2
C26H23ClN4O
C24H22N4O4S2
C28H21N3OS
8.90
9.15
10.50
12.78
11.50
9.11
11.00
12.66
11.34
9.39
cipitate of the 4-pyrazolecarboxylic acid was filtered
off, dried, and recrystallized from glacial acetic acid.
were distilled off, the residue was washed with
hexane and crystallized from a mixture benzene
hexane, 3: 1.
3-Aryl(heteryl)-1-phenylpyrazole-4carbonyl
chlorides IIIa f. To a suspension of 0.002 mol of
acid IIa e, h in 15 ml of anhydrous toluene was
added 0.05 mol of thionyl chloride, 3 4 drops of
dimethylformamide, and the mixture was boiled for
2 h. Then the excess thionyl chloride and solvent
3-Aryl(heteryl)-1-phenylpyrazole-4-carbox-
amides IVa h. To a solution of 0.0025 mol of
chloride IIIa c, f in 10 ml of toluene was added at
stirring 0.0025 mol of amine and 0.4 ml of triethyl-
amine. The mixture was heated to boiling for 3 h and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 4 2001

4-FUNCTIONALLY SUBSTITUTED 3-HETERYLPYRAZOLES: III.
555
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