Synthesis of 3-substituted arylpyrazole-4-carboxylic acids

Article abstract of DOI:10.1007/s11176-005-0318-7

A method was suggested for preparing previously unknown 3-aryl-substituted pyrazole-4-carboxylic acids, involving Vilsmeier formylation of semicarbazones of 26 available mono- and disubstituted acetophenones and 2-acetylthiophene followed by oxidation of

Full text of DOI:10.1007/s11176-005-0318-7

Russian Journal of General Chemistry, Vol. 75, No. 5, 2005, pp. 782 789. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 5, 2005,
pp. 829 835.
Original Russian Text Copyright
2005 by Lebedev, Lebedeva, Sheludyakov, Kovaleva, Ustinova, Kozhevnikov.
Synthesis of 3-Substituted Arylpyrazole-4-carboxylic Acids
A. V. Lebedev, A. B. Lebedeva, V. D. Sheludyakov,
E. A. Kovaleva, O. L. Ustinova, and I. B. Kozhevnikov
State Research Institute of Chemistry and Technology of Organoelement Compounds,
State Research Center, Moscow, Russia
Received December 26, 2003
Abstract A method was suggested for preparing previously unknown 3-aryl-substituted pyrazole-4-carb-
oxylic acids, involving Vilsmeier formylation of semicarbazones of 26 available mono- and disubstituted
acetophenones and 2-acetylthiophene followed by oxidation of the resulting 3-aryl-substituted pyrazole-4-
carboxaldehydes under the action of potassium permanganate. The mechanism of the formylation reaction is
discussed. The method successfully works even with acetophenones containing alkyl substituents. In the latter
case, an additional stage that involves isolation of pyrazole-4-carboxylic acids as their silyl esters is used.
It is known [1] that semicarbazones of certain
methyl aryl ketones react with phosphoryl chloride in
DMF to form 3-arylpyrazole-4-carboxaldehydes.
Taking into account that the pyrazole ring is a con-
stituent of natural amino acids [2 4], as well as that
pyrazolecarboxylic acids are attractive as inter-
mediates in the synthesis of new medicinals and their
precursors, we have studied the conversion of a wide
range of available methyl aryl ketones I into pre-
viously unknown 3-arylpyrazole-4-carboxylic acids
VI via the intermediate Vismeier formylation of semi-
carbazones II to pyrazolecarboxaldehydes III, and
oxidation of the latter with potassium permanganate.
It was found that available semicarbazones II, as
would be expected, are formylated under the action of
2 mol of POCl3 DMF complex IV to form the corre-
sponding 3-arylpyrazole-4-carboxaldehydes III.
R
N
OCH
1) 2POCl3 HC(O)N(CH3)2 (IV);
H2NNHC(O)HN2 HCl
2) NaOH/H2O
CH3CR
O
CH3CR
NNHC(O)NH2
NaOC(O)CH3
N
H
Ia Iaa
IIa IIaa
IIIa IIIaa
R = C6H5 (a), 4-ClC6H4 (b), 4-HOC6H4 (c), 4-FC6H4 (d), 4-CH3C6H4 (e), 4-O2NC6H4 (f), 4-C2H5C6H4 (g), 4-(CH3)2
CHC6H4 (h), 4-CH3OC6H4 (i), 4-BrC6H4 (j), 4-C2H5OC6H4 (k), 4-CH3(CH2)3OC6H4 (l), 3-FC6H4 (m), 3-BrC6H4 (n),
3-O2NC6H4 (o), 3-CH3OC6H4 (p), 3-HOC6H4 (q), 3-CH3C6H4 (r), 2-FC6H4 (s), 2-CH3OC6H4 (t), 2,4-(CH3)2C6H3 (u),
3,4-(CH3)2C6H3 (v), 2,5-(CH3)2C6H3 (w), 3,4-(CH3O)2C6H3 (x), 2,5-(CH3O)2C6H3 (y), 3-Cl-4-C2H5OC6H3 (z),
2-thienyl (aa).
The yields of pure pyrazolecarboxaldehydes III
vary from 31 to 87% based on semicarbazones II
which, in their turn, were isolated in 78 95% yields.
The purity of the aldehydes after their recrystallization
from water was 96 99%. With other solvents, worse
results were obtained in terms of both yields and purity.
followed by ring closure to give pyrazoles V, and
formylation of the latter with a further molecule of
complex IV into the 4-position of the pyrazole ring.
Evidence for the suggested scheme that involves
two successful attacks of complex IV on molecules II
and V comes from the detection of pyrazoles Vb, Vf,
1
Vg, and Vo by H NMR spectroscopy and GC MS.
The reaction evidently proceeds via intermediate
formylation of the methyl group in semicarbazones II
Pyrazoles V are difficult to separate from pyrazole-
1070-3632/05/7505-0782 2005 Pleiades Publishing, Inc.

SYNTHESIS OF 3-SUBSTITUTED ARYLPYRAZOLE-4-CARBOXYLIC ACIDS
783
+
|
|
POCl3 + (CH3)2NCHO
(CH3)2N
CHOPOCl2 Cl
IV
R
(1) IV;
(2) NaOH/H2O
II
N
RCCH2CH(OPOCl2)N(CH3)2
NNHC(O)NH2 HCl
IIIa IIIaa
CO2, NH3,
(CH3)2NH, POCl3
N
H
Va Vaa
ecarboxaldehydes III, and, therefore, semicarbazones
II should be formylated with at least 2.25 mol of
POCl3 to exclude presence of pyrazoles Va Vaa in
the reaction mixture.
pounds III are difficult to isolate pure without con-
siderable losses.
R
N
HOOC
KMnO4
NaOH/H2O
IIIa IIIaa
Pyrazolecarboxaldehydes III are solid substances
1
N
(except for IIIw which is a viscous oil). Their H
VIa VIaa
NMR spectra reveal a characteristic tautomerism of
3- and 5-substituted pyrazoles (two resonance signals
of the CH group at the heteroring nitrogen), associated
with intermolecular NH N hydrogen bonding [5].
It should be noted that the chosen oxidation
method proved insufficiently effective with certain
pyrazolecarboxaldehydes methylated in the benzene
group, since the methyl group is partially oxidized
into carboxyl. Thus formed diacids (8 10%) are in-
separable by conventional methods, such as recrystal-
lization, reprecipitation, or chromatography. Therefore,
for purification we made use of distillation of silyl
pyrazolecarboxylates and their subsequent base
hydrolysis. Thus the purity of the target products
could be brought to 98 99%. The process was accom-
plished by the following scheme.
Pyrazolecarboxaldehydes III are readily soluble in
aqueous alkalis. For this reason, we chose potassium
permanganate to oxidize compounds III into 3-aryl-
pyrazole-4-carboxylic acids VI. The reaction occurs in
high yield (86 95%) and, therefore, it could be
performed with crude aldehydes III just after formyla-
tion of semicarbazones II. This allows the yields of
compounds VIa VIaa to be much improved (by 5
15% based on starting acetophenones I), since com-
R2
HOOC
VIe, VIr, VIu +
R1
N
KMnO4, NaOH/H2O
IIIe, IIIr, IIIu
N
H
VIIa VIIc
R2
(1) distillation;
(2) H2O/NaOH;
(3) HCl
R
Me3SiOOC
Me3SiOOC
R1
(Me3Si)2NH
H2SO4
VIe, VIr, VIu
(from distillate)
+
VIIa VIIc
(from bottoms)
N +
N
N
SiMe3
SiMe3
VII, R1 = H, R2 = 4-COOH (a); R1 = H, R2 = 3-COOH (b); R1 = 2(4)-CH3, R2 = 4(2)-COOH (c). VIII, R = 4-CH3C6H4
(a), 3-CH3C6H4 (b), 2,4-(CH3)2C6H3 (c). IX, R1 = H, R2 = 4-CO2SiMe3 (a), R1 = H, R2 = 3-CO2SiMe3 (b), R1 = 2(4)-
CH3, R2 = 4(2)-CO2SiMe3 (c).
1
According to the H NMR spectra, pyrazolecarb-
exhibit no tautomerism of substituent position, which
is evidenced by the observation of a single signal of
oxylic acids VI, unlike pyrazolecarboxaldehydes III,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

784
LEBEDEV et al.
the CH group on nitrogen and is explained by the fact
360.14 MHz. The mass spectra were obtained on a
QP 5000 instrument at an ionizing energy of 70 eV.
Gas chromatography mass spectrometry was per-
formed on the same instrument using an SE-30
capillary column (50 m).
that
hydrogen bonding involving the COOH group is
favored over NH N.
The yields and physicochemical characteristics of
pyrazolecarboxaldehydes III and pyrazolecarboxylic
acids VI and their derivatives are listed in the table.
Semicarbazones IIa IIaa. A thoroughly ground
mixture of 100 g of semicarbazide hydrochloride and
100 g of anhydrous sodium acetate was suspended in
1 l of ethanol, and the suspension was refluxed for
45 min and filtered while hot. Methyl aryl ketone I,
0.83 mol, was added to the mother liquor under reflux,
and the mixture was refluxed for 1 h, cooled to 20 C,
EXPERIMENTAL
1
The H NMR spectra were measured in DMSO-d6
on a Bruker AM-360 spectrometer, working frequency
Yields and physicochemical characteristics of synthesized pyrazoles
Found, %
Calculated, %
M+
(m/z)
mp,
C
1H NMR spectrum, , ppm
Formula
C
H
C
H
IIIa
87
145
172 7.10 t (1H, CH), 7.30 t (2H, 2CH), 69.59 4.65 C10H8N2O
7.70 d (2H, 2CH), 8.00 and 8.38 d (1H,
CHN), 9.88 s (1H, CHO), 13.60 s (1H,
NH)
69.76 4.68
IIIb
IIIc
32
49
142 144 206 7.45 d (2H, 2CH), 7.89 d (2H, 2CH), 58.00 3.37 C10H7ClN2O
8.12 and 8.40 d (1H, CHN), 9.91 s (1H,
CHO), 13.60 s (1H, NH)
202 204 188 6.88 d (2H, 2CH), 7.63 d (2H, 2CH), 63.69 4.24 C10H8N2O2
8.10 and 8.40 d (1H, CHN), 9.70 s (1H,
58.13 3.41
63.82 4.28
OH), 9.87 s (1H, CHO), 13.59 s (1H,
NH)
IIId
IIIe
85
54
172 174 190 7.30 t (2H, 2CH), 7.90 t (2H, 2CH), 63.15 3.71 C10H7FN2O
8.22 and 8.40 d (1H, CHN), 9.90 s (1H,
CHO), 13.60 s (1H, NH)
123 125 186 2.40 s (3H,CH3), 7.29 d (2H, 2CH), 70.86 5.38 C11H10N2O
7.67 d (2H, 2CH), 8.00 and 8.40 d (1H,
63.16 3.71
70.95 5.41
CHN), 9.87 s (1H, CHO), 13.63 s (1H,
NH)
IIIf
76
49
198 200 217 8.23 d (2H, 2CH), 8.32 d (2H, 2CH), 55.36 3.26 C10H7N3O3
8.47 s (1H, CHN), 9.97 s (1H, CHO),
55.30 3.25
71.98 6.04
13.73 s (1H, NH)
IIIg
93 95
200 1.22 t (3H, CH3), 2.65 q (2H, CH2), 71.91 6.02 C12H12N2O
7.34 d (2H, 2CH), 7.70 d (2H, 2CH),
8.26 d (1H, CHN), 9.89 s (1H, CHO),
13.68 s (1H, NH)
IIIh
55
66 68
214 1.23 d (6H, 2CH3), 2.95 m (1H, CH), 72.80 6.57 C13H14 N2O 72.87 6.59
7.37 d (2H, 2CH), 7.71 d (2H, 2CH),
8.28 s (1H, CHN), 9.88 s (1H, CHO),
13.70 s (1H, NH)
IIIi
IIIj
63
55
163 165 202 3.78 s (3H, OCH3), 7.05 d (2H, 2CH), 65.32 4.95 C11H10N2O2
7.70 d (2H, 2CH), 8.23 d (1H, CHN),
9.88 s (1H, CHO), 13.65 s (1H, NH)
145 147 251 7.40 d (2H, 2CH), 7.88 d (2H, 2CH), 47.83 2.80 C10H7BrN2O
8.10 and 8.40 d (1H, CHN), 9.90 s (1H,
65.34 4.98
47.86 2.81
CHO), 13.60 s (1H, NH)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

SYNTHESIS OF 3-SUBSTITUTED ARYLPYRAZOLE-4-CARBOXYLIC ACIDS
785
Table. (Contd.)
Found, %
Calculated, %
M+
(m/z)
mp,
C
1H NMR spectrum, , ppm
Formula
C
H
C
H
IIIk
IIIl
59
50
170 173 216 1.24 t (3H, CH3), 4.06 q (2H, OCH2), 66.61 5.57 C12H12N2O2
7.04 d (2H, 2CH), 7.72 d (2H, 2CH),
66.65 5.59
8.10 and 8.40 d (1H, CHN), 9.87 s (1H,
CHO), 13.63 s (1H, NH)
179 181 244 0.97 t (3H, CH3), 1.43 m (2H, CH2), 68.73 6.62 C14H16N2O2
1.71 m (2H, CH2), 4.03 t (2H, OCH2),
68.83 6.60
7.03 d (2H, 2CH), 7.72 d (2H, 2CH),
8.25 d (1H, CHN), 9.87 s (1H, CHO),
13.63 s (1H, NH)
IIIm
IIIn
IIIo
81
53
51
137 138 190 7.29 t (1H, CH), 7.52 q (1H, CH), 63.16 3.70 C10H7FN2O
7.73 m (2H, 2CH), 8.48 s (1H, CHN),
63.16 3.71
47.86 2.81
55.30 3.25
9.91 s (1H, CHO), 13.80 s (1H, NH)
149 151 251 7.25 d (1H, CH), 7.56 t (1H, CH), 47.84 2.81 C10H7BrN2O
7.70 m (2H, 2CH), 8.44 s (1H, CHN),
9.90 s (1H, CHO), 13.82 s (1H, NH)
156 158 217 7.70 t (1H, CH), 8.27 d (1H, CH), 55.27 3.22 C10H7N3O3
8.38 d (1H, CH), 8.70 d (1H, CHN),
8.81 s (1H, CH), 9.95 s (1H, CHO),
13.90 s (1H, NH)
IIIp
44
158 161 202 3.77 s (3H, OCH3), 7.10 d (1H, CH), 65.31 4.96 C11H10N2O2
7.42 m (2H, 2CH), 7.55 t (1H, CH),
65.34 4.98
8.34 d (1H, CHN), 9.90 s (1H, CHO),
13.81 s (1H, NH)
IIIq
IIIr
31
75
204 205 188 6.87 d (1H, CH), 7.18 d (2H, 2CH), 63.72 4.25 C10H8N2O2
7.29 t (1H, CH), 8.27 d (1H, CHN),
9.60 s (1H, OH), 9.88 s (1H, CHO),
13.82 s (1H, NH)
98 102 186 2.25 s (3H, CH3), 7.20 d (1H, CH), 70.88 5.39 C11H10N2O
7.32 t (1H, CH), 7.50 m (2H, 2CH),
63.82 4.28
70.95 5.41
8.30 d (1H, CHN), 9.88 s (1H, CHO),
13.60 s (1H, NH)
IIIs
IIIt
61
50
146 148 190 7.30 m (2H, 2CH), 7.54 m (2H, 2CH), 63.15 3.71 C10H7FN2O
8.28 d (1H, CHN), 9.88 s (1H, CHO),
63.16 3.71
65.34 4.98
13.62 s (1H, NH)
153 154 202 3.76 s (3H, OCH3), 7.10 m (2H, 2CH), 65.34 4.98 C11H10N2O2
7.46 m (2H, 2CH), 8.00 and 8.40 d (1H,
CHN), 9.68 s (1H, CHO), 13.58 s (1H,
NH)
IIIu
IIIv
46
52
73 75
200 2.16 s (3H, CH3), 2.32 s (3H, CH3), 71.85 6.06 C12H12N2O
7.09 d (1H, CH), 7.16 s (1H, CH),
71.98 6.04
71.98 6.04
7.21 d (1H, CH), 8.20 s (1H, CHN),
9.60 s (1H, CHO), 13.60 s (1H, NH)
103 105 200 2.18 s (3H, CH3), 2.34 s (3H, CH3), 71.95 6.02 C12H12N2O
7.15 m (3H, 3CH), 8.22 s (1H, CHN),
9.70 s (1H, CHO), 13.50 s (1H, NH)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

786
LEBEDEV et al.
Table. (Contd.)
Found, %
Calculated, %
M+
(m/z)
mp,
C
1H NMR spectrum, , ppm
Formula
C
H
C
H
IIIw
IIIx
IIIy
IIIz
50
40
62
71
200 2.14 s (3H, CH3), 2.30 s (3H, CH3), 71.88 6.01 C12H12N2O
7.14 s (1H, CH), 7.20 q (2H, 2CH),
8.25 s (1H, CHN), 9.80 s (1H, CHO),
13.40 s (1H, NH)
71.98 6.04
62.06 5.21
62.06 5.21
150 152 232 3.81 s (6H, 2OCH3), 7.08 d (1H, CH), 62.05 5.20 C12H12N2O3
7.39 d (1H, CH), 7.45 s (1H, CH),
8.22 d (1H, CHN), 9.89 s (1H, CHO),
13.62 s (1H, NH)
156 158 232 3.77 s (3H, OCH3), 3.80 s (3H, OCH3), 62.03 5.18 C12H12N2O3
7.15 d (1H, CH), 7.22 d (1H, CH),
7.44 s (1H, CH), 8.20 d (1H, CHN),
9.90 s (1H, CHO), 13.60 s (1H, NH)
191 193 250 1.38 t (3H, CH3), 4.18 q (2H, OCH2), 57.50 4.42 C12H11ClN2O2 57.50 4.42
7.22 d (1H, CH), 7.81 d (1H, CH),
8.00 s (1H, CH), 8.57 s (1H, CHN),
9.87 s (1H, CHO), 13.72 s (1H, NH)
IIIaa
Vb
45
8a
4a
3a
69 71
178 7.17 t (1H, CH), 7.62 d (1H, CH), 53.78 3.34 C8H6N2OS
8.03 d (1H, CHS), 8.54 s (1H, CHN),
53.92 3.39
9.97 s (1H, CHO), 13.68 c (1H, NH)
178 6.62 d (1H, CH), 7.38 d (2H, 2CH),
7.62 d (1H, CHN), 7.78 d (2H, 2CH),
12.85 s (1H, NH)
189 6.72 d (1H, CH), 7.62 d (1H, CHN),
8.02 d (2H, 2CH), 8.21 d (2H, 2CH),
13.00 s (1H, NH)
172 1.21 t (3H, CH3), 2.66 q (2H, CH2),
6.47 d (1H, CH), 7.17 d (2H, 2CH),
7.48 d (1H, CHN), 7.53 d (2H, 2CH),
13.40 s (1H, NH)
C9H7ClN2
C9H7N3O2
C11H12N2
Vf
Vg
Vo
3a
98
95
98
88
93
189 6.70 d (1H, CH), 7.60 m (2H, 2CH),
8.08 d (1H, CH), 8.31 d (1H, CH),
8.60 s (1H, CH), 12.95 s (1H, NH)
188 7.07 t (1H, CH), 7.25 t (2H, 2CH), 63.69 4.24 C10H8N2O2
7.63 d (2H, 2CH), 8.06 s (1H, CHN),
C9H7N3O2
VIa
VIb
VId
VIe
VIf
>270
>270
>270
>270
>270
63.82 4.28
12.80 br (2H, NH + COOH)
222 7.38 d (2H, 2CH), 7.81 d (2H, 2CH), 53.89 3.14 C10H7ClN2O2 53.95 3.17
8.20 s (1H, CHN), 13.00 br (2H, NH +
COOH)
206 7.23 t (2H, 2CH), 7.82 t (2H, 2CH), 58.24 3.41 C10H7FN2O2
8.20 s (1H, CHN), 13.05 s (2H, NH +
COOH)
202 2.34 s (3H, CH3), 7.23 d (2H, 2CH), 65.29 4.96 C11H10N2O2
7.61 d (2H, 2CH), 8.07 s (1H, CHN),
58.26 3.42
65.34 4.98
51.51 3.03
12.70 br (2H, NH + COOH)
233 8.06 d (2H, 2CH), 8.26 d (2H, 2CH), 51.46 3.01 C10H7N3O4
8.30 s (1H, CHN), 13.50 br (2H, NH +
COOH)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

SYNTHESIS OF 3-SUBSTITUTED ARYLPYRAZOLE-4-CARBOXYLIC ACIDS
787
Table. (Contd.)
Found, %
Calculated, %
M+
(m/z)
mp,
C
1H NMR spectrum, , ppm
Formula
C
H
C
H
VIi
VIj
VIk
99
96
97
>270
218 3.78 s (3H, OCH3), 7.00 d (2H, 2CH), 60.55 4.60 C11H10N2O3
7.63 d (2H, 2CH), 8.20 s (1H, CHN),
12.90 br (2H, NH + COOH)
267 7.30 d (2H, 2CH), 7.77 d (2H, 2CH), 44.93 2.67 C10H7BrN2O2 44.99 2.64
60.55 4.62
>270
>270
8.12 s (1H, CHN), 13.10 s (2H, NH +
COOH)
232 1.26 t (3H, CH3), 4.03 q (2H, OCH2), 62.02 5.18 C12H12N2O3
7.02 d (2H, 2CH), 7.67 d (2H, 2CH),
8.15 s (1H, CHN), 13.00 br (2H, NH +
COOH)
260 0.93 t (3H, CH3), 1.44 m (2H, CH2), 64.55 6.16 C14H16N2O3
1.71 m (2H, CH2), 4.01 t (2H, OCH2),
6.97 d (2H, 2CH), 7.66 d (2H, 2CH),
8.05 s (1H, CHN), 12.7 br (2H, NH +
COOH)
62.06 5.21
64.60 6.20
VIl
98
>270
VIm
VIn
VIo
VIp
VIr
99
98
92
98
86
>270
>270
>270
>270
>270
206 7.22 t (1H, CH), 7.45 q (1H, CH), 58.25 3.42 C10H7FN2O2
7.62 d (2H, 2CH), 8.20 s (1H, CHN),
13.00 br (2H, NH + COOH)
267 7.18 d (1H, CH), 7.49 t (1H, CH), 44.97 2.63 C10H7BrN2O2 44.99 2.64
7.64 m (2H, 2CH), 8.14 s (1H, CHN),
13.28 br (2H, NH + COOH)
233 7.73 t (1H, CH), 8.24 m (2H, 2CH), 51.62 3.07 C10H7N3O4
8.32 s (1H, CHN), 8.68 s (1H, CH),
13.60 br (2H, NH + COOH)
218 3.78 s (3H, OCH3), 6.96 m (1H, CH), 60.51 4.59 C11H10N2O3
7.33 m (3H, 3CH), 8.10 s (1H, CHN),
12.60 br (2H, NH + COOH)
202 2.34 s (3H, CH3), 7.21 d (1H, CH), 65.24 4.92 C11H10N2O2
7.29 t (1H, CH), 7.50 d (2H, 2CH),
58.26 3.42
51.51 3.03
60.55 4.62
65.34 4.98
8.07 s (1H, CHN), 12.80 br (2H, NH +
COOH)
VIs
VIt
VIu
98
96
93
>270
>270
>270
206 7.26 m (2H, 2CH), 7.47 m (2H, 2CH), 58.25 3.40 C10H7FN2O2
8.14 s (1H, CHN), 12.60 br (2H, NH +
58.26 3.42
60.55 4.62
66.65 5.59
COOH)
218 3.78 s (3H, OCH3), 7.03 m (2H, 2CH), 60.51 4.60 C11H10N2O3
7.38 m (2H, 2CH), 8.03 s (1H, CHN),
13.00 br (2H, NH + COOH)
216 2.08 s (3H, CH3), 2.31 s (3H, CH3), 66.62 5.57 C12H12N2O2
7.03 d (1H, CH), 7.10 d (2H, 2CH),
8.01 s (1H, CHN), 12.60 br (2H, NH +
COOH)
VIv
VIx
95
97
>270
>270
216 2.10 s (3H, CH3), 2.33 s (3H, CH3), 66.60 5.61 C12H12N2O2
7.07 m (3H, 3CH), 8.08 s (1H, CHN),
12.70 br (2H, NH + COOH)
248 3.79 s (6H, 2OCH3), 7.02 d (1H, CH), 58.01 4.83 C12H12N2O4
7.32 d (1H, CH), 7.37 s (1H, CH),
66.65 5.59
58.06 4.87
8.11 s (1H, CHN), 12.70 br (2H, NH +
COOH)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

788
LEBEDEV et al.
Table. (Contd.)
Found, %
Calculated, %
M+
(m/z)
mp,
C
1H NMR spectrum, , ppm
Formula
C
H
C
H
VIy
VIx
96
95
>270
248 3.76 s (3H, OCH3), 3.80 s (3H, OCH3), 58.03 4.85 C12H12N2O4
7.09 d (1H, CH), 7.15 d (1H, CH),
7.35 s (1H, CH), 8.08 s (1H, CHN),
12.72 br (2H, NH + COOH)
266 1.40 t (3H, CH3), 4.18 q (2H, OCH2), 54.02 4.16 C12H11ClN2O3 54.05 4.16
7.18 d (1H, CH), 7.72 d (1H, CH),
7.86 s (1H, CH), 8.10 s (1H, CHN),
12.70 br (2H, NH + COOH)
194 7.03 t (1H, CH), 7.30 d (1H, CH), 8.03 t 49.38 3.06 C8H6N2O2S
58.06 4.87
>270
>270
VIaa
VIIa
VIIb
VIIc
90
8
49.48 3.11
(2H, CHS + CHN), 12.52 br (2H, NH +
COOH)
232 7.82 d (2H, 2CH), 8.00 d (2H, 2CH),
8.17 s (1H, CHN), 12.70 br (3H, NH +
2COOH)
232 7.52 d (1H, CH), 7.97 m (2H, 2CH),
8.18 s (1H, CHN), 8.30 s (1H, CH),
12.75 br (3H, NH + 2COOH)
246 2.25 s (3H, CH3), 7.30 d (1H, CH),
7.75 d (1H, CH), 7.82 s (1H, CH),
8.10 s (1H, CHN), 12.60 br (3H, NH +
2COOH)
C11H8N2O4
C11H8N2O4
C12H10N2O4
10
6
VIIIa
VIIIb
96
96
346
C17H26N2O2Si2
346 0.02 s (9H, 3CH3), 0.06 s (9H, 3CH3), 58.72 7.49 C17H26N2O2Si2 58.92 7.56
2.35 s (3H, CH3), 7.21 d (1H, CH),
7.31 t (1H, CH), 7.53 d (2H, 2CH),
8.06 s (1H, CHN)
a
Detected only at II/IV = 1:2.
allowed to stand for 10 h, and the precipitate that
formed was filtered off, washed with a little ethanol
after which 1 mol of semicarbazone II was added so
as the temperature of the reaction mixture did not rise
cooled to 5 C, and dried to isolate semicarbazones II. over 40 50 C and uniform gas evolution was ob-
The mother liquor was reduced to 150 200 ml and
poured into 1 l of water. The precipitate that formed
was filtered off, heated for 1 h in 70 100 ml of
ethanol under reflux, and cooled to 5 C. The precip-
itate was filtered off and washed with a little ethanol
cooled to 5 C to obtain an additional crop of semi-
carbazone II. In the case of acetophenones Ic and IIq,
the alcohol was removed immediately after the syn-
thesis had been complete. The yields of semicarba-
zones were 90 95%, except for compounds IIc and
IIq (78 and 82%, respectively).
served. After all semicarbazone had been added, the
mixture was stirred for 1.5 h at 80 C and quickly
poured onto 1.5 kg of ice. Most ice melted. The mix-
ture was treated with 30% aqueous NaOH to pH 8 9,
allowed to stand for 30 min, and treated with conc.
HCl until heterogenization (pH 5 7). After 18 h, the
solid material was separated (pH 7), washed with
water, recrystallized from water (0.5 5.0 g of com-
pound per 1 l of water), and dried at 50 C to obtain
pyrazole III. Pyrazole IIIw was extracted with chloro-
form after recrystallization. For direct oxidation of
crude pyrazoles III, they were extracted from the
heterogeneous mixture with chloroform and used
without recrystallization. After the syntheses with
2 mol of POCl3 and recrystallization, from semicar-
bazones IIb, IIf, IIg, and IIo we obtained compounds
3-Arylpyrazole-4-carboxaldehydes
IIIa IIIaa.
Freshly distilled POCl3, 353 g, was added dropwise
at 0 C to 440 ml of dry DMF. The mixture was al-
lowed to stand for 20 min at 20 C and cooled to 0 C,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

SYNTHESIS OF 3-SUBSTITUTED ARYLPYRAZOLE-4-CARBOXYLIC ACIDS
789
IIIb, IIIf, IIIg, and IIIo mixed with compounds
Vb, Vf, Vg, and Vo which were identified with H
NMR and GC MS.
collecting as the first high-boiling fraction silyl esters
VIII. The latter were treated with 400 ml of 5%
aqueous NaOH, the mixture was stirred for 1 h at
100 C, cooled, and extracted with ether (2 40 ml).
The aqueous layer was acidified with HCl to pH 3.
Pure compounds VId, VIr, and VIu precipitated and
were treated as described above. The bottoms were
subjected to base hydrolysis and acidified to obtain
compounds VII mixed with 15 20% of compounds
VId, VIr, and VIu. Given are comp. no. and bp, C
(p, mm Hg): VIIIa, 173 175 (2.5); VIIIb, 190 192
(4); and VIIIc, 196 198 (3).
1
3-Arylpyrazole-4-carboxylic acids VIa VIaa.
Aldehyde III, 0.17 mol, was dissolved with stirring
in a solution of 33 g of NaOH in 650 ml of water. The
solution was cooled to 15 C, and a solution of 22.5 g
of KMnO4 in 650 ml of water was quickly added. The
mixture was stirred for 1 h at 20 C, heated to 96
98 C, allowed to decolorize, and cooled. The MnO2
precipitate was filtered off and washed with 200 ml
of water. The combined mother liquor was acidified
with conc. HCl to pH 3. The precipitate was filtered
off, washed with water, and dried at 110 120 C. The
dry residue was thoroughly ground and suspended in
800 ml of water. The suspension was stirred at 10 min
and filtered. The filtrate was washed with water to
neutral and evaporated at 100 C to obtain acids VI as
white fine powders.
REFERENCES
1. Kira, M.A., Aboul-Enein, M.N., and Korkor, M.I.,
J. Heterocycl. Chem., 1970, vol. 7, no. 1, p. 25.
2. Noe, F. and Fowden, L., Biochem. J., 1960, vol. 77,
no. 3, p. 543.
Crude aldehydes were oxidized in a similar way.
In this case, aldehydes III were dissolved in the alkali,
and the undissolved material was filtered off or ex-
tracted with chloroform, after which the solution of
KMnO4 was added dropwise. To purify acids VId,
VIr, and VIu, which contained 8 12% of diacids VII,
they were treated with 60 ml of hexamethyldisilazane,
2 4 drops of conc. H2SO4 was added, and the mixture
was refluxed for 2 h, cooled, and distilled in a vacuum,
3. Dunnil, P. and Fowden, L., Biochem. J., 1963, vol. 86,
no. 3, p. 388.
4. Takeschita, M., Nishizuka, J., and Hayaishi, O., J. Biol.
Chem., 1963, vol. 238, no. 2, p. 660.
5. Jacobs, T.L., Heterocyclic Compounds, Elderfield, R.C.,
New York: Wiley, 1957, vol. 5. Translated under the
title Geterotsiklicheskie soedineniya, Moscow: Inostran-
naya Literatura, 1961, vol. 5, pp. 71 72.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005