Esterification of 3,5-dimethyl-1-phenylpyrazol-4-ylacetic acid

Full text of DOI:10.1134/S1070363212090320

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 9, pp. 1610–1612. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © O.S. Attaryan, A.A. Sahakyan, A.E. Akopyan, L.A. Sahakyan, G.V. Asratyan, 2012, published in Zhurnal Obshchei Khimii, 2012,
Vol. 82, No. 9, pp. 1575–1577.
LETTERS
TO THE EDITOR
Esterification of 3,5-Dimethyl-1-phenylpyrazol-4-ylacetic Acid
O. S. Attaryan, A. A. Sahakyan, A. E. Akopyan, L. A. Sahakyan, and G. V. Asratyan
Institute of Organic Chemistry of Scientific-Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, Azatutyan av. 26, Yerevan, 0014 Armenia
e-mail: sahakyan.arsen@gmail.com
Received March 19, 2012
DOI: 10.1134/S1070363212090320
The ortho-disubstituted phenylacetic acids in whose
structure the carboxy group is not directly connected to
the benzene ring are easier subjected to esterification
in comparison with the ortho-disubstituted benzoic
acids. Previously [1] we studied the esterification with
methanol of ortho-disubstituted pyrazole-4-ylcarbo-
xylic acid. This acid as an analog of ortho-disubsti-
tuted benzoic acid was shown to be not esterified.
The synthesis of nitrile III by the Kolbe method in
a water–alcohol mixture failed. 3,5-Dimethyl-1-phenyl-
4-chloromethylpyrazole I, as an analog of the substi-
tuted benzyl halides (which are prone to react by must
be deleted SN1 mechanism), leads mainly to the
pyrazole ether II.
Since the dipolar aprotic solvents (acetone, DMF,
DMSO, etc.) favor the SN2 reaction mechanism, the
synthesis of nitrile III was carried out in a
dimethylsulfoxide environment. 2-(3,5-Dimethyl-1-
phenyl-1H-pyrazol-4-yl)acetonitrile III was obtained
in 52% yield. In addition, the solvolysis product VII of
the reactive chloride I was isolated and identified.
Compound VII undergoes the cross-coupling to form
In order to identify the spatial character of the effect of
the pyrazole ring on the esterification process, in this
work we studied the esterification of 3,5-dimethyl-1-
phenylpyrazol-4-ylacetic acid V with methanol. The
synthesis of 3,5-dimethyl-1-phenylpyrazol-4-ylacetic
acid V was performed (Scheme 1).
Scheme 1.
Me
Et
O
N
Me
N
O
Me
NH2
N
Me
Cl
Me
N
II
N
D
+ NaCN
Me
N
M
Me
SO
N
−
H
O
o
0
C
N
IV
5
Me
O
O
N
O
Me
Me
1
0
0 o
I
OH
C
Me
N
N
Me
Me
N
N
CH3OH
H+
III
VI
V
1610

1611
Me
ESTERIFICATION OF 3,5-DIMETHYL-1-PHENYLPYRAZOL-4-YLACETIC ACID
Scheme 2.
Me
Me
Me
Me
Me
O
Cl
OH
N
N
N
N
N
N
Me Me
H2O
Δ
Me Me
Δ
N
N
Me
Me
N
N
N
N
CH2O
IX
VIII
I
VII
the corresponding symmetrical ether VIII. When
distilling, the latter splits off a formaldehyde molecule
to give compound IX. The formation route of bis(3,5-
dimethyl-1-phenylpyrazol-4-yl)methane IX have been
studied in detail in [2, 3] (Scheme 2).
4-(Ethoxymethyl)-3,5-dimethyl-1-phenyl-1H-
pyrazole (II). To a solution of 1.9 g of sodium cyanide
in 10 ml of water was added dropwise a solution of
8.4 g of compound I in 15 ml of ethanol while stirring
at 75–80°C. The stirring was continued for 11 h at
room temperature. Then the mixture was extracted
with 50 ml of chloroform, the extract was dried with
magnesium sulfate. After distilling off the solvent the
residue was distilled in a vacuum. Yield 4.0 g (51%),
mp 140°C (1 mm Hg), nD20 1.5526. IR spectrum, ν, cm–1:
1360 (pyrazole), 1580 (C6H5), 1070–1080 (C–O–C).
1Н NMR spectrum, (СDCl3), δН, ppm, (J, Hz): 1.25 t
(3H, CH2CH3, J 7.0), 2.31 s (3H, 3-СH3), 2.33 s (3H,
5-CH3), 3.53 q (2H, CH2CH3, J 7.0), 4.35 s (2H, CH2),
7.30–7.51 m (5H, Ph). Found, %: C 73.31; H 8.12; N
12.45. C13H14O2. Calculated, %: C 73.04; H 7.82; N
12.17.
Due to the low carbonyl-type activity of the nitrile
group (especially in aromatic nitriles), the hydrolysis
of 2-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)acetonitrile
III was carried out in 50% solutions of sodium hydroxide.
At 50–60°C the hydrolysis of compound III
proceeds slowly with the low yield and stops at the
stage of the amide IV formation. The hydrolysis rate
increases at 95–100°C to give carboxylic acid V.
Even the initial experiments showed that 3,5-dimethyl-
1-phenylpyrazol-4-ylacetic acid V is easily esterified
with methanol in the presence of hydrochloric acid, i.
e., it behaves like the ortho-disubstituted phenylacetic
acid. These results and the results of [1] give reason to
believe that when the carboxy group is directly linked
to the pyrazole ring, the latter creates steric hindrances
to the attack of the alcohol molecule on the carboxyl
carbon, and vice versa.
2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)acet-
amide (IV). A mixture of 2.1 g of compound III and
0.4 g of potassium hydroxide was dissolved in 3 ml of
water and stirred for 4 h at 60°C. After cooling, the
reaction mixture was decanted, and the aqueous layer
was extracted with 30 ml of chloroform. After the
removal of the solvent the resulting crystals were
recrystallized from hexane. Yield 0.08 g (10%). IR
spectrum, ν, cm–1: 1560 (pyrazole), 1580 (C6H5), 1680
(C=O), 3200–3400 (NH2). 1Н NMR spectrum,
(DMSO-d6), δН, ppm, (J, Hz): 2.18 s (3H, 3-CH3), 2.28
s (3H, 5-СH3), 3.16 s (2H, CH2), 6.58 br. s (1H, NH2),
6.89 m (1H, NH2), 7.31 m (1H, Ph), 7.41–7.44 m (4H,
Ph). Found, %: C 68.44; H 6.89; N 18.10. C13H15N3O.
Calculated, %: C 68.12; H 6.55; N 18.34.
Due to the fact that the carbonyl group has a
trigonal planar form (owing to the sp2-hybridized
carbon atom), the reagent can attack it with any of the
two sides with equal probability. Therefore the
pyrazole ring should not cause steric hindrances to the
esterification. On the other hand, in pyrazol-4-
ylcarboxylic acids the bulky pyrazole substituent is
directly bonded with the carbon atom of the carboxyl
group, and in the pyrazol-4-ylacetic acid molecule this
bonding is performed via the methylene bridge.
2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)aceto-
nitrile (III). A mixture of 1.4 g of sodium cyanide at
60°C was dissolved in 15 ml of DMSO and cooled to
30°C. Then to the mixture was added dropwise a
solution of 6.1 g of compound I in 5 ml of DMSO at
45°C. The stirring was continued for 1 h at 60°C. After
cooling, 10 ml of water was added to dissolve the salt.
The solution was extracted with chloroform; the
It is also known that the rate of carboxylic acids
esterification decreases, if the reagent species occupies
a large volume or the carbonyl group is surrounded
with bulky groups. As expected, a similar dependence
of the carbonyl group reactivity on the size of the
neighboring substituents is also observed in pyrazol-4-
ylcarboxylic and pyrazol-4-ylacetic acids.
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1612
ATTARYAN et al.
extract was dried over magnesium sulfate. The solvent
was distilled off, and the residue was distilled in a
vacuum. Yield 3 g (52%), mp 178–180°C (1 mm Hg),
nD20 1.5720. IR spectrum, ν, cm–1: 1550 (pyrazole),
1580 (C6H5), 2230 (C=N). 1Н NMR spectrum,
(СDCl3), δН, ppm, (J, Hz): 2.32 s (3H, 3-CH3), 2.34 s
(3H, 5-СH3), 4.37 s (2H, CH2), 7.33–7.50 m (5H, Ph).
Found, %: C 73.61; H 6.48; N 20.01. C13H13N3.
Calculated, %: C 73.93; H 6.16; N 19.90.
Found, %: C 67.58; H 6.31; N 12.35. C13H14N2O2.
Calculated, %: C 67.82; H 6.08; N 12.17.
1-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)-2-
methoxymethanone (VI). To a mixture of 0.8 g of V
in 20 ml of methanol was added a catalytic amount of
conc. hydrochloric acid. The mixture was refluxed for
12 h. After cooling the solvent was removed without
heating. The residue was neutralized with Na2CO3
solution and extracted with chloroform. The extract
was dried over magnesium sulfate. After the solvent
removal the resulting crystals were recrystallized from
water. Yield 0.7 g (80%), mp 61–62°C. IR spectrum, ν,
1,2-Bis(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-
methane (IX). Yield 1.2 g (24.5%), mp 258–262°C
(1 mm Hg), mp 117–118°C (water–acetone). IR spectrum,
ν, cm–1: 1550 (pyrazole), 1580 (C6H5). 1Н NMR
spectrum, (DMSO-d6), δН, ppm, (J, Hz): 2.1 s (6H, 3-
CH3), 2.23 s (6H, 5-СH3), 3.52 s (2H, CH2), 7.27–7.46
m (10H, Ph). Found, %: C 77.30; H 6.89; N 15.34.
C23H24N4. Calculated, %: C 77.52; H 6.74; N 15.73.
1
cm–1: 1550 (pyrazole), 1580 (C6H5), 1690 (C=O). Н
NMR spectrum, (DMSO-d6–CCl4, 1:3), δН, ppm, (J,
Hz): 2.18 s (3H, 3-CH3), 2.28 s (3H, 5-СH3), 3.37 s
(2H, CH2), 7.31 m (1H, Ph), 7.39–7.47 m (4H, Ph).
Found, %: C 68.31; H 6.22; N 11.31. C14H16N2O2.
Calculated, %: C 68.85; H 6.55; N 11.47.
1-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)-2-hyd-
roxyethanone (V). A mixture of 1.1 g of compound
III and 0.57 g of potassium hydroxide was dissolved
in 2.5 ml of water and heated to reflux for 18 h until
the release of ammonia ceased. The solution was
extracted with chloroform. The aqueous residue was
neutralized with hydrochloric acid and extracted with
chloroform. The extract was dried with magnesium
sulfate. After the solvent removal, the resulting
crystals were recrystallized from water. Yield 0.8 g
(70%), mp 122–129°C. IR spectrum, ν, cm–1: 1550
(pyrazole), 1580 (C6H5), 1700 (C=O), 3200–3400
1
The H NMR spectra were recorded on a Varian
Mercury spectrometer (300 MHz) using DMSO-d6–
CCl4 mixture (1:3) as a solvent. The IR spectra were
obtained on a Specord 75-IR instrument (thin film).
REFERENCES
1. Sahakyan, A.A., Zh. Obshch. Khim., 2011, vol. 81,
no. 8, p. 1403.
2. Attaryan, O.S., Gevorkyan, A.A., Antanosyan, S.K.,
Martirosyan, S.S., Panosyan, G.A., and Matsoyan, S.G.,
Zh. Obshch. Khim., 2005, vol. 75, no. 9, p. 1575.
1
(OH). Н NMR spectrum, (DMSO-d6), δН, ppm, (J,
Hz): 2.19 s (3H, 3-CH3), 2.28 s (3H, 5-СH3), 3.28 s
(2H, CH2), 7.31 m (1H, Ph), 7.40–7.47 (4H, Ph).
3. Attaryan, O.S., Gevorkyan, A.A., Antanosyan, S.K.,
Martirosyan, S.S., and Matsoyan, S.G., Zh. Obshch.
Khim., 2007. vol. 77, no. 6, p. 1053.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 9 2012