Alkylation of pyrazoles with ethyl chloroacetate under phase-transfer catalysis and hydrolysis of the esters obtained

Full text of DOI:10.1134/S1070363214080350

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 8, pp. 1641–1643. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © V.I. Rstakyan, A.E. Hakobyan, G.B. Zakaryan, S.S. Hayotsyan, H.S. Attaryan, G.V. Asratyan, 2014, published in Zhurnal Obshchei
Khimii, 2014, Vol. 84, No. 8, pp. 1397–1399.
LETTERS
TO THE EDITOR
Alkylation of Pyrazoles with Ethyl Chloroacetate
under Phase-Transfer Catalysis and Hydrolysis
of the Esters Obtained
V. I. Rstakyan, A. E. Hakobyan, G. B. Zakaryan,
S. S. Hayotsyan, H. S. Attaryan, and G. V. Asratyan
Institute of Organic Chemistry, Scientific-Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: vrstakyan@gmail.com
Received March 12, 2014
Keywords: phase-transfer catalysis, pyrazole, alkylation, ester
DOI: 10.1134/S1070363214080350
Phase-transfer catalyzed reactions of the esters of
haloacetic acids with pyrazoles have not been studied
so far, although alkylation of pyrazoles with bromo-
acetates has been known [1]. The approach towards
synthesis of (3,5-dimethyl-1H-pyrazol-1-yl)acetic acid
via condensation of ethyl hydrazinylacetate hydro-
chloride and acetylacetone followed by hydrolysis has
been reported [2]. However, this method is laborious
due to ethyl hydrazinylacetate hydrochloride in-
stability of; yield of the target compounds does not
exceed 65%.
obtain 1H-pyrazol-1-yl-acetic acid by reacting
pyrazole with chloroacetic acid have failed, as the
pyrazole basicity (pKa 2.53) is significantly different
from the basicity of 3,5-dimethylpyrazole (pKa 4.3).
This method has also proved to be inappropriate for
synthesis of the individual isomers of 3-methyl- and
(5-methyl-1H-pyrazol-1-yl)acetic acids.
Extending our previous findings on the synthesis of
1-substituted azoles [4, 5], herein we report the
interaction of pyrazoles I and III with ethyl chloro-
acetate under phase-transfer catalysis conditions
(Scheme 1).
In [3] the authors have proposed the alkylation of
3,5-dimethylpyrazole with chloroacetic acid in
aqueous medium followed by neutralization of hydro-
chloric acid with sodium formate, making possible to
isolate amphoteric (3,5-dimethyl-1H-pyrazol-1-yl)-
acetic acid with yield of 84%. Numerous attempts to
The alkylation was carried out in acetone medium
using triethylbenzylammonium chloride (Et3BnNCl) as
catalyst and K2CO3 as base. The highest yields (45–
63%) of IV–VI were achieved at the ratios of
pyrazole : ethyl chloroacetate : K2CO3 equal to 1 : 2 : 2.5
Scheme 1.
R
R
O
K2CO3
N
Cl
N
+
R'
R'
O
Et3BnNCl
N
N
H
O
O
I_III
IV_VI
I, IV, R = R' = H; II, R = CH3, R' = H or R = H, R' = CH3; Vа, R = CH3, R' = H; Vb, R = H, R' = CH3; III, VI, R = R' = CH3.
1641

1642
RSTAKYAN et al.
Scheme 2.
O
O
O
K2CO3
Cl
HO
Cl
+
O
OH
OH
O
Et3BnNCl
VIIа, VIIb
O
O
O
O
Cl
O
O
O
O
O
+
O
O
Cl
K2CO3, TEBAC
O
VIII
IX
Scheme 3.
R
R
N
N
_
R'
R'
N
(1) OH
N
(2) HCl
O
HO
O
IV_VI
O
X_XII
IV, X, R = R' = H; Vа, XIa, R = CH3, R' = H; Vb, XIb, R = H, R' = CH3; VI, XII, R = R' = CH3.
and 1 : 1 : 1.5. Low yields of the desired products were
caused by side reactions occurring. In particular,
alkylation of pyrazoles I–III in the presence of excess
of ethyl chloroacetate resulted in IV–VI along with the
side products VIII and IX, whose formation was most
likely rationalized by partial hydrolysis of ethyl
chloroacetate to VIIa and VIIb followed by alkylation
(Scheme 2).
3 : 2 ratio (1H NMR) with the overall yield of 60%.
Attempts to separate them by fractionation at 150°C
(1 mmHg) failed due to the partial hydrolysis yielding
XIa and XIb.
Hydrolysis of the esters IV–VI was carried out with
an aqueous NaOH solution at room temperature to
obtain acids X–XII in yields of 78–80%.
Ethyl (1H-pyrazol-1-yl)acetate (IV). A mixture of
6.8 g (0.1 mol) of pyrazole I, 24.5 g (0.3 mol) of ethyl
chloroacetate, 1 g Et3BnNCl, 27.6 g (0.2 mol) K2CO3,
and 150 mL of acetone was stirred during 4 h at 50–
55°C, then cooled, and filtered. After the solvent
removal, the residue was distilled in vacuum. The
resulting condensate [a mixture of ethyl pyrazo-
lylacetate IV with esters VIII and IX] was treated with
10% aqueous hydrochloric acid (100 mL). Compounds
VIII and IX were extracted with diethyl ether. The
aqueous layer was basified to pH 8, and the ester IV
was extracted with chloroform (3 × 50 mL). The
extract was dried over magnesium sulfate and
evaporated. The residue was distilled in vacuum. Yield
6.9 g (45.0%), bp 95–98°C (1 mmHg), nD20 1.4690. IR
spectrum, ν, cm–1: 1510 (ring), 15710 (C=O). 1Н NMR
In addition, partial hydrolysis of IV–VI occurred
presumably under the action of K2CO3 [6]; potassium
salts of pyrazoleacetic acids remained in the reaction
mixture. That suggestion was supported by the fact
that the product yield in the alkylation reaction of
pyrazole I was reduced from 45 to 30% when the
reaction time was up from 5 h to 10 h (Scheme 3).
As expected, alkylation of 3,5-dimethylpyrazole III
proceeded slower (within 10 h) compared to that of
pyrazole I (within 5 h), likely due to steric hindrances
[6, 7]; 3(5)-methylpyrazole II was an intermediate
case.
Alkylation of 3(5)-methylpyrazole II afforded
isomeric mixture of pyrazoles Va and Vb [8] in the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 8 2014

ALKYLATION OF PYRAZOLES WITH ETHYL CHLOROACETATE
1643
spectrum (DMSO-d6–CCl4, 1 : 4, 300 MHz), δ, ppm
(J, Hz): 1.29 t (3H, CH2CH3, J 7.1), 4.79 s (2H,
CH2CH3, J 7.1), 4.94 s (2H, NCH2), 6.21 d.d (1H, H4,
J 1.8, 2.4), 7.37 d.d (1H, H3, J 1.8, 0.7), 7.58 d.d (1H,
H5, J 2.4, 0.7). Found, %: C 54.29; H 6.85; N 18.37.
C7H10N2O2. Calculated, %: C 54.54; H 6.49; N 18.18.
treated with hydrochloric acid. White crystals were
filtered off and dried. Yield 10 g (80%), mp 175°C [6].
[3(5)-Methyl-1H-pyrazol-1-yl]acetic acid (XIa,
XIb) was obtained similarly from 16.8 g (0.1 mol) of
ethyl 3(5)-methylpyrazol-1-ylacetate Va, Vb. Yield
11.5 g (82%), mp 160–168°C [6].
Ethyl [3(5)-methyl-1H-pyrazol-1-yl]acetate (Va,
Vb) was obtained similarly from 3(5)-methylpyrazole
II (8.2 g, 0.1 mol), reaction time 6 h. Yield 9.2 g
(55%), bp 104–105°C (3 mmHg). IR spectrum, ν, cm–1:
1520 (ring), 1700 (C=O). Found, %: C 57.45; H 7.35;
N 16.38. C8H12N2O2. Calculated, %: C 57.14; H 7.14;
N 16.66.
(3,5-Dimethyl-1H-pyrazol-1-yl) acetic acid (XII)
was obtained similarly from 18.2 g (0.1 mol) of ethyl
3,5-dimethylpyrazol-1-yl-acetate VI. Yield 12.3 g
(80%), mp 188–190°C [6].
IR spectra were obtained with the Nexus spectro-
1
meter (Thermo Nicolet Corporation, USA). H NMR
spectra (DMSO-d6–CCl4 or D2O–CF3COOH) were
recorded with the Varian Mercury spectrometer
(300 MHz). TLC analysis was performed using Silufol
UV-254 plates, eluting with a benzene-acetone (4 : 1)
mixture and developing with iodine vapor.
Ethyl (3,5-dimethyl-1H-pyrazol-1-yl)acetate (VI)
was obtained similarly from 3,5-dimethylpyrazole III
(9.6 g, 0.1 mol), reaction time 10 h. Yield 11.4 g
(63%), bp 110–115°C (3 mmHg), nD20 1.4700. IR
1
spectrum, ν, cm–1: 1550 (ring), 1750 (C=O). Н NMR
spectrum (DMSO-d6–CCl4, 1 : 4, 300 MHz), δ, ppm
(J, Hz): 1.30 t (3H, CH3CH2O, J 7.1), 2.12 s (3H,
3-CH3, J 7.1), 2.18 s (3H, 5-CH3), 4.19 q (2H,
OCH2CH3, J 7.1), 4.72 s (2H, NCH2), 5.73 br.s (1H,
H4). Found, %: C 59.68; H 7.32; N 15.71. C9H14N2O2.
Calculated, %: C 59.34; H 7.69; N 15.38.
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