Alkylation of pyrazoles with ethylene chlorohydrin under phase transfer catalysis

Article abstract of DOI:10.1134/S107036320911022X

Alkylation reactions of pyrazoles with ethylene chlorohydrin under phase transfer catalysis were studied. Effect of solvent nature on alkylation process was established. 3(5)-Methylpyrazole alkylation products were isolated and identified.

Full text of DOI:10.1134/S107036320911022X

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 11, pp. 2417–2419. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.O. Baltayan, V.I. Rstakyan, S.K. Antanosyan, F.S. Kinoyan, O.S. Attaryan, G.V. Asratyan, 2009, published in Zhurnal Obshchei
Khimii, 2009, Vol. 79, No. 11, pp. 1890–1894.
Alkylation of Pyrazoles with Ethylene Chlorohydrin
under Phase Transfer Catalysis
A. O. Baltayana, V. I. Rstakyana, S. K. Antanosyana,
F. S. Kinoyana, O. S. Attaryanb, and G. V. Asratyanb
a Institute of Organic Chemistry, National Academy of Sciences of Armenia,
ul. Zakaria Sarkavag, 167, Yerevan, 375091 Armenia
e-mail: angelabaltayan@mail.ru
bInstitute of Applied Chemistry ARIAK, Yerevan, Armenia
Received April 7, 2009
Abstract—Alkylation reactions of pyrazoles with ethylene chlorohydrin under phase transfer catalysis were
studied. Effect of solvent nature on alkylation process was established. 3(5)-Methylpyrazole alkylation
products were isolated and identified.
DOI: 10.1134/S107036320911022X
Pyrazoles I–III were shown earlier to be readily
alkylated by dichloro(bromo)ethane and 2,2'-dichloro-
ethyl ether under the phase transfer catalysis (PTC) in
liquid–liquid system (water–reagent–NaOH–benzyltri-
ethylammonium chloride) [1–3]. In extension of this
research we examined pyrazoles I–III alkylation with
ethylene chlorohydrin under PTC conditions.
regularities were found in the case of alkylation of
pyrazoles with dichloro(bromo)ethane and 2-chloro-
ethylamine [1, 2, 4].
Maximum product IV-VI yields (70–80%) were
achieved at the following reagents ratio: pyrazoles I :
NaOH : ethylene chlorohydrin 1:1.5:2.0; 3(5)-methyl-
pyrazole II : NaOH : ethylene chlorohydrin 1:2.0:2.5;
3,5-dimethylpyrazole III : NaOH : ethylene chloro-
hydrin 1 : 3.0 : 3.5.
R
R
Cl
OH
N
N
PTC
R'
R'
N
H
N
The products VII–IX of additional alkylation of
monoalkylated products IV–VI were isolated from the
reaction mixture, when pyrazoles I–III were alkylated
in the presence of reagents excess.
OH
I−III
IV−VI
R
R
I, IV, R = R' = H; II, Vа, Vb, R = CH3, R' = H (а); R = H,
R' = CH3 (b); III, VI, R = R' = CH3.
OH
Cl
N
N
R'
R'
N
N
We established that pyrazoles I-III alkylation with
ethylene chlorohydrin in liquid–liquid system (water–
reagent–NaOH–benzyltriethylammonium chloride)
virtually did not proceed (yields ~5–10%), what is
probably due to ethylene oxide formation as a result of
ethylene chlorohydrin dehydrochlorination.
O
OH
OH
IV−VI
VII−IX
IV, VII, R = R' = H; Vа, Vb, VIII, R = CH3, R' = H (а);
R = H, R' = CH3 (b); VI, IX, R = R' = CH3.
The reaction was shown to occur in a solid-liquid
system (dioxane–reagent–NaOH–benzyltriethylammo-
nium chloride). At equimolar reagents ratio the alkyla-
tion products yield decreases sufficiently on passing
from pyrazoles I to 3,5-dimethylpyrazole III. Similar
Study of the solvent nature effect on pyrazole I
alkylation with ethylene chlorohydrin showed that the
reaction with ethylene oxide at 80˚С under normal
pressure and on passing ethylene oxide excess through
2417

2418
BALTAYAN et al.
dioxane solution of pyrazole I in alkaline medium
gives rise to compound IV with yield 60%. If this
reaction is carried out under similar conditions using
water, the product IV yield is only 5–6%. Therefore,
poor solubility of ethylene oxide in water is the most
likely reason why the reaction does not proceed in
water medium [5].
mixture was stirred for 1.5 h more. Then the mixture
was cooled, filtered, and concentrated. The product
was isolated by vacuum distillation. Yield 8.9 g (80%),
bp 71–72°C (1 mm Hg), nD20 1.5030, d420 1.1120. IR
1
spectrum, ν, cm–1: 1520 (ring), 3200–3300 (ОН). Н
NMR spectrum (DMSO-d6), δ, ppm: 3.79 q (2Н,
СН2ОН, J 5.5 Hz), 4.18 t (2H, N-CH2, J 5.5 Hz), 4.41
t (1Н, ОН, J 5.5 Hz), 6.5 d.d (1H, 4-H, J 2.3 and 1.8
Hz), 7.35 d (1H, 3-H, J 1.8 Hz), 7.55 d (1Н, 5-Н, J
2.3 Hz). Found, %: С 53.41; Н 7.25; N 25.21.
С5Н8N2О. Calculated, %: С 53.57; Н 7.14; N 25.00.
The alkylation of pyrazoles asymmetrical deri-
vatives is known to result usually in the mixture of two
isomers Vа and Vb [1–4, 6–10].
As was expected, the alkylation of 3(5)-
methylpyrazole II produces the mixture of isomeric
pyrazoles Vа and Vb in an overall yield 75%. Accord-
ing to the Н NMR spectral data the ratio of them is
1:1. We succeeded in separating and identifying these
1-[2'-(2'-Hydroxyethoxy)ethyl]pyrazole (VII) was
also isolated from the reaction mixture. Yield 1.5 g, bp
125–130°C (1 mm Hg), nD20 1.4990. 1Н NMR spectrum
(DMSO-d6), δ, ppm: 3.41–3.45 m (2Н, СН2), 3.47–
3.53 m (2H, CH2), 3.78 t (2Н, СН2, J 5.5 Hz), 4.21 t
(1H, ОH, J 5.5 Hz), 4.26 t (2H, N-CH2, J 5.5 Hz), 6.14
d.d (1Н, 4-Н, J 2.3 and 1.8 Hz), 7.32 d (1Н, 3-Н, J
1.8 Hz), 7.57 d (1H, 5-H, J 2.3 Hz). Found, %: С
53.61; Н 7.38; N 17.71. С7Н12N2О2. Calculated, %: С
53.84; Н 7.69; N 17.94.
1
isomers Vа and Vb.
The signal of the methyl group is the most charac-
1
teristic distinction of Н NMR spectra of 1-substituted
3-methylpyrazoles from their 1-substituted 5-methyl-
isomers [1–4].
1
In the Н NMR spectrum the signal of the methyl
1-(2'-Hydroxyethyl)-3(5)-methylpyrazole (Vа, Vb)
was prepared similarly from 8.2 g of compound II, 8 g
of sodium hydroxide, and 20.0 g of ethylene chloro-
hydrin. Yield 9.4 g (75%), bp 79–83°C (1 mm Hg),
nD20 1.5050, d420 1.0760, isomers ratio 1:1 (by GLC). IR
group in compound Vа is observed at 2.18 ppm,
whereas the protons of methyl group in compound Vb
appear at 2.29 ppm., i. е. the upfield shift for com-
pound Vа is 0.11 ppm.
1
spectrum, ν, cm–1: 1530 (ring), 3300-3400 (ОН). Н
Moreover, in the spectrum of compound Vb the
signal of ring proton is in the stronger field at 7.20 ppm
(d, 1Н, 3-Н), than the similar signal of proton of iso-
mer Vа, 7.38 ppm (d, 1H, 5-H). The location of signals
of ring protons 4-Н in the spectra of compounds Vа
and Vb are virtually not distinguishable (5.86–
5.87 ppm).
NMR spectrum (DMSO-d6), δ, ppm: 2.18 s (3Н, 3-
СН3), 2.29 s (3H, 5-CH3), 3.68 m (2Н, СН2), 4.0 m
(2H, N-CH2), 4.42 m (1H, ОH), 5.86 d (1Н, 4-Н, J
1.8 Hz), 7.20 d (1H, 3-H, J 1.8 Hz), 7.38 d (1Н, 5-Н, J
2.2 Hz). Found, %: С 56.84; Н 7.77; N 19.91.
С6Н10N2О. Calculated, %: С 57.14; Н 7.93; N 22.22.
1-[2'-(2'-Hydroxyethoxy)ethyl]-3(5)-methyl-
pyrazole (VIII) was also isolated from the reaction
mixture. Yield 2.0 g, bp 139–145°C (1 mm Hg), nD20
1.5000. 1Н NMR spectrum (DMSO-d6), δ, ppm: 2.17 s
(3Н, 3-СН3), 2.28 s (3H, 5-CH3), 341-360 m (4Н,
СН2СН2О), 3.78 m (2H, N–CH2–CH2), 4.05 m (1Н,
ОН), 4.18 m (2Н, N–CH2), 5.87 d (1Н, 4-Н, J 2.2 Hz),
7.18 d (1H, 3-H, J 2.0 Hz), 7.36 d (1H, 5-H, J 2.3 Hz).
Found, %: С 56.08; Н 8.11; N 16.28. C8Н14N2О2.
Calculated, %: С 56.45; Н 8.28; N 16.45.
EXPERIMENTAL
The IR spectra were obtained on a UR-20 spectro-
photometer (film, КВr pellets). The Н NMR spectra
1
were recorded on a Varian Mercury-300 instrument in
(СD3)2SО. GLC analysis was performed on an LKhM-
8MD chromatograph, column (1 m) filled with Inerton
AW-HMDS impregnated with 10% Carbovax-20М,
carrier gas helium, flow rate 40 ml min–1, detector
temperature 220°C.
A rectification column 50×4 cm filled with metal
packing was used to separate the isomers Vа and Vb.
The temperature of the upper column part was 82–85°C,
still temperature 140°C, pressure 3 mm Hg, R = 30
(reflux ratio). 120 g of the isomer Va and Vb mixture
was charged into the still and fractioned. 1-(2'-
1-(2'-Hydroxyethyl)pyrazole (IV). To a mixture
of 6.8 g of pyrazole I, 6 g of sodium hydroxide, 50 ml
of dioxane, and 1.2 g of benzyltriethylammonium chlo-
ride was dropwise added 6.0 g of ethylene chloro-
hydrin within 1 h at 80°C under stirring. The reaction
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 11 2009

ALKYLATION OF PYRAZOLES WITH ETHYLENE CHLOROHYDRIN
2419
Hydroxyethyl)-3-methylpyrazole (Vа), yield 30 g, bp
4-H). Found, %: С 58.32; Н 8.41; N 14.90. С9Н16N2О2.
Calculated, %: С 58.69; Н 8.69; N 15.21.
1
79-80°C (1 mm Hg), nD20 1.5000. Н NMR spectrum
(DMSO-d6), δ, ppm: 2.17 s (3Н, 3-СН3), 3.78 t (2H,
N–CH2–CH2, J 5.3 Hz), 3.95 t (2Н, N–CH2, J 5.3 Hz),
4.40 t (1Н, ОH, J 5.3 Hz), 5.86 d (1Н, 4-Н, J 2.2 Hz),
7.36 d (1H, 5-H, J 2.3 Hz). 1-(2'-Hydroxyethyl)-5-
methylpyrazole (Vb), yield 20 g, bp 85–87°C (1 mm
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1
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5.3 Hz), 4.01 t (2Н, N–CH2, J 5.3 Hz), 4.41 t (1Н, ОH,
J 5.3 Hz), 5.87 d (1Н, 4-Н, J 2.2 Hz), 7.18 d (1H, 3-H,
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sodium hydroxide, and 28.0 g of ethylene chlorohydrin.
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1
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(1Н, ОН), 5.61 s (1H, 4-H). Found, %: С 59.36; Н
8.36; N 19.28. С7Н12N2О. Calculated, %: С 60.00; Н
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pyrazole (IХ) was also isolated from the reaction
1
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