Vilsmeier-Haack formylation of 2-(1H-pyrazol-1-yl)ethanol and its methyl derivatives

Full text of DOI:10.1134/S1070363215050333

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 5, pp. 1191–1193. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © V.I. Rstakyan, A.E. Akopyan, A.H. Baltayan, H.S. Attaryan, G.V. Asratyan, 2015, published in Zhurnal Obshchei Khimii, 2015,
Vol. 85, No. 5, pp. 862–864.
LETTERS
TO THE EDITOR
Vilsmeier–Haack Formylation of 2-(1H-Pyrazol-1-yl)ethanol
and Its Methyl Derivatives
V. I. Rstakyan, A. E. Akopyan, A. H. Baltayan, 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, ave. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: vrstakyan@gmail.com
Received February 16, 2015
Keywords: formylation, hydroxyethylpyrazole, 1-chloroethylpyrazole
DOI: 10.1134/S1070363215050333
It is known that 2-(3,5-dimethyl-1H-pyrazol-1-yl)
ethanol does not undergo the Vilsmeier–Haack for-
mylation [1]; the reaction results was the replacement
of the hydroxyl group with the chlorine atom. Apparently,
this is caused by the decreased nucleophilicity of the
pyrazole ring due to the quaternization of the pyridine
nitrogen atom. This assumption is supported by the
fact that the direct Vilsmeier–Haack formylation of 1-
(2-chloroethyl)-3,5-dimethylpyrazole affords the target
product in 70% yield [2], and the reaction does not
occur in the presence of hydrochloric acid.
allowed formylation of the pyrazole ring at position 4
[1, 4]. Acylation of compounds I–III and VII with
vinyl acetate in the presence of a catalytic amount of
copper acetate afforded 2-(1H-pyrazol-1-yl)ethyl acetate
VIII and its methyl derivatives IX–XI, which in turn
were easily subject to formylation via the Vilsmeier–
Haack reaction to form 2-(4-formyl-1H-pyrazol-1-yl)-
ethyl acetate XII and its methyl derivatives XIII–XV.
Hydrolysis of the latter yielded the corresponding
aldehydes XVI–XIX (Scheme 2).
In addition, 1-(2-chloroethyl)pyrazole-4-carbalde-
hydes XX–XXIII were isolated from the reaction
mixture with yields of 7–10% (Scheme 3).
In this work we found that 2-(1H-pyrazol-1-yl)-
ethanol I, 2-(3-methyl-1H-pyrazol-1-yl)ethanol II, and
2-(5-methyl-1H-pyrazol-1-yl)ethanol III underwent no
formylation under the Vilsmeier–Haack reaction condi-
tions, but were transformed into 1-(2-chloroethyl)pyra-
zoles IV–VI (Scheme 1).
The starting compounds I–III, VII–XI were ob-
tained as described elsewhere [4, 5].
1-(2-Chloroethyl)pyrazole (IV). 30 g (0.2 mol) of
phosphorus oxychloride was added to a mixture of
11.2 g of (0.1 mol) of 2-(1H-pyrazol-1-yl)ethanol I and
95.0 g (0.6 mol) of DMF upon stirring at 90°C
(maintaining the temperature below 120°C). The reac-
The Vilsmeier–Haack formylation of compounds I–
III and VII [4, 5] required their protection. In
particular, prior acetylation of the hydroxyl group
Scheme 1.
R1
R1
N
N
R2
Cl
DMF
R2
N
N
POCl3
HO
IV_VI
I_III
R1 = R2 = H (I, IV); R1 = Me, R2 = H (II, V); R1 = H, R2 = Me (III, VI).
1191

1192
RSTAKYAN et al.
Scheme 2.
O
R1
O
R1
R1
N
R1
O
N
N
R2
R2
R2
N
N
N
N
R2
N
DMF
OH
O
POCl3
Cu+2
O
O
O
O
OH
I_III, VII
OH
ХVI_XIX
XII_XV
VIII_XI
R1 = R2 = H (I, VIII, XII, XVI); R1 = Me, R2 = H (II, IX, XIII, XVII); R1 = H, R2 = Me (III, X, XIV, XVIII); R1 = R2 =
Me (VII, XI, XV, XIX).
Scheme 3.
O
O
R1
R1
DMF
N
N
R2
R2
POCl3
N
N
Cl
XX_XXIII
OH
I_III, VII
tion mixture was stirred during 1 hour at 100°C,
cooled, and neutralized with aqueous Na2CO3. The
reaction product was extracted with chloroform and
dried over magnesium sulfate. After removing the
solvent, the residue was distilled in vacuum. Yield 9.7 g
(75%), bp 47–48°C (1 mmHg), nD20 1.5020, d420
pyrazol-1-yl)ethyl acetate VIII and 95 g (0.6 mol) of
DMF upon stirring at 90°C (maintaining the tem-
perature below 120°C). The reaction mixture was
stirred during 1 hour at 100°C, cooled, and neutralized
with aqueous Na2CO3. The reaction products were
extracted with chloroform, the extract was dried over
magnesium sulfate. After removing the solvent, the
residue was distilled under vacuum collecting the
fraction with bp 150–155°C (1 mmHg). According to
1H NMR data, it contained 2-(4-formyl-1H-pyrazol-1-
yl)ethyl acetate XII and 1-(2-chloroethyl)-1H-pyra-
zole-4-carbaldehyde XX. The resulting mixture was
hydrolyzed with a solution of 8 g (0.2 mol) NaOH in
50 mL of water at stirring during 3 h at room
temperature. The reaction product was extracted with
diethyl ether and then with chloroform. After removing
chloroform, the residue was distilled in vacuum. Yield
9.7 g (69%), bp 160–170°С (1 mmHg), nD20 1.5370. IR
spectrum, ν, cm–1: 1520 (ring), 1680 (CHO), 3200–
1
1.1190 g/mL. IR spectrum, ν, cm–1: 1520 (ring). H
NMR data coincided with that in [6].
1-(2-Chloroethyl)-3-methylpyrazole (V) was pre-
pared similarly from 12.6 g of 2-(3-methyl-1H-pyrazol-
1-yl)ethanol II. Yield 11.6 g (80%), bp 55–60°С
(1 mmHg), nD20 1.5000. IR spectrum, ν, cm–1: 1530
(ring). 1H NMR data coincided with that in [6].
1-(2-Chloroethyl)-5-methylpyrazole (VI) was pre-
pared similarly from 12.6 g of 2-(5-methyl-1H-
pyrazol-1-yl)ethanol III. Yield 10.3 g (71.5%), bp 63–
65°С (1 mmHg), nD20 1.5050. IR spectrum, ν, cm–1:
1540 (ring). 1H NMR data coincided with that in [6].
1
3400 (OH). H NMR spectrum (DMSO-d6), δ, ppm
1-(2-Hydroxyethyl)-1H-pyrazol-4-carbaldehyde
(XVI). 30 g (0.2 mol) of phosphorus oxychloride was
added to a mixture of 15.4 g (0.1 mol) of 2-(1H-
(J, Hz): 3.82 q (2H, CH2OH, J 5.13), 4.22 t (2H,
NCH2, J 5.3), 4.56 t (1H, OH, J 5.5), 7.32 s (1H, H3),
7.53 s (1H, H5), 9.80 s (CHO). Found, %: C 51.87; H
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 5 2015

VILSMEIER–HAACK FORMYLATION OF 2-(1H-PYRAZOL-1-YL)ETHANOL
1193
5.83; N 20.95. C6H8N2O2. Calculated, %: C 51.42; H
5.72; N 20.00.
(1H, CHO). Found, %: C 45.84; H 4.58; N 18.23; Cl
22.68. C6H7N2Cl. Calculated, %: C 45.43; H 4.42; N
17.67; Cl 22.40.
From the ethereal extract 1.3 g (8%) of 1-(2-chloro-
ethyl)-1H-pyrazole-4-carbaldehyde XX was isolated,
bp 151°С (1 mmHg), nD20 1.5395. IR spectrum, ν, cm–1:
1520 (ring), 1680 (CHO). 1H NMR spectrum (DMSO-
d6), δ, ppm (J, Hz): 2.46 t (2H, CH2Cl, J 6.1), 3.93 t
(2H, NCH2, J 6.1), 7.73 s (1H, H3), 8.14 s (1H, H5),
9.80 s (1H, CHO). Found, %: C 45.73; H 4.68; N
18.05; Cl 22.73. C6H7N2Cl. Calculated, %: C 45.43; H
4.42; N 17.67; Cl 22.74.
1-(2-Hydroxyethyl)-3,5-dimethyl-1Н-pyrazole-4-
carbaldehyde (XIX) was obtained similarly from
17.0 g (0.1 mol) of 2-(3,5-dimethyl-1Н-pyrazol-1-yl)
ethyl acetate XI. Yield 12 g (75%), bp 160–170°С
(1 mmHg), mp 64–66°С (CCl4). IR spectrum, ν, cm–1:
1510 (ring), 1680 (CHO). 1H NMR spectrum (DMSO-
d6), δ, ppm (J, Hz): 2.34 s (3H, 3-CH3), 2.52 s (3H, 5-
CH3), 2.73 q (2H, OCH2, J 5.4), 4.02 t (2H, NCH2, J
5.4), 4.68 t (1H, OH, J 5.4), 9.81 s (1H, CHO).
1-(2-Hydroxyethyl)-3-methyl-1H-pyrazole-4-carb-
aldehyde (XVII) was prepared similarly from 16.8 g
(0.1 mol) of 2-(3-methyl-1H-pyrazol-1-yl)ethyl acetate
IX. Yield 8.9 g (63.0%), bp 168–175°С (1 mmHg), mp
82°С (hexane). IR spectrum, ν, cm–1: 1530 (ring), 1680
(CHO), 3200–3400 (OH). 1H NMR spectrum (DMSO-
d6), δ, ppm (J, Hz): 2.41 s (3H, 3-CH3), 3.72 q (2H,
CH2OH, J 5.6), 4.51 t (2H, NH2, J 5.6), 4.62 t (1H,
OH, J 5.6), 8.35 s (1H, H5), 9.8 s (1H, CHO). Found,
%: C 52.69; H 5.83; N 17.95. C7H10N2O2. Calculated,
%: C 54.54; H 6.49; N 18.19.
1-(2-Chloroethyl)-3,5-dimethyl-1Н-pyrazole-4-
carbaldehyde (XXIII). Yield 1.9 g (≈10%), bp 140–
145°С (1 mmHg), mp 50°С (CCl4). IR spectrum, ν,
1
cm–1: 1535 (ring), 1670 (CHO). H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.36 s (3H, 3-CH3), 2.54 s
(3H, 5-CH3), 3.93 t (2H, NCH2, J 5.9), 4.31 t (2H,
CH2Cl, J 5.9), 9.84 s (1H, CHO). Found, %: C 51.63;
H 6.12; N 15.42; Cl 12.27. C6H7N2Cl. Calculated, %:
C 51.47; H 5.90; N 15.01; Cl 19.09.
IR spectra were recorded using a Nexus Thermo
Nicolet spectrometer. 1Н NMR spectra of the solutions
in DMSO-d6–CCl4 were registered with a Varian
Mercury (300 MHz) instrument.
1-(2-Chloroethyl)-3-methyl-1Н-pyrazole-4-carb-
aldehyde (XXI). Yield 1.7 g (10%), bp 130–140°С
(1 mmHg), mp 37–38°С (CCl4), nD20 1.5370. IR
1
spectrum, ν, cm–1: 1530 (ring), 1670 (CHO). H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.40 s (3H, 3-
CH3), 3.93 t (2H, NCH2, J 5.8), 4.41 t (2H, CH2Cl, J
5.9), 8.24 s (1H, H5), 9.82 s (1H, CHO). Found, %: C
48.69; H 5.72; N 16.73; Cl 20.81. C7H9N2ClO.
Calculated, %: C 48.86; H 5.21; N 16.23; Cl 20.57.
REFERENCES
1. Attaryan, H.S., Antanosyan, S.K., Grigoryan, R.T.,
Martirisyan, S.S., and Matsoyan, S.G., Khim. Zh.
Armenii, 2005, vol. 58, nos. 1–2, p. 131.
1-(2-Hydroxyethyl)-5-methyl-1Н-pyrazole-4-carb-
aldehyde (XVIII) was obtained similarly from 16.8 g
(0.1 mol) of 2-(5-methyl-1Н-pyrazol-1-yl)ethyl acetate
X. Yield 8.0 g (56.6%), bp 177°С (1 mmHg), nD20
1.5325. IR spectrum, ν, cm–1: 1550 (ring), 1670 (CHO),
2. Martirosyan, S.S., Candidate Sci. (Chem.) Dissertation,
Yerevan, 2004.
3. McOmie, J.T.W., Protective Groups in Organic
Chemistry, London; New York: Plenum Press, 1973,
p. 391.
4. Rstakyan, V.I., Akopyan, A.E., Zakaryan, G.B.,
Attaryan, H.S., and Asratyan, G.V., Russ. J. Gen.
Chem., 2014, vol. 84, no. 4, p. 796. DOI: 10.1134/
S1070363214040343.
1
3200–3400 (OH). H NMR spectrum (DMSO-d6), δ,
ppm (J, Hz): 2.26 s (3H, 5-CH3), 3.70 q (2H, CH2OH,
J 5.6), 4.62 t (1H, OH, J 5.6), 8.12 s (1H, H3), 9.8 s
(1H, CHO).
5. Baltayan, A.O., Rstakyan, V.I., Antanosyan, S.K.,
Kinoyan, F.S., Attaryan, H.S., and Asratyan, G.V.,
Russ. J. Gen. Chem., 2009, vol. 79, no. 11, p. 2417.
DOI: 10.1134/S107036320911022X.
6. Attarian, O.S., Matsoyan, S.G., and Martirosyan, S.S.,
Chem. Heterocycl. Compd., 2005, vol. 41, no. 4, p. 452.
DOI: 10.1007/s10593-005-0170-z.
1-(2-Chloroethyl)-5-methyl-1Н-pyrazole-4-carb-
aldehyde (XXII). Yield 1.5 g (8.5%), bp 130–135°С
(1 mmHg), nD20 1.5425. IR spectrum, ν, cm–1: 1530
(ring), 1690 (CHO). 1H NMR spectrum (DMSO-d6), δ,
ppm (J, Hz): 2.45 s (3H, 5-CH3), 3.95 t (2H, NCH2, J
5.9), 4.42 t (2H, CH2Cl, J 5.9), 7.95 s (1H, H3), 9.9 s
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 5 2015