Chloromethylation of pyrazole ring

Full text of DOI:10.1134/S1070363215110262

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 11, pp. 2663–2664. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © V.I. Rstakyan, A.A. Saakyan, H.S. Attaryan, A.G. Hasratyan, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 11,
pp. 1924–1926.
LETTERS
TO THE EDITOR
Chloromethylation of Pyrazole Ring
V. I. Rstakyan, A. A. Saakyan, H. S. Attaryan, and A. G. Hasratyan
Institute of Organic Chemistry, Scientific and 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 July 7, 2015
Keywords: chloromethylated pyrazole, 1-phenyl-3,5-dimethylpyrazole
DOI: 10.1134/S1070363215110262
It is known that chloromethylation of 1,3,5-tri-
methyl-1H-pyrazole with paraformaldehyde in the
presence of concentrated HCl is competed by
formation of methane-4,4'-diylbis(1,3,5-trimethyl-1H-
pyrazole) [1]. However, chloromethylation of 1,3,5-
triphenyl-1H-pyrazole has afforded the corresponding
chloromethyl derivative as the only reaction product
[1]. In addition, methanediylbis(1H-pyrazole) deriva-
tives have not been obtained when the pyrazole ring
contains aromatic and heteroaromatic substituents in
positions 1 and 4 [2]. That was explained by the stab-
ilizing effect of the substituents.
The reaction did not stop at the stage of (3,5-
dimethyl-1-phenyl-1H-pyrazol-3-yl)methanol 2 forma-
tion. In the presence of hydrochloric acid, the alkyla-
tion occurred at the position 4 of pyrazole ring of
compound 1 (route a) to form methane-4,4'-diylbis-
(3,5-dimethyl-1H-pyrazole) 3. Alkylation of alcohol 2
(route b) yielded the symmetrical ester 4; the latter
underwent elimination of formaldehyde upon distilla-
tion to form bispirazolylmethane 3 (route d) [3]. Reac-
tion of the intermediate pyrazolecarbinol 2 with
concentrated HCl resulted in formation of 3,5-di-
methyl-1-phenyl-4-(chloromethyl)-1H-pyrazole 5 (route c)
(Scheme 1).
In the present study we investigated chloro-
methylation of pyrazoles containing methyl and phenyl
substituents. Chloromethylation of 3,5-dimethyl-1-phenyl-
1H-pyrazole 1 proceeded as electrophilic substitution.
Similarly, chloromethylation of 3(5)-methyl-1-
phenyl-1H-pyrazole 6 yielded 3(5)-methyl-1-phenyl-4-
Scheme 1.
+
HO
H2C
H+
CH2O
HCl
N
+ H2O
N
N
N
N
N
Ph
1
Ph
2
Ph
А
b
а
c
+Cl−
−H+
−H+
+ 2
+ 1
Cl
O
d, Δ
N
N
N
N
N
−CH2O
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
5 (10%)
4 (17%)
2663
3 (33%)

2664
RSTAKYAN et al.
b. The reaction was performed similarly. The pro-
Scheme 2.
ducts were extracted with butanol, and 15 mL of
pyridine was added to capture the 4-(chloromethyl)
derivative. The resulting quaternary salt was filtered
off. After removal of butyl alcohol, the residue
crystallized. The crystals were filtered off and washed
with petroleum ether to yield methane-4,4'-diylbis-
(3,5-dimethyl-1-phenyl-1H-pyrazole) 3 (5.8 g, 33%).
After removal of petroleum ether, 3.2 g (17%) of
oxydimethane-4,4'-diylbis(3,5-dimethyl-1-phenyl-1H-
pyrazole 4 (viscous liquid, nD20 1.5485) was isolated.
IR spectrum, ν, cm–1: 1100 (CH2OCH2), 1540 (ring).
1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.21 s
(6Н, 3-CH3), 2.30 s (6H, 5-CH3), 4.26 s (4H, О(CH2)2),
7.28–7.47 m (10H, 2C6H5).
Cl
CH2O
HCl
N
+
N
N
N
N
N
N
N
Ph
7 (20%)
Ph
Ph
Ph
6
8 (25%)
(chloromethyl)-1H-pyrazole 7 and methanediylbispyra-
zole 8 (Scheme 2).
Since all the above reactions proceeded via
carbocation A formation, the stabilizing effect of
substituents [2] as well as the substrate nucleophilicity
affected the reaction route.
Nucleophilicity of 1,3,5-trimethyl-1H-pyrazole was
somewhat higher compared with that of 3,5-dimethyl-
1-phenyl- (1) and 3(5)-methyl-1-phenyl-1H-pyrazole
(6); therefore, bispyrazolylmethane formation was the
predominant reaction pathway.
Hydroxymethylation of 3(5)-methyl-1-phenyl-
1Н-pyrazole 6 was carried out similarly. 4-Chloro-
methyl-3(5)-methyl-1-phenyl-4-chloromethyl-1Н-
pyrazole (7). Yield 4.1 g (20%), bp 130–135°С
(1 mmHg), n2D0 1.5835. IR spectrum, ν, cm–1: 1530
(ring). 1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
2.20 s (3Н, 3-CH3), 2.32 s (3H, 5-CH3), 4.28 s (2H,
CH2Cl), 7.19 s (1H, H3), 7.30 s (1H, H5), 7.40 m (5H,
C6H5). Found, %: С 63.49; Н 5.85; Cl 17.4; N 13.2.
С11Н11ClN2. Calculated, %: С 63.92; Н 5.32; Cl 17.19;
N 13.59.
To conclude, increasing the number of methyl
substituents in the pyrazole ring prevented chloro-
methylation reaction, and the presence of phenyl
substituents had the opposite effect.
Hydroxymethylation of 3,5-dimethyl-1-phenyl-
1H-pyrazole (1). a. A mixture of 17.1 g (0.1 mol) of
3,5-dimethyl-1-phenyl-1H-pyrazole 1, 3 g of para-
formaldehyde, and 50 mL of conc. HCl was refluxed
during 1.5 h. The reaction mixture was neutralized
with NaOH solution. The reaction products were
extracted with butanol. The extract was dried over
MgSO4 and concentrated. The residue was distilled in
vacuum to give 3,5-dimethyl-1-phenyl-4-chloro-
methyl-1H-pyrazole 5 in yield of 2.2 g (10%), bp 140°С
(1 mmHg), n2D0 1.5844. IR spectrum, ν, cm–1: 1540
(ring). 1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
2.21 s (3Н, 3-CH3), 2.36 s (3H, 5-CH3), 4.61 s (2H,
CH2Cl), 7.42 m (5H, C6H5). Found, %: С 65.81; Н
5.44; Cl 16.35; N 12.24. С12Н13ClN2. Calculated, %: С
65.30; Н 5.89; Cl 16.09; N 12.69.
Bis[3(5)-methyl-1-phenylpyrazol-4-yl]methane
(8). Yield 4.0 g (25%), bp 245–250°С (1 mmHg),
viscous liquid, nD20 1.5428. IR spectrum, ν, cm–1: 1580
(ring). 1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
1.98 s (6Н, 3-CH3), 2.0 s (6H, 5-CH3), 3.31 s (2H,
CH2), 7.21 s (1H, H3), 7.31 s (1H, H5), 7.45 m (10H,
2C6H5). Found, %: С 76.99; Н 6.48; N 17.31.
С21Н20N4. Calculated, %: С 76.82; Н 6.09; N 17.07.
IR spectra were obtained with a Nexus Thermo
Nicolet spectrometer. 1Н NMR spectra were registered
using a Varian Mercury instrument (300 MHz).
REFERENCES
On top of that, methane-4,4'-diylbis(3,5-dimethyl-
1-phenyl-1H-pyrazole) 3 was isolated with 60% yield
(10.6 g), bp 260°С (1 mmHg), mp 118°C (water–
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CH3), 2.23 s (6H, 5-CH3), 3.52 s (2H, CH2), 7.27–7.46
m (10H, C6H5). Found, %: С 77.21; Н 6.96; N 15.38.
С23Н24N4. Calculated, %: С 77.52; Н 6.74; N 15.73.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 11 2015