Reactions of 3,5-dimethyl-1-phenyl-1h-pyrazole with electrophiles

Article abstract of DOI:10.1134/S1070363212100143

Reactions of 3,5-dimethyl-1-phenyl-1H-pyrazole with various electrophilic reagents were studied. Electrophilic attack occurred regioselectively at the C⁴ atom in the pyrazole ring. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070363212100143

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 10, pp. 1724–1727. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © O.S. Attaryan, V.I. Rstakyan, A.G. Hasratyan, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 10, pp. 1720–1723.
Reactions of 3,5-Dimethyl-1-phenyl-1H-pyrazole
with Electrophiles
O. S. Attaryan, V. I. Rstakyan, and A. G. Hasratyan
Institute of Organic Chemistry of Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences, pr. Azatutyana 26, Yerevan, 0014 Armenia
e-mail: vrstakyan@gmail.com
Received July 28, 2011
Abstract—Reactions of 3,5-dimethyl-1-phenyl-1H-pyrazole with various electrophilic reagents were studied.
Electrophilic attack occurred regioselectively at the C4 atom in the pyrazole ring.
DOI: 10.1134/S1070363212100143
Growing interest in the pyrazole chemistry and
methods of its functionalization is related to extension
of application of its derivatives in the design of new
materials. Pyrazole possesses many properties intrinsic
to aromatic compounds [1]. Unlike pyrrole whose
aromaticity is determined by the presence of an sp2-
hybridized nitrogen atom in the ring [2], the presence
of two nitrogen atoms in pyrazole molecule reduces its
reactivity toward electrophiles [3]. Electrophilic attack
on pyrazole ring is generally directed at the 4-position
which is characterized by the maximal π-electron
density [4]. The reactivity of pyrazole at C4 is inter-
mediate between the reactivities of phenol and benzene
[5]. However, no detailed studies were performed with
a view to compare the ease of substitution in pyrazole
ring and other aromatic systems.
Taking the above stated into account, it was
interesting to compare the reactivities of the pyrazole
and benzene rings in 3,5-dimethyl-1-phenyl-1H-
pyrazole (I); in addition, it should be kept in mind that
pyrazolium cation is less reactive than benzenium [5].
Initially, we performed bromination of compound I,
which is a common method for the preparation of
bromo derivatives of pyrazole requiring no catalyst [1].
The bromination of pyrazole I in acetic acid gave 4-
bromo-3,5-dimethyl-1-phenyl-1H-pyrazole (II) which
was isolated from the reaction mixture in 70% yield.
O
Me
Et
Br
Me
Me
N
N
Me
N
N
Br2, AcOH
EtCOCl, AlCl3
Me
N
Me
N
II
III
O
O
Ph
Me
Me
Me
H
POCl3, DMF
PhCOCl, Δ
N
I
N
N
Me
N
IV
V
1724

REACTIONS OF 3,5-DIMETHYL-1-PHENYL-1H-PYRAZOLE
1725
The product structure was assigned on the basis of its
1H NMR spectrum which contained no 4-H signal, and
the intensity of signals from protons in the phenyl
group was very consistent with structure II. Friedel–
Crafts acylation of 3,5-dimethyl-1-phenyl-1H-pyrazole
(I) with propionyl chloride [6] afforded 4-propionyl-
substituted pyrazole III. 4-Benzoyl derivative IV was
synthesized in 68% yield by heating compound I in
benzoyl chloride in the absence of aluminum chloride.
In no case substitution in the benzene ring was
observed. We also examined formylation of 3,5-
dimethyl-1-phenyl-1H-pyrazole (I) with dimethyl-
formamide in the presence of POCl3 (Vilsmeier–Haack
reaction [7]). It may be expected that, like aromatic
amines, the benzene ring in molecule I will react more
readily than the pyrazole ring [8]. However, the
reaction involved exclusively the pyrazole ring with
formation of aldehyde V.
Me
Cl
Me
Me
N
N
N
Me
CH2O, HCl
N
Me Me
N
N
I
+
VII
VI
By chloromethylation of 3,5-dimethyl-1-phenyl-
1H-pyrazole (I) with paraformaldehyde and hydrogen
chloride we obtained a mixture of 10% of 4-chloro-
methyl-3,5-dimethyl-1-phenyl-1H-pyrazole (VI) and
60% of bis(1-phenyl-3,5-dimethylpyrazol-4-yl)methane
(VII). We previously showed [9] that heating of 1,3,5-
trimethyl-1H-pyrazol-4-ylmethanol (VIII) in the presence
of phenol leads to C-alkylation of the aromatic ring in
the latter. The reaction of VIII with pyrazole I
involved not only C-alkylation of the pyrazole ring in I
but also intermolecular dehydration of alcohol VIII
with formation of symmetric ether IX. In the course of
distillation, the latter lost formaldehyde molecule, thus
being converted into bis(1,3,5-trimethyl-1H-pyrazol-4-
yl)methane (X). The formation of compound X was
studied by us in detail previously [10–12].
Me
Me
Me
Me
Δ
O
N
N
N
N
N
_CH2O
N
N
N
HO
Me
Me
Me
Me
Me
Me
Me
Me
Δ
Me
I
+
IX
X
N
Me
N
Me
Me
N
Me
VIII
N
N
N
Me
Me
Me
XI
Our results in combination with the data of [13]
EXPERIMENTAL
The IR spectra were measured on a Specord 75-IR
spectrometer from thin films. The H NMR spectra
were recorded on a Varian Mercury instrument at
300 MHz from solutions in DMSO-d6.
allowed us to conclude that methyl groups in the
pyrazole ring stabilize σ-complex XII rather than
alternative structure XIII; therefore, substitution in the
pyrazole ring is more favorable.
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 10 2012

1726
ATTARYAN et al.
Me
9.8 g of benzoyl chloride was heated for 10 h under
H
Me
N
reflux. The mixture was neutralized with a solution of
sodium carbonate and extracted with chloroform. The
solvent was distilled off from the extract, and the
residue was distilled under reduced pressure. Yield
19 g (68.8%), bp 210°C (1 mm), mp 99–100°C (from
petroleum ether [14]). IR spectrum, ν, cm–1: 1530,
E
N
C+
Me
N
Me
N
C+H
E
1
1580 (ring); 1670 (C=O). H NMR spectrum (DMSO-
d6), δ, ppm: 2.16 s (3H, 3-CH3), 2.26 s (3H, 5-CH3),
7.38–7.59 m (8H) and 7.70–7.74 m (2H) (C6H5).
Found, %: C 78.64; H 5.21; N 9.69. C18H16N2O.
Calculated, %: C 78.26; H 5.79; N 10.14.
H
XIII
XII
E stands for electrophile.
3,5-Dimethyl-1-phenyl-1H-pyrazole-4-carbalde-
hyde (V). A mixture of 17.0 g of pyrazole I and 50 ml
of DMF was heated under stirring to 110°C, and 31.0 g
of POCl3 was added at the same temperature. After
cooling, the mixture was neutralized with aqueous
sodium hydroxide, maintaining the temperature below
20°C, and extracted with chloroform, the extract was
dried over MgSO4, the solvent was distilled off, and
the residue was distilled under reduced pressure. Yield
14.6 g (73.0%), bp 170°C (1 mm), mp 121–122°C. IR
4-Bromo-3,5-dimethyl-1-phenyl-1H-pyrazole (II).
A solution of 6 ml of bromine in 10 ml of acetic acid
was added dropwise under stirring over a period of 1 h
at room temperature to a mixture of 17.0 g of 3,5-
dimethyl-1-phenyl-1H-pyrazole (I), 20.0 g of sodium
acetate, and 70 ml of water. The mixture was
neutralized with a solution of sodium carbonate and
extracted with chloroform (3 × 50 ml), the extracts
were dried over magnesium sulfate, the solvent was
distilled off, and the residue was distilled under
reduced pressure. Yield 17.6 g (70%), bp 133°C
(1 mm), nD20 = 1.5940. IR spectrum: ν 1530 cm–1
1
spectrum, ν, cm–1: 1540 (ring), 1680 (C=O). H NMR
spectrum (DMSO-d6–CCl4, 1 : 3), δ, ppm: 2.45 s (3H,
3-CH3), 2.57 s (5H, 3-CH3), 7.40–7.54 m (5H, C6H5),
9.95 s (1H, CHO). Found, %: C 72.41; H 6.34; N 13.86.
C12H12N2O. Calculated, %: C 72.00; H 6.00; N 14.00.
1
(ring). H NMR spectrum (DMSO-d6), δ: 2.11 s (3H,
3-CH3), 2.35 s (3H, 5-CH3), 7.45 m (5H, C6H5).
Found, %: C 52.26; H 4.71; Br 31.26; N 11.65.
C11H11BrN2. Calculated, %: C 52.58; H 4.38; Br 31.87;
N 11.15.
4-Chloromethyl-3,5-dimethyl-1-phenyl-1H-pyra-
zole (VI). A mixture of 17.0 g of pyrazole I, 3 g of
paraformaldehyde, and 50 ml of concentrated hydro-
chloric acid was heated for 1.5 h under reflux. The
mixture was neutralized with aqueous sodium hyd-
roxide and extracted with butanol, the extract was
dried over MgSO4, the solvent was distilled off, and
the residue was distilled under reduced pressure. Yield
2.2 g (10%) bp 140°C (1 mm), nD20 = 1.5844. IR
1-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)propan-
1-one (III). A mixture of 54.0 g of AlCl3 and 200 ml of
CCl4 was cooled to –5 to –10°C, 17.0 g of pyrazole I
was added dropwise under stirring, 18.0 g of propionyl
chloride was then added, and the mixture was stirred
for 2 h at 15–20°C and left to stand for 24 h. The
mixture was treated with ice water and aqueous
sodium carbonate, and the precipitate was filtered off.
The filtrate was extracted with diethyl ether, the extract
was dried over MgSO4 and evaporated, and the residue
was distilled under reduced pressure. Yield 7.3 g
(32%), bp 160°C (1 mm), nD20 = 1.5800. IR spectrum,
1
spectrum: ν 1540 cm–1 (ring). H NMR spectrum
(DMSO-d6), δ, ppm: 2.21 s (3H, 3-CH3), 2.36 s (3H, 5-
CH3), 4.61 s (2H, CH2Cl), 7.42 m (5H, C6H5). Found,
%: C 65.81; H 5.44; Cl 16.35; N 12.24. C12H13ClN2.
Calculated, %: C 65.30; H 5.89; Cl 16.09; N 12.69.
In addition, bis(3,5-dimethyl-1-phenyl-1H-pyrazol-
4-yl)methane (VII) was isolated from the reaction
mixture. Yield 10.6 g (60%), bp 260°C (1 mm), mp
118°C (from aqueous acetone). IR spectrum: ν
1
ν, cm–1: 1550 (ring), 1670 (C=O). H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 1.14 t (3H, CH2CH3, J =
7.2), 2.46 s (3H, 3-CH3), 2.51 s (3H, 5-CH3), 2.76 q
(2H, CH2CH3, J = 7.2), 7.37–7.53 m (5H, C6H5).
Found, %: C 73.21; H 6.39; N 12.68. C14H16N2O.
Calculated, %: C 73.68; H 7.01; N 12.28.
1
1550 cm–1 (ring). H NMR spectrum (DMSO-d6), δ,
ppm: 2.1 s (6H, 3-CH3), 2.23 s (6H, 5-CH3), 3.52 s
(2H, CH2), 7.27–7.46 m (10H, C6H5). Found, %: C
77.21; H 6.96; N 15.38. C23H24N4. Calculated, %: C
77.52; H 6.74; N 15.73.
(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)phenyl-
methanone (IV). A mixture of 17.2 g of pyrazole I and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 10 2012

REACTIONS OF 3,5-DIMETHYL-1-PHENYL-1H-PYRAZOLE
1727
3. Comprehensive Heterocyclic Chemistry II, Katritzky, A.R.,
Rees, C.W., and Scriven, E.F.V., Oxford: Pergamon,
1996, vol. 5, p. 250.
Bis(1,3,5-trimethyl-1H-pyrazol-4-yl)methane (X)
and 4-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-
1,3,5-trimethyl-1H-pyrazole (XI). A mixture of
17.2 g of pyrazole I and 3 g of 1,3,5-trimethyl-1H-
pyrazol-4-ylmethanol (IX) was heated for 4–5 h under
reflux. Excess pyrazole I was distilled off, the residue
was dissolved in 30 ml of petroleum ether, the solution
was cooled, and the precipitate was filtered off. Yield
of bis(1,3,5-trimethyl-1H-pyrazol-4-yl)methane (X)
0.9 g (38%), mp 67–68°C. IR spectrum: ν 1540 cm–1
4. Katija, M., Bull. Chem. Soc. Jpn., 1970, vol. 43,
p. 3344.
5. Comprehensive Organic Chemistry, Barton, D. and
Ollis, W.D., Eds., Oxford: Pergamon, 1979, vol. 4.
Translated under the title Obshchaya organicheskaya
khimiya, Moscow: Khimiya, 1985, vol. 8, p. 751.
6. Becker, H.G.O., Organikum. Organisch-chemisches
Grundpraktikum, Berlin: Wissenschaften, 1964, 3rd ed.
Translated under the title Obshchii praktikum po
organicheskoi khimii, Moscow: Mir, 1965, p. 678.
1
(ring). H NMR spectrum (DMSO-d6), δ, ppm: 1.96 s
(6H, 3-CH3), 2.05 s (6H, 5-CH3), 3.35 s (2H, CH2),
3.65 s (6H, NCH3). Found, %: C 67.58; H 8.36; N
24.56. C13H20N4O. Calculated, %: C 67.24; H 8.62; N
24.14.
7. Vilsmeier, A. and Haack, A., Ber., 1927, vol. 60, no. 1,
p. 119.
8. Minkin, V.I. and Dorofeenko, G.N., Usp. Khim., 1960,
The filtrate was evaporated, and the residue was
distilled under reduced pressure. Yield of 4-(3,5-
dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-1,3,5-tri-
methyl-1H-pyrazole (XI) 2.5 g (42.5%), bp 230°C (1
vol. 29, p. 1301.
9. Attaryan, O.S., Gevorkyan, A.A., Antanosyan, S.K.,
Panosyan, G.A., and Hasratyan, G.V., Russ. J. Gen.
Chem., 2008, vol. 78, no. 3, p. 506.
10. Attaryan, O.S., Gevorkyan, A.A., Antanosyan, S.K.,
Martirosyan, S.S., Panosyan, G.A., and Matsoyan, S.G.,
Russ. J. Gen. Chem., 2005, vol. 75, no. 9, p. 1500.
11. Attaryan, O.S., Gevorkyan, A.A., Antanosyan, S.K., and
Matsoyan, S.G., Russ. J. Gen. Chem., 2007, vol. 77,
no. 6, p. 1139.
20
mm), nD = 1.5740. IR spectrum: ν 1560 cm–1 (ring).
1H NMR spectrum (DMSO-d6 ), δ, ppm: 2.20 s (6H, 3-
CH3), 2.32 s (6H, 5-CH3), 3.41 s (2H, CH2), 3.65 s
(3H, NCH3), 7.22–7.40 m (5H, C6H5). Found, %: C
73.18; H 7.21; N 19.44. C18H22N4. Calculated, %: C
73.46; H 7.48; N 19.04.
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