Synthesis of 3,5-diaryl-4-(1H-imidazol- 2-yl)-1H-pyrazoles from 2-phenacyl- 1H-imidazole

Article abstract of DOI:10.1007/s10593-010-0471-8

A method of synthesis is proposed for previously unknown 3,5-diaryl-4-(1H-imidazol-2-yl)-1H-pyra-zoles based on the thermal intramolecular cyclocondensation of aroylhydrazones of 2-phenacyl-1H-imidazole.

Full text of DOI:10.1007/s10593-010-0471-8

Chemistry of Heterocyclic Compounds, Vol. 46, No. 1, 2010
SYNTHESIS OF 3,5-DIARYL-4-(1H-IMIDAZOL-
2-YL)-1H-PYRAZOLES FROM 2-PHENACYL-
1H-IMIDAZOLE
I. B. Dzvinchuk1*, A. M. Nesterenko1, and M. O. Lozinskii1
A method of synthesis is proposed for previously unknown 3,5-diaryl-4-(1H-imidazol-2-yl)-1H-pyra-
zoles based on the thermal intramolecular cyclocondensation of aroylhydrazones of 2-phenacyl-
1H-imidazole.
Keywords: aroylhydrazines, aroylhydrazones, imidazoles, pyrazoles, tautomerism.
Previously we showed that the interaction of 2-phenacyl-1H-benzimidazoles with aroylhydrazines at
increased temperatures proceeds through the corresponding aroylhydrazones, which are then cyclized into
2-(3,5-diaryl-1H-pyrazol-4-yl)-1H-benzimidazoles [1, 2]. Probably this reaction has a more general character,
and in the present study we used it for the synthesis of previously unknown derivatives of pyrazole with an
imidazole substituent.
H
Ph
Ph
n-BuOH, Et3N,
3 h, ∆
O
N
N
N
N
+
H2NNHCOAr
+
NH
Ar
_
– H2O,
– Et3N·HCl
N
Cl
O
2a–e
H
H
1
3a–e
Ph
H
H
Ph
PhNMe2,
N
N
N
1.5–8.0 h, ∆
N
N
H
N
– H2O
N
O
N
H
Ar
Ar
H
3'a–e
4a–e
2, 3, 3', 4 a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 4-O2NC6H4, d Ar = 3-pyridyl,
e Ar = 4-pyridyl
_______
* To whom correspondence should be addressed, e-mail: Rostov@bpci.kiev.ua.
1 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 77-83, January, 2010. Original
article submitted February 18, 2009.
66
0009-3122/10/4601-0066©2010 Springer Science+Business Media, Inc.

We found that the interaction of the hydrochloride of 2-phenacyl-1H-imidazole 1 with aroylhydrazines
2a-e leads smoothly to the corresponding aroylhydrazones 3a-e, which on boiling in N,N-dimethylaniline is
cyclized with the formation of 3,5-diaryl-4-(1H-imidazol-2-yl)-1H-pyrazoles 4a-e.
The first stage of the synthesis, proceeding on boiling in 1-butanol in the presence of triethylamine (to
bind the hydrogen chloride) gives aroylhydrazones in 78-86% yield. The second stage in the majority of
examples proceeds during 1.5 h and leads to the desired product 4a,c-e in 75-90% yield. The exception was the
cyclization of the anisoylhydrazone 3b which, judging by TLC data, was not complete even after heating for
8 h. A further increase in reaction time was undesirable due to resinification, and product 4b was isolated by us
in a yield of only 34%.
The composition and structure of the synthesized compounds were confirmed by data of elemental
analysis (Table 1) and of 1H NMR spectra (Table 2).
According to data of 1H NMR spectra, tautomerism is characteristic for compounds 4, and is caused by
the migration of proton between the nitrogen atoms in both heterocycles. For compounds 4a,c-e the separate
tautomers A and B (see Scheme to Table 3) are not fixed due to their rapid interconversion. On the other hand in
the spectrum of compound 4b, containing the most electron-donating substituent Ar = 4-MeOC6H4, doubling
was observed of the doublet signal of its H-3,5 protons, while doublets at 6.86 and 6.94 ppm are converted into
one doublet at 6.91 ppm after acceleration of the exchange processes by the addition of acetic acid to the sample
being investigated (Fig. 1). With the aid of quantum-chemical calculations for tautomers A and B of this
compound in DMSO we calculated the enthalpy of formation (76.91 and 78.78 kcal/mol) and the charge
distribution. From these values a tendency became apparent towards the greater stability of tautomer A in which
the substituent 4-MeOC6H4 is found at position 5, and the lowest electron surplus appears in it. Consequently the
more low field of the two doublets in the spectrum of compound 4b is assigned to tautomer A, the content of
which is about 60% judging by the integral intensity of the signals of each of the tautomers.
The tautomerism was displayed differently (Table 3) for the structural analogs of compounds 4a-e
containing 2-benzimidazole in place of the 2-imidazole fragment (Table 3). For example, only for two
compounds (Ar = Ph, 4-MeOC6H4) was the doubling of the signals of substituents in the 1H NMR spectrum not
a characteristic, but for a different reason. The first contains phenyl substituents in positions 3 and 5 of the
pyrazole ring which are displayed as equivalent due to the rapid migration of proton between the pyrazole
TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
N
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
C18H16N4O
70.87
71.04
68.07
68.25
61.76
61.89
66.67
66.87
66.72
66.87
75.35
75.51
71.96
72,14
65.12
65.25
5.42
5.30
5.66
5.43
4.58
4.33
5.08
4.95
5.12
4.95
5.11
4.93
5.15
5.10
4.03
3.95
18.32
18.41
16.52
16.76
19.83
20/05
22.79
22.94
22.73
22.94
19.33
19.57
17.53
17.71
21.07
21.14
230.5-232.0
230.0-231.5
244.5-246.0
234.5-236.0
216.0-217.5
303.5-305.0
249.5-251.0
280.0-281.5
265.0-266.5
278.0-279.5
80
81
84
86
78
75
34
95
94
92
C19H18N4O2
C18H15N5O3
C17H15N5O
C17H15N5O
C18H14N4
C19H16N4O
C18H13N5O2
C17H13N5
70.85
71.07
70.92
71.07
4.68
4.56
4.54
4.56
24.18
42.37
24.25
42.37
C17H13N5
67

nitrogen atoms. The second compound contains a 4-methoxyphenyl substituent in position 5. It is stabilized in
form A, forming an energetically favorable chain of conjugation with the benzimidazole fragment. These data
indicate the influence of the electronic nature of the hetaryl fragment on the tautomerism of 2,5-diaryl-
4-hetarylpyrazoles.
TABLE 2. 1H NMR Spectra of the Synthesized Compounds
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
3a
3b
4.29 (2H, s, CH2); 6.98-7.11 (2H, m, Н-4,5); 7.46 (3H, m, H-3,4,5 Ph);
7.56-7.66 (3H, m, H-3,4,5 COPh); 7.96 (2H, m, H-2,6 Ph);
8.13 (2H, d, J = 7.2, H-2,6 COPh); 12.36 (1H, s, H-1); 13.16 (1H, s, CONH)
3.86 (3H, s, OCH3); 4.29 (2H, s, CH2); 6.98-7.10 (2H, m, Н-4,5);
7.11 (2H, d, J = 7.8, H-3,5 Ar); 7.46 (3H, m, H-3,4,5 Ph); 7.96 (2H, m, H-2,6 Ph);
8.12 (2H, d, J = 7.8, H-2,6 COPh); 12.36 (1H, s, H-1); 13.05 (1H, s, CONH)
3c
4.32 (2H, s, CH2); 7.08 (2H, s, Н-4,5); 7.48 (3H, m, H-3,4,5 Ph); 7.98 (2H, m, H-2,6 Ph);
8.36, 8.44 (2H, 2H, two d, J = 8.4, Ar); 12.19 (1H, s, H-1); 12.94 (1H, s, CONH)
3d
4.33 (2H, s, CH2); 7.04 (2H, s, Н-4,5); 7.47 (3H, m, H-3,4,5 Ph);
7.62 (1H, m, H-5 Ar); 7.97 (2H, m, H-2,6 Ph); 8.45 (1H, d, J = 5.7, H-6 Ar);
8.81 (1H, d, J = 2.8, H-4 Ar); 9.28 (1H, s, H-2 Ar); 12.17 (1H, s, H-1);
13.03 (1H, s, CONH)
3e
4.32 (2H, s, CH2); 7.07 (2H, s, Н-4,5); 7.48 (3H, m, H-3,4,5 Ph); 7.97 (2H, m, H-2,6 Ph);
8.03, 8.86 (2H, 2H, two d, J = 5.1, Ar); 12.19 (1H, s, H-1); 12.89 (1H, s, CONH)
4a
7.14 (2H, s, H-4',5'); 7.30-7.33 (6H, m, H-3,4,5 Ph); 7.42-7.44 (4H, m, H-2,6 Ph);
12.04 (1H, s, H-1'); 13.57 (1H, s, H-1)
4b
4b*
3.74 (3H, s, CH3O); 6.86, 6.94 (0.8H, 1.2H, two d, J = 7.2, H-3,5 Ar); 7.13 (2H, s, H-4',5');
7.26-7.43 (7H, m, H-2,6 Ar, 5H Ph); 12.01 (1H, s, H-1'); 13.43 (1H, s, H-1)
3.75 (3H, s, CH3O); 6.91 (2H, d, J = 8.7, H-3,5 Ar); 7.14 (2H, s, H-4',5');
7.28-7.33 (3H, m, H-3,4,5 Ph); 7.38 (2Н, d, J = 9.0, H-2,6 Ar); 7.43 (2H, m, H-2,6 Ph);
12.13 (1H, br. s, H-1'); 13.03 (1H, br. s, H-1)
4c
7.19 (2H, s, H-4',5'); 7.36-7.38 (3H, m, H-3,4,5 Ph); 7.43-7.45 (2H, m, H-2,6 Ph);
7.67, 8.20 (2H, 2H, two d, J = 8.7, 4H Ar); 12.14 (1H, s, H-1'); 13.92 (1H, s, H-1)
4d
7.10, 7.22 (1H, 1H, two s, H-4',5'); 7.35 (4H, m, H-3,4,5 Ph, H-5 Ar);
7.44-7.46 (2H, m, H-2,6 Ph); 7.78 (1H, d, J = 8.1, H-6 Ar); 8.48 (1H, s, H-4 Ar);
8.61 (1H, s, H-2 Ar); 12.10 (1H, s, H-1'); 13.77 (1H, s, H-1)
4e
7.19 (2H, s, H-4',5'); 7.33-7.35 (5H, m, H-3,4,5 Ph, H-2,6 Ar); 8.50 (2H, m, H-3,5 Ar);
12.16 (1H, s, H-1'); 13.88 (1H, s, H-1)
_______
*Spectrum after adding drops of acetic acid to a solution of the compound.
TABLE 3. Comparison of the Tautomeric Properties of 4-(2-Azolyl)-
1H-pyrazoles in DMSO-d6
Ph
Ph
H
N
N
N
N
Het
Het
H
Ar
Ar
A
B
Composition of the equilibrium tautomeric mixture, %
Ar
Het = 2-imidazolyl
Het = 2-benzimidazolyl
Ph
A ≡ B = 100
A = 60, B = 40
A ≡ B = 100
A ≡ B = 100
A ≡ B = 100
A ≡ B = 100 [1]
4-MeOC6H4
4-O2NC6H4
3-Pyridyl
A = 100, B = 0 [2]
A = 20, B = 80 [1, 2]
A = 31, B = 69 [1]
A = 21, B = 79 [1]
4-Pyridyl
68

The molecular diagram of the electronic structure of benzimidazole [3] demonstrates the pulling out of
electron density from the imidazole ring into the o-phenylene fragment. It follows that the imidazole substituent
is surpassed by benzimidazole in electron-withdrawing properties and surpasses it in basicity (pKa of imidazole
and of benzimidazole, for example, are 6.95 and 5.53 respectively [4]). It is notable that for all the
Fig. 1. Fragment of the 1H NMR spectrum of compound 4b: a – reflecting absorption of aromatic
protons; b – the same after adding drops of acetic acid to the solution.
pyrazolylbenzimidazoles mentioned above inhibited migration of protons between the nitrogen atoms of the
benzimidazole ring was observed, which is reflected in the 1H NMR spectra by the split resonance of its H-4 and
H-7 protons [1, 2]. On the other hand, for the large portion of compounds of type 4 such migrations in the
imidazole fragment are accelerated, and its aromatic protons resonate in the range 7.13-7.19 ppm as a generall
narrow multiplet. In compounds 4a-e the low sensitivity of substituents Ar towards discrimination of positions
3 and 5 of the pyrazole ring is therefore possibly caused by the weak resonance component of the electron-
withdrawing properties of the 2-imidazolyl fragment, and also its increased basicity, which probably aids
acceleration of the exchange processes. In such a case the exception of the 4-MeOC6H4 substituent is in
agreement with the fact that it, unlike other substituents, forms the energetically most favorable conjugation
system with the imidazole fragment.
It is characteristic that the formation of compounds 4a-e (especially 4-methoxyphenyl-substituted 4b)
occurs with significantly more difficulty than their benzimidazolyl analogs. This is also probably linked with the
weakly expressed electron-withdrawing properties of the 2-imidazolyl fragment, and consequently with the
69

reduced acidity of the methylene group of hydrazines of type 3. This hinders their isomerization into
imidazolidines of form 3', through which, in our opinion [2], subsequent cyclization with the formation of the
pyrazole ring is effected.
Fig. 2. Charge distribution and enthalpy of formation of tautomers A (∆H0 = 76.91 kcal/mol) and
B (∆H0 = 78.78 kcal/mol) of compound 4b in DMSO, according to data of quantum-chemical
calculation.
We note that 4-(1H-imidazol-2-yl)-1H-pyrazoles containing only one aryl substituent in the pyrazole
ring have been described previously [5]. However condensation of 2-phenacyl-1H-imidazoles with triethyl
orthoformate accompanied by cyclocondensation of the obtained β-ethoxyvinyl ketones with hydrazine, was
used for their synthesis.
The thermal intramolecular cyclization of aroylhydrazones of 2-phenacyl-1H-imidazoles may therefore
be considered as a new method of synthesis of 4-(1H-midazol-2-yl)-1H-pyrazoles, which permits the preparation
of previously unknown 3,5-diaryl derivatives.
EXPERIMENTAL
A check on the progress of reactions and on the purity of the synthesized compounds was carried out by
1
TLC on Silufol UV-254 plates in the solvent system benzene–ethanol, 9:1, visualizing with UV light. The H
70

NMR spectra of compounds were recorded on a Varian VXR-300 (300 MHz) spectrometer in DMSO-d6,
standard was TMS. Quantum-chemical calculations were carried out using the MOPAC2007 program in the
semiempirical PM3 approximation allowing for the effect of solvent [6].
Benzoylhydrazone of 2-Phenacyl-1H-imidazole (3a). A mixture of compound 1 [7] (1.115 g, 5 mmol),
benzoylhydrazine (2a) (0.68 g, 5 mmol), triethylamine (1.0 ml, 7 mmol), and 1-butanol (5.0 ml) was maintained
at 115-120oC in an oil bath for 3 h. The reaction mixture was diluted with water (2.0 ml) with stirring and after
cooling the separated product 3a was filtered off, washed with 2-propanol, with water, and once again with
2-propanol. The product was ready for further conversion, an analytical sample was obtained by crystallization
from a mixture of pyridine–water, 2:1.
Hydrazones 3b-e were obtained analogously from compound 1 and aroylhydrazines 2b-e.
4-(1H-Imidazol-2-yl)-3,5-diphenyl-1H-pyrazole (4a). A mixture of compound 3a (1.0 g) and N,N-di-
methylaniline (3.0 ml) was heated in an oil bath at 220-230oC for 1.5 h. The hot mixture was diluted with
toluene (3.0 ml) with stirring. The cooled mass was filtered, the solid was washed with toluene, and with a small
quantity of cold 2-propanol. Product 4a was obtained in an analytically pure state.
Compounds 4b-e were obtained analogously from hydrazones 3b-e. In the synthesis of 4b heating was
continued for 8 h, and the product was recrystallized from a mixture of acetic acid–water, 1:1, and a mixture of
ethanol–water, 3:1, with addition of 20% aqueous ammonia solution (0.5 ml).
REFERENCES
1.
2.
3.
4.
I. B. Dzvinchuk, A. V. Vypirailenko, V. V. Pirozhenko, and M. O. Lozinskii, Khim. Geterotsikl.
Soedin., 1512 (1999). [Chem. Heteterocycl. Comp., 35, 1319 (1999)].
I. B. Dzvinchuk, A. V. Turov, and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 1186 (2009). [Chem.
Heterocycl. Comp., 45, 942 (2009)].
V. I. Ivanskii, Chemistry of Heterocyclic Compounds [in Russian], Vyssh. Shkola, Moscow (1978),
p. 161.
A. F. Pozharskii, Theoretical Basis of Heterocyclic Chemistry [in Russian], Khimiya, Moscow (1985),
126 pp.
5.
6.
M. D. Nair and J. A. Desai, Indian J. Chem., 23B, 5, 480 (1984).
J. J. P. Stewart, MOPAC2007, Stewart Computational Chemistry, Version 8.032W; web:
http://openmopac.net
7.
A. A. Macco, E. F. Godefroi, and J. J. M. Drouen, J. Org. Chem., 40, 2, 252 (1975).
71