Synthesis and tautomerism of 2-(3,5-diaryl-1H-pyrazol-4-yl)-1-methyl-1H- benzimidazoles

Article abstract of DOI:10.1007/s10593-011-0691-6

The cyclocondensation of 1-methyl-2-phenacyl-1H-benzimidazole with aroylhydrazines yields 2-(3,5-diaryl-1H-pyrazol-4-yl)-1-methyl-1H- benzimidazoles. The ¹H NMR spectra indicate that these products display tautomerism. The more stable tautomers have structures containing electron-donor aryl substituents at C-5 and electron-withdrawing aryl substituents at C-3 of the pyrazole ring.

Full text of DOI:10.1007/s10593-011-0691-6

Chemistry of Heterocyclic Compounds, Vol. 46, No. 12, 2011
SYNTHESIS AND TAUTOMERISM OF 2-(3,5-DIARYL-
1H-PYRAZOL-4-YL)-1-METHYL-1H-BENZIMIDAZOLES
I. B. Dzvinchuk1* and M. O. Lozinskii1
The cyclocondensation of 1-methyl-2-phenacyl-1H-benzimidazole with aroylhydrazines yields 2-(3,5-
1
diaryl-1H-pyrazol-4-yl)-1-methyl-1H-benzimidazoles. The H NMR spectra indicate that these products
display tautomerism. The more stable tautomers have structures containing electron-donor aryl
substituents at C-5 and electron-withdrawing aryl substituents at C-3 of the pyrazole ring.
Keywords: aroylhydrazines, benzimidazoles, pyrazoles, tautomerism.
The tautomerism of pyrazole and its derivatives has long been known [1] but is still under investigation
[2-11] since this phenomenon is an inherent characteristic for many compounds, including recently synthesized
derivatives. This feature reveals subtle structural aspects related to intramolecular and solvation interactions.
Increasingly advanced methods are revealing new correlations concerning this tautomerism.
We have developed a method for the formation of the pyrazole ring, in which well-known
aroylhydrazines are used for the first time as a 1,3-N,N,C-nucleophile-electrophile. Thus, the cyclocondensation
of these hydrazines with 2-phenacyl-1H-benzimidazole leads to 2-(3,5-diaryl-1H-pyrazol-4-yl)-1H-benzimida-
1
zoles of 1 type. The H NMR spectra of benzimidazoles 1 have some double signals due to proton migration
between the pyrazole ring nitrogen atoms, leading to the formation of tautomers A and B [12, 13] (Scheme 1).
Similarly, 2-(3,5-diaryl-1H-pyrazol-4-yl)-1H-imidazoles of 2 type are obtained from the aroylhydrazones of
2-phenacyl-1H-imidazole. In contrast, no signal doubling is noted in the spectra of imidazoles 2 in most cases
[14].
Scheme 1
Ph
Ph
R1
R1
R1
R1
H
N
N
N
N
N
N
N
N
H
R
Ar
R
Ar
1–3
A
B
1 R = H, R1 + R1 = CH=CH–CH=CH; 2 R = R1 = H; 3 R = Me, R1 + R1 = CH=CH–CH=CH
_______
* To whom correspondence should be addressed, e-mail: Rostov@ioch.kiev.ua.
1Institute of Organic Chemistry, National Academy of Sciences, Kiev 02094, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1800-1805, December, 2010.
Original article submitted May 28, 2010. Submitted after revision October 15, 2010.
1454
0009-3122/11/4612-1454©2011 Springer Science+Business Media, Inc.

TABLE 1. Characteristics of Synthesized Compounds*
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
mp, С
С
Н
N
3a
3b
3c
3d
3e
3f
C23H18N4
78.75
78.83
75.57
75.77
69.75
69.86
75.07
75.19
68.33
68.11
71.58
71.78
5.07
5.18
5.24
5.30
4.18
4.33
4.64
4.88
5.45
5.72
4.38
4.45
15.85
15.99
14.58
14.73
17.63
17.71
19.78
19.93
12.38
12.22
14.47
14.56
279-280
69
71
70
72
51
67
C24H20N4O
C23H17N5O2
С22H17N5
242-245
265.0-266.5
223.0-24.5
142-145
C26H24N4O3·Н2О
C23H17ClN4
220-222
_______
*The reaction time of the synthesis is 30 min for 3a,c-e and 50 min for 3b,f.
This heterocyclization is probably a general reaction and the tautomerism of its products depends on the
nature of the hetaryl substituent at C-4 of the pyrazole ring. Previously unreported 4-hetarylpyrazoles 3, in
which the hetaryl moiety is a 1-methyl-1H-benzimidazol-2-yl group, were synthesized in the present work in
order to test this hypothesis.
Fusing 1-methyl-2-phenacyl-1H-benzimidazoles (4) and aroylhydrazines 5a-f at 200°C gave 2-(3,5-
diaryl-1H-pyrazol-4-yl)-1-methyl-1H-benzimidazoles 3a-f in 51-78% yield (Scheme 2).
Scheme 2
Ph
N
Ph
N
O
N
H
Ph
N
N
O
H
N
N
N
200°C
–H2O
Ar
N
N
H2NNHCOAr
+
Ar
Me
–H2O
Me
5a–f
3a–f
4
Me
3, 5 a Ar = Ph, b Ar = C6H4OMe-p, c Ar = C6H4NO2-p, d Ar = 4-pyridyl,
e Ar = C6H2(OMe)3-m,m',p, f Ar = C6H4Cl-o
This reaction proceeds using benzoic acid as the catalyst. The reaction without catalyst is accompanied
by disproportionation of the aroylhydrazines, leading to 1,2-diaroylhydrazines and complicating isolation of the
desired products. The reaction time (30-50 min) depends on the reactivity of the carbonyl group of the starting
aroylhydrazine. The reaction course is readily monitored relative to the release of water vapor.
The composition and structure of the resultant products 3 were supported by their elemental analysis
(Table 1) and the 1H NMR spectral data (Table 2).
1H NMR spectroscopy indicates that benzimidazoles 3b-d,f exist in DMSO-d6 as an equilibrium mixture
of tautomers A and B (Scheme 1), which is seen in a doubling of the signals of some of the protons (see
Table 2). The spectra of benzimidazoles 3a,e do not show doubled signals, which, however does not exclude the
existence of the product 3e in different tautomeric forms. In the case of product 3a, where Ar = Ph, forms A and
B are identical: A ≡ B. In order to study the tautomerism of benzimidazoles 3a-f, we used benzimidazoles 6a
and 6b (see Fig. 1), which differ in the substitution of the pyrazole ring, as reference compounds. These
structural analogs have an NMe group instead of an NH group as well as two 4-methoxyphenyl (6a) or two
4-nitrophenyl substituents (6b).
1455

_
O
+
N
O
MeO
3.69
6.83
7.32
8.18
7.67
7.65
7.45
7.67
7.47
N
N
N
N
N
N
7.21–
7.29
7.20–
7.22
3.89
N
4.03
Me
N
Me
Me
3.26
Me
3.34
7.36
6.93
7.74
8.25
3.72
MeO
O2N
6b
6a
1
Fig. 1. Model compounds 6a,b with H NMR chemical shifts (, ppm). The major
donor-acceptor interactions are indicated by arrows.
1
The synthesis and assignment of H NMR signals of these compounds using NOE and COSY
experiments were assigned in our previous work [13]. We established that the protons of the 5-Ar substituent,
regardless of their electronic nature, are seen at lower field than the protons of the 3-Ar substituent. The aryl
substituent at C-5 probably is subject to an overall electron-withdrawing effect of the 1-methylbenzimidazol-
2-yl fragment, while the aryl substituent at C-3 is subject only to the inductive effect of this fragment and
possibly the electron-donor effect of the pyrrole nitrogen atom of the pyrazole ring. These data were used to
determine the tautomer composition and dependence of this composition on the nature of the aryl substituent
using the chemical shifts and integral intensities in the 1H NMR spectra (see Scheme 1 and Table 3). The proton
migration between the nitrogen atoms in the case of a pyrazole ring with substituents possessing similar
electronic properties is probably so fast that individual tautomers cannot be seen in the spectrum
(benzimidazole 3e). Tautomers A and B are seen in the spectra when there is a large difference between the aryl
and phenyl substituents. The tautomers with an electron-donor substituent at C-5 and electron-withdrawing
substituent at C-3 are more stable (tautomer A for benzimidazole 3b and tautomers B for benzimidazoles 3c,d).
Comparison of the tautomer data for benzimidazoles 3a-f and their structural analogs 1a-d and 2a-d
(Table 3) shows that an electron-donor aryl substituent stabilizes tautomer A (in the case of 1b), while the
introduction of a methyl group into the benzimidazolyl fragment (3b) or replacement of this fragment with an
imidazolyl group (2b) markedly destabilizes tautomer A. In contrast, tautomers B are more stable in the case of
electron-withdrawing Ar groups (1c,d), while introduction of a methyl group into the benzimidazolyl fragment
somewhat lowers the stability of tautomers B (3c,d). There are no marked differences between forms A and B in
1
the imidazolyl analogs of these compounds (2c,d) and these forms do not appear individually in the H NMR
spectra. These features are probably related to both steric and electronic factors, namely, the existence of the
bulky electron-donor methyl group in benzimidazoles 3 not favorable for -orbital overlap of the conjugation
system of the benzimidazolyl fragment with the Ar substituent and the presence of the less electron-withdrawing
but more basic imidazolyl fragment in imidazoles 2.
It is interesting that the tautomeric forms for benzimidazole 3f are not equivalent but, nevertheless, equal
in energy. The tautomeric forms are seen as inequivalent since the signals of the NH group of the tautomers differ
in their chemical shifts by 0.16 ppm (by 0.03-0.08 for compound 3b,d), while these forms are seen to be equal in
energy since integral intensity ratio of their signals is 1:1. The o-chlorophenyl substituent differs significantly
from the phenyl group in its steric and deshielding effects on the proton at the pyrrolic nitrogen
1456

TABLE 2. Parameters of the 1H NMR Spectra of Compounds Synthesized
Com-
pound
Chemical shifts, , ppm (J, Hz)
3a
3b
3.29 (3H, s, NCH3); 7.26-7.33 (8H, m, m-, p-H Ph, H-5,6); 7.39-7.41 (4H, m, o-H Ph);
7.51-7.54 (1H, m, H-7); 7.70-7.73 (1H, m, H-4); 13.88 (1H, s, NH)
3.29 (3H, s, NCH3); 3.69 and 3.72 (1.29H and 1.71H, two s, OCH3);
6.83 and 6.93 (0.82H and 1.18H, two d, J1 = J2 = 8.4, m-H Ar);
7.25-7.38 (9H, m, o-, m-, p-H Ph, o-H Ar, H-5,6); 7.51-7.54 (1H, m, H-7);
7.70-7.72 (1H, m, H-4); 13.72 and 13.75 (0.57H and 0.43H, two s, NH)
3c
3.31 (3H, s, NCH3); 7.26-7.38 (7H, m, H-5,6, o-, m-, p-H Ph); 7.54-7.56 (1H, m, H-7);
7.68-7.74 (3H, m, o-H Ar, H-4);
8.16 and 8.21-8.23 (1.50H and 0.50H, d, J = 8.1 and m, m-H Ar); 14.20 (1H, s, NН)
3d
3.33 (3H, s, NCH3); 7.27-7.38 (9H, m, H-5,6, o-, m-, p-H Ph, o-H Ar);
7.55-7.58 (1H, m, H-7); 7.73-7.75 (1H, m, H-4);
8.49, 8.55-8.57 (1.46H and 0.54H, d, J = 4.8 and m, m-H Ar);
14.18 and 14.26 (0.73H and 0.27H, two s, NН)
3e
3f
3.30 (3H, s, NCH3); 3.46 (6H, s, m-OCH3); 3.61 (3H, s, p-OCH3);
6.80 (2H, s, C6H2); 7.25-7.35 (5H, m, H-5,6, m-, p-H Ph); 7.46 (2H, d, J = 7.8, o-H Ph);
7.52-7.55 (1H, m, H-7); 7.71-7.74 (1H, m, H-4); 13.86 (1H, s, NН)
2.24, 3.26 (1.5H and 1.5H, two s, NCH3); 7.16-7.34 (2H, m, H-5,6);
7.31-7.45 (10H, m, H-7, o-, m-, p-H Ph, o-, m-, p-H Ar); 7.58-7.60 (1H, m, H-4);
13.79, 13.95 (0.50H and 0.50H, two s, NН)
TABLE 3. Content of Tautomer A in Benzimidazoles 3 and Their
Structural Analogs 1 and 2 in Equilibrium Mixture with Tautomer B from
1H NMR Spectral Data
Content of А, %
Ar
3
1
2 [14]
Ph (a)
А ≡ B
59
А ≡ B [12]
100 [13]
20 [12, 13]
21 [12]
—
А ≡ B
60
C6H4OMe-p (b)
C6H4NO2-p (c)
4-Pyridyl (d)
C6H2(OMe)3-m,m',p (e)
C6H4Cl-o (f)
25
—*
—*
—
27
—*
50
—
—
_______
* The 1H NMR spectrum does not distinguish between tautomers A and B.
group and this difference accounts for the lower rate of tautomeric interconversions such that each tautomer is
clearly seen in the spectrum.
Thus, 2-(3,5-diaryl-1H-pyrazol-4-yl)-1-methyl-1H-benzimidazoles are readily obtained in the cyclo-
condensation of 1-methyl-2-phenacyl-1H-benzimidazoles with aroylhydrazines. Introduction of a methyl group
at the nitrogen atom of the benzimidazole fragment does not alter the preferential stabilization for the tautomers
with electron-withdrawing aryl substituents at C-3 and electron-donor substituents at C-5 of the pyrazole ring
but reduces the difference between substituents at these positions.
EXPERIMENTAL
The 1H NMR spectra of these compounds were taken on a Varian VXR-300 spectrometer at 300 MHz in
DMSO-d6 with TMS as the internal standard. Monitoring of the course of the reactions and purity of the
products was carried out by thin-layer chromatography on Silufol UV-254 plates using benzene–ethanol, 9:1, as
the eluent and development with UV light.
1457

2-(3,5-Diphenyl-1H-pyrazol-4-yl)-1-methyl-1H-benzimidazole (3a). A mixture of benzimidazole 4
(0.250 g, 1 mmol), aroylhydrazine 5a (0.136 g, 1 mmol), and benzoic acid (0.030 g, 0.25 mmol) was fused on a
bath at 195-200°C for 30 min. The cooled melt was dissolved in 1.5 ml pyridine heated to reflux. The solution
was diluted by carefully adding water with stirring until the onset of crystallization was observed. The cooled
mass was filtered. The precipitate was washed with cold 2-propanol and dried in vacuum at a water pump at
115°C to give 0.241 g analytically pure 3a.
Products 3b-f were obtained analogously from benzimidazole 4 and aroylhydrazines 5b-f. The reaction
times are given in Table 1.
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