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

Article abstract of DOI:10.1007/s10593-010-0429-x

2-(3,5-Diaryl-1H-pyrazol-4-yl)-1H-benzimidazoles have been obtained by the cyclocondensation of 2-phenacyl-1H-benzimidazoles with 4-nitro- and 4-methoxybenzoylhydrazines. The reaction mechanism and the isomerism of the obtained products are discussed. Acc

Full text of DOI:10.1007/s10593-010-0429-x

Chemistry of Heterocyclic Compounds, Vol. 45, No. 11, 2009
SYNTHESIS AND ISOMERISM OF 2-(3,5-DIARYL-
1H-PYRAZOL-4-YL)-1H-BENZIMIDAZOLES
I. B. Dzvinchuk1*, A. V. Turov2, and M. O. Lozinskii1
2-(3,5-Diaryl-1H-pyrazol-4-yl)-1H-benzimidazoles have been obtained by the cyclocondensation of
2-phenacyl-1H-benzimidazoles with 4-nitro- and 4-methoxybenzoylhydrazines. The reaction mechanism
1
and the isomerism of the obtained products are discussed. According to the data of H NMR
spectroscopy the stabilized isomer is that in which the electron-withdrawing aryl substituent is located
in position 3 and the electron-donating substituent in position 5 of the pyrazole ring.
Keywords: aroylhydrazines, aroylhydrazones, benzimidazoles, pyrazoles, tautomerism.
It was found previously [1] that acylhydrazones of β-dicarbonyl compounds are cyclized into pyrazoles
as a result of condensation of the carbonyl group of the acylhydrazone fragment and an activated methylene
group, when a methyl or phenyl substituent is present on the nitrogen atom next to the carbonyl group of the
hydrazone fragment. Later [2] we showed that aroylhydrazones of 2-phenacyl-1H-benzimidazole in the absence
of such substituents also undergo an analogous cyclocondensation with the formation of 2-(3-aryl-5-phenyl-1H-
pyrazol-4-yl)-1H-benzimidazoles on heating to 200oC. In this case it is possible to combine the preparation of
the hydrazones and their cyclocondensation in one process, however the reaction proceeds only with
benzoylhydrazine and with its derivatives containing electron-withdrawing substituents in the benzene ring. Up
to the present time we have produced new experimental data which indicate the broader possibilities of this
reaction and enable elucidation of its mechanism.
We have found that the interaction of a series of 2-phenacyl-1H-benzimidazoles 1a-e with 4-nitro-
benzoylhydrazine 2a, proceeding through hydrazones 3a-e and their subsequent cyclocondensation, leads to
2-[5-aryl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-benzimidazoles 4a-e. Derivatives 4a,c,d with various aryl
substituents in positions 3 and 5 of the pyrazole ring therefore exist in DMSO-d6 solution in equilibrium with the
tautomeric forms 4'a,c,d.
The reaction occurs smoothly on heating in DMSO at 150oC for 1 h with triethylamine hydrochloride as
catalyst.
4-Methoxybenzoylhydrazine 2b, the electrophilicity of the carbonyl group of which is reduced due to
the electron-donating effect of the MeO group, reacts under more rigid conditions. The interaction of reactants
1a and 2b occurs at 200oC, in the presence of a small amount of diglyme preventing crystallization of
_______
* To whom correspondence should be addressed, e-mail: Rostov@bpci.kiev.ua.
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine.
2Kiev Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail: NMRLab@univ.kiev.ua.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, 1651-1657, November, 2009.
Original article submitted December 24, 2008. Revised version submitted October 5, 2009.
0009-3122/09/4511-1325©2009 Springer Science+Business Media, Inc.
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hydrazone 3f, and is complete after 5 h with the formation exclusively of product 4'f. The analogous
cyclocondensation involving reactant 1b is complicated by side reactions. In this case it is far more convenient
to carry out the reaction in two stages. First hydrazone 3g is obtained, which is then cyclized in boiling ethylene
glycol, and is complete after 5 h with the formation of product 4g.
Ar
Ar
O
O
H
N
N
N
N
N
N
∆
+
Ar 1
NH
Ar 1
H2N
– H2O
O
H
H
2a,b
1a–e
3a–g
∆
– H2O
Ar
H
Ar
N
N
N
N
N
N
N
N
H
Ar1
H
H
Ar1
4a–e, g
4'a,c,d,f
1 a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 3,4,5-(MeO)3C6H2, d Ar = 3-O2NC6H4,
e Ar = 4-O2NC6H4; 2 a Ar1 = 4-O2NC6H4, b Ar1 = 4-MeOC6H4; 3,4,4' a−e Ar1 = 4-O2NC6H4,
a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 3,4,5-(MeO)3C6H2, d Ar = 3-O2NC6H4, e Ar = 4-O2NC6H4;
f Ar = Ph, Ar1 = 4-MeOC6H4; g Ar = Ar1 = 4-MeOC6H4
We also carried out the methylation of product 4e with methyl iodide, using potassium hydroxide as
base, and product 4g with the dimethylacetal of DMF, and obtained the dimethyl derivatives 5a,b, which are
convenient as comparison subjects when studying the isomerism of compounds of types 4 and 4' by 1H NMR.
Ar
Me
N
N
N
MeI
4e,g
N
or Me2NCH(OMe)2
Ar
5a,b
Me
5 a Ar = 4-O2NC6H4, b Ar = 4-MeOC6H4
The structure and composition of the synthesized compounds 3g, 4a-e,g, 4'f, and 5a,b were confirmed
by data of elemental analysis (Table 1) and 1H NMR spectra (Table 2).
1
Assignment of the signals in the H NMR spectra of model compounds 5a,b was made with the aid of
NOE and COSY experiments. The protons of the nitrophenyl substituents gave doublets at 7.67, 8.18 and 7.74,
8.25 ppm, and the protons of the methoxyphenyl groups at 6.83, 7.32 and 6.93, 7.36 ppm. The spin connection
between them follows from the presence of COSY spectra correlations. In both compounds the lower field
signals correspond to the 5'-substituent of the pyrazole ring. This follows from the presence of a NOE
1326

correlation in the NOESY spectrum between the ortho protons of this aryl substituent and the signal of the 1'-Me
group. Such a spectral picture is possibly caused by the fact that the electron-donating effect of the pyrazole ring
nitrogen atom acts on the substituent at position 3' and the electron-withdrawing influence of the benzimidazole
fragment acts on the substituent at position 5'.
TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
N
3g
4a
4b
4c
4d
4e
4'f
4g
5а
5b
C24H22N4O3
69.32
69.55
69.15
69.28
67.07
67.15
63.47
63.69
59.52
59.46
61.85
61.97
75.27
75.39
72.56
72.71
5.48
5.35
3.75
3.96
4.08
4.16
4.36
4.49
3.52
3.63
3.24
3.31
4.78
4.95
4.94
5.08
13.38
13.52
18.18
18.36
16.86
17.02
14.68
14.85
18.72
18.91
19.58
19.71
15.18
15.29
13.95
14.13
243.5-245.0
312.0-313.5
304.0-305.5
284.0-285.5
183.0-184.5
> 360.0
86
88
81
57
88
88
92
78
72
85
С22H15N5O2
C23H17N5O3
C25H21N5O5
C22H14N6O4×Н2О
C22H14N6O4
C23H18N4O
259.5-261.0
282.0-283.5
259.0-260.5
145.0-146.5
C24H20N4O2
C24H18N6O4
C26H24N4O2
63.27
63.43
73.44
73.57
4.12
3.99
5.53
5.70
18.24
18.49
13.07
13.20
On comparing the 1H NMR spectra of model compounds 5a,b and also of compounds 4a-e,g and 4'f the
following special features of their isomerism were established.
For compounds 4d,e,g, containing Ar and Ar1 substituents of the same or closely similar electronic
nature, a rapid migration of proton between the pyrazole ring nitrogens is characteristic, though the proton is
found with practically the same probability on each of them. In this case the individual tautomers were not
distinguished since the substituents Ar and Ar1 are not different in belonging to positions 3 and 5 of the pyrazole
ring and, when Ar = Ar1, appear equivalent.
For compounds 4a,c with substituents Ar and Ar1 differing significantly in electronic nature, the
appearance in the spectrum of individual tautomers as a doubling of the corresponding signals is characteristic.
The chemical shifts and the integrated intensities of these signals permits discrimination of the tautomers and
their relative content. Tautomers 4a,c, in which the electron-withdrawing substituent occupies position 3', (80
and 75% respectively in the equilibrium mixture) are the more stable.
For compounds 4b and 4'f, in which one aryl substituent is 4-MeOC6H4 and the second is 4-O2NC6H4 or
Ph, the individual tautomers also did not appear. The compounds exist practically completely in the form of the
isomer with location of the electron-donating aryl substituent at position 5', in which it probably forms an
energetically advantageous system of conjugation with the benzimidazole fragment.
It should be mentioned that, according to data of 1H NMR spectra, hydrazone 3g contains contamination
by the compound of isomeric structure (~7%). Separation of the isomers is laborious since they readily
interconvert. Although we previously proposed an enehydrazine structure [2] for the analogous isomer of the
benzoylhydrazone of 2-phenacyl-1H-benzimidazole, we propose an argument in favor of a heterylidene structure of
type 3' in this work. First of all, tautomerism of this type is characteristic of the initial keto compounds 1a-e, and
they exist predominantly in the heterylidene form [3, 4]. Their hydrazones [4, 5], alkyl- [6, 7], and arylhydrazones
1327

TABLE 2. Parameters of 1H NMR Spectra of the Synthesized Compounds
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
3g and 3.81, 3.88 (3H, 3H, two s, CH3O); 4.49 (2H, s, CH2); 7.03 (2H, d, J = 8.7, H-3,5 Ar);
3'g
7.16-7.23 (4H, m, H-3,5 COAr, H-5,6); 7.51-7.54, 7.62-7.65 (1H, 1H, two m, H-7,4);
7.95, 8.18 (2H, 2H, two d, J = 7.5, H-2,6 Ar, H-2,6 COAr);
12.71, 12.78 (1H, 1H, two s, H-1, NHCO) and 3.76, 3.77 (3H, 3H, two s, CH3O);
5.44 (1Н, s, =CH–C=N), 6.94 (2H, d, J = 8.7, H-3,5 Ar); 7.41-7.44 (2H, m, H-4,7);
10.40, 10.48, 12.10 (1H, 1H, 1H, three s, H-1,3, NHCO),
remaining signals are overlapped by the signals of 3g
4a
7.20-7.23 (2H, m, H-4,5); 7.28-7.30 (1H, m, H-4 Ph);
7.38-7.48 (5H, m, H-2,3,5,6 Ph, H-7); 7.71-7.75 (3H, m, H-4, H-2,6 NC6H4);
8.17, 8.25 (1.60H, 0.40H, two d, J = 8.4, H-3,5 NC6H4); 12.59 (1H, s, H-1);
14.07 (1H, s, H-1')
4b
4c
3.73 (3H, s, CH3O); 6.94 (2H, d, J = 8.1, H-3,5 OC6H4); 7.21-7.24 (2H, m, H-4,5);
7.41-7.44 (3H, m, H-7, H-2,6 OC6H4); 7.71-7.74 (3H, m, H-4, H-2,6 NC6H4);
8.18 (2H, d, J = 8.1, H-3,5 NC6H4); 12.56 (1H, s, H-1); 13.93 (1H, s, H-1')
3.48, 3.55, 3.63 (0.45Н, 5.55H, 3Н, three s, 3CH3O);
6.85, 6.92 (0.30H, 1.70H, two s, C6H2); 7.22-7.25 (2H, m, H-4,5);
7.43-7.46 (1H, m, H-7); 7.70-7.77 (3H, m, H-4, H-2,6 NC6H4);
8.20, 8.25 (1.70H, 0.30H, d, J = 7.5, m, H-2,6 NC6H4); 12.62 (1H, s, H-1);
14.04 (1H, s, H-1')
4d
7.21-7.26 (2H, m, H-4,5); 7.43-7.45 (1H, m, H-7);
7.63-7.76 (4H, m, H-4, H-5 3-NC6H4, H-2,6 4-NC6H4); 7.88 (1H, d, J = 7.5, H-6 3-NC6H4);
8.18-8.25 (3H, m, H-4 3-NC6H4, H-3,5 4-NC6H4); 8.51 (1H, br. s, H-2 3-NC6H4);
12.61 (1H, s, H-1); 14.35 (1H, s, H-1')
4e
7.22-7.25 (2H, m, H-4,5); 7.43-7.46 (1H, m, H-7); 7.73-7.76 (5H, m, H-4, 2H-2,6 NC6H4);
8.23-8.25 (4H, m, 2H-3,5 NC6H4); 12.64 (1H, s, H-1); 14.40 (1H, s, H-1')
4'f
3.71 (3H, s, CH3O); 6.89 (2H, d, J = 8.7, H-3,5Ar); 7.17-7.22 (2H, m, H-4,5);
7.29 (2H, d, J = 8.7, H-2,6 Ar); 7.31-7.34 (1H, m, H-7); 7.40-7.48 (5H, m, C6H5);
7.67-7.70 (1H, m, H-4); 12.48 (1H, s, H-1); 13.61 (1H, s, H-1')
4g
5a
3.70 (6H, s, CH3O); 6.85-6.89 (4H, m, 2H-3,5 Ar); 7.18-7.21 (2H, m, H-4,5);
7.38-7.41 (5H, m, 2H-2,6 Ar, H-7); 7.67-7.69 (1H, m, H-4); 12.45 (1H, s, H-1);
13.46 (1H, s, H-1')
3.34 (3H, s, 1-CH3); 4.03 (3H, s, 1'-CH3); 7.21-7.29 (2H, m, H-4,5);
7.48 (1H, d, J = 7.2, H-7); 7.66-7.68 (3H, m, H-4, H-2,6 3-Ar);
7.74 (2H, d, J = 8.7, H-2,65-Ar); 8.18 (2H, d, J = 8.7, H-3,5 3-Ar);
8.25 (2H, d, J = 8.7, H-3,5 5-Ar)
5b
3.26 (3H, s, 1-CH3); 3.69 (3H, s, 3-CH3O Ar); 3.72 (3H, s, 5-CH3O NC6H4);
3.89 (3H, s, 1'-CH3); 6.83 (2H, d, J = 8.0, H-3,5 3-Ar); 6.93 (2H, d, J = 8.0, H-3,5 5-Ar);
7.20-7.22 (2H, m, H-4,5); 7.32 (2H, d, J = 8.0, H-2,6 3-Ar);
7.36 (2H, d, J = 8.0, H-2,6 5-Ar); 7.44-7.46 (1H, m, H-7); 7.64-7.66 (1H, m, H-4)
[8-10] do not display an inclination towards such isomerism, since they contain a less acidic methylene group. In
their turn acylhydrazones are distinguished by the high polarity of the hydrazone azomethine bond, and
1
consequently in their nature they are closer to the initial keto compounds 1a-e. Secondly, in the H NMR
spectrum of compound 3g many signals of its isomer (both OMe, H-1,3,4,7, NHC=O, different Ar portion),
were displaced towards high field. This may be caused by the electron-donating influence of the nitrogen atoms
of the heterylidene fragment and permits the 3'g configuration to be definitely probable for the minor isomer.
On the other hand in the enehydrazone form the benzimidazole fragment shows an electron-withdrawing action,
which must lead to a displacement of the indicated signals towards low field.
We suggest that these circumstances clarify the mechanism of the cyclocondensation being studied.
Probably, the significant moment of the process is the isomerization of aroylhydrazones 3a-g into the
hetarylidene forms 3'a-g, in which there is a nucleophilic center of the enamine type, sufficiently reactive at
elevated temperatures for intramolecular attack at the carbonyl group. The increased electrophilicity of this
carbonyl group assists cyclization, which is also shown in the clear difference discovered by us of the conditions
of carrying out the reaction with aroylhydrazines 2a,b.
1328

OMe
NH
H
Ar
N
H
N
N
3a–g
N
H
4a-e,g, 4'f
O
N
– H2O
N
O
N
Ar 1
H
H
3'a–g
MeO
3'g
The cyclocondensation of 2-phenacyl-1H-benzimidazoles with aroylhydrazines is therefore a fairly
general method of obtaining 2-(3,5-diaryl-1H-pyrazol-4-yl)-1H-benzimidazoles, but in individual cases the
synthesis is best carried out in two stages with the intermediate isolation of the aroylhydrazone.
EXPERIMENTAL
A check on the progress of reactions and the purity of the synthesized compounds was carried out by
TLC on Silufol UV-254 plates in the solvent system benzene–ethanol, 9 : 1, visualizing with UV light. Before
carrying out elemental analysis and spectral investigations compounds 4a-e,g, 4'f, and 5a were dried for 3 h at
150oC, and 5b for 6 h at 115oC in a water-jet pump vacuum. The 1H NMR spectra of compounds were recorded
on a Varian VXR-300 spectrometer (300 MHz) in DMSO-d6, standard was TMS. The NOE and COSY
experiments were carried out on a Varian Mercury 400 spectrometer (400 MHz).
4-Methoxybenzoylhydrazone of 2-(4-Methoxyphenacyl)-1H-benzimidazole (3g). A mixture of
compound 1b (1.065 g, 4 mmol) and hydrazide 2b (0.664 g, 4 mmol), 1-butanol (4 ml) and glacial acetic acid
(4 drops) was maintained at 120oC for 3 h. The cooled mass was filtered, the solid product 3g was washed with
2-propanol, and crystallized from a mixture of pyridine–water, 2, 1.
2-[3-(4-Nitrophenyl)-5-phenyl-1H-pyrazol-4-yl]-1H-benzimidazole (4a). A mixture of compound 1a
(0.236 g, 1 mmol), hydrazide 2a (0.199 g, 1.1 mmol), triethylamine hydrochloride (0.028 g, 0.2 mmol), and
DMSO (2 ml) was maintained at 145-150oC for 1 h. The reaction mixture was cooled to 100oC, diluted with
water (1.0 ml), and heated with stirring until crystallization began. The cooled mixture was filtered, the solid
product 4a was washed with a 2-propanol–water, 1:1 mixture, and crystallized from a pyridine–water, 2:1
mixture.
Products 4b-e were obtained from compounds 1b-e and 2a analogously. On isolating compound 4c the
reaction mixture was diluted with water (3 ml). Compound 4e was crystallized from a mixture of DMF–water, 2:1.
2-[5-(4-Methoxyphenyl)-3-phenyl-1H-pyrazol-4-yl]-1H-benzimidazole (4'f). A mixture of compound 1a
(2.36 g, 10 mmol), hydrazide 2b (1.80 g, 11 mmol), and diglyme (2.0 ml) was heated using an oil bath at 200-
205oC for 5 h. After cooling, the reaction mixture was diluted with ethanol (5 ml), warmed with stirring until
crystallization began, and diluted with water (5 ml). The cooled mass was filtered, product 4'f was washed with
an ethanol–water 2:1 mixture, and after drying was obtained in an analytically pure state.
2-[3,5-Bis(4-methoxyphenyl)-1H-pyrazol-4-yl]-1H-benzimidazole (4g). A mixture of hydrazone 3g
(0.414 g, 1 mmol) and ethylene glycol (2.0 ml) was boiled for 5 h. The cooled mass was filtered, the solid
product 4g was washed with a 2-propanol–water, 1:1 mixture, and recrystallized from a DMF–H2O, 2:1 mixture.
1329

1-Methyl-2-[1-methyl-3,5-bis(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-benzimidazole (5a). Methyl iodide
(0.312 ml, 5 mmol) was added dropwise during 15 min with stirring by a magnetic stirrer to a mixture of
compound 4e (0.426 g, 1 mmol), finely powdered potassium hydroxide (0.56 g, 10 mmol), and DMSO (3 ml) at
15-20oC. The mixture was stirred for a further 30 min and diluted with water (5 ml). The resulting solid product
5a was filtered off, washed with a mixture of 2-propanol–water, 1:1, and crystallized from DMF–water, 3:1.
2-[3,5-Bis(4-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl]-1-methyl-1H-benzimidazole (5b). A mixture of
compound 4g (0.396 g, 1 mmol), DMF dimethylacetal (1.5 ml), and anhydrous dioxane (2.5 ml) was maintained
at 105oC for 10 h. The reaction mixture was carefully diluted with water (4 ml) with stirring. The cooled mass
was filtered, the solid product 5b was dried, and obtained in analytically pure form.
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