Selective recyclization of 2-aroylmethyl-1H-benzimidazole hydrazones by condensation with dimethylformamide

Article abstract of DOI:10.1023/A:1013223531612

2-Aroylmethyl-1H-benzimidazole hydrazones are converted to 1-[pyrazol-3(5)-yl]benzimidazoles by refluxing in dimethylformamide in the presence of trifluoroacetic acid. The same products are obtained by refluxing 2-aroylmethyl-1H-benzimidazoles with hydrazine hydrochloride in dimethylformamide. Electron donor substituents in the para position of the aryl fragment of the starting compounds do not favor the reaction.

Full text of DOI:10.1023/A:1013223531612

Chemistry of Heterocyclic Compounds, Vol. 37, No. 9, 2001
SELECTIVE RECYCLIZATION OF
2-AROYLMETHYL-1H-BENZIMIDAZOLE
HYDRAZONES BY CONDENSATION
WITH DIMETHYLFORMAMIDE
I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii
2-Aroylmethyl-1H-benzimidazole hydrazones are converted to 1-[pyrazol-3(5)-yl]benzimidazoles by
refluxing in dimethylformamide in the presence of trifluoroacetic acid. The same products are obtained
by refluxing 2-aroylmethyl-1H-benzimidazoles with hydrazine hydrochloride in dimethylformamide.
Electron donor substituents in the para position of the aryl fragment of the starting compounds do not
favor the reaction.
Keywords: benzimidazoles, hydrazones, pyrazoles, condensation, recyclization, selectivity.
As is known [1], recyclization can lead to the preparation of functionalized heterocycles which are only
obtainable with difficulty by other synthetic methods. Via a study of previously used conditions involving the
potential rebuilding of a benzimidazole ring to give pyrazole compounds, we have reported the following
sequence of reactions. Treatment of 2-methylbenzimidazole (1) with benzoyl chloride (2a) gave the product of
C-, N-, and O-tribenzoylation 3a which gives 2-phenacylbenzimidazole (4a) upon morpholinolysis [2].
Compound 4a reacts with hydrazines to form the moderately stable hydrazones; recyclization of the latter could
be achieved only by carrying out the reaction under acylation conditions [3-5]. Hence the reaction of hydrazone
5a to the (o-aminophenylamino)pyrazole 6a occurs, as we have already reported [6], in refluxing
dimethylformamide (DMF) in the presence of benzoic acid and is accompanied by condensation with the
solvent to form the N-pyrazolylbenzimidazole 7a. In our work we now report the preparative potential of this
reaction and we investigate the effect of substituents on its course.
Synthesis of the novel starting materials (the hydrazones 5b-d) occurs, as we have shown, quite
efficiently using the three stage scheme referred to with the use of the aroyl chlorides 2b-d and hydrazine
hydrate to give the compounds 3b-d and 4b-d in the intermediate stages.
We have found that the reaction studied occurs more readily when benzoic acid is exchanged for
trifluoroacetic acid. Thus the reaction of compound 5a in the presence of trifluoroacetic acid is completed after
3 h in 91% yield (with benzoic acid after 7 h and in 88% yield). Under the same conditions the hydrazones 5b,c
give the N-pyrazolylbenzimidazoles 7b,c after 1 and 2 h in 87 and 80% yields respectively.
An increase in the reaction times for the hydrazones 5b,c, respectively to 4 and 6 h, leads to a lowering
of the yields to 80 and 64%. Appreciable difficulties are observed when converting the methoxy-substituted
hydrazone 5d; judging by its disappearance from the reaction mixture (TLC method) the reaction is completed
after 10 h but the yield of the final product 7d is 35%. The compounds 7a-d were obtained in lower yields by
refluxing the 2-aroylmethylbenzimidazoles 4a-d with hydrazine hydrochloride in DMF.
__________________________________________________________________________________________
Institute of Organic Chemistry, Ukrainian Academy of Sciences, Kiev 253660 e-mail:
iochkiev@sovam.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1195-1200,
September, 2001. Original article submitted October 25, 1999.
1096
0009-3122/01/3709-1096$25.00©2001 Plenum Publishing Corporation

H ...O
N
COAr
N
H
morpholine
(n-BuOH)
ArCOCl
Ar
N
N
2a–d
Me
NEt3
N
N
Ar
1
4a–d
ArCOO
.
H2O
3a–d
N2H4
[HOAc]
H
N
NH2
NH
N
N
DMF,
CF3COOH
DMF
N
H2N
5a–d
Ar
N
N
N
N
N
H
Ar
6a–d
H
Ar
7a–d
N2H4 2HCl,
.
DMF
4a–d
2-7 a Ar = Ph, b 4-O2NC6H4 , c 4-ClC6H4, d 4-CH3OC6H4
The synthesized compounds 4b-d and 7b-d are stable, crystalline materials and the hydrazones 5b-d
darken upon prolonged standing at 20-25°C. Compound 4b has a dark red coloration, compounds 4c,d, 5b and
7b are yellowish, and the rest are colorless. Compounds 4b-d give a green coloration with a methanol solution
of ferric chloride.
Several characteristics are given for the novel compounds 4b-d, 5b-d, and 7b-d in Table 1 and their
1
structures were confirmed through their H NMR spectra (Table 2). From these spectra it is apparent that
compounds 4b-d exist in solution in equilibrium with the enamino ketone forms 4'b-d. The signals for the
methylene group protons are seen at 4.61-4.79 and the methine protons of the ketovinyl fragment at
6.02-6.15 ppm.
The enamino-keto form contents are decreased according to a decrease in the electron-acceptor
properties of the aryl substituent and amount to 96, 88, and 48% respectively. For compound 4a, as previously
found [2], the tautomer 4'a content is 79%.
H ...O
N
H
N
Ar
N
H2N
5'a–d
N
Ar
N
H
H
4'a–d
a Ar = Ph, b 4-O2NC6H4 , c 4-ClC6H4, d 4-CH3OC6H4
For the hydrazones 5b,c, like 5a [6], the tendency to tautomerize is not observed. Evidently, their
structure is stabilized by an energetically favored system of conjugation in which there is the possibility of
transferring the electronic effect from the hydrazone amino group donor to the aryl fragment acceptor. The
spectrum of the methoxy-substituted hydrazone 5d shows the presence of 20% of the enhydrazine form 5'd. The
methylene group protons absorb at 4.20 ppm and the methine proton of the vinyl fragment at 4.72 ppm. The
relative stability of tautomer 5'd is evidently due to the formation of an energetically favored conjugative
system in which transfer of the electronic effect to the heterocyclic acceptor from the hydrazine fragment is
supplemented by the electron donor effect of the methoxy group.
1097

TABLE 1. Characteristics for the Synthesized Compounds 4b-d, 5b-d, and
7b-d
Found, %
——————
Calculated, %
Com-
Empirical
mp, °C*
Yield, %
pound formula
С
Н
N
С15H11N3O3
64.18
64.05
3.81
3.94
14.98
14.94
296-297
226-228
208-209
187-189*3
173-174
206-208
342.5-344
250-51*3
201-202
69*2
85*2
82*2
88
4b
4c
4d
5b
5c
5d
7b
7c
7d
C15H11ClN2O
C16H14N2O2
C15H13N5O2
C15H13ClN4
C16H14N4O
C16H11N5O2
C16H11ClN4
C17H14N4O
66.64
4.06
10.22
66.55
4.10
10.35
72.31
72.16
5.18
5.30
10.60
10.52
59.88
4.49
23.66
61.01
4.44
23.72
63.11
63.27
4.63
4.60
19.61
19.68
86
69.23
5.19
20.22
90
69.05
5.07
20.13
62.76
62.94
3.43
3.63
22.73
22.94
87*4
80*4
35*4
65.35
3.59
18.86
65.20
3.76
19.01
70.51
70.33
4.69
4.86
19.20
19.30
_______
* Compounds were crystallized from a mixture of BuOH–DMF, 2:1 (4b,c),
BuOH (4d, 5b-d), DMF (7b), aqueous DMF, 1:4 (7c), and MeCN–DMF
(7d).
*2 Calculated from 2-methylbenzimidazole (1).
*3 With decomposition.
*4 Using method B the yields were, %: 66 (7b), 55 (7c), 35 (7d).
In the pyrazolylbenzimidazoles 7b-d the pyrazole ring 4-H proton appears at 7.15-7.72 ppm and the
benzimidazole ring 5-, 6-H protons as a narrow multiplet at 7.31-7.44 ppm (the 4-H and 7-H protons are
observed separately at 7.79-7.81 and 8.11-8.12 ppm respectively) and this is in agreement with data for
1-arylbenzimidazoles [7].
The 2-H protons of the benzimidazole ring in compounds 7a-d appear at virtually the same position at
8.75-8.76 ppm and this may be due to the absence of efficient conjugation between the aryl substituents and the
benzimidazole ring. The signal for the proton at position 1 of the pyrazole ring (NH) is found at
13.41-13.93 ppm and this is lost on addition of D2O.
We have observed trends in the investigated reaction. According to the yields, all of the substituents
investigated hinder its course. However, the products 7b,c, which contain electron acceptor substituents, can be
obtained in preparatively acceptable yields. Lowering of the yields of these compounds, as mentioned already,
increases with an increase in reaction time and is very likely due to concurrent processes (e.g. oxidation and
substitution) involving the substituents themselves. The electron donor methoxy group is the only one which
differs markedly. Hence the pattern is , in our view, readily explicable.
Representation of the reaction is complex. It can be separated into two basic processes, i.e. recyclization
and condensation with DMF. We consider that the effect of the substituent on each or these processes separately
does not touch upon the question of the limiting stage.
The ease of the recyclization reaction depends upon the nucleophilicity of the hydrazone amino group
and the electrophilicity of the C(2) atom of the heterocycle in the starting compounds 5a-d. One should bear in
mind a number of circumstances. Firstly, the electron effect of the substituent can be distributed at both reaction
centers since, in the reaction conditions, all of the starting hydrazones can cross to the enhydrazine forms 5'a-d.
1098

1
TABLE 2. H NMR Spectra of Compounds 4b-d, 5b-d, 7b-d and their
Tautomeric Forms 4'b-d, 5'd
Compound
1Н NMR spectrum, δ, ppm, J (Hz)
4b*
4'b
4.79 (2Н, s, СН2СO); 8.17-8.36 (4Н, m, p-С6Н4)*2
6.15 (1Н, s, СНСO); 7.18-7.74 (4Н, m, o-С6Н4); 8.10-8.32 (4Н, m, p-С6Н4);
12.43 (1Н, s, NH)
4c*
4'c
4.70 (2Н, s, СН2СO); 7.50-8.03 (4Н, m, p-С6Н4)*2
6.05 (1Н, s, СНСO); 7.63-8.12 (4Н, m, p-С6Н4); 7.15-7.59 (4Н, m, o-С6Н4);
12.29 (1Н, s, NH)
4d*
4'd
5b
3.82 (3Н, s, OСН3); 4.61 (2Н, s, СН2СO); 7.07-8.09 (4Н, m, p-С6Н4);
7.13-7.53 (4Н, m, o-С6Н4); 12.36 (1Н, s, NH)
3.86 (3Н, s, OСН3); 6.02 (1Н, s, СНСO); 7.00-7.84 (4Н, m, p-С6Н4);
12.21 (1Н, s, NH)*2
4.29 (2Н, s, СН2); 7.12-7.49 (4Н, m, o-С6Н4); 7.69 (2Н, s, NH2);
7.96-8.19 (4Н, m, p-С6Н4); 12.37 (1Н, s, NH)
4.22 (2Н, s, СН2); 7.12-7.52 (4Н, m, o-С6Н4); 7.20 (2Н, br. s, NH2);
5c
7.36-7.79 (4Н, m, p-С6Н4); 12.37 (1Н, br. s, NH)
5d*3
3.75 (3Н, s, СН3); 4.20 (2Н, s, СН2); 6.87-7.23 (4Н, m, p-С6Н4);
6.96 (2Н, br. s, NH2); 7.12-7.50 (4Н, m, o-С6Н4); 12.38 (1Н, br. s, NH)
4.72 (2H, s, CH); 6.92-7.94 (4Н, m, p-С6Н4)*2
5'd
7b
7.32-7.44 (2Н, m, 5-, 6-H); 7.52 (1H, s, 4'-H); 7.79 (1H, d, J = 8, 4-H);
8.11 (1H, d, J = 8, 7-H); 8.12-8.43 (4H, m, p-С6Н4); 8.76 (1H, s, 2-H);
13.93 (1H, s, NH)
7.30 (1H, s, 4'-H); 7.31-7.44 (2Н, m, 5-, 6-Н); 7.61-7.91 (4Н, m, p-С6Н4);
7.79 (1H, d, J = 8, 4-Н); 8.11 (1Н, d, J = 8, 7-Н); 8.75 (1H, s, 2-H);
13.63 (1H, s, NH)
3.83 (3H, s, CH3); 7.09-7.82 (4H, m, p-С6Н4); 7.15 (1Н, s, 4'-H);
7.31-7.43 (2Н, m, 5-, 6-Н); 7.79 (1Н, d, J = 7, 4-Н); 8.12 (1Н, d, J = 8, 7-Н);
8.75 (1H, s, 2-H); 13.41 (1H, s, NH)
7c
7d
_______
* Tautomeric ratio of 4 and 4' 4:96 (b), 12:88 (c), 52:48 (d).
*2 Remaining signals obscured by the signals of the tautomer.
*3 Tautomeric ratio of 5d and 5'd 80:20.
Secondly, the transfer from the hydrazone form to the enhydrazine leads to an increase in the nucleophilicity of
the amino group in compounds with electron-acceptor substituents and, on the other hand, to its lowering with
the methoxy-substituted compound. Thirdly, in the hydrazone form the effect of the substituent on the
electrophilic center is insignificant but shows up in the nucleophile (an electron acceptor lowering its reactivity
and a methoxy group increasing it). Fourthly, and contrariwise, in the enhydrazine form the effect of the
substituent on the nucleophilic center is insignificant but shows up in the electrophile (an electron acceptor
increases its activity and a methoxy group lowers it). Correlation of such complex electronic effects with
experimental data obtained is possible if one infers that the tendency of the hydrazones discussed towards
recyclization is determined by the reactivity of the electrophilic center. It follows from this that: 1) the
recyclization of compounds with electron acceptor substituents is highly favored in the enhydrazine form; 2) for
recyclization of compound 5a in the enhydrazine form a long reaction time is necessary; and 3) the tendency of
the methoxy-substituted compound 5d to recyclize is distinctly weak, particularly in the enhydrazine form.
It should also be born in mind that the values of the aromatic indices for the benzimidazole and pyrazole
rings are extremely similar (0.050 and 0.055 respectively [8]). Hence the thermodynamic factors do not favor
reconstruction of the benzimidazole ring to a pyrazole. This recyclization probably has an equilibrium character;
separation of its products without the use of DMF could not be achieved.
DMF reacts with the recyclization products 6a-d at the amino group of the o-phenylenediamine
fragment. Its reactivity is typical of an aniline and is virtually independent of the effect of the substituent in the
pyrazole ring due to the absence of system conjugation. Of course, DMF can react at both the amino group of
1099

the starting hydrazones 5a-d and their enhydrazine forms 5a'-d. The relative contribution of this effect to the
overall result depends on the reactivity of the nucleophilic center. As we have shown, it is at a minimum for the
nitro-substituted compound 5b and a maximum for the methoxy-substituted 5d.
With the effects of these factors in mind we can propose the following. Under the reaction conditions
there exists an equilibrium between the hydrazones 5a-d and the recyclization products 6a-d. For compounds
5a-c it is achieved quite rapidly and condensation with DMF occurs principally at the amino group of the
recyclization products 6a-c which also leads to the final compounds 7a-c in high yields. In these examples DMF
plays the role of a reagent selectively binding the more reactive recyclization products with virtually no effect
on the starting hydrazones. Formation of the product is thus effected resulting in a shift of the reaction
equilibrium towards its formation. Recyclization of the methoxy-substituted hydrazone 5d occurs slowest. In
addition, in this case, the selectivity of the reaction of the recyclization product with DMF is absent. However,
here the DMF stabilizes the product and compound 7d is separated from the reaction mixture thanks to its
lowered solubility.
Finally, the role of the aid. Without it, as we have shown [6], the reaction becomes poorly selective. The
action of the acid at the DMF reflux temperature is probably a varying one. Evidently protonation of the
nitrogen atom of the starting benzimidazole ring, the hydrazone fragment, and the solvent itself can occur. This
can enable an increase in the reactivity of the ring electrophile center transferring to the reactive enhydrazine
form and finally the product of recyclization with DMF.
Hence 2-aroylmethyl-1H-benzimidazole hydrazones, when refluxed in DMF in the presence of acid, are
recyclized to form 1-[pyrazol-3(5)-yl]benzimidazoles. An electron-donor substituent in the para position of the
aryl fragment does not favor the reaction course.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian VXR-300 (300 MHz) instrument using DMSO-d6 solvent
and TMS internal standard. The course of the reaction and the purity of the synthesized compounds was
monitored by TLC (Silufol UV-254, benzene–ethanol, 9:1),
Compounds 3b-d, 4b-d, and 5b-d. These were obtained similarly to compounds 3a, 4a [5], and 5a [6].
Compounds 3b-d were used after separation without purification. Compound 4b was prepared by refluxing
compound 3b (2 mmol) in a mixture of n-butanol (1 ml) and DMF (1 ml) for 0.5 h. The product precipitated on
cooling.
1-[Pyrazol-3(5)-yl]benzimidazoles (7a-d). A. The corresponding hydrazone 5a-d (2 mmol) and
trifluoroacetic acid (3 mmol) were refluxed in DMF (2 ml). The reaction times were: 3 h (a), 1 h (b), 2 h (c),
and 10 h (d). Water was added to the hot solution until crystallization began. After cooling, the precipitate was
filtered off, washed with 2-propanol, and recrystallized.
B. The corresponding compound 4a-d (2 mmol) and hydrazine hydrochloride (3 mmol) were refluxed in
DMF (2 ml). The reaction times were: 3 h (a), 9 h (b), 5 h (c), and 4 h (d). The reaction mixture was worked up
similarly to method A.
REFERENCES
1.
H. C. van der Plas, Ring Transformations of Heterocycles, Academic Press, London-New York (1973),
Vols. 1 and 2.
I. B. Dzvinchuk, M. O. Lozinskii, and A. V. Vypirailenko, Zh. Org. Khim., 30, 909 (1994).
I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii, Zh. Org. Khim., 32, 1759 (1996).
I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii, Zh. Org. Khim., 33, 116 (1997).
2.
3.
4.
1100

5.
I. B. Dzvinchuk, A. V. Vypirailenko, E. B. Rusanov, A. N. Chernega, and M. O. Lozinskii, Zh. Obshch.
Khim., 69, 856 (1999).
6.
7.
I. B. Dzvinchuk, A. V. Vypirailenko, and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 1136 (1997).
A. F. Pozharskii, O. V. Dyablo, V. V. Kuz'menko, and E. F. Evgrafova, Khim. Geterotsikl. Soedin., 1347
(1996).
8.
A. F. Pozharskii, Theoretical Basis for the Chemistry of Heterocycles [in Russian], Khimiya, Moscow
(1985), p. 48.
1101