Synthesis of N-unsubstituted 2-arylpyrazolo[1,5-a]benzimidazoles from 1-benzylideneamino-2-methylbenzimidazole and the role of acylotropic and acylotropic-prototropic isomerization

Article abstract of DOI:10.1007/s11172-011-0085-z

2-Aryl-4H-pyrazolo[1,5-a]benzimidazoles were synthesized for the first time from 1-benzyl-ideneamino-2-methylbenzimidazole by the benzoylation of the methyl group followed by the cyclization of the resulting vinyl acylates in concentrated HCl. The key steps of the process were studied by quantum chemical methods for model systems. It was shown that the concerted intramolecular acylotropic and acylotropic-prototropic transformations play an important role in this process.

Full text of DOI:10.1007/s11172-011-0085-z

Russian Chemical Bulletin, International Edition, Vol. 60, No. 3, pp. 548—556, March, 2011
548
Synthesis of Nꢀunsubstituted 2ꢀarylpyrazolo[1,5ꢀa]benzimidazoles
from 1ꢀbenzylideneaminoꢀ2ꢀmethylbenzimidazole and the role of
acylotropic and acylotropicꢀprototropic isomerization
T. A. Kuz´menko, L. N. Divaeva, and A. S. Morkovnik
Institute of Physical and Organic Chemistry, Southern Federal University,
194/2 prosp. Stachki, 344090 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863) 243 4028. Eꢀmail: asmork2@ipoc.rsu.ru
2ꢀArylꢀ4Hꢀpyrazolo[1,5ꢀa]benzimidazoles were synthesized for the first time from 1ꢀbenzylꢀ
ideneaminoꢀ2ꢀmethylbenzimidazole by the benzoylation of the methyl group followed by the
cyclization of the resulting vinyl acylates in concentrated HCl. The key steps of the process
were studied by quantum chemical methods for model systems. It was shown that the concerted
intramolecular acylotropic and acylotropicꢀprototropic transformations play an important role
in this process.
Key words: 1ꢀbenzylideneaminoꢀ2ꢀmethylbenzimidazole, 4Hꢀpyrazolo[1,5ꢀa]benzimidꢀ
azole, quantum chemical calculations, density functional theory, B3LYP density functional,
transition states, acylotropic and acylotropicꢀprototropic isomerization.
Compounds of the 4Hꢀpyrazolo[1,5ꢀa]benzimidazole
(2)13 by the benzoylation at the methyl group followed by
the cyclization of the resulting vinyl benzoates 3a—d in
concentrated HCl.
series have found wide use in color photography.1,2 They
are also used in the synthesis of various dye composites3,4
and organic electronic materials.5 Methods for the synꢀ
thesis of 4Hꢀpyrazolo[1,5ꢀa]benzimidazoles have been exꢀ
tensively developed (see, for example, the review6). Nevꢀ
ertheless, investigations in this field are still important.
There are two general approaches to the synthesis of
the fused system under consideration. In the chronologiꢀ
cally first approach, which has been most well elaborated,
pyrazole derivatives (pyrazolones, aminopyrazolones,
chloropyrazoles) are used as the starting reagents.6—8 In
another, more recent approach, the pyrazole ring annuꢀ
lated to the benzimidazole ring is formed in 1,2ꢀdiaminoꢀ
or 2ꢀacetylꢀ1ꢀaminomethylthiobenzimidazoles,9,10 which
became available only after the development of methods
for the direct Nꢀamination of benzimidazoles.11
Results and Discussion
Our investigations showed that benzylideneamino deꢀ
rivative 2, like its 1H and 1ꢀEt analogs,14,15 easily underꢀ
goes benzoylation with aroyl chlorides in the presence
of Et3N to form C,Oꢀdibenzoylation products 3a—d
(Scheme 1). The reaction occurs in THF with 2 moles of
aroyl chloride at 20—25 °C to give products in virtually
quantitative yield.
Vinyl benzoates 3a—d are crystalline pale yellow comꢀ
pounds with a very labile Oꢀbenzoylic bond. In particular,
it was shown by an example of esters 3a,d that these comꢀ
pounds easily undergo morpholinolysis to form 2ꢀphenꢀ
acyl derivatives 4 (cf. lit. data16).
Earlier,12 N(4)ꢀalkylpyrazolo[1,5ꢀa]benzimidazoles
have been successfully synthesized by the reactions of
1ꢀaminoꢀ2ꢀmethylꢀ3Rꢀbenzimidazolium salts with acid anꢀ
hydrides in the presence of K2CO3. It was hypothesized
that these reactions afford methylene bases as intermediꢀ
ates, which undergo Cꢀacylation and cyclization. Howevꢀ
er, Nꢀunsubstituted pyrazolo[1,5ꢀa]benzimidazoles are not
generated from 1ꢀaminoꢀ2ꢀmethylbenzimidazole under
these conditions; instead, the bisꢀacylation of the amino
groups occurs.12
1
According to the H NMR data, compounds 4, like
their 1H analogs,16 exist in solution in equilibrium with
enamino ketone form 4´. The signals for the methylene
and methine protons of both tautomeric forms, from which
it is convenient to determine the ratio of tautomers 4 and
4´, are observed at δ 4.75—4.80 and 6.45—6.53, respecꢀ
tively. For compound 4a (Ar = Ph) in CDCl3, this ratio is
~1 : 1. An increase in the electronꢀdonating ability of the
aryl substituent (Ar = pꢀMeOC6H4) leads to an increase in
the fraction of tautomer 4 to ~75%.
In the present study, 2ꢀarylꢀ4Hꢀpyrazolo[1,5ꢀa]benzꢀ
imidazoles 1a—d were synthesized for the first time startꢀ
ing from 1ꢀbenzylideneaminoꢀ2ꢀmethylbenzimidazole
Esters 3a—d undergo cyclization to 4Hꢀpyrazolobenzꢀ
imidazoles 1a—d in 60—65% yields under reflux in conꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 535—543, March, 2011.
1066ꢀ5285/11/6003ꢀ548 © 2011 Springer Science+Business Media, Inc.

NꢀUnsubstituted 2ꢀarylpyrazolo[1,5ꢀa]benzimidazoles Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
549
Scheme 1
Ar = Ph (a), pꢀMeC6H4 (b), pꢀClC6H4 (c), pꢀMeOC6H4 (d)
centrated HCl for 1.5 h. To exclude undesired side transꢀ
formations, the reaction was performed during the first
15 min with azeotropic removal of benzaldehyde that
formed. The 1H NMR spectra of compounds 1 show sigꢀ
nals for aromatic protons of the aryl substituent and the
benzimidazole moiety at δ 7.0–7.8 along with singlets for
the proton H(3) of the pyrazole ring at δ 6.0 and the proꢀ
ton of the NH group at δ 11.
Undoubtedly, pyrazolobenzimidazoles 1 are directly
formed from 1ꢀaminoꢀ2ꢀphenacylbenzimidazoles 5, which
we failed to detect and which were assumed to be products
of the hydrolytic C=N and ArCO—O bond cleavage in
benzoates 3. However, we unexpectedly found that the
transition 3 → 5 occurs in a more complex way through
the intermediate aroylation of the Nꢀamino group in
1ꢀamino derivatives 6 and the formation of amides 7. Comꢀ
pounds 7c,d were isolated and identified. According to the
TLC data, amides 7 were virtually the only transformation
products of vinyl benzoates 3 within 15—20 min after the
beginning of the reaction.
Unlike compounds 3, amides 7 are colorless substancꢀ
es of low chromatographic mobility (Rf ≈ 0.05). The IR
spectra of these compounds show a strong common
absorption band of two carbonyl groups at 1665 cm–1 and
a lowꢀintensity band of the secondary amino group at
3254 cm–1. The structure of acyl derivatives 7 was conꢀ
firmed by the mass spectrum of product 7d (m/z 415 [M]+)
1
and the H NMR spectra of compounds 7c,d, which are
superpositions of the spectra of ketone 7 and enamino
ketone 7´ tautomeric forms similar to those formed by
acetophenones 4.
To study the chemism of a series of key steps in the
synthesis of pyrazolobenzimidazoles 1, we performed
quantum chemical calculations. Based on the results of

550
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
Kuz´menko et al.
the calculations, the mechanism of the acylation of
2ꢀmethylbenzimidazoles at the methyl group in the presꢀ
ence of bases, which has been very poorly covered in the
literature, was characterized and the unusual concerted
mechanism of the intramolecular isomerization of esters 6
to amides 7 was shown to occur.
Results of quantum chemical study of acylotropic proꢀ
cesses occurring in the synthesis of pyrazolobenzimidazoles
1. We studied the acylation at the methyl group in position
2 of benzimidazoles by an example of the model reaction
of 1,2ꢀdimethylbenzimidazole (8) with acetyl chloride (9)
by the density functional theory method with the use of
the B3LYP functional and the standard 6ꢀ31G** basis set.
According to the results of calculations, the acylation
of benzimidazole 8 with acid chloride 9 occurs via a fourꢀ
step mechanism involving the bimolecular nucleophilic
substitution of the chlorine atom in AcCl (see Refs 17—19)
to form Nꢀacetylbenzimidazolium salt 10 as the initial
step (Scheme 2).
The Nꢀacylation involves the formation of a weaklyꢀ
bound collision complex of the reagents followed by
the formation of a highly polar (μcalc = 10.1 D) transition
state (TS) of the reaction TS1 (Fig. 1, Table 1). The TS1
contains the tetragonalꢀcoordinated carbon atom of the
CO group. This atom forms loosened N—C and C—Cl
bonds with the entering and leaving groups, which have
almost equal Mulliken bond orders (BO) (0.47 and 0.55,
respectively).
The Gibbs free energy of activation Δ≠G°calc of the gasꢀ
phase Nꢀacylation is 21.3 kcal mol–1, which is unexpectꢀ
edly high for the highly reactive starting compounds. Howꢀ
ever, this energy should sharply decrease in the liquid phase
Scheme 2
TS is the transition state, 11•MeCOCl is the collision complex.

NꢀUnsubstituted 2ꢀarylpyrazolo[1,5ꢀa]benzimidazoles Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
551
1.200
(1.82)
zation of the highly polar TS of the reaction typical also
for the SN2 substitution of the halogen atom at the
sp3ꢀhybridized carbon atom.20
NꢀAcylium salt 10 is very unstable and readily decomꢀ
poses to the starting reagents 8 and 9 because of the fact
that the N—Ac bond is relatively weak (BO = 0.70,
dC—N = 1.538 Å) and is easily cleaved after the SN2 attack
by the chloride counterion. In the absence of solvation, the
a
1.734
(0.47)
C
O
2.217
(0.55)
C
C
C
N
97.6
2.403
(0.09)
Cl
C
C
C
C
C
C
N
C
dissociation of salt 10 is nearly barrierless (Δ≠G°dis
≈
≈ 1 kcal mol–1). Hence, it is not surprising that Nꢀacylbenzꢀ
imidazolium salts only with such a weakly nucleophilic
anion as SbCl6– were preparatively isolated.21
C
In the next step, salt 10 containing the CHꢀacidic
2ꢀmethyl group is deprotonated with triethylamine to give
methylene base 11, which is acylated with acid chloride 9
at the strongly nucleophilic methylene group to form
C,Nꢀdiacyl derivative 12. The latter is the structural anaꢀ
log of esters 3. This unusual reactivity of the CH2 group is
evidently associated with the fact that the binding of an
electrophile is very energetically favorable due to aromatizaꢀ
tion of the fiveꢀmembered heterocyclic moiety. Like the
electrophilic aromatic substitution, the reaction under considꢀ
eration involves the axial attack of the π system of the
substrate, which is favorable for the efficient interaction
between the frontier molecular orbitals of the reagents. In the
weakly endoergic starting collision complex that formed,
the substrate and the electrophile are arranged in parallel
planes, AcCl being located directly above the methylene
group of base 11. The electrophilic and nucleophilic centers
of the reacting molecules are at a large distance from each
other (3.48 Å). Then the collision complex is transformed
into TS of Cꢀacylation TS2 (see Fig. 1). The latter is transꢀ
b
2.057
(0.66)
1.202
(1.78)
O
H
C
C
C
2.104
(0.34)
C
N
C
Cl
1.392
(1.39)
98.8
N
99.4
C
C
O
Fig. 1. Structures of the transitions states TS1 (a) and TS2 (b) of
the Nꢀ and Cꢀacylation, respectively. Here and in Figs 2 and 3,
the bond lengths (Å), the Mulliken bond orders (in parentheꢀ
ses), and the N—C—Cl angles at the carbon atoms, at which the
nucleophilic Nꢀsubstitution occurs, are given.
and, in particular, in polar media, and the reaction rate
should be substantially higher due to the solvation stabiliꢀ
Table 1. Physicochemical characteristics of intermediates, reagents, final products, and transition
states of the acylation of 1,2ꢀdimethylbenzimidazole at 25 °C
Structure
–G°/au
Δ≠G° /kcal mol–1
μ
calc/D
––ν /cm–1
i
8
9
C*
Σ**
TS1
10
11
TS2
12
458.3837124
613.43224228
1071.8091743
1071.81595468
1071.7752721
1071.7765613
610.9723634
1224.367600
763.5938398
763.58236587
763.6067507
779.616047
—
—
—
03.8
02.9
06.6
—
10.1
12.1
03.3
05.6
04.7
04.9
03.7
—
—
—
—
—
160
—
—
314
—
272
—
—
—
21.3
0.80
—
23.2
—
7.20
—
—
TS3
13
6e
TS4
7″e
6eH+
TS5
779.56065570
779.6111424
780.010164735
779.96144401
34.7
—
—
06.4
05.2
—
306
—
—
30.6
—
204
* The collision complex.
** The sum of the energies of the reagents.

552
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
Kuz´menko et al.
formed into the protonated form of the diacyl derivative
12H+, which is the formal analog of the σ complex of the
usual aromatic electrophilic substitution. The further
deprotonation with triethylamine affords free base 12. The
a
C
C
O
2.104
(0.25)
O
1.188
(1.96)
activation energy of Cꢀacylation ΔG≠calc is 23.2 kcal mol–1
.
63.5
C
C
1.672
(0.53)
78.3
The concerted intramolecular 1,5ꢀN→O acylotropic
isomerization of compound 12 is the final step in the acyꢀ
lation of benzimidazole 8 giving the final product, viz.,
vinyl acetate 13. This transformation occurs through the
moderately polar (μcalc = 4.9 D) TS3 (Fig. 2), which has a
structure with the tetragonal carbon atom of the CO group
classical for the intramolecular acylotropy.22 This carbon
atom is bound to two nucleophilic centers by the Ac—O
and Ac—N bonds, which are loosened to approximately
the same degree. The orders of these bonds and of the
C=O bond are 0.53, 0.45, and 1.86, respectively. The acetyl
group of TS3 is involved in the nonpolar sixꢀmembered
cyclic reaction unit and deviates from the common plane
passing through the other nonhydrogen atoms. Since the
N→O acylotropy under consideration is accompanied by
the aromatization of the imidazole ring, it is very fast. This
is evident from the energy Δ≠G°calc = 7.2 kcal mol–1, which
is very low for acylotropic processes.
H
1.770
(0.13)
C
95.9
C
N
H
N
H
N
1.040
1.175
(2.03)
2.167
(0.19)
b
C
C
O
C
112.0
C
O
H
C
118.2
78.7
1.773
(0.43)
C
109.9
As follows from the aforesaid, either the acylation of
the methylene base or a particular deprotonation proꢀ
cess is the rateꢀdetermining step of the bisꢀacylation of
Nꢀsubstituted 2ꢀmethylbenzimidazoles.
N
H
H
N
H
N
It should be emphasized that the bisꢀacylation, conꢀ
trary to the reasonable, at the first glance, opposite hypothꢀ
esis, occurs without the intermediate formation of
Cꢀmonoacylation products, viz., 1ꢀRꢀ2ꢀCH2COR´ꢀbenzꢀ
imidazoles and their tautomeric forms.
Using model structure 6e, we also showed that the
isomerization of esters 6 to amides 7 in the route to pyrꢀ
azolobenzimidazoles 1 occurs via an unusual intramolecꢀ
ular concerted mechanism.
Fig. 3. Structures of the transitions states TS4 (a) and TS5 (b) of
the dyotropic (acylotropicꢀprototropic) intramolecular isomerꢀ
ization of compound 6e and its protonated form 6eH+, resꢀ
pectively.
As can be seen from the structures of compounds 6,
they are not acylotropic isomers of amides 7 and, conseꢀ
quently, they cannot, even theoretically, undergo pure
acylotropic isomerization to amides 7 or their enol tautoꢀ
meric forms 7″ (Scheme 3). At the same time, compounds
6 can undergo isomerization to enols 7″ via a more comꢀ
plex intramolecular acylotropicꢀprototropic mechanism
through the concerted exchange of the acetyl group and
the proton between the sp3ꢀhybridized N and O atoms.
This is confirmed by the existence of the corresponding
TS4 for compound 6e (Fig. 3). The reaction is a special
case of concerted dyotropic23 processes* accompanied by
the double group transfer25 (in the case under consiꢀ
deration, of the acetyl group and the proton). Therefore,
114.0
110.6
1.207
(1.86)
O
1.642
(0.53)
C
125.7
O
C
C
C
C
95.5
H
105.7
C
1.786
(0.45)
H
N
N
H
C
H
* Apparently, the double proton transfer, which can occur both
in an interꢀ and intramolecular fashion, is the most wellꢀknown
representative of dyotropic processes (see, for example, Ref. 24).
Fig. 2. Structure of the transitions state TS3 of the intramolecuꢀ
lar acylotropic O→N isomerization of vinyl acetate 12.

NꢀUnsubstituted 2ꢀarylpyrazolo[1,5ꢀa]benzimidazoles Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
553
Scheme 3
compounds 6e and 7″e can be considered as a pair of
dyotropomers (cf. Ref. 26).
group and a proton but via a twoꢀstep mechanism to form
a tetrahedral intermediate.27
The dyotropic transition state TS4 has a sevenꢀmemꢀ
bered cyclic reaction unit, which, like that in TS3, conꢀ
tains the tetragonalꢀcoordinated carbon atom of the CO
group (see Fig. 3). The acylotropic group of TS, that miꢀ
grates toward O→N in the course of the reaction, substanꢀ
tially deviates from the common plane passing through
the other atoms of the heterocyclic core and the reaction
unit. As opposed to the purely acylotropic TS1 and TS3,
this group in TS4 is bound to two nucleophilic centers in
quiet different ways. Thus, the bond with the Nꢀamino
group (the Ac—N bond order is 0.53, the bond length is
1.671 Å) is stronger, whereas the bond with the Oꢀnucleoꢀ
The acylotropicꢀprototropic isomerization of comꢀ
pound 6e is evidently asynchronous. The initial step inꢀ
volves the migration exclusively of the acetyl group, whereꢀ
as the migration of the proton of the NH group begins
only after the reaction system reaches the transition state
TS4. At this moment, the ratio between the acidity of the
N—H bond and the nucleophilicity of the protonꢀacceptꢀ
ing oxygen atom becomes favorable for the prototropy. In
the structure of TS, the asynchronous character of the
dyotropy is reflected in the fact that the prototropic
hydrogen atom forms only one strong bond with the nitroꢀ
gen atom, whereas the oxygen atom is involved only in
a relatively weak hydrogen bond (the length is 2.408 Å; the
N—H…O angle is 115.5°).
The dyotropic transformation under consideration is
characterized by the relatively high activation enerꢀ
gy Δ≠G°calc = 34.7 kcal mol–1, which is much higher
than that for the isomerization of ketone 12. This difꢀ
ference is not surprising taking into account that the
double group transfer should occur in the course of isomerꢀ
ization of vinyl acetate 6e and that the sevenꢀmemꢀ
bered reaction unit is much more strained compared
philic center is much weaker (BOAc—O = 0.25, dAc—O
=
= 2.104 Å). The fact that the transition state TS4 relates
compound 6e not to ketoamide 7e but to its enol form 7″e
(see Scheme 3) is confirmed by the character of the transꢀ
formation of compound 6e as it moves along the reaction
coordinate that includes the aboveꢀmentioned TS.
The dyotropic reaction occurs via a concerted mechaꢀ
nism, as opposed to the known twoꢀstep dyotropic isomerꢀ
ization of Sꢀacetylꢀ2ꢀaminoethanethiol, in which the sulꢀ
fur and nitrogen atoms are also exchanged with the acetyl

554
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
Kuz´menko et al.
to the sixꢀmembered reaction unit that is present in
ketone 12.
tically unfavorable, whereas the charge localization in the
cationic TS is favorable because it facilitates the delocalizaꢀ
tion of the positive charge over a larger number of atoms.
The aboveꢀconsidered data provide evidence that the
method developed for the preparation of Nꢀunsubstituted
2ꢀarylpyrazolo[1,5ꢀa]benzimidazoles has considerable
synthetic potential and that the monoꢀ and dyotropic proꢀ
cesses accompanied by the intermolecular and intramoleꢀ
cular acyl group transfer play an important role in this
approach. These transformations belong to a large and very
important class of chemical and biochemical acylotropic
reactions, whose kinetics and mechanism have been earlier
studied in detail in the Institute of Physical and Organic
Chemistry of the Southern Federal University, where the
intramolecular degenerate acylotropic tautomerism was
discovered.22
The strongly acidic medium used for the synthesis of
pyrazolobenzimidazoles 1 would seem to substantially
hinder or even completely prevent the acylotropicꢀprotoꢀ
tropic isomerization of intermediates 6 as a result of the
Nꢀprotonation and a decrease in the nucleophilicity of the
Nꢀamino group. Nevertheless, the study of compound 6e
showed that the protonated forms of diacyl derivatives 6
also undergo this isomerization (see Scheme 3). Moreꢀ
over, it was found that the protonation of compounds 6 at
the imidazole ring should even accelerate the dyotropic
process, which, consequently, should be acidꢀcatalyzed.
The transition state TS5 (see Fig. 3) of the acylotropicꢀ
protoropic isomerization of the protonated form of comꢀ
pound 6e, viz., the cation 6eH+ (see Scheme 3), is strucꢀ
turally very similar to the transition state TS4. It should be
noted that the prototropic hydrogen atom in TS5 does not
form a hydrogen bond, and the Ac—N and Ac—O bonds
are much more loosened (their BO are 0.43 and 0.19,
respectively). The activation energy Δ≠G°calc of the reacꢀ
tion is 30.6 kcal mol–1, which is 4.1 kcal mol–1 lower than
that for the isomerization of the main form 6e.
Experimental
The solidꢀstate IR spectra were recorded on a Varian Excalꢀ
ibur 3100 FTꢀIR instrument. The 1H NMR spectra (Table 2)
were measured on a Varian Unityꢀ300 spectrometer (300 MHz)
2
with internal stabilization of the polarꢀresonance H line of the
The above data show that the decrease in the rate of
the dyotropic process due to a decrease in the nucleophiꢀ
licity of the Nꢀamino group in the cationic form is relaꢀ
tively small because the protonation occurs not at this
group but at the N atom of the imidazole ring, which is
nonꢀconjugated with the Nꢀamino group. Under these
conditions, it is apparently more important that the addiꢀ
tional total positive charge on the acyl group necessary for the
acylotropy28 is much more easily accumulated of the cation
6eH+. In the electroneutral TS, this process is hindered
because the separation of the opposite charges is electrostaꢀ
deuterated solvent. The mass spectra were obtained on a Finniꢀ
gan MAT INCOSꢀ50 instrument (70 eV, direct inlet). The course
of the reactions was monitored and the purity of the compounds
was checked by TLC on Al2O3 plates (Brockmann activity III)
using CHCl3 as the eluent; the spots were visualized with
iodine vapor.
The standard Gibbs free energies G° corresponding to
T = 298.15 °C and p = 1 atm (105 Pa) were calculated with the
use of the PC Gamess program package29 in an ideal gas approxiꢀ
mation assuming the harmonic mode of vibrations of atoms and
the absence of thermally accessible excited electronic states for
the systems under consideration. The zeroꢀpoint energy (ZPE)
Table 2. Yields, melting points, and the results of elemental analysis and 1H NMR spectroscopy for pyrazolo[1,5ꢀа]benzimidazoles 1b—d
Comꢀ Yield
pound (%)
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
1H NMR spectrum
(DMSOꢀd6, δ, J/Hz)
(%)
С
Н
N
1b
1c
1d
64
63
67
256—258
(EtOH)
77.90 5.24
77.71 5.30
17.25
16.99
С16Н13N3
2.37 (s, 3 Н, Me); 6.08 (s, 1 Н, Н(3)); 7.08—7.24
(m, 4 Н, Н(6), H(7) + 2 Н(3´)); 7.35 (d, 1 Н, Н(5),
J = 8.4); 7.67—7.79 (m, 3 Н, Н(8) + 2 Н(2´));
11.24 (s, 1 Н, NН)
6.17 (s, 1 Н, Н(3)); 7.06—7.28 (m, 2 Н, Н(6), H(7));
7.38 (d, 2 Н, Н(3´), J = 8.6); 7.50—7.61 (m, 1 Н,
Н(5)); 7.74 (d, 1 Н, Н(8), J = 7.5); 7.89 (d, 2 Н,
Н(2´), J = 8.2); 11.37 (s, 1 Н, NH)
3.82 (s, 3 Н, ОMe); 6.05 (s, 1 Н, Н (3)); 6.91
(d, 2 Н, Н(3´), J = 8.5); 7.03—7.24 (m, 2 Н,
Н(6), H(7)); 7.35 (d, 1 Н, H(5), J = 8.0); 7.65 (d, 1 H,
H(8), J = 8.0); 7.72 (d, 1 Н, Н(2´), J = 7.8);
11.20 (s, 1 Н, NH)
290—292
(EtOH)
67.15 3.98
67.30 3.77
15.82
15.70
С15Н10ClN3*
С16Н13N3О
202—203
(PhH)
73.21 5.17
72.99 4.98
15.87
15.96
* Found (%): Cl, 13.01. Calculated (%): Cl, 13.24.

NꢀUnsubstituted 2ꢀarylpyrazolo[1,5ꢀa]benzimidazoles Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
555
correction at T = 0 was calculated with the use of the scale factor
equal to 0.961.30 The stationary points on the potential energy
surfaces for the molecules under consideration and the reactions
systems were identified as minima or transition states by calcuꢀ
lating the corresponding forceꢀconstant matrices with the use of
the same basis set as that for the final geometry optimization.
The assignment of TS to a particular reaction was confirmed by
the study of the behavior of the reaction system by their moveꢀ
ment along the reaction coordinate.
2ꢀ(2ꢀBenzoyloxyꢀ2ꢀphenylvinyl)ꢀ1ꢀbenzylideneaminobenzimidꢀ
azole (3a). Benzoyl chloride (0.45 mL, 4 mmol) was added dropꢀ
wise with stirring to a solution of 1ꢀbenzylideneaminoꢀ2ꢀmethꢀ
ylbenzimidazole (2)13 (0.47 g, 2 mmol) and triethylamine
(0.58 mL, 4 mmol) in anhydrous THF (10 mL) cooled on an ice
bath for 5 min. The reaction mixture was stirred for 30 min and
then kept at 20—25 °C for 12 h. The solvent was evaporated, the
residue was treated with water (10 mL), and the precipitate was
filtered off. The yield was 0.88 g (99%). Paleꢀyellow crystals,
m.p. 201—202 °C (with decomp., from MeCN), Rf 0.9 (Rf of the
starting compound was 0.5). Found (%): C, 78.72; H, 4.51;
N, 9.63. C29H21N3O2. Calculated (%): C, 78.54; H, 4.77; N, 9.47.
1H NMR (CDCl3), δ: 7.14—7.30 (m, 2 H, H(5), H(6) of the
benzimidazole moiety); 7.35—7.48 (m, 4 H, H arom.); 7.51
(s, 1 H, CH=C—O); 7.52—7.72 (m, 7 H, H arom.); 7.76—7.82
(m, 2 H, oꢀH, Ph); 7.90—7.98 (m, 2 H, oꢀH, PhCH=); 8.32—8.36
(m, 2 H, oꢀH, Bz); 8.90 (s, 1 H, CH=N).
J = 8.5 Hz); 6.97 (d, 2 H, H(2´), 4´d, J = 8.7 Hz); 7.23—8.00
(m, 20 H, superposition of multiplets for arom. H of forms 4d
(9 H) and 4´d (11 H)); 8.06 (d, 2 H, H(3´), 4d, J = 8.5 Hz); 8.92
and 8.95 (both s, 1 H each, CH=N, 4d, 4´d); the ratio of the
forms 4d : 4´d ≈ 3 : 1.
1ꢀ(4ꢀChlorobenzoylamino)ꢀ2ꢀ(4ꢀchlorophenacyl)benzimidꢀ
azole (7c). A suspension of ester 3c (1.02 g, 2 mmol) in concenꢀ
trated HCl (15 mL) was refluxed for 15 min with azeotropic
removal of benzaldehyde that formed and then cooled. The preꢀ
cipitate was filtered off and washed with water. The yield was
0.73 g (87%). Colorless crystals, m.p. 228—229 °C (from EtOH),
Rf 0.05. Found (%): C, 62.47; H, 3.28; Cl, 16.50; N, 9.72.
C22H15Cl2N3O2. Calculated (%): C, 62.26; H, 3.54; Cl, 16.74;
N, 9.91. 1H NMR (CDCl3), δ: 5.55 (s, 2 H, CH2, 7c); 6.06 (s, 1 H,
C=CHCO, 7´c); 7.15—7.29 (m, superposition of multiplets for
the protons H(4)—H(7) of form 7´c (4 H) and for the protons
H(5), H(6) of form 7c (2 H)); 7.37 (d, 2 H, H(3´), 7´c, J = 8.6
Hz); 7.47 (d, 2 H, H(3´), 7c, J = 8.5 Hz); 7.52 (d, 2 H, H(3´), 7c,
J = 8.5 Hz); 7.59 (d, 2 H, H(3´), J = 8.6 Hz); 7.71—7.76 (m, 2 H,
H(4), H(7), 7c); 7.86 (d, 2 H, H(2´), 7´c, J = 8.6 Hz); 7.99
(d, 2 H, H(2´), 7c, J = 8.7 Hz); 8.05 (d, 2 H, H(2´), 7c, J = 8.6 Hz);
8.11 (d, 2 H, H(2´), 7c, J = 8.6 Hz); 11.91 and 11.95 (both s,
1 H each, NH, 7c, 7´c).
1ꢀ(4ꢀMethoxybenzoylamino)ꢀ2ꢀ(4ꢀmethoxyphenacyl)benzꢀ
imidazole (7d) was synthesized by analogy with compound 7c.
The yield was 74%, colorless crystals, m.p. 154—155 °C (from
EtOH), Rf 0.05. Found (%): C, 69.27; H, 5.12; N, 10.31.
C24H21Cl2N3O4. Calculated (%): C, 69.40; H, 5.00; N, 10.12.
IR, ν/cm–1: 1665 (CO), 3254 (NH). 1H NMR (DMSOꢀd6),
δ: 3.81 and 3.90 (both s, 3 H each, 2 MeO, 7d + 7´d);
4.36 (strongly br.d, 2 H, CH2 7d); 4.53 (strongly br.dd,
2 H, CH2, 7d); 5.94 (s, 1 H, CH=C, 7´d); 6.90 (d, 2 H, H(2´),
7´d, J = 8.8 Hz); 6.94 (d, 2 H, H(2´), 7d, J = 8.8 Hz); 6.98
(d, 2 H, H(2´), 7d, J = 8.8 Hz); 7.06 (d, 2 H, H(2´), 7´d,
J = 8.5 Hz); 7.11—7.31 (m, 2 H, H(5), H(6), 7d, and 4 H,
H(4)—H(7), 7´d); 7.58 (d, 2 H, H(4), H(7), 7d, J = 7.1 Hz);
7.78 (d, 2 H, H(3´), 7´d, J = 8.8); 7.94 (d, 2 H, H(3´), 7d,
J = 8.5 Hz); 8.01 (d, 2 H, H(3´), 7d, J = 8.8 Hz); 8.06 (d, 2 H,
H(3´), 7´d, J = 8.5 Hz); 11.56 and 11.74 (both s, 1 H each,
2 NH, 7d, 7´d). MS, m/z (Irel (%)): 415 [M]+ (3), 387 [M – CO]+
(1), 135 [pꢀMeOC6H4CO]+ (100), 107 [C7H7O]+ (17), 92
[C6H4O]+ (27), 77 [C6H5]+ (41), 76 [C6H4]+ (5), 64 [C5H4]+
(10), 63 [CH3O3, C5H3] (7), etc. Analogous intense peaks at
m/z = 63, 64, 77, 107, and 135 (100%) are characteristic also of
p,p´ꢀdimethoxybenzyl.31
Esters 3b—d were synthesized according to the same proceꢀ
dure. Chromatographically individual paleꢀyellow crystals with
Rf 0.9, which were difficultly soluble in boiling MeOH and
MeCN, were obtained. The recrystallization from butanol led to
the decomposition of the crystals. Hence, compounds 3b, 3c,
and 3d, with m.p. 191—192 (with decomp.), 222—224 (with deꢀ
comp.), and 187—189 °C (with decomp.), respectively, were
introduced into further transformations without additional puꢀ
rification.
1ꢀBenzylideneaminoꢀ2ꢀphenacylbenzimidazole (4a). A soluꢀ
tion of compound 3a (0.88 g, 2 mmol) and morpholine (0.55 mL,
6 mmol) in MeOH (15 mL) was refluxed for 10 min, diluted
with water (5 mL), and cooled. The precipitate that formed was
filtered off. The yield was 0.62 g (92%). Yellow crystals, m.p.
159—160 °C (from MeCN), Rf 0,5. Found (%): C, 77.68;
H, 4.91; N, 12.52. C22H17N3O. Calculated (%): C, 77.86;
1
H, 5.05; N, 12.38. H NMR (CDCl3), δ: 4.81 (s, 2 H, CH2, 4a);
6.56 (s, 1 H, CH=C, 4´a); 7.32—8.00 (m, superimposed sigꢀ
nals for the protons of the oꢀphenylene and phenyl groups,
except for oꢀH (OCOPh), of tautomer 4a (12 H) and signals
for the protons of the oꢀphenylene and phenyl groups of
tautomer 4´a (14 H)); 8.06 (d, 2 H, oꢀH, Bz, 4a, J = 7.7 Hz);
8.95 and 9.05 (both s, 1 H each, CH=N, 4a, 4´a). The ratio of
the forms 4a and 4´a in CDCl3 and DMSOꢀd6 is ~1 : 1 and 1 : 3,
respectively.
1ꢀBenzylideneaminoꢀ2ꢀ(4ꢀmethoxyphenacyl)benzimidazole
(4d). A solution of ester 3d (1.00 g, 2 mmol) and morpholine
(0.55 mL, 6 mmol) in DMF (2 mL) was heated on a boiling
water bath for 10 min, diluted with H2O (2 mL), and slowly
cooled. The paleꢀyellow precipitate that formed was filtered off.
The yield was 0.70 g (94%), m.p. 161—163 °C (from EtOH),
Rf 0.5. Found (%): C, 74.85; H, 5.30; N, 11.51. C23H19N3O2.
Calculated (%): C, 74.78; H, 5.18; N, 11.37. 1H NMR (CDCl3),
δ: 3.80 (s, 3 H, OMe, 4´d); 3.87 (s, 3 H, OMe, 4d); 4.78 (s, 2 H,
CH2, 4d); 6.45 (s, 1 H, C=CH, 4´d); 6.93 (d, 2 H, H(2´), 4d,
2ꢀPhenylꢀ4Hꢀpyrazolo[1,5ꢀa]benzimidazole (1a). A suspenꢀ
sion of dibenzoyl derivative 3a (1.33 g, 3 mmol) in concentrated
HCl (20 mL) was refluxed for 20 min with azeotropic removal of
benzaldehyde that formed and then boiled with a reflux conꢀ
denser for 1 h. The caramelꢀlike reaction mixture gradually soꢀ
lidified. After cooling, the precipitate of hydrochloride of comꢀ
pound 1a was filtered off. The base was isolated by treating the
precipitate of the salt with concentrated NH4OH. The yield was
0.47 g (67%). Colorless crystals, m.p. 256—257 °C (with deꢀ
comp., from EtOH)7. 1H NMR (DMSOꢀd6), δ: 6.13 (s, 1 H,
H(3)); 7.10—7.30 (m, 3 H, H(6), H(7) + H(4´) arom.);
7.30—7.41 (m, 3 H, H(5) + 2 H(3´) arom.); 7.73 (d, 1 H, H(8),
J = 7.7 Hz); 7.87 (d, 2 H, H(2´) arom., J = 7.4 Hz); 11.27
(s, 1 H, NH).
Pyrazolobenzimidazoles 1b—d (see Table 2) were syntheꢀ
sized according to the same procedure.

556
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
Kuz´menko et al.
15. I. B. Dzvinchuk, M. O. Lozinskii, A. V. Vypirailenko,
Zh. Org. Khim., 1994, 30, 909 [Russ. J. Org. Chem. (Engl. Transl.),
1994, 30, 971].
16. I. B. Dzvinchuk, M. O. Lozinskii, A. V. Vypirailenko, Khim.
Geterotsikl. Soedin., 2001, 1195 [Chem. Heterocycl. Compd.
(Engl. Transl.), 2001, 37, 1096].
17. D. N. Kevill, W. F. K. Wang, J. Chem. Soc., Perkin Trans. 2,
1998, 2631.
18. J. M. Fox, O. Dmitrenko, Lianꢀan Liao, R. D. Bach, J. Org.
Chem., 2004, 69, 7317.
19. I. Lee, D. D. Sung, Curr. Org. Chem., 2004, 8, 557.
20. C. Reichardt, Solvents and Solvent Effects in Organic Cheꢀ
mistry, 3d ed., WilleyꢀVCH, Weinheim, 2003, p. 165.
21. T. V. Stupnikova, A. I. Serdyuk, E. N. Portsel´, A. K. Sheiꢀ
nkman, Dokl. Akad. Nauk Ukr. SSR, Ser. B [Dokl. Ac. Sci.,
Ukr. SSR, Ser. B], 1977, 47 (in Russian).
22. L. P. Olekhnovich, V. I. Minkin, Yu. A. Zhdanov, Moleꢀ
kulyarnyi dizain tautomernykh sistem [Molecular Design of
Tautomeric Systems], Izdꢀvo RGU, RostovꢀonꢀDon, 1977,
p. 50 (in Russian).
23. M. T. Reetz, Adv. Organomet. Chem., 1977, 16, 33; M. T.
Reetz, Angew. Chem., 1972, 11, 129.
24. A. S. Morkovnik, L. N. Divaeva, Izv. Akad. Nauk, Ser. Khim.,
2009, 866 [Russ. Chem. Bull., Int. Ed., 2009, 58, 883].
25. I. Fernandez, M. A. Sierra, F. P. Cossio, J. Org. Chem.,
2007, 72, 1488.
References
1. R. D. Theys, G. Sosnovsky, Chem. Rev., 1997, 97, 83.
2. US Pat. 5776669, 1998; http://v3.espacenet.com/publicaꢀ
tionDetails/biblio? DB= EPODOC&adjacent=true&loꢀ
cale=en_EP&FT=D&date=19980707&CC=US&NR=
5776669A&KC=A1.
3. US Pat. 2002/0152558 A1; http://v3.espacenet.com/publiꢀ
cationDetails/biblio?DB= EPODOC&adjacent=true&loꢀ
cale=en_EP&FT=D&date=20021024&CC=US&NR=
2002152558A1&KC=A1.
4. US Pat, 2009/0074701 A1; http://v3.espacenet.com/publiꢀ
cationDetails/biblio?DB= EPODOC&adjacent=true&loꢀ
cale=en_EP&FT=D&date=20090319&CC=US&NR=
2009074701A1&KC=A1.
5. Pat. WO 2008/006738 A1; http://v3.espacenet.com/publiꢀ
cationDetails/biblio?DB= EPODOC&adjacent=true&loꢀ
cale=en_EP&FT=D&date=20091224&CC=US&NR=
2009318691A1&KC=A1.
6. M. A. Khan, V. L. T. Ribeiro, Monatsh. Chem., 1983,
114, 425.
7. H. Wilde, S. Hauptmann, G. Ostermann, G. Mann, J. Prakt.
Chem., 1984, 326, 829.
8. C. Carra, T. Bally, A. Albini, J. Am. Chem. Soc., 2005,
127, 5552.
9. C. Romano, E. De la Cuesta, C. Avendano, J. Org. Chem.,
1991, 56, 74.
10. US Pat. 5210209,1993; http://v3.espacenet.com/publicaꢀ
tionDetails/biblio?DB= EPODOC&adjacent=true&localeꢀ
=en_EP&FT=D&date=19930511&CC=US&NR=
5210209A&KC=A1.
11. V. V. Kuz´menko, A. F. Pozharskii, Adv. Heterocycl. Chem.,
1992, 53, 85.
12. V. V. Kuz´menko, V. N. Komissarov, A. M. Simonov, Khim.
Geterotsikl. Soedin., 1980, 814 [Chem. Heterocycl. Compd.
(Engl. Transl.), 1980, 16, 634].
13. T. A. Kuz´menko, V. V. Kuz´menko, V. A. Anisimova,
Zh. Org. Khim., 1996, 32, 114 [Russ. J. Org. Chem. (Engl. Transl.),
1996, 32].
26. C. Wilson, J. A. K. Howard, Acta Crystallogr., Sect. C, 1998,
54, Part 4, 544.
27. R. E. Barnett, W. P. Jencks, J. Am. Chem. Soc., 1969,
91, 2358.
28. A. B. Maude, A. Williams, J. Chem. Soc., Perkin Trans. 2,
1997, 179.
29. A. A. Granovsky, PC GAMESS/Firefly version 7.1, http://
classic.chem.msu.su/gran/gamess/index.html.
30. K. K. Irikura, R. D. Johnson III, R. N. Kacker, J. Phys.
Chem., A, 2005, 109, 8430.
31. Spectral Database for Organic Compounds, http://
www.aist.go.jp/RIODB/SDBS/menuꢀe.html.
14. J. D. Albright, R. G. Shepherd, J. Heterocycl. Chem., 1973,
10, 899.
Received April 12, 2010;
in revised form February 9, 2011