Reaction of substituted pyrido[1,2-a]benzimidazoles with electrophilic agents

Article abstract of DOI:10.1016/j.tetlet.2015.08.014

The reactivity of substituted pyrido[1,2-a]benzimidazoles toward electrophilic aromatic substitution has been studied. An unusual introduction of an electrophilic species at the ortho position with respect to an electron-withdrawing group was found, and investigated. Changing the substituent nature from a meta director to an ortho/para director did not alter the selectivity of electrophilic substitution. Assignment of the proton and carbon spectra for the products of S_EAr reactions were carried out using 1D and 2D NMR and the structures of selected nitro- and dinitropyrido[1,2-a]benzimidazoles were confirmed by single crystal X-ray diffraction.

Full text of DOI:10.1016/j.tetlet.2015.08.014

Accepted Manuscript
Reaction of substituted pyrido[1,2-a]benzimidazoles with electrophilic agents
Roman S. Begunov, Alexandr A. Sokolov, Valeria O. Belova, Artem N.
Fakhrutdinov, Alexander S. Shashkov, Ivan V. Fedyanin
PII:
S0040-4039(15)01295-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.08.014
TETL 46598
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
25 March 2015
11 July 2015
5 August 2015
Please cite this article as: Begunov, R.S., Sokolov, A.A., Belova, V.O., Fakhrutdinov, A.N., Shashkov, A.S.,
Fedyanin, I.V., Reaction of substituted pyrido[1,2-a]benzimidazoles with electrophilic agents, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.08.014
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Graphical Abstract
Reaction of substituted pyrido[1,2-a]
Leave this area blank for abstract info.
benzimidazoles with electrophilic agents
Roman S. Begunov, Alexandr A. Sokolov, Valeria O. Belova, Artem N. Fakhrutdinov, Alexander S. Shashkov,
and Ivan V. Fedyanin

1
Tetrahedron Letters
Reaction of substituted pyrido[1,2-a]benzimidazoles with electrophilic agents
Roman S. Begunova,, Alexandr A. Sokolova , Valeria O. Belovaa, Artem N. Fakhrutdinovb , Alexander S.
Shashkovb , and Ivan V. Fedyaninc
a P. G. Demidov Yaroslavl State University, Sovetskaya Str., 14, Yaroslavl 150000, Russian Federation
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991, Russian Federation
c A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilova Str., 28, Moscow 119991, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reactivity of substituted pyrido[1,2-a]benzimidazoles towards electrophilic aromatic
substitution has been studied. An unusual introduction of an electrophilic species at the ortho
position with respect to an electron-withdrawing group was found, and investigated. Changing
the substituent nature from a meta director to an ortho/para director did not alter the selectivity
of electrophilic substitution. Assignment of the proton and carbon spectra for the products of
SEAr reactions were carried out using 1D and 2D NMR and the structures of selected nitro- and
dinitropyrido[1,2-a]benzimidazoles were confirmed by single crystal X-ray diffraction.
Available online
Keywords:
pyrido[1,2-a]benzimidazoles
nitration
2015 Elsevier Ltd. All rights reserved.
halogenation
regioselectivity
single crystal X-ray diffraction analysis
Substituted pyrido[1,2-a]benzimidazoles (PBI) are an
important class of heterocyclic compounds which possess a broad
spectrum of biological activities that include: antibacterial,1-4
antifungal,5 anticancer,6-8 antimalarial,9 and perforin inhibition
activity.10 Therefore, it is expected that new PBIs would also
show high pharmacological activity. In order to expand the
structural variety of this class of compounds, we have studied the
functionalization of previously reported11 substituted pyrido[1,2-
a]benzimidazoles by SEAr reactions (Scheme 1).
Scheme 2. Nitration of 5(6)-nitrobenzimidazole.
Introduction of the nitrogroup was initially examined using
pyrido[1,2-a]benzimidazole 1a and potassium nitrate in H2SO4
(Table 1, entry 1). It was observed that a single dinitrosubstituted
product formed within 1 hour at 20 °C in 91 % yield. This
indicated that the process had occurred with high selectivity and
that compound 1a was highly reactive under electrophilic
substitution conditions. In comparison, the reaction with
nitrobenzimidazole occurred in 2 h under reflux conditions and
was noted to have low regioselectivity.14,15,19
High resolution mass spectrometry allowed the determination
of the molecular formula as C11H6N4O4, which corresponded to
1
the assumed dinitro derivative (m/z [M+H]+ 259.0468). The H
NMR spectrum indicated that the hydrogen atom at position 8
had been substituted by a nitro group. The observed signals,
namely, a doublet at  9.39, a doublet at  7.87, a doublet of
doublets of doublets at  7.85, and a triplet of doublets at  7.30,
were assigned to the H1, H4, H3 and H2 protons, respectively. The
singlet at  8.54 was assigned to H6, while the singlet at  9.48
belonging to H9 showed a NOE with the Н1.
Scheme 1. Synthesis of 2,4-R1-7-R2-pyrido[1,2-a]benzimidazoles.
It was expected that incorporation of an electrophilic moiety at
the ortho position with respect to the electron-withdrawing
substituent would be observed for azaheterocycles of this type, in
a similar manner to the nitration of 5(6)-nitrobenzimidazoles
(Scheme 2).12-19
———
 Corresponding author. Tel.: +7-4852-44-29-28; fax: +7-4852-79-77-51; e-mail address: begunov@bio.uniyar.ac.ru

2
Tetrahedron Letters
Table 1
Synthesis of 2,4-R1-7-R2-8-nitropyrido[1,2-a]benzimidazolesa,b
Entry
1
Substrate
Product
Yieldc (%)
91a; 95b
2
3
4
5
6
7
92a; 96b
49a (2c) + 44a (2d)
41b (2c) + 51b (2d)
88a; 90b
94 (2e)a
88 (2e)b + 7 (2h)b
94a; 96b
95a; 97b
a Reaction conditions: substrate (1 mmol) and KNO3 (1.1 mmol), H2SO4, r.t., 1 h.
b Reaction conditions: substrate (1 mmol) and KNO3 (1.1 mmol), H2SO4, 30 ºС, 1.5 h.
c Isolated yield.
Similar outcomes were observed in the cases of PBIs 1b-g
(Table 1). The product yields were generally exellent. Changing
the substituent nature from meta- directors in 1a-e (entries 1-5) to
ortho/para directors in 1f as well as the introduction of two
Scheme 3. Nitration of 7-chloro-8-nitropyrido[1,2-a]benzimidazole.
methyl groups to the pyridine moiety 1g did not change the
selectivity of nitro group introduction. Nitration of non-
substituted pyrido[1,2-a]benzimidazoles and benzimidazo[1,2-
a]quinolines have been reported to also occurr at position 8.20-23
The low yield of product 2c (49%) could be explained by
partial hydrolysis of the cyano group and formation of a mixture
of compounds (2c, 2d). Separation of these compounds was
carried out by heating in a 2:1 isopropanol–DMF solution at
reflux in which nitrile 2c was insoluble. Increasing the reaction
temperature to 30 ºС and the time to 1.5 h increased the yields of
2а,b,d,f,g by 2-4 %, whereas the yields of 2c,e decreased to 41%
and 88%, respectively. The decrease in yield was due to
increased hydrolysis of the cyano and ester functional groups,
giving 8-nitropyrido[1,2-a]benzimidazole-7-carboxamide 2d and
Halogenation is another reaction often used for the
functionalization of aromatic compounds. Halosuccinimides in
acetic acid24-25 or sulfuric acid26-28 are widely used for the
efficient electrophilic introduction of halogen atoms onto arenes.
Therefore, we began by examining synthesis of bromo-
substituted PBIs by the reaction of 1b with N-bromosuccinimide
(NBS) in acid solvents at various temperatures (Table 2).
When the reaction was carried out in acetic acid, a
considerable amount of the substrate remained unreacted.
Increasing the temperature did not significantly increase the yield
of the brominated PBI. The highest yield of 4a was observed
using sulfuric acid at 30 °C. Increasing the temperature decreased
the amount of product formed due to side reactions. Therefore,
the time was increased to 9 hours, giving 4a in 89% yield.
8-nitropyrido[1,2-a]benzimidazole-7-carboxylic
acid
2h,
respectively. The hydrolysis products were isolated and their
structures confirmed by NMR and HRMS.
According to the NMR spectroscopic data for compound 4а,
the C-8 position of the heterocyclic system was also the reactive
center for bromination. These conditions were subsequently used
to incorporate Br and Cl atoms onto a series of substituted PBI
(Table 3).
The substituent nature at the C-7 position was found to
influence the introduction of a second nitro group into nitro
products 2. 7-Chloro-6,8-dinitropyrido[1,2-a]benzimidazole 3
was synthesized in 6 h at 100 ºС in 94 % yield (Scheme 3).
However, under similar conditions, introduction of a second nitro
group onto compounds 2b-e did not occur.

3
Table 2
Screening of reaction conditionsa
Table 4
HOMO frontier electron density indices of PBI’s
Entry
Solvent
Temperature
Time (h)
Yieldb (%)
(°C)
30
60
90
30
60
90
30
1
2
3
4
5
6
7
AcOH
AcOH
AcOH
H2SO4
H2SO4
H2SO4
H2SO4
3
3
3
3
3
3
9
47
53
65
73
65
15
89
HOMO FED*
R
H
NO2
CF3
Cl
C(1)
C(2)
C(3)
C(4)
C(6)
C(7)
C(8)
C(9)
0.096
0.043
0.044
0.092
0.118
0.013
0.230
0.107
0.108
0.054
0.040
0.109
0.124
0.009
0.199
0.095
0.107
0.046
0.047
0.103
0.106
0.016
0.227
0.091
0.051
0.001
0.069
0.020
0.037
0.168
0.184
0.002
a Reagents and conditions: 1a (2.0 mmol), NBS (2.2 mmol), solvent (20
mL).
b Isolated yield.
As seen from the calculation results, the greatest coefficient of
the HOMO of structure (1') was at the C-8 atom. This was found
to be true for both unsubstituted and substituted PBIs. Therefore,
according to Fukui’s theory,29 the 8-position of the PBI was the
preferred center for electrophilic attack. This agreed well with the
experimental data (Table 1).
Table 3
Halogenation of 7-R1-pyrido[1,2-a]benzimidazolesa
№
Substrate
Product
Yieldb
(%)
The structures of compounds 2a (Figure 1), 1b, and 2b were
also determined by single crystal X-ray diffraction.
1
89
87
53
80
71
2
3
4
5
Figure 1. Molecular structure of 7,8-dinitropyrido[1,2-a]benzimidazole 2a.
Ellipsoids are drawn at the 50% probability level.
Single crystals of 2a were obtained by gradual cooling of a
solution of the compound in DMF or a 1:1 i-PrOH–DMF
mixture. Yellow needle-like crystals were obtained in the first
case, whereas crystallization from i-PrOH-DMF gave red
prismatic crystals. According to X-ray diffraction data, the
yellow crystals were solvates of the dinitro compound with DMF
molecules. Therefore, single crystals of compounds 1b, 2a, and
2b were obtained from i-PrOH–DMF solvent system.
The bond lengths and angles in the three compounds (1b, 2a,
and 2b) were found to be very close to the mean values in
substituted imidazo[1,2-a]pyridines (IP) (except for the C(5А)-
С(9А) bond) and pyrido[1,2-a]benzimidazoles (PBI). The mean
values were calculated from 105 (IP) and 13 (PBI) substituted
heterocycles selected from the Cambridge Structural database
(CSD). The smallest bond lengths in structures 1b, 2a and 2b
were observed between the N(5) and C(4A) atoms: 1.3303(16),
1.3351(17), 1.3396(17), respectively. The largest distances were
found between the C(2)-C(3) and C(4)-C(4A) pyridine ring
atoms 1.4139(18)–1.4255(18) Å respectively. Introduction of a
nitro group to position 8 did not affect the bond length
distribution, except for the N(5)–C(5а) bond, which was 0.013(3)
and 0.008 (3) Å shorter in 2b and 2a than in the mono-substituted
compound. The nitro group in the crystal of 2b deviated from the
plane of the heterocyclic system by 44.60 (14)°, which is most
likely the result of steric interactions between the -NO2 and -CF3
a Reagents and conditions: 1 (2.0 mmol), NBS or NCS (2.2 mmol), H2SO4
(20 mL), 30 ºC, 9 h.
b Isolated yield.
The high regioselectivity of the reaction of substituted
pyrido[1,2-a]benzimidazoles with electrophilic agents was
explained using an approach based on assessment of the
distribution of the frontier electron density (FED) proposed by
Fukui.29 The effectiveness for the estimation of reactivity of
condensed polyazaheterocycles in SEAr reactions has been
demonstrated by Breza and Milata30 who carried out quantum-
chemical modeling, in which contributions of the possible
reaction centers in the HOMO of the protonated substrate were
assessed. Good correlations for this parameter with the
experimental data for nitration of various benzazoles were
obtained.
Quantum-chemical calculations (see ESI) were carried out for
PBI cations (1'), the formation of which occurred as a result of
protonation of the imine nitrogen atom in the acidic reaction
media. The distribution of electron density in the HOMO 1' are
shown in Table 4.

4
Tetrahedron
22. Varlamov, A. V.; Krapivko, A.P.; N’ende, D. L.; Levov, A. N.;
Prostakov, N. S. Chem. Heterocycl. Compd. 1996, 32, 459.
23. Sаunders, K. H. J. Chem. Soc. 1955, 3, 3275.
24. Hoffmann, K. J.; Carlsen, P. H. J. Synth. Commun. 1999, 29,
1607.
25. Srinivasan, C.; Chellamani, A. React. Kinet. Catal. Lett. 1981,
18, 187.
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44, 954.
27. Duan, J.; Zhang, L. H.; Dolbier, W. R. Synlett. 1999, 8, 1245.
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groups. Both nitro groups in the structure of 2a were outside the
plane of the heterocyclic ring, with interplane angles being
42.80(14)° and 38.33 (14)° for the groups at positions 7 and 8.
The ortho arrangement of the two NO2 groups results in the O (2)
... O (3) (2.722 (2) Å) intramolecular contact between them. The
molecules in all three crystal structures are involved in π-stacking
to give infinite stacks in 1b and 2b and dimers in 2a. The most
compact packing was observed in 2b, with a minimum C ... C
distance of 3.350 (2) Å in comparison with 3.439 (2) Å in 1b and
3.380 (2) Å in 2a. All other shortened interatomic distances in
the crystals were due to weak nonspecific interactions.
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The C(8) atom of the pyrido[1,2-a]benzimidazole system were
found to be the reactive center for attack by a nitronium cation
and halonium ion, instead of C(9), as might be expected on the
basis of the electronic effects of electron-withdrawing group. The
nature or absence of a substituent at the benzene moiety of a PBI
did not affect the selectivity of electrophilic aromatic
substitution. The obtained results allowed us to refine the data
that we previously reported31 concerning the orientation of 7-
(trifluoromethyl)pyrido[1,2-a]benzimidazole nitration.
Acknowledgments
This work was supported by the Ministry of Education and
Science of the Russian Federation (project no. 178).
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