Reductive acid-catalyzed rearrangement of 3-(2-nitrobenzyl)quinoxalin-2(1Н)-ones in the presence of Na2S2O4 – effective method for the synthesis of 2-(indol-2-yl)benzimidazoles

Article abstract of DOI:10.1007/s10593-017-2166-x

[Figure not available: see fulltext.] An effective one-step method is proposed for the synthesis of 2-(indol-2-yl)benzimidazoles from 3-(2-nitrobenzyl)quinoxalin-2(1Н)-ones without using metal catalysts and reagents. This method is based on the Mamedov rearrangement of 3-(2-aminobenzyl)quinoxalin-2(1Н)-ones, formed in situ by the action of Na₂S₂O₄, giving 2-(indol-2-yl)benzimidazoles as the products.

Full text of DOI:10.1007/s10593-017-2166-x

DOI 10.1007/s10593-017-2166-x
Chemistry of Heterocyclic Compounds 2017, 53(9), 1033–1044
Reductive acid-catalyzed rearrangement
of 3-(2-nitrobenzyl)quinoxalin-2(1Н)-ones
in the presence of Na2S2O4 – effective method
for the synthesis of 2-(indol-2-yl)benzimidazoles
Vakhid A. Mamedov1,2*, Elena A. Khafizova1,2, Victor V. Syakaev1,
Olga B. Bazanova1, Anastasiya I. Zamaletdinova1,2, Il'dar Kh. Rizvanov1,
Shamil K. Latypov1, Oleg G. Sinyashin1,2
1 A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the Russian Academy of Sciences,
8 Akademika Arbuzova St., Kazan 420088, Tatarstan, Russia; e-mail: mamedov@iopc.ru
2 Kazan National Research Technological University,
68 Karla Marksa St., Kazan 420015, Tatarstan, Russia
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(9), 1033–1044
Submitted July 7, 2017
Accepted August 5, 2017
An effective one-step method is proposed for the synthesis of 2-(indol-2-yl)benzimidazoles from 3-(2-nitrobenzyl)quinoxalin-2(1Н)-ones
without using metal catalysts and reagents. This method is based on the Mamedov rearrangement of 3-(2-aminobenzyl)quinoxalin-
2(1Н)-ones, formed in situ by the action of Na2S2O4, giving 2-(indol-2-yl)benzimidazoles as the products.
Keywords: 3-(2-aminobenzyl)quinoxalin-2(1Н)-ones, 1',4'-dihydro-3'H-spiro(indoline-2,2'-quinoxalin)-3'-ones, 2-(indol-2-yl)benzimidazoles,
3-(2-nitrobenzyl)quinoxalin-2(1Н)-ones, Mamedov rearrangement.
Benzo-fused nitrogen-containing heterocyclic com-
pounds have a major importance in drug discovery efforts.
Of particular interest are benzimidazole derivatives, the
best known of which is N-ribosyldimethylbenzimidazole,
the axial ligand present in B12 vitamin, which is involved in the
coordination of cobalt ion.1 Some authors have recognized it
as an example of the so-called privileged molecules,2
compounds that exhibit several types of activity and are
widely used in the search for biologically active
substances. Benzimidazole and its various derivatives serve
as an optimal starting point for the design of new drug
molecules. A series of benzimidazole hetaryl derivatives have
been shown to possess various types of pharmaceutical
activity, such as antimicrobial,3 antitumor,4 antiviral,5
anthelmintic,6 antioxidant,7 antiulcer,8 antihypertensive,9 and
tuberculostatic10 effects. For example, the benzimidazole-
quinoline conjugate dovitinib (Fig. 1) is a powerful inhibitor of
EGFR-3, and is currently in phase III clinical trials for the
treatment of metastatic renal cancer.11 The thiazolyl-
benzimidazole derivative thiabendazole acts as anthel-
mintic drug,12 while the pyridazinonylbenzimidazole deri-
vative pimobendan is used as a vasoconstrictor medication for
the treatment of cardiomyopathy in dogs.13a–c The Hoechst
dye, which contains two benzimidazole rings, is widely used
for staining of DNA in fluorescent microscopy, immuno-
histochemistry, and flow cytometry13d (Fig. 1).
Figure 1. Examples of biologically active molecules containing a benzimidazole system.
0009-3122/17/53(09)-1033©2017 Springer Science+Business Media New York
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Chemistry of Heterocyclic Compounds 2017, 53(9), 1033–1044
Due to the major importance of benzimidazoles in the
yield.23 The copper-catalyzed cross-coupling reaction of
indoles with 1,3-azoles using a double С–Н-activation and
chelation of pyridine group at the indole ring nitrogen atom
also generally proceeded relatively smoothly with the
formation of the desired products, but the yield was merely
28% in the case of methylbenzimidazole.24 When the Cu(I)-
or Pd(II)-catalyzed cross coupling of geminal dihalo-
alkenes with azoles, proceeding via the tandem process of
С–heteroatom coupling and C–H-activation, was applied for
the preparation of benzo-fused hetarylazoles, the yields of
2-(5-chlorobenzofuran-2-yl)methylbenzimidazole and 2-(6-
methylbenzofuran-2-yl)methylbenzimidazole reached 64
and 66%, respectively.25 We did not find any examples of
such metal-catalyzed reaction for N-unsubstituted
benzimidazole derivatives.
search for new drugs, significant efforts have been devoted
to the development of short and simple methods for the
synthesis of new benzimidazole derivatives.14 The standard
approach is based on the use of Weidenhagen reaction –
condensation of о-phenylenediamines with aldehydes or
ketones in the presence of an acidic, basic,15 or metal
catalyst.16 Another approach involves the use of Phillips–
Ladenburg reaction – condensation of о-phenylenediamines
with carboxylic acids, nitriles, and orthoesters under
dehydrating conditions. The dehydration reactions of
N-acylated о-phenylenediamines by using acetic acid,17а–с
p-TSA,17d or Amberlyst-1517e also have been shown to
provide benzimidazoles.
Even though the described methods are effective and
often used, it is also important to note their limitations. For
example, the condensation of о-phenylenediamine and
aldehyde in the presence of an acid or base requires a
longer reaction time and leads to N-1 benzylated
benzimidazoles as undesirable by-products, which are often
very difficult to separate from the desired reaction
products.18 Metal-catalyzed condensation reactions often
require high temperatures, while the residual metal
impurities present in the product can cause toxic effects
during the pharmaceutical use.19 The main drawback of
these methods is the impossibility of using them in the
synthesis of biheterocyclic systems, which would require
laborious multistep processes that would result in
decreased yields of the final products. This may be the
reason why we did not find any indolylbenzimidazole
derivatives among the many biheterocyclic systems with
useful properties, even though biaryl structures containing
an indole nucleus are present in many pharmaceutical
substances, biologically active compounds, and functional
materials, thus attracting significant attention of synthetic
chemists to the reactions of indole-arene cross coupling.20
In particular, methods based on direct C–H-functionali-
zation21 enable the cross coupling of unactivated indoles
and could serve as alternatives to the more common cross-
coupling reactions of halides or metal-catalyzed reactions.22
However, the methods of direct C–H-functionalization usually
require the use of expensive palladium catalysts in
combination with the copper- or silver-based oxidants that
are needed for these reactions. With regard to the cross-
coupling reactions in the synthesis of biheterocyclic
compounds, their success primarily depends on the
availability of the necessary aryl halides and organo-
metallic derivatives of the other aromatic compound, which
together serve as electrophilic and nucleophilic reagents,
respectively.
Hetaryl derivatives of benzimidazole can be easily
obtained using acid-catalyzed rearrangement of quinoxa-
line derivatives by the action of nucleophilic reagents (the
Mamedov rearrangement).26 As shown in the general
scheme below, ''any spiro derivative of 1,2,3,4-tetrahydro-
quinoxalin-3-one with at least one acidic hydrogen atom in
its spiro-forming component is on the pathway to
benzimidazole derivatives with a spiro-forming component
at position 2'' (Fig. 2),26b,c – this is one of the variants of
Mamedov rearrangement, a reaction that is used for the
introduction of heterocyclic moiety at position 2 of
benzimidazole ring system. In order to achieve this, it is
necessary to first synthesize the respective functionalized
derivatives of quinoxalinones, which allow to introduce the
given heterocyclic nucleus at position 2 as the spiro-
forming moiety, with subsequent acid-catalyzed rearran-
gement providing the desired product.
In order to obtain 2-(indol-2-yl)benzimidazoles 4, it was
necessary to synthesize a quinoxalinone derivative with
such a functional group (for example, compound 2) that
would allow in situ introduction of an indole moiety into
the quinoxalinone molecule, with the C-2 carbon atom
serving as the spiro-forming site for both heterocycles
(compound 3, Scheme 1). Among the many possible
approaches to the synthesis of indoles,27 we selected the
Reissert reaction as the method for introducing the spiro-
forming moiety at position 2 of indole nucleus,28 by
considering 3-(2-nitrobenzyl)quinoxalin-2(1Н)-one deriva-
tives 1 as hetero analogs of о-nitrophenylpyruvate esters 5
(Scheme 1),26b with compounds 1 readily formed by an
interaction of the latter with о-phenylenediamine and its
Despite certain achievements in the synthesis of
biheterocyclic systems by using metal catalysts, we have
found only a few examples for the synthesis of similar
compounds with benzimidazole ring system where the
yields exceeded 50%. For example, the synthesis of
4-hetarylquinolines via Pd/Cu-catalyzed coupling reaction
of 1-methylbenzimidazole and 2-oxoquinolin-4-yl triflate,
in contrast to the effective coupling with benzothiazoles,
benzoxazoles, thiazoles, and oxazoles, gave only a 56%
Figure 2. The general scheme for one of the variants of the
Mamedov rearrangement.
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Chemistry of Heterocyclic Compounds 2017, 53(9), 1033–1044
Scheme 1
7
6
H
1
H2N
N
O2N
N
5
N
H
O2N
O
8'
N1'
2
N
4
7'
6'
2'
3'
3
H
N
H
4
N
H
H
N
O
N
H
O
N
H
O
H4'
5'
R
R
R
R
EtO
O
3
2
1
5
derivatives substituted in the benzene ring, according to the
Körner-Hinsberg reaction (Table 1).29
respective enamine forms C and D of these regioisomers
(Scheme 2).
At the same time, it should be noted that the synthesis of
ethyl о-nitrophenylpyruvate 5 was accomplished by
following a slightly modified procedure involving the
reaction of о-nitrotoluene with diethyl oxalate in the
presence of t-BuOK in toluene, but not in Et2O, as
described in the literature.30a The reaction proceeded
smoothly and gave good yields, producing compound 5
that was suitable for use without additional purification in
the synthesis of quinoxalin-2(1Н)-ones by a reaction with
1,2-diaminobenzenes (Table 1).30b,c
The presence of о-nitrobenzyl moiety at the С-3 imine
carbon atom of quinoxalin-2(1Н)-one system allowed to
introduce an indole system at this position under the
conditions of nitro group reduction with Na2S2O4 according
to the Reissert reaction. The imino group participated in
this reaction as a hetero analog of carbonyl group in the
о-nitrophenylpyruvate esters 5. Refluxing of the reaction
mixture in the presence of HCl led to a rearrangement with
the formation of 2-(indol-2-yl)benzimidazoles 4a–h. In the
case when derivatives 1d–h were used, the presence of
benzimidazole tautomerism led to indistinguishable (by
1Н NMR spectroscopy) regioisomers of compounds 4d–h.
This occurred regardless of the ratio of regioisomers A and
B in the starting compounds 1d,f–h, as well as their
tautomeric forms C and D in solutions of compounds 1g,h or
regioisomers E and F in compound 1е. At the same time, it
should be noted that in the case when dinitro derivative 1g
was used, the reduction of both nitro groups under the
reaction conditions led to the formation of 6-amino-
2-(indol-2-yl)benzimidazole 4g, instead of its nitro analog
(Scheme 3).
The reactions of pyruvate 5 with monosubstituted 1,2-di-
aminobenzenes 6d–h, in contrast to the reactions of 2-di-
aminobenzene 6а and its symmetrically substituted
derivatives 6b,c, proceeded with the formation of a mixture
of regioisomers А and В in the case of starting compounds
1d,f–h (Scheme 2а), or a mixture of regioisomers E and F
at various ratios (Scheme 1) in the case of compound 1е as
the starting material (Scheme 2b). Furthermore, in the case
of monosubstituted 1,2-diaminobenzenes 6g,h, according
1
to H NMR spectral data, a DMSO-d6 solution contained
besides the imine forms of regioisomers А and В also the
Table 1. Synthesis of substituted 3-(2-nitrobenzyl)quinoxalin-2(1Н)-ones 1a–h
Compound
R1
R2
R3
R4
Product*
Yield**, %
H
H
H
Me
Cl
H
Me
Cl
H
H
H
H
H
H
H
H
H
96
92
6a
6b
6c
6d
6e
6f
1a
1b
H
96
1c
H
Me
H
1dA + 1dB
71 (53:47)
51 (72:28)
88 (58:42)
82 (45:25:30:traces)
86 (58:37:5:traces)
Me
H
H
1eE + 1eF
Cl
H
1fA + 1fB
H
NO2
CO2H
H
1gB + 1gA + 1gD + 1gC
1hB + 1hA + 1hD + 1hC
6g
6h
H
H
* Lower case letters indicate the substituents in the benzene ring of the quinoxalinone system, upper case letters – regioisomers and their tautomeric forms
(Scheme 2).
** The ratio of isomers was calculated from 1Н NMR spectra.
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Chemistry of Heterocyclic Compounds 2017, 53(9), 1033–1044
Scheme 2
Scheme 3
The described transformation is an acid-catalyzed pro-
sequence of cross correlations (cross peaks) starting from the
characteristic 3-СН2 signal at the 3-C atom (38.9 ppm). The
spiro and quinoxaline fragments were linked by cross peaks
between the 3-СН2 signal and N-1' atom (88.9 ppm) and the
3'-C atom (164.4 ppm). The further chain linked the 1'-NН
group (7.52 (1Н) and 88.9 (15N) ppm) to the C-8' carbon atom
(115.0 ppm) and then with the singlet signal of Н-8' proton
(6.93 ppm). This interpretation overlapped and was confirmed
by the cross peaks of 4'-Н proton (10.76 ppm) and the 3'-C
carbon atom (164.4 ppm) (a weak cross peak) and 2'-C (2-С)
carbon atom (75.7 ppm) (a strong cross peak), and to the
other side between the C-5' (115.4 ppm) and C-8а' (132.5 ppm)
atoms, the latter of which gave a weak cross peak with the
Н-8' proton signal.
cess. The use of a large excess of acid allowed to isolate the
reaction products without additional steps, except for the treat-
ment of reaction mixture with water. Thus, the acid in this
process served as a catalyst and facilitated the conversion
of excess sodium dithionite into water-soluble inorganic salts.
The analysis of 1Н NMR spectrum of the reaction
mixture formed upon treatment of 6,7-dichloro-3-(2-nitro-
benzyl)quinoxalin-2(1Н)-one (1с) with a sixfold excess of
Na2S2O4 (dithionite was added to the reaction mixture in
three portions at 3 h intervals) prior to refluxing in the pre-
sence of hydrochloric acid indicated that the reaction mixture
contained only the respective amine 2с and spiro com-
pound 3с without any impurities of other organic com-
pounds (Scheme 4). The formation of compound 2с was
evidenced by the presence of a singlet signal due to methy-
lene group (3.97 ppm) along with the signals of benzene
ring protons, while the formation of compound 3с was
indicated by the presence of two doublet signals of pyrroline
ring methylene group (2.92 and 3.89 ppm) with a geminal
spin-spin coupling constant of 16.3 Hz, besides the benzene
ring proton signals of the quinoxaline and indole systems.
The structure of compound 3с was established conclusively
by using two-dimensional COSY, 13C–1H HSQC, 13C–1H
HMBC, 15N–1H HSQC, and 15N–1H HMBC experiments.
The signals of spiro moiety were assigned by using a
Scheme 4
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Chemistry of Heterocyclic Compounds 2017, 53(9), 1033–1044
The main amount of amine 2с, in contrast to the spiro
xalin)-3'(4'H)-ones as a result of intramolecular nucleo-
philic addition of amine nitrogen atom at the imine С-3
carbon atom of quinoxalinone system. It is expected that
the proposed method can serve as the synthetic basis for
expanding the libraries of biheterocyclic systems of indole
and benzimidazole series, which are applicable for the
design of potential new medicinal compounds. The
synthetic approaches to such systems are currently being
developed at our laboratory.
compound 3с, was easily isolated from the product mixture
as a pure sample by extraction with EtOAc. Both the
refluxing of pure amine 2с, as well as the mixture of
compounds 2с and 3с in butanol in the presence of catalytic
amounts of H2SO4 led to a high yield of the rearrangement
product 4c (Scheme 5).
Scheme 5
Experimental
IR spectra in the range of 4000–400 cm–1 were recorded
for KBr pellets on a Bruker Tensor 27 spectrometer with
optical resolution of 4 cm–1 and accumulation of 64 scans.
1H NMR spectra were acquired on Bruker Avance II 400
(400 MHz), Avance III 500 (500 MHz), or Avance 600
(600 MHz) spectrometers, while 13С NMR spectra were
acquired on a Bruker Avance III 500 spectrometer
(125 MHz) in DMSO-d6 solution, with the solvent signals
On the basis of known data from the chemistry of nitro-
compounds,31 amines,32 imines,33 quinoxalines,29,34 also
including our own previously reported results26b,c and
observations from this study, the following scheme can be
proposed for the formation of 2-(indol-2-yl)benzimida-
zoles. The first step involves the reduction of nitro group to
amino group, with the formation of compound 2, which
undergoes an intramolecular nucleophilic addition with the
participation of amine nitrogen atom and the imine С-3
carbon atom of the quinoxalinone system, forming the
spiro derivative – compound 3. This intermediate then
undergoes a series of cascade transformations: а) ring
opening with the cleavage of N(1')–C(2') bond in the spiro
compound 3, giving the indole derivative G,
b) intramolecular nucleophilic attack by amino group at the
carbonyl carbon atom, followed by elimination of a water
molecule and formation of final product 4 (Scheme 6).
1
as internal standards (2.5 ppm for Н nuclei, 39.5 ppm for
13С nuclei). NMR experiments with compounds 1d–g, 4a,c–h,
and 3с were performed on a Bruker Avance III 500
spectrometer (15N NMR at 51 MHz) at 303 K temperature
in DMSO-d6 solution. The spectrometer had a 5 mm two-
channel gradient sensor with magnetic field pulse gradient of
53.5 G cm-1 in the z-direction. 15N NMR chemical shifts
are given in the δ scale relative to external standard –
CD3NO2 (380.2 ppm for 15N nuclei). The typical parameters
1
for Н NMR spectra – spectral width 12020 Hz, pulse
length (π/3) 3.7 µs, acquisition time 2 s, and relaxation
delay 2 s. The following parameters were used for
13C NMR spectra – spectral width 27 kHz, pulse length
(π/3) 3.2 µs, acquisition time 1 s, and relaxation delay 4 s;
WALTZ-16 scheme was used for broadband proton
decoupling. The assignment of NMR signals was achieved
by relying on a set of two-dimensional NMR experiments –
COSY, 1H–13C gs-HSQC and gs-HMBC, as well as 1H–15N
gs-HSQC and gs-HMBC. The two-dimensional NMR
experiments were performed and processed by using
the standard software suite provided for NMR
Scheme 6
1. Na2S2O4
O2N
2. EtOH–H2O
3. HCl–H2O
N
N
N
H
4
N
H
N
H
1
O
R
R
1
spectrometers by Bruker. The main parameters for H–13C
– H2O
gs-HSQC and gs-HMBC spectra were the following:
NH
2O
1
spectral width 8000 Hz for H nuclei and 25 kHz for 13C
H2N
N4
nuclei, the number of scans was 8 for the gs-HMQC
spectra and 16 for the gs-HMBC spectra, and the relaxation
N
H
3
R
HN
1
delay was 3 s. H–13C HSQC spectra were optimized for
G
2
N
O
1
R
H
1JCH = 145 Hz, 1H–13C HMBC – for 1JCH = 145 and nJCH = 8 Hz.
H
2
For the 1H–15N two-dimensional NMR spectra, the spectral
N
H
1'
N
1
width was 8000 Hz for H nuclei, 10.5 kHz for 15N nuclei
2'
in gs-HSQC experiments, 28 kHz for 15N nuclei in
gs-HMBC experiments with the number of scans equal to 8
(gs-HMQC) or 32 (gs-HMBC), and the relaxation delay
N 3'
O
H
H
H4'
R
3
Thus, we have proposed an effective one-step method
for the synthesis of 2-(indol-2-yl)benzimidazoles from 3-(2-
nitrobenzyl)quinoxalin-2(1Н)-ones. This method is based
on the transformation of 3-(2-aminobenzyl)quinoxalin-2(1Н)-
ones, which are formed in situ by the action of Na2S2O4,
according to the scheme of the Mamedov rearrangement,
including the formation of 1'H-spiro(indolino-2,2'-quino-
was 23 s. 1H–15N HMBC spectra were optimized for 1JNH
=
n
96 Hz and JNH = 6 Hz. In gs-HSQC spectra, decoupling
from the X-nuclei was achieved by GARP-modulation.
Prior to the Fourier transform, the FID data were
supplemented by zeroes along both axes to obtain a data array
of 4024 × 2048 elements, using a weighting function with
sin2 along both axes. MALDI mass spectra were recorded
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Chemistry of Heterocyclic Compounds 2017, 53(9), 1033–1044
on an UltraFlex III TOF/TOF mass spectrometer (Bruker
(J, Hz): 4.53 (2H, s, 3α-CH2); 7.21 (1H, ddd, J = 7.7,
J = 7.5, J = 1.1, H-6 Q); 7.29 (1H, d, J = 7.9, Н-8 Q); 7.44–
7.48 (2H, m, H-5,7 Q); 7.54–7.59 (2H, m, H-4,6 B); 7.70
(1H, ddd, J = 8.1, J = 5.7, J = 1.2, H-5 B); 8.05 (1H, dd,
J = 6.7, J = 1.0, H-3 B); 12.44 (1H, s, NH). Found, m/z:
413.9837 [M+Cs]+. C15H11CsN3O3. Calculated, m/z:
413.9849.
Daltonik GmbH). In order to obtain mass spectra in high
resolution mode and to determine the accurate mass values
of molecular ions, the mass spectra were recorded in
reflectron mode (resolution 10000) with the registration of
positively charged ions while using a metallic target. The
data were processed using the FlexAnalysis 3.0 program
(Bruker Daltonik GmbH). 2,5-Dihydroxybenzoic acid
(DHB) or p-nitroaniline (p-NA) were used as the matrix
compounds. Mass spectra with accurate mass values were
obtained by using a mixture consisting of the sample in
DMF (5 mg/ml) and a reference compound in MeCN
(1 mg/ml, PEG-400) in 1:5 ratio, followed by coating on
the target and evaporation of 0.5 µl of matrix solution
(10 mg/ml) in MeCN and 0.5 µl of the mixture. The
indicated composition allowed to ensure that the absolute
error of mass determination did not exceed 0.0030 amu.
Melting points were determined in glass capillaries on an
Electrothermal IA9200 apparatus.
6,7-Dimethyl-3-(2-nitrobenzyl)quinoxalin-2(1Н)-one
(1b) was obtained from ethyl о-nitrophenylpyruvate 5 (0.47 g,
2 mmol) and 4,5-dimethyl-о-phenylenediamine (6b) (0.27 g,
2 mmol). Yield 0.57 g (92%), pink powder, mp 274–275°С
(mp 215–217°С30c). IR spectrum, ν, cm–1: 3445, 3154,
2918, 2866, 2792, 1655, 1630, 1556, 1520, 1496, 1444,
Synthesis of compounds 1a–h (General method). A
solution of о-nitrotoluene (0.96 g, 7 mmol) and diethyl
oxalate (5.11 g, 35 mmol) in toluene (20 ml) was stirred at
50°С and treated by the addition of t-BuOK (0.78 g,
7 mmol). The temperature was then increased to 100°С and
stirring was continued for another 2 h. After the reaction
was complete (the reaction progress was controlled by TLC
(EtOAc–hexane, 1:1)), the reaction mixture was quenched
with saturated aqueous solution of NH4Cl (10 ml) and
extracted with toluene (3×50 ml). The combined organic
layer was dried over MgSO4, filtered, the solvent was
evaporated under water aspirator vacuum, resulting in the
isolation of crude product (7.15 g) containing 17.5% of
ethyl о-nitrophenylpyruvate, 58.0% of diethyl oxalate, and
24.5% of toluene according to the data of 1Н NMR
spectroscopy, pointing to the formation of the desired
product 5 (1.25 g, 75%), which was not isolated from the
mixture. A characteristic 1H NMR feature for ethyl
о-nitrophenylpyruvate 5 was the singlet of СН2 group at
4.49 ppm, which was in agreement with the literature
data.30а Part of the reaction mixture (2.7 g) containing
compound 5 (0.47 g, 2 mmol) was dissolved in a 10:1
mixture of EtOH–AcOH, the appropriate 1,2-diamino-
benzene 6 (2 mmol) was added, and the mixture was stirred
at room temperature for 6 h. The precipitate that formed was
filtered off, providing compounds 1a–h.
1
1358, 1208, 1003, 934, 859, 796, 737, 724, 594. H NMR
spectrum (400 MHz), δ, ppm (J, Hz): 2.20 (3H, s, CH3);
2.27 (3H, s, CH3); 4.50 (2H, s, 3α-CH2); 7.04 (1H, s, H-5
Q); 7.23 (1H, s, H-8 Q); 7.54–7.58 (2H, m, H-4,6 B); 7.70
(1H, ddd, J = 8.1, J = 7.0, J = 1.1, H-5 B); 8.05 (1H, d, J = 8.4,
H-3 B); 12.29 (1H, s, NH). Found, m/z: 442.0161 [M+Cs]+.
C17H15CsN3O3. Calculated, m/z: 442.0162.
6,7-Dichloro-3-(2-nitrobenzyl)quinoxalin-2(1Н)-one
(1c) was obtained from ethyl о-nitrophenylpyruvate 5
(0.47 g, 2 mmol) and 4,5-dichloro-о-phenylenediamine
(6c) (0.35 g, 2 mmol). Yield 0.67 g (96%), beige powder,
mp 271–272°С. IR spectrum, ν, cm–1: 3144, 3044, 2977,
2888, 2809, 1665, 1607, 1562, 1526, 1467, 1384, 1361,
1
1274, 1203, 1117, 914, 886, 859, 789, 730. H NMR
spectrum (400 MHz), δ, ppm (J, Hz): 4.53 (2H, s, 3α-CH2);
7.44 (1Н, br. s, H-5(8) Q); 7.55–7.59 (2H, m, H-4,6 B);
7.68 (1Н, br. s, H-8(5)); 7.71 (1H, dd, J = 7.7, J = 7.4,
H-5 B); 8.07 (1H, br. d, J = 8.2, H-3 B); 12.59 (1H, s, NH).
Found, m/z: 371.9902 [M(35Cl)+Na]+. C15H9Cl2N3NaO3.
Calculated, m/z: 371.9913. Found, m/z: 373.9877 [M(37Cl)+Na]+.
C15H9Cl2N3NaO3. Calculated, m/z: 373.9886.
3-(2-Nitrobenzyl)quinoxalin-2(1Н)-one
(1a) was
obtained from ethyl о-nitrophenylpyruvate 5 (0.47 g,
2 mmol) and о-phenylenediamine (6a) (0.22 g, 2 mmol).
Yield 0.54 g (96%), beige powder, mp 232–234°С (mp 232–
234°С30b). IR spectrum, ν, cm–1: 3105, 2966, 2841, 1657,
1611, 1568, 1516, 1350, 1142, 1108, 902, 861, 948, 756,
723, 703, 687, 595. 1H NMR spectrum (400 MHz), δ, ppm
6-Methyl-3-(2-nitrobenzyl)quinoxalin-2(1Н)-one
(1dA)
and 7-methyl-3-(2-nitrobenzyl)quinoxalin-2(1Н)-one (1dB)
1038

Chemistry of Heterocyclic Compounds 2017, 53(9), 1033–1044
(53:47 mixture of isomers) was obtained from ethyl
(C-6 B); 124.4 (C-3 B); 124.0 (C-6 Q); 113.1 (C-8 Q); 37.0
(3α-C); 16.1 (CH3). 15N NMR spectrum (51 MHz), δ, ppm:
149.3 (N-1 Q); 321.7 (N-4 Q); 376.6 (NO2 B).
о-nitrophenylpyruvate 5 (0.47 g, 2 mmol) and 3,4-diamino-
toluene (6d) (0.24 g, 2 mmol). The overall yield was 0.42 g
(71%), light-pink powder, mp 225–226°С. IR spectrum,
ν, cm–1: 3307, 2922, 2861, 1660, 1624, 1556, 1524, 1400,
1338, 1318, 1271, 1164, 896, 862, 816, 796, 731, 671.
1
Regioisomer F (28%). H NMR spectrum (500 MHz),
δ, ppm (J, Hz): 2.41 (3H, s, СН3); 4.55 (2H, s, 3α-CН2);
7.09–7.11 (1H, m, H-6 Q); 7.29 (1H, d, J = 8.0, H-5 Q);
7.30 (1H, d, J = 8.0, H-7 Q); 7.56–7.58 (1H, m, H-6 B);
7.58–7.60 (1H, m, H-4 B); 7.71–7.73 (1H, m, H-5 B); 8.06
(1H, dd, J = 7.8, J = 1.3, H-3 B); 11.78 (1H, s, NH).
13C NMR spectrum, δ, ppm: 158.2 (C-3 Q); 154.7 (C-2 Q);
149.4 (C-2 B); 143.9 (C-4a Q); 133.4 (C-4 B); 133.3 (C-5 B);
131.9 (C-1 B); 131.3 (C-8 Q); 130.8 (C-7 Q); 128.6 (C-6 B);
126.1 (C-5 Q); 124.5 (C-3 B); 124.0 (C-8a Q); 122.7 (C-6 Q);
36.5 (3α-C); 16.7 (CH3). 15N NMR spectrum (51 MHz),
δ, ppm: 149.3 (N-1 Q); 325.9 (N-4 Q); 376.5 (NO2 B). Found,
1
Regioisomer A (53%). H NMR spectrum (500 MHz),
δ, ppm (J, Hz): 2.30 (3H, s, СН3); 4.53 (2H, s, 3α-CН2);
7.18 (1H, d, J = 8.1, H-8 Q); 7.26 (1H, s, H-5 Q); 7.29 (1H,
dd, J = 8.1, J = 1.3, H-7 Q); 7.55–7.57 (1H, m, H-4 B); 7.56–
7.58 (1H, m, H-6 B); 7.70–7.72 (1H, m, H-5 B); 8.04 (1H,
dd, J = 7.5, J = 1.1, H-3 B); 12.36 (1H, s, NH). 13C NMR
spectrum, δ, ppm 158.6 (C-3 Q); 154.1 (C-2 Q); 149.3 (C-2 B);
133.4 (C-5 B); 133.4 (C-6 B); 132.6 (C-6 Q); 132.1 (C-1 B);
131.1 (C-4a Q); 130.8 (C-7 Q); 129.4 (C-8a Q); 128.1 (C-4 B);
127.7 (C-5 Q); 124.5 (C-3 B); 115.0 (C-8 Q); 36.6 (3α-C);
20.1 (CH3). 15N NMR spectrum (51 MHz), δ, ppm: 149.8
(N-1 Q); 324.6 (N-4 Q); 376.5 (NO2 B).
m
/
z
:
428.0020 [M+Cs]+. C16H13CsN3O3. Calculated, m/z:
428.0006.
1
Regioisomer B (47%): H NMR spectrum (500 MHz),
δ, ppm (J, Hz): 2.39 (3H, s, СН3); 4.51 (2H, s, 3α-CН2);
7.02 (1H, dd, J = 8.2, J = 1.3, H-6 Q); 7.06 (1H, s, H-8 Q);
7.34 (1H, d, J = 8.2, H-5 Q); 7.54–7.56 (1H, m, H-4 B);
7.57–7.59 (1H, m, H-6 B); 7.70–7.72 (1H, m, H-5 B); 8.04
(1H, dd, J = 7.5, J = 1.1, H-3 B); 12.36 (1H, s, NH).
13C NMR spectrum, δ, ppm: 157.4 (C-3 Q); 154.3 (C-2 Q);
149.4 (C-2 B); 139.8 (C-7 Q); 133.4 (C-5 B); 133.3 (C-6 B);
132.0 (C-1 B); 131.6 (C-8a Q); 129.4 (C-4a Q); 128.1 (C-4 B);
127.8 (C-5 Q); 124.5 (C-3 B); 124.4 (C-6 Q); 114.9
(C-8 Q); 36.4 (3α-C); 21.1 (CH3). 15N NMR spectrum
(51 MHz), δ, ppm: 149.2 (N-1 Q); 324.7 (N-4 Q); 376.5 (NO2 B).
Found, m/z: 428.0014 [M+Cs]+. C16H13CsN3O3. Calculated,
m/z: 428.0006.
6-Chloro-3-(2-nitrobenzyl)quinoxalin-2(1Н)-one (1fA)
and 7-chloro-3-(2-nitrobenzyl)quinoxalin-2(1Н)-one (1fB)
(58:42 mixture of isomers) were obtained from ethyl
о-nitrophenylpyruvate 5 (0.47 g, 2 mmol) and 4-chloro-
о-phenylenediamine (6f) (0.29 g, 2 mmol). The overall
yield 0.56 g (88%), dark-pink powder, mp 248–249°С.
IR spectrum, ν, cm–1: 3442, 2989, 2918, 2833, 1667, 1612,
1522, 1485, 1344, 1310, 1116, 1079, 946, 862, 822, 726,
564. Regioisomer A (58%). 1H NMR spectrum (500 MHz),
δ, ppm (J, Hz): 4.54 (2H, s, 3α-CН2); 7.29 (1H, d, J = 8.9,
H-8 Q); 7.46 (1H, d, J = 2.3, H-5 Q); 7.51 (1H, dd, J = 8.9,
J = 2.3, H-7 Q); 7.55–7.57 (1H, m, H-4 B); 7.58–7.60 (1H,
m, H-6 B); 7.69–7.71 (1H, m, H-5 B); 8.06 (1H, d, J = 7.5,
H-3 B); 12.57 (1H, s, NH). 13C NMR spectrum, δ, ppm:
160.4 (C-3 Q); 154.0 (C-2 Q); 149.3 (C-2 B); 133.5
(C-5 B); 133.4 (C-6 B); 131.7 (C-1 B); 130.6 (C-4a Q);
130.7 (C-8a Q); 129.6 (C-7 Q); 128.3 (C-4 B); 127.0
(C-5 Q); 126.8 (C-6 Q); 124.6 (C-3 B); 117.0 (C-8 Q); 36.7
(3α-C). 15N NMR spectrum (51 MHz), δ, ppm: 148.5 (N-1 Q);
321.5 (N-4 Q); 377.0 (NO21B).
5-Methyl-3-(2-nitrobenzyl)quinoxalin-2(1Н)-one
(1еE) and 8-methyl-3-(2-nitrobenzyl)quinoxalin-2(1Н)-
one (1eF) (72:28 mixture of isomers) were obtained from
ethyl о-nitrophenylpyruvate 5 (0.47 g, 2 mmol) and 2,3-
diaminotoluene (6e) (0.24 g, 2 mmol). The overall yield
0.30 g (51%), light-brown powder, mp 203–204°С.
IR spectrum, ν, cm–1: 3437, 3103, 2976, 2921, 2849, 1665,
1610, 1524, 1355, 1130, 866, 787, 778, 706, 666, 543.
Regioisomer B (42%). H NMR spectrum (500 MHz),
δ, ppm (J, Hz): 4.52 (2H, s, 3α-CН2); 7.21 (1H, dd, J = 8.8,
J = 2.3, H-6 Q); 7.28 (1H, s, H-8 Q); 7.45 (1H, d, J = 8.8,
H-5 Q); 7.55–7.57 (1H, m, H-4 B); 7.58–7.60 (1H, m, H-6 B);
7.69–7.71 (1H, m, H-5 B); 8.06 (1H, d, J = 7.5, H-3 B);
12.51 (1H, s, NH). 13C NMR spectrum, δ, ppm: 159.3
(C-3 Q); 154.0 (C-2 Q); 149.3 (C-2 B); 133.7 (C-7 Q); 133.5
(C-5 B); 133.4 (C-6 B); 131.8 (C-8a Q); 131.7 (C-1 B); 129.9
(C-4a Q); 129.7 (C-5 Q); 128.2 (C-4 B); 124.6 (C-3 B);
123.2 (C-6 Q); 114.6 (C-8 Q); 36.6 (3α-C). 15N NMR
spectrum (51 MHz), δ, ppm: 148.3 (N-1 Q); 322.3 (N-4 Q);
377.0 (NO2 B). Found, m/z: 447.9461 [M(35Cl)+Cs]+.
C15H10ClCsN3O3. Calculated, m/z: 447.9460.
1
Regioisomer E (72%). H NMR spectrum (500 MHz),
δ, ppm (J, Hz): 2.20 (3H, s, СН3); 4.57 (2H, s, 3α-CН2);
7.05 (1H, d, J = 7.1, H-6 Q); 7.11 (1H, d, J = 7.1, H-8 Q);
7.33 (1H, d, J = 7.1, H-7 Q); 7.55–7.57 (1H, m, H-6 B); 7.57–
7.59 (1H, m, H-4 B); 7.69–7.71 (1H, m, H-5 B); 8.08 (1H,
dd, J = 7.5, J = 1.1, H-3 B); 12.38 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 156.5 (C-3 Q); 154.2 (C-2 Q); 149.7
(C-2 B); 136.2 (C-4a Q); 133.4 (C-4 B); 133.4 (C-5 B); 131.9
(C-1 B); 131.7 (C-8a Q); 129.6 (C-5 Q); 129.5 (C-7 Q); 128.1
1039

Chemistry of Heterocyclic Compounds 2017, 53(9), 1033–1044
C-5 Q); 109.8 (C-8 Q); 100.6 (3α-C). 15N NMR spectrum
(51 MHz), δ, ppm: 104.5 (N-4 Q); 134.1 (N-1 Q); 368.0
(NO2 B). Found, m/z: 349.0534 [M+Na]+. C15H10N4NaO5.
Calculated, m/z: 349.0543.
7-Nitro-3-(2-nitrobenzyl)quinoxalin-2(1Н)-one (1gB),
6-nitro-3-(2-nitrobenzyl)quinoxalin-2(1Н)-one
(1gA),
(3Е)-7-nitro-3-(2-nitrobenzylidene)-3,4-dihydroquinoxa-
lin-2(1H)-one (1gD), (3Е)-6-nitro-3-(2-nitrobenzylidene)-
3,4-dihydroquinoxalin-2(1H)-one
(1gC)
(45:25:30
mixture of isomers, tautomer С was present in trace
amounts) were obtained from ethyl о-nitrophenylpyruvate
5 (0.47 g, 2 mmol) and 4-nitro-о-phenylenediamine (6g)
(0.31 g, 2 mmol). The overall yield 0.54 g (82%), light-
orange powder, mp 225–227°С. IR spectrum, ν, cm–1:
3083, 2932, 2858, 2807, 1669 (br), 1614, 1573, 1525,
1414, 1402, 1342, 1141, 1112, 1087, 1078, 922, 886, 865,
845, 790, 738, 723, 714.
2-(2-Nitrobenzyl)-3-oxo-3,4-dihydroquinoxaline-6-
carboxylic acid (1hB), 3-(2-nitrobenzyl)-2-oxo-1,2,3,4-
tetrahydroquinoxaline-6-carboxylic acid (1hA), (3E)-
2-(2-nitrobenzylidene)-3-oxo-1,2,3,4-tetrahydroquinoxaline-
6-carboxylic acid (1hD), (3E)-3-(2-nitrobenzylidene)-2-
oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (1hC)
(58:37:5 mixture of isomers, tautomer С was present in
trace amounts) were obtained from ethyl о-nitro-
phenylpyruvate 5 (0.47 g, 2 mmol) and 3,4-diaminobenzoic
acid (6h) (0.30 g, 2 mmol). The overall yield 0.56 g (86%),
beige powder, mp 278–279°С. IR spectrum, ν, cm–1: 3069,
2846, 1694, 1665, 1612, 1561, 1525, 1428, 1415, 1344, 1302,
1277, 1139, 1116, 927, 856, 787, 770, 757, 724, 710, 611.
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 4.55 (2H, s,
3α-СН2 A); 4.56 (2H, s, 3α-СН2 B); 6.51 (1H, s, 3α-СН2 D); 7.05
(1Н, d, J = 8.5, H-5 Q D); 7.34 (1H, d, J = 8.5, H-8 Q A); 7.51
(1H, d, J = 8.5, H-5 Q B); 7.46–7.59 (6H, m); 7.69–7.72
(4H, m); 7.82 (1H, d, J = 7.7, Н-6 Q В or H-6 Q D); 7.89
(1H, d, J = 1.4, H-8 Q B); 7.92 (1H, d, J = 1.7, H-5 Q A); 7.98
(1H, dd, J = 8.5, J = 1.8, H-7 Q A); 8.02–8.07 (4H, m);
9.83 (1H, s, H-4 Q D); 11.25 (1Н, s, NH D); 12.59 (1Н, s, NH
B); 12.70 (1H, s, NH A). Found, m/z: 457.9736 [M+Cs]+.
C16H11CsN3O5. Calculated, m/z: 457.9748.
Synthesis of compounds 4a–h (General method). A
solution of compound 1 (2 mmol) in a mixture of EtOH (5
ml) and Н2O (5 ml) was stirred and treated by the addition
of Na2S2O4 (8 mmol), then refluxed for 3 h and treated with
with another 4 mmol of Na2S2O4. Refluxing was then
continued for additional 3 h. The reaction mixture was
quenched with 20% HCl solution (10 ml) and refluxed for
additional 3 h, then left overnight. The reaction mixture
was poured into H2O (100 ml), the crystals that precipitated
were seperated by filtration after 4 h, and recrystallized
from EtOH if necessary.
1
Regioisomer B (45%). H NMR spectrum (500 MHz),
δ, ppm (J, Hz): 4.59 (2H, s, 3α-CН2); 7.58–7.60 (1H, m,
H-4 B); 7.59–7.61 (1H, m, H-6 B); 7.65 (1H, d, J = 8.8,
H-5 Q); 7.75–7.77 (1H, m, H-5 B); 7.96 (1H, dd, J = 8.8,
J = 1.9, H-6 Q); 8.07–8.09 (1H, m, H-3 B); 8.09–8.10 (1H,
m, H-8 Q); 12.78 (1H, s, NH). 13C NMR spectrum, δ, ppm:
163.1 (C-2 Q); 153.9 (C-3 Q); 149.2 (C-2 B); 146.8 (C-7 Q);
134.6 (C-4a Q); 133.6 (C-5 B); 133.6 (C-6 B); 132.1 (C-8a Q);
131.4 (C-1 B); 129.4 (C-5 Q); 128.4 (C-4 B); 124.7
(C-3 B); 117.4 (C-6 Q); 110.9 (C-8 Q); 37.0 (3α-C).
15N NMR spectrum (51 MHz), δ, ppm: 149.2 (N-1 Q);
319.7 (N-4 Q); 375.9 (NO2 B).
1
Regioisomer А (25%). H NMR spectrum (500 MHz),
δ, ppm (J, Hz): 4.57 (2H, s, 3α-CН2); 7.44 (1H, d, J = 9.1,
H-8 Q); 7.58–7.60 (1H, m, H-4 B); 7.59–7.61 (1H, m, H-6 B);
7.74–7.76 (1H, m, H-5 B); 8.07–8.09 (1H, m, H-3 B); 8.15
(1H, d, J = 2.5, H-5 Q); 8.30 (1H, dd, J = 9.1, J = 2.5, H-7 Q);
12.96 (1H, s, NH). 13C NMR spectrum, δ, ppm: 161.7 (C-2 Q);
154.2 (C-3 Q); 149.3 (C-2 B); 142.8 (C-4a Q); 137.0
(C-8a Q); 133.7 (C-5 B); 133.5 (C-6 B); 131.3 (C-1 B); 130.0
(C-6 Q); 128.1 (C-4 B); 124.7 (C-3 B); 124.4 (C-7 Q); 123.4
(C-5 Q); 116.8 (C-8 Q); 36.7 (3α-C). 15N NMR spectrum
(51 MHz), δ, ppm: 151.5 (N-1 Q); 321.2 (N-4 Q); 375.9
(NO2 B).
1
Regioisomer D (30%). H NMR spectrum (500 MHz),
δ, ppm (J, Hz): 6.62 (1H, s, 3α-CН); 7.09 (1H, d, J = 8.9,
H-5 Q); 7.53–7.55 (1H, m, H-4 B); 7.75 (1H, s, Н-8 Q); 7.76
(1H, ddd, J = 7.3, J = 7.3, J = 1.1, H-5 B); 7.81 (1H, d,
J = 7.3, H-6 B); 7.81 (1H, d, J = 8.9, H-6 Q); 8.07–8.09
(1H, m, H-3 B); 10.16 (1H, s, 4-NH Q); 11.41 (1H, s,
1-NH Q). 13C NMR spectrum, δ, ppm: 157.3 (C-2 Q);
147.8 (C-2 B); 139.2 (C-7 Q); 134.2 (C-4a Q); 133.6 (C-5 B);
130.8 (C-6 B); 130.6 (C-2 Q); 129.6 (C-1 B); 128.1 (C-4 B);
125.1 (C-8a Q); 124.7 (C-3 B); 119.6 (C-6 Q); 113.3
2-(1Н-Indol-2-yl)-1Н-benzimidazole (4a). Yield 0.46 g
(98%), light-orange powder, mp 282–283°С (mp 328–329°С35а,
1
160–162°С35b). H NMR spectrum (500 MHz), δ, ppm
1040

Chemistry of Heterocyclic Compounds 2017, 53(9), 1033–1044
(J, Hz): 7.17 (1H, ddd, J = 7.2, J = 7.2, J = 0.9, H-5 Ind);
J = 1.1, H-5 Ind); 7.34 (1Н, ddd, J = 7.5, J = 7.5, J = 1.1,
H-6 Ind); 7.35 (1H, d, J = 8.1, H-5 BI); 7.57 (1H, dd,
J = 8.2, J = 1.1, H-7 Ind); 7.60 (1H, s, H-7 BI); 7.68 (1H, d,
J = 8.2, H-4 BI); 7.69 (1H, s, H-3 Ind); 7.77 (1H, d, J = 7.8,
H-4 Ind); 12.42 (1H, s, NH Ind). 13C NMR spectrum, δ,
ppm: 142.7 (C-2 BI); 137.8 (C-7a Ind); 135.5 (C-6 BI);
132.3 (C-7a BI); 130.2 (C-3a BI); 127.1 (C-5 BI); 127.0
(C-3a Ind); 125.3 (C-6 Ind); 121.9 (C-4 Ind); 121.8 (C-2
Ind); 120.9 (C-5 Ind); 113.4 (C-4 BI); 113.2 (C-7 BI); 112.3
(C-7 Ind); 107.7 (C-3 Ind); 21.1 (CH3). 15N NMR spectrum
(51 MHz), δ, ppm: 134.5 (N-1 Ind). Found, m/z: 248.1175
[M+H]+. C16H13N3. Calculated, m/z: 248.1182.
7.35 (1H, ddd, J = 7.5, J = 6.7, J = 0.9, H-6 Ind); 7.53–7.54
(2H, m, H-5,6 BI); 7.58 (1H, dd, J = 7.8, J = 1.0, H-7 Ind);
7.74 (1H, d, J = 1.0, H-3 Ind); 7.78 (1H, d, J = 7.8, H-4
Ind); 7.81–7.82 (2H, m, H-4,7 BI); 12.46 (1H, s, Ind).
13C NMR spectrum, δ, ppm: 143.0 (C-2 BI); 137.9 (C-7a Ind);
131.9 (C-3a,7a BI); 127.1 (C-3a Ind); 125.6 (C-5,6 BI); 125.5
(C-6 Ind); 122.0 (C-4 Ind); 121.4 (C-2 Ind); 121.0 (C-5
Ind); 113.7 (2С, C-4,7 BI); 112.3 (C-7 Ind); 108.2 (C-3 Ind).
15N NMR spectrum (51 MHz), δ, ppm: 133.9 (N-1 Ind).
Found, m/z: 234.1025 [M+H]+. C15H11N3. Calculated, m/z:
234.1026.
2-(1Н-Indol-2-yl)-5,6-dimethyl-1Н-benzimidazole
(4b).
1
Yield 0.45 g (86%), light-red powder, mp 236–238°С. H
NMR spectrum (600 MHz), δ, ppm (J, Hz): 2.26 (6H, s,
CH3); 7.08 (1H, dd, J = 7.3, J = 7.2, H-5 Ind); 7.22 (1Н, s,
H-4(7) BI); 7.24 (1H, dd, J = 8.2, J = 7.2, H-6 Ind); 7.39
(1Н, s, H-4(7) BI); 7.49 (1H, d, J = 8.1, H-7 Ind); 7.57 (1Н,
s, H-3 Ind); 7.68 (1H, d, J = 8.1, H-4 Ind); 10.48 (1H, s, NH
BI); 11.77 (1H, s, NH Ind). Found, m/z: 262.1330 [M+H]+.
C17H15N3. Calculated, m/z: 262.1339.
2-(1H-Indol-2-yl)-7-methyl-1H-benzimidazole (4e).
1
Yield 0.83 g (68%), black powder, mp 242–244°С. H NMR
spectrum (500 MHz), δ, ppm (J, Hz): 2.68 (3H, s, CH3);
7.17 (1H, dd, J = 7.7, J = 7.2, H-5 Ind); 7.32 (1H, d, J = 7.7,
H-6 BI); 7.35 (1H, dd, J = 7.7, J = 7.3, H-6 Ind); 7.42 (1H,
dd, J = 7.9, J = 7.8, H-5 BI); 7.58 (1H, d, J = 8.0, H-7 Ind);
7.61 (1H, d, J = 8.0, H-4 BI); 7.75 (1H, s, H-3 Ind); 7.78
(1H, d, J = 7.8, H-4 Ind); 12.56 (1H, s, NH Ind); 14.93 (1H,
s, NH BI). 13C NMR spectrum, δ, ppm: 142.8 (C-2 BI);
137.8 (C-7a Ind); 131.8 (C-3a BI); 131.6 (C-7a BI); 127.1
(C-3a Ind); 126.0 (C-6 BI); 125.7 (C-5 BI); 125.5 (C-6 Ind);
124.2 (C-7 BI); 122.0 (C-4 Ind); 121.6 (C-2 Ind); 121.0 (C-
5 Ind); 112.3 (C-7 Ind); 110.9 (C-4 BI); 108.0 (C-3 Ind);
16.8 (CH3). 15N NMR spectrum (51 MHz), δ, ppm: 132.8
(N-1 Ind). Found, m/z: 248.1186 [M+H]+. C16H13N3.
Calculated, m/z: 248.1182.
5,6-Dichloro-2-(-1H-indol-2-yl)-1H-benzimidazole (4c).
1
Yield 0.53 g (88%), orange powder, mp >370°С. H NMR
spectrum (500 MHz), δ, ppm (J, Hz): 7.07 (1H, ddd, J = 7.5,
J = 7.2, J = 0.9, H-5 Ind); 7.21 (1H, ddd, J = 7.9, J = 7.5,
J = 0.9, H-6 Ind); 7.32 (1H, d, J = 1.4, H-3 Ind); 7.48 (1H,
d, J = 7.9, H-7 Ind); 7.66 (1H, d, J = 8.1, H-4 Ind); 7.86
(2H, s, H-4,7 BI); 12.048 (1H, s, NH Ind). 13C NMR
spectrum, δ, ppm: 142.3 (C-2 BI); 138.2 (C-3a,7a BI);
137.5 (C-7a Ind); 127.6 (C-3a Ind); 126.9 (C-2 Ind); 124.8
(C-5,6 BI); 123.5 (C-6 Ind); 121.1 (C-4 Ind); 120.0 (C-5
Ind); 115.9 (C-4,7 BI); 112.1 (C-7 Ind); 103.5 (C-3 Ind).
15N NMR spectrum (51 MHz), δ, ppm: 134.2 (N-1 Ind).
Found, m/z: 302.0248 [M(35Cl)+H]+. C15H9Cl2N3. Calculated,
m/z: 302.0246. Found, m/z: 304.0225 [M(37Cl)+H]+.
C15H9Cl2N3. Calculated, m/z: 304.0219.
6-Chloro-2-(1H-indol-2-yl)-1H-benzimidazole
(4f).
Yield 0.41 g (76%), brownish-green powder, mp 290–
1
292 С (mp 198–200°С35b). H NMR spectrum (400 MHz),
δ, ppm (J, Hz): 7.14 (1H, ddd, J = 7.3, J = 7.2, J = 1.0, H-5
Ind); 7.31 (1H, ddd, J = 7.9, J = 7.2, J = 1.0, H-6 Ind); 7.46
(1H, dd, J = 8.6, J = 1.9, H-5 BI); 7.55 (1H, dd, J = 8.2,
J = 1.0, H-7 Ind); 7.66 (1H, s, H-3 Ind); 7.74 (1H, d,
J = 7.8, H-4 Ind); 7.76 (1H, d, J = 8.4, H-4 BI); 7.81 (1H,
d, J = 1.9, H-7 BI); 12.37 (1H, s, NH Ind). 13C NMR
spectrum, δ, ppm: 144.9 (C-2 BI); 137.8 (C-7a Ind); 134.7
(C-6 BI); 132.5 (C-7a BI); 129.0 (C-3a BI); 127.2 (C-3a Ind);
125.1 (C-6 Ind); 125.0 (C-5 BI); 122.0 (C-2 Ind); 121.8
(C-4 Ind); 120.8 (C-5 Ind); 115.0 (C-4 BI); 113.7 (C-7 BI);
112.3 (C-7 Ind); 107.2 (C-3 Ind). 15N NMR spectrum
(51 MHz), δ, ppm: 133.9 (N-1 Ind). Found, m/z:
268.0631 [M(35Cl)+H]+. C15H10ClN3. Calculated, m/z:
268.0636.
2-(1H-Indol-2-yl)-6-methyl-1H-benzimidazole (4d).
Yield 0.47 g (96%), orange powder, mp 254–256°С (mp
148–150°С35b). 1H NMR spectrum (500 MHz), δ, ppm
(J, Hz): 2.50 (3H, s, CH3); 7.17 (1H, ddd, J = 7.1, J = 6.9,
1041

Chemistry of Heterocyclic Compounds 2017, 53(9), 1033–1044
IR spectrum of the mixture, ν, cm–1: 3403, 3330, 3037,
2987, 2894, 2818, 1667 (sh), 1608, 1563. 1527, 1464,
1385, 1345, 1123, 909, 753.
3-(2-Aminobenzyl)-6,7-dichloroquinoxalin-2(1Н)-one
(2с). Yield 0.29 g (45%), light-yellow powder, mp 247–248°С.
IR spectrum, ν, cm–1: 3443, 3331, 3024, 2900, 2830, 1665,
1611, 1560, 1457, 1374, 1351, 1210, 1157, 1025, 857, 751.
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 3.97 (2H, s,
CH2); 6.72 (1Н, dd, J = 7.4, J = 7.4); 7.05 (1Н, dd, J = 8.4,
J = 7.4); 7.16 (1Н, d, J = 7.7); 7.44 (1H, с); 7.48 (1Н, d,
J = 8.4); 7.90 (1H, с); 12.57 (1H, s, NH).
6-Amino-2-(1H-indol-2-yl)-1H-benzimidazole
(4g).
Yield 0.36 g (72%), dark-brown powder, 224–228°С.
1H NMR spectrum (500 MHz), δ, ppm (J, Hz): 7.15 (1H,
ddd, J = 7.3, J = 6.9, J = 0.9, H-5 Ind); 7.32 (1H, ddd,
J = 7.1, J = 6.9, J = 0.9, H-6 Ind); 7.41 (1H, d, J = 8.4, H-4
BI); 7.54 (1H, dd, J = 7.8, J = 0.9, H-7 Ind); 7.70 (1H, s,
H-3 Ind); 7.75 (1H, dd, J = 7.5, J = 0.9, H-4 Ind); 7.76 (1H,
s, H-7 BI); 7.82 (1H, d, J = 8.6, H-5 BI); 12.43 (1H, s, NH
Ind). 13C NMR spectrum, δ, ppm: 144.5 (C-2 BI); 137.8
(C-7a Ind); 133.6 (C-6 BI); 133.6 (C-7a BI); 130.8 (C-3a
BI); 127.2 (C-3a Ind); 125.2 (C-6 Ind); 122.5 (C-2 Ind);
121.8 (C-4 Ind); 120.9 (C-5 Ind); 119.6 (C-4 BI); 114.9
(C-5 BI); 112.3 (C-7 Ind); 107.5 (C-3 Ind); 107.4 (C-7 BI).
15N NMR spectrum (51 MHz), δ, ppm: 55.3 (N-1 BI); 133.9
(N-1 Ind). Found, m/z: 249.1134 [M+H]+. C15H12N4.
Calculated, m/z: 249.1135.
1',4'-Dihydro-6',7'-dichloro-3'H-spiro(indolin-2,2'-quin-
oxalin)-3'-one (3c). 1H NMR spectrum (500 MHz), δ, ppm
(J, Hz): 2.92 (1H, d, J = 16.8, 3-СH2); 3.89 (1H, d, J = 16.8,
3-СH2); 6.37 (1H, d, J = 7.3, H-7); 6.59 (1H, ddd, J = 7.4,
J = 7.4, J = 1.0, H-5); 6.93 (1H, s, H-8'); 6.94 (1H, dd,
J = 7.3, J = 7.4, H-6); 6.99 (1H, s, H-5'); 7.07 (1H, d,
J = 7.3, H-4); 7.52 (1H, s, 1'-NH); 10.76 (1H, s, 4'-NH).
13C NMR spectrum, δ, ppm: 164.4 (3'-C); 148.0 (C-7a);
132.5 (C-8a'); 127.4 (C-6); 126.0 (C-4a'); 125.1 (C-3a);
123.9 (C-4); 120.0 (C-7'); 119.2 (C-6'); 117.5 (C-5); 115.4
(C-5'); 115.0 (C-8'); 107.4 (C-7); 75.7 (2-C/2'-C); 38.9 (3-C).
15N NMR spectrum (51 MHz), δ, ppm: 88.9 (N-1'); 129.3 (N-4').
5,6-Dichloro-2-(-1H-indol-2-yl)-1H-benzimidazole (4c).
A solution of compound 2c (0.1 g, 0.3 mmol) or a mixture
of compounds 2с and 3с (obtained according to the
procedure described above) in n-BuOH (5 ml) was stirred
and treated with 2 drops of concentrated H2SO4 and then
refluxed for 5 h. The solvent was then evaporated under
water aspirator vacuum; the resulting viscous, partially
crystalline residue was washed with aqueous 5% NaHCO3
solution (50 ml). The crystals that precipitated were filtered
off, washed with water (3×10 ml), and air-dried, providing
compound 4с (0.09 g, 96%). The spectral data were
identical to those of sample obtained from 6,7-dichloro-
3-(2-nitrobenzyl)quinoxalin-2(1Н)-one (1c). In the case
when a mixture of compounds 2с and 3с was used, the
yield of product 4с was 98%.
2-(1H-Indol-2-yl)-1H-benzimidazole-6-carboxylic acid
(4h). Yield 0.40 g (72%), orange powder, mp 299–301°С.
1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 7.14 (1H,
ddd, J = 7.3, J = 7.2, J = 0.9, H-5 Ind); 7.31 (1H, ddd,
J = 7.8, J = 7.0, J = 0.9, H-6 Ind); 7.56 (1H, dd, J = 7.8,
J = 0.9, H-7 Ind); 7.62 (1H, s, H-3 Ind); 7.75 (1H, dd,
J = 7.6, J = 0.9, H-4 Ind); 7.81 (1H, d, J = 8.4, H-4 BI);
8.03 (1H, dd, J = 8.6, J = 1.5, H-5 BI); 8.26 (1H, d, J = 8.5,
H-7 BI); 12.31 (1H, s, NH Ind). 13C NMR spectrum,
δ, ppm: 167.0 (CO2H BI); 146.1 (C-2 BI); 137.9 (C-7a
Ind); 137.3 (C-3a BI); 134.4 (C-7a BI); 127.3 (C-3a Ind);
126.8 (C-6 BI); 125.6 (C-5 BI); 124.9 (C-6 Ind); 123.5
(C-2 Ind); 121.7 (C-4 Ind); 120.7 (C-5 Ind); 115.6 (C-7
BI); 113.9 (C-4 BI); 112.3 (C-7 Ind); 106.9 (C-3 Ind).
15N NMR spectrum (51 MHz), δ, ppm: 132.9 (N-1 Ind).
Found, m/z: 278.0915 [M+H]+. C16H11N3О2. Calculated,
m/z: 278.0924.
Synthesis of compounds 2с and 3c. A solution of
compound 1с (2 mmol) in a mixture of EtOH (5 ml) and
Н2O (5 ml) was stirred and treated by the addition of
Na2S2O4 (12 mmol) in tree portions at 3 h intervals. The
reaction mixture was filtered, the filtrate was evaporated
under water aspirator vacuum, washed with a saturated
aqueous NaCl solution, and extracted with EtOAc. The
organic layer was collected, dried over Na2SO4, and
evaporated, providing compound 2с. The collected
precipitate was washed with a large amount (5×50 ml) of
aqueous sodium carbonate solution (рН 9). The crystals
that precipitated in the filtrate were filtered off, giving a
mixture of compounds 2c and 3c in the ratio of 64:36
according to the data of 1H NMR spectroscopy. The overall
yield 0.23 g (36%), light-yellow powder, mp 216–219°С.
The work was supported in part by the Russian Science
Foundation (project No. 14-23-00073-p).
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