Mendeleev
Communications
Mendeleev Commun., 2012, 22, 312–313
Synthesis of pyrido[1,2-a]benzimidazoles by electroreductive
heterocyclization of 1-(2-nitroaryl)pyridinium chlorides
Aleksandr A. Sokolov,a Mikhail A. Syroeshkin,*b Roman S. Begunov,a
Nadezhda N. Rusakovaa and Vadim P. Gultyaib
a P. G. Demidov Yaroslavl State University, 150000 Yaroslavl, Russian Federation
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: guvp@ioc.ac.ru
DOI: 10.1016/j.mencom.2012.11.011
The electrochemical reduction of N-(2-nitro-4-R-phenyl)pyridinium chlorides (R = CF3, CN, CO2Et) at a lead cathode in HCl/PriOH/H2O
affords the corresponding 7-R-pyrido[1,2-a]benzimidazoles in 70–94% yields.
Cl
The development of novel methods for the synthesis of sub-
stituted pyrido[1,2-a]benzimidazoles is topical1–6 since they are
NO2
+
of interest, e.g., as DNA intercalators,4 antibacterial, antifungal,
90 °C, Py
antitumor and antiviral drugs.1–3 Since N-(2-nitrophenyl)pyri-
N
dinium chlorides can be readily obtained from pyridines and
the corresponding o-nitrochlorobenzenes, they were transformed
into pyrido[1,2-a]benzimidazoles by their reductive heterocycliza-
tion, in particular, by the action of tin(ii) chloride,7–10 phenyl-
hydrazine, or by catalytic hydrogenation.11 It is assumed12 that
the mechanism of these transformations includes the reduction
of the nitro group into hydroxyamino one followed by hetero-
cyclization. Since N-arylhydroxylamines are typical products of
electrochemical reduction of nitroaromatic compounds in protic
media,13 it could be assumed that the electrolysis of N-(2-nitro-
phenyl)pyridinium chlorides would be accompanied by the forma-
tion of pyrido[1,2-a]benzimidazoles.
R
Cl–
N
4 F
N
R
Pb cathode
PriOH, 4% HCl
R
N
O2N
1a–c
2a–c
a R = CF3
b R = CN
c R = CO2Et
Scheme 1
and 4% hydrochloric acid (1:1) was of choice. Lead was used as
a cathode, since it is one of the most suitable materials for
transformations of this type, in particular, having a high over-
voltage of hydrogen.13 Electrolysis was carried out in a galvano-
static mode in a divided cell.‡ The point of exhaustive electrolysis
was the beginning of intense hydrogen evolution, which occurred
on passing of 4 F electricity. Then, the catholyte was treated with
a 25% ammonia solution to neutral pH and extracted with chloro-
form. The corresponding pyrido[1,2-a]benzimidazoles 2a–c were
obtained in high (70–94%) yields‡ (see Scheme 1).
N-(2-Nitrophenyl)pyridinium chlorides containing trifluoro-
methyl (1a), nitrile (1b) or ethoxycarbonyl (1c) substituents in
the para-position of the benzene ring were prepared by heating of
the corresponding o-nitrochloro derivatives in pyridine (Scheme 1) †
.
In literature,12 the best yields of 1 ® 2 transformation (see
Scheme 1) were achieved when the SnCl2-assisted heterocycli-
zation was carried out in mixtures of alcohols (MeOH, EtOH,
PriOH) and dilute (2–6%) HCl on gentle (~40°C) heating. Similar
conditions are often used for the electroreduction of nitroaromatic
compounds,13 when hydrochloric acid simultaneously provides
electroconductivity of the solution and serves as a proton donor.
Therefore, for electroreduction of 1a–c, a mixture of isopropanol
‡
A B-5-71/1 power source (Profigrupp, St. Petersburg, Russia) was used.
Cathode was a lead plate with a surface area of 50 cm2. In a typical experi-
ment, a substrate (1 g) was taken, the catholyte was a mixture of isopropanol
(40 ml) and 4% HCl (aq., 40 ml). Anolyte was 15% H2SO4. Anode was a
platinum mesh. Electrolysis was carried out at I = 0.2 A and 40–45°C.
For 2a: yield 94%; mp 233–235°C. 1H NMR (300 MHz, CDCl3) d: 8.50
(d, 1H), 8.20 (s, 1H), 7.98 (d, 1H), 7.76 (d, 1H), 7.60 (d, 1H), 7.53 (t, 1H),
6.96 (t, 1H). 13C NMR (75 MHz, CDCl3) d: 149.29, 142.75, 131.17, 130.23,
128.63, 128.20, 126.32, 125.57, 117.99, 117.31, 111.82, 111.33. HRMS,
m/z: 237.0637 [M + H]+ (calc. for C12H8F3N2: 237.0634).
†
Synthesis of N-(2-nitrophenyl)pyridinium chlorides 1a–c. 2-Nitro-
4-R-chlorobenzene (0.022 mol) was added to pyridine (0.154 mol), and
the mixture was stirred at 90°C for 1 h. The precipitate formed was filtered
off and washed with acetone (30 ml).
For 1a: yield 98%; mp 260–262°C. 1H NMR (300 MHz, D2O) d: 9.09
(d, 2H), 8.90 (s, 1H), 8.87 (t, 1H), 8.41 (d, 1H), 8.31 (t, 2H), 8.09 (d, 1H).
13C NMR (75 MHz, D2O) d: 148.88, 145.45, 137.35, 133.26, 130.38, 128.37,
124.85. HRMS, m/z: 269.0543 [M]+ (calc. for C12H8F3N2O2: 269.0532).
For 1b: yield 99%; mp 263–265°C. 1H NMR (300 MHz, D2O) d: 9.10
(d, 2H), 8.99 (s, 1H), 8.88 (t, 1H), 8.46 (d, 1H), 8.32 (t, 2H), 8.09 (d, 1H).
13C NMR (75 MHz, D2O) d: 215.33, 149.05, 145.36, 139.92, 131.23,
130.39, 128.41, 116.91, 115.86, 30.23. HRMS, m/z: 226.0626 [M]+ (calc.
for C12H8N3O2: 226.0611).
1
For 2b: yield 70%; mp 242–244°C. H NMR (300 MHz, CDCl3) d:
8.56 (d, 1H), 8.08 (s, 1H), 8.00 (d, 1H), 7.62 (d, 1H), 7.49 (d, 1H), 7.45
(t, 1H), 6.90 (t, 1H). 13C NMR (75 MHz, CDCl3) d: 148.02, 140.52, 132.02,
130.02, 126.17, 123.31, 122.51, 118.26, 116.08, 112.48, 111.88, 108.40.
HRMS, m/z: 194.0713 [M + H]+ (calc. for C12H8N3: 194.0713).
1
For 2c: yield 74%; mp 179–182°C. H NMR (300 MHz, CDCl3) d:
For 1c: yield 87%; mp 191–193 °C. 1H NMR (300 MHz, D2O) d: 9.10
(d, 2H), 9.02 (s, 1H), 8.86 (t, 1H), 8.62 (d, 1H), 8.30 (t, 2H), 8.01 (d, 1H),
4.47 (q, 2H), 1.40 (t, 3H). 13C NMR (75 MHz, D2O) d: 164.99, 148.73,
145.41, 137.72, 136.49, 135.04, 129.73, 128.31, 127.71, 63.52, 13.31.
HRMS, m/z: 273.0878 [M]+ (calc. for C14H13N2O4: 273.0870).
8.65 (s, 1H), 8.50 (d, 1H), 8.08 (d, 1H), 7.93 (d, 1H), 7.76 (d, 1H), 7.51
(t, 1H), 6.94 (t, 1H), 4.45 (q, 2H), 1.45 (t, 3H). 13C NMR (75 MHz, CDCl3):
166.75, 149.18, 142.97, 131.22, 130.75, 128.44, 125.59, 122.54, 121.86,
118.05, 111.56, 110.45, 61.27, 14.43. HRMS, m/z: 241.0974 [M + H]+
(calc. for C14H13N2O2: 241.0972).
© 2012 Mendeleev Communications. All rights reserved.
– 312 –
Sokolov, Aleksandr A.
