Effect of reducer's nature on the reduction of N-(2-nitrophenyl)pyridinium chlorides

Full text of DOI:10.1134/S1070428013050291

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 5, pp. 773−776. © Pleiades Publishing, Ltd., 2013.
Original English Text © R.S. Begunov, A.A. Sokolov, T.V. Shebunina, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 5, pp. 789−791.
SHORT
COMMUNICATIONS
Effect of Reducer’s Nature on the Reduction
of N-(2-Nitrophenyl)pyridinium Chlorides
R. S. Begunov, A. A. Sokolov, and T. V. Shebunina
Demidov Yaroslavl’State University, Yaroslavl’, 150000 Russia
e-mail: begunov@bio.uniyar.ac.ru
Received October 29, 2012
DOI: 10.1134/S1070428013050291
Pyrido[1,2-а]benzimidazoles and the other fused poly-
cyclic imidazole derivatives containing a nodal nitrogen
atom belong to the most interesting classes of organic
compounds since they exhibit versatile biological activ-
ity: antitumor [1], immunomodulating [2], antiphlogistic
[3], antibacterial, and fungicidal [4]. They are besides
bioisosteric analogs of nitrogen bases and are capable of
insertion into the DNA double helix [5]. Due to the high
fluorescence activity these heterocyclic compounds are
employed in the paints production [6].
occur alternative to the intramolecular amination: the
reduction of the pyridine fragment into piperidine moiety
[8, 9], the formation of 1-(2-aminophenyl)derivative [9],
the reaction of the pyridinium salt with the reagent (at the
reduction with phenylhydrazine) [8].
The investigation of the effect of the reducer nature
on the reaction direction was performed using reagents
operating in the acid medium: TiCl3, FeCl2, SnCl2. The
use of Na2S and the other agents for the reduction of the
nitro compounds at рН > 7 is prevented by the hydrolysis
of pyridinium salts occurring with the ring opening [10].
Therefore a great number of publications appears de-
scribing the new or modifications of the previously known
procedures for the synthesis of similar heterocyclic sys-
tems [7]. The most promising and yet the least studied is
the method based on the building up of the imidazole ring
of the pyrido[1,2-а]-benzimidazole system through the
reductive intramolecular cyclization of 1-(2-nitrophenyl)
pyridinium salts. This methods is used seldom since there
are insufficient data on the effect of various factors on the
process of the reductive amination. The most essential
factor is here the nature of electron donor [8, 9]. Depend-
ing on the structure of the latter a number of process may
The reduction of 1-[2-nitro-4-(trifluoromethyl)phenyl]
pyridinium chloride (Iа) with titanium(III) chloride in
the acidic water-alcohol solution led to an intractable
mixture from which we isolated in a small yield (up to
23%) a compound that according to the 1H NMR and mass
spectra corresponded to the product II resulting from the
reduction of the nitro group. The 1H NMR spectrum of
compound II contains the signals of pyridine protons:
9.15 d (2Н, Н2,6, J 8.5 Hz), 8.75 m (1Н, Н4), 8.35 m (2Н,
Н3,5). The singlet of the amino group protons appears at
6.22 ppm due to the presence of an electron-acceptor
CF3
CF3
CF3
CF3
3'
5'
6'
,
TiCl3
HCl
NH4OH
_NH4Cl
NO2
NH2
=N
Cl_
NH2
Cl_
N+
N+
HN
O
2
6
5
HN
n
3
4
Ia
II
773

BEGUNOV et al.
774
substituent in the ortho-position (the positively charged
nitrogen atom of the pyridine ring). The benzene protons
are observed as an АВС system: 7.55 d (1Н, Н6', J 9.5 Hz),
7.35 d (1Н, Н3', J 1.0 Hz), 7.00 d.d (1Н, Н5', J 9.5, 1.0 Hz).
Thus the study of the effect of the electron donor na-
ture on the reduction of 1-(2-nitro-4-R-phenyl)pyridinium
chlorides showed that at the use of TiCl3 formed the
primary amine, whereas the intramolecular cyclization
occurred under the action of FeCl2 and SnCl2 in acidic
water-alcohol solution.
The formation of a multicomponent mixture at the re-
duction with TiCl3 is caused apparently by the hydrolysis
of the main reaction product II during the isolation under
the treatment of the reaction mixture with NH4OH. The
pyridine ring of product II evidently suffers ring open-
ing under the action of hydroxide ions. The possibility of
this process is confirmed by the presence in the 1Н NMR
spectrum of the reaction mixture of a singlet of an alde-
hyde proton at 10.23 ppm.
1-[2-Amino-4-(trifluoromethyl)phenyl]
pyridinium chloride (II). To a solution of 1 g (3.3
mmol) of salt I in 20 ml of 2-propanol was added at 20°C
70 ml (23.1 mmol) of 5% TiCl3 solution in 3% HCl.
After 10 min the reaction mixture was alkalinized with
25% ammonia solution to рН 7–8 and extracted with
several portions of chloroform (200 ml), the extract was
evaporated. Yield 0.21 g (23%). Mass spectrum, m/z (Irel,
%): 239 (100) [M – Cl]+, 170 (18), 78 (15.2), 39 (22).
Found, %: С 52.08; H 3.34; N 10.19. С12H10ClF3N2.
Calculated, %: C 52.46; H 3.64; N 10.20. M 239.22.
At the use of salt Ia and SnCl2 the product of the
intramolecular reductive cyclization IIIа was obtained
whose composition and structure was proved by elemental
analysis, 1Н NMR and mass spectra. 1Н NMR spectrum
of cyclization product IIIа contains the signals of seven
aromatic and heteroaromatic protons: four signals of the
pyridine ring protons 9.15 d (1H, H1, J 7.5 Hz), 7.75 d
(1H, H4, J 9 Hz), 7.66 t (1H, H3, J 8 Hz), 7.09 t (1H, H2,
J 7 Hz); and three sigals of benzene ring protons 8.53 d.d
(1H, H8, J 8, 2 Hz), 8.16 d (1H, H6, J 1.5 Hz), 7.68 d
(1H, H9, J 8 Hz).
Pyrido[1,2-a]benzimidazoles IIIа–IIIl were ob-
tained similarly. In the synthesis of compounds IIIа–IIIk
10 mmol of SnCl2·2Н2О was used per 3.3 mmol of the
salt, in the synthesis of amine IIIl, 20 mmol.
7-(Trifluoromethyl)pyrido[1,2-a]benzimidazole
(IIIа). Yield 0.76 g (98%), mp 233–235°C. Mass
spectrum, m/z (Irel, %): 236 (100) [M]+, 217 (20), 186 (12),
167 (4), 118 (5), 69 (5), 63 (11), 51 (17), 39 (20). Found,
%: С 60.79; H 2.96; N 12.01. С12H7N2. Calculated, %:
C 61.02; H 2.99; N 11.86. M 236.12.
R1
R3
R1
2
R3
Cl_
N+
1
9
8
SnCl2
N
R4
3
R4
7-Nitropyrido[1,2-a]benzimidazole (IIIb). Yield
0.64 g (91%), mp 290–292°C. 1Н NMR spectrum, δ, ppm:
7.11 t (1H, H2, J 7 Hz), 7.67 t (1H, H3, J 7.5 Hz), 7.78 d
(1H, H4, J 9 Hz), 8.20 d.d (1H, H8, J 2.0, 8.5 Hz), 8.50 d
(1H, H9, J 8.5 Hz), 8.64 d (1H, H6, J 1.5 Hz), 9.13 d (1H,
H1, J 7 Hz). Mass spectrum, m/z (Irel, %): 213 (100) [M]+,
183 (4), 167 (91), 155 (14), 140 (28), 78 (12), 63 (11),
51 (9). Found, %: С 61.88; H 3.14; N 20.01. С11H7N3.
Calculated, %: C 61.97; H 3.29; N 19.71. M 213.20.
7
4
R2
6
N
R2
N+
5
O
Iа_Ik
O–
IIIа_IIIl
R1 = R2 = R3 = H, R4 = CF3 (а), NO2 (b), CN (c), COOH
(d), CONH2 (e), COОMe (f), COОEt (g); R1 = R2 = H,
R3 = R4 = CN (h); R1 = R2 = Me, R3 = H, R4 = CN (i);
R3 = R4 = CN (j); R1 = R2 = Н, R4 = Me, R3 = CF3 (k);
R1 = R2 = R3 = H, R4 = NН2 (l).
Pyrido[1,2-a]benzimidazole-7-carbonitrile (IIIc).
Yield 0.61 g (96%), mp 242–244°C. 1Н NMR spectrum,
δ, ppm: 7.10 t (1H, H2, J 6.5 Hz), 7.67 t (1H, H3, J 7 Hz),
7.74 d (1H, H4, J 9.5 Hz), 7.75 d (1H, H9, J 8.5 Hz), 8.35 d
(1H, H6, J 1.5 Hz), 8.51 d.d (1H, H8, J 2.0, J 8.5 Hz),
9.15 d (1H, H1, J 6.5 Hz). Mass spectrum, m/z (Irel, %):
193 (100) [M]+, 167 (6), 165 (4), 154 (4), 139 (9), 97 (9),
78 (8), 63 (7), 51 (12), 39 (15). Found, %: С 74.64; H
3.60; N 21.87. С12H7N3. Calculated, %: C 74.61; H 3.64;
N 21.76. M 193.21.
Compound IIIa formed also at the reduction of salt
Ia with FeCl2, but only in the 58% yield. The rest of the
reaction mixture was an intractable mixture of substances.
Therefore further we used for the synthesis of a
wide series of substituted pyrido[1,2-a]benzimidazoles
IIIа–IIIl the reductive intramolecular amination under
the action of SnCl2. All compounds III (save IIIk where
isomers mixture formed) were obtained in high yields,
86–98%, showing that the initial substrate was consumed
only in the formation of the target fused heterocyclic
products.
Pyrido[1,2-a]benzimidazole-7-carboxylic acid
1
(IIId). Yield 0.65 g (93%), mp >300°C. Н NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 5 2013

EFFECT OF REDUCER’S NATURE
775
spectrum, δ, ppm: 7.05 m (1Н, Н2), 7.60 t (1Н, Н3,
J 8.5 Hz), 7.70 d (1Н, Н4, J 9.0 Hz), 7.95 d.d (1Н, Н8,
J 2.0, J 8.0 Hz), 8.35 d (1Н, Н9, J 8.0 Hz), 8.40 d (1Н,
Н6, J 1.0 Hz), 9.10 d (1Н, Н1, J 7.5 Hz), 12.85 s (1Н,
СООН). Mass spectrum, m/z (Irel, %): 212 (100) [M]+,
167 (38), 140 (15), 78 (10), 51 (6). Found, %: С 68.21;
H 3.72; N 13.24. С12H8N2. Calculated, %: C 67.92; H
3.79; N 13.21. M 212.21.
Pyrido[1,2-a]benzimidazole-7-carboxamide (IIIe).
Yield 0.63 g (91%), mp >300°C. 1Н NMR spectrum, δ,
ppm: 7.01 t (1Н, Н2, J 9.0 Hz), 7.30 c (1H, CONH2),
7.56 t (1Н, Н3, J 10.0 Hz), 7.66 d (1Н, Н9, J 9.5 Hz),
7.88 d (1Н, Н4, J 9.5 Hz), 8.06 с (1Н, CONH2), 8.32 d
(1Н, Н8, J 10.0 Hz), 8.38 d (1Н, Н6, J 1.0 Hz), 9.08 d
(1Н, Н1, J 8.5 Hz). Mass spectrum, m/z (Irel, %): 211
(100) [M]+, 167 (94), 140 (30), 78 (40), 63 (37), 51 (33),
39 (24). Found, %: С 68.19; H 4.21; N 20.02. С12H9N3.
Calculated, %: C 68.24; H 4.29; N 19.91. M 211.23.
1Н NMR spectrum, δ, ppm: 7.32 d (1Н, Н3, J 0.5 Hz),
7.64 d.d (1Н, Н8, J 1.5, 8 Hz), 8.24 d (1Н, Н6, J 1.5 Hz),
8.38 d (1Н, Н9, J 8.5 Hz), 8.77 d (1Н, Н1, J 0.5 Hz).
Mass spectrum, m/z (Irel, %): 221 (100) [M]+, 140 (3),
97 (7), 90 (7), 78 (13), 63 (15), 51 (17), 39 (18). Found,
%: С 75.93; H 4.91; N 19.13. С14H11N3. Calculated, %:
C 76.02; H 4.99; N 19.00. M 221.26.
2,4-Dimethylpyrido[1,2-а]benzimidazole-7,8-
dicarbonitrile (IIIj). Yield 0.72 g (89%), mp 298–300°C.
1Н NMR spectrum, δ, ppm: 7.55 d (1Н, Н3, J 0.5 Hz),
8.65 d (1Н, Н6, J 0.5 Hz), 8.92 d (1Н, Н1, J 0.5 Hz), 9.15 d
(1Н, Н9, J 0.5 Hz). Mass spectrum, m/z (Irel, %): 246 (100)
[M]+, 97 (7), 77 (13), 65 (14), 51 (17), 39 (41). Found,
%: С 72.98; H 4.14; N 22.85. С15H10N4. Calculated, %:
C 73.15; H 4.09; N 22.76. M 246.27.
4-Methyl-7-(trifluoromethyl)pyrido[1,2-a]
benzimidazole (IIIk). Yield 0.60 g (71%) after recrys-
1
tallization from 2-propanol, mp 107–111°C. Н NMR
Methyl pyrido[1,2-a]benzimidazole-7-carboxylate
(IIIf). Yield 0.65 g (87%), mp 226–228°C. 1Н NMR spec-
trum, δ, ppm: 3.90 s (3Н, СН3), 7.03 t (1Н, Н2, J 7.5 Hz),
7.55 t (1Н, Н3, J 8.5 Hz), 7.68 d (1Н, Н4, J 8.0 Hz),
7.94 d.d (1Н, Н8, J 1.5, 7.5 Hz), 8.37 d (1Н, Н9, J 8.0 Hz),
8.39 (1Н, Н6, J 1.0 Hz), 9.08 d (1Н, Н1, J 7.5 Hz). Mass
spectrum, m/z (Irel, %): 226 (100) [M]+, 195 (86), 167
(74), 140 (31), 78 (34), 63 (29), 51 (37), 39 (22). Found,
%: С 68.97; H 4.34; N 12.42. С13H10N4О2. Calculated,
%: C 69.01; H 4.44; N 12.39. M 226.24.
spectrum, δ, ppm: 2.48 s (3H, СH3), 7.02 t (1H, H2,
J 6.8 Hz), 7.47 d.d (1H, H3, J 6.75, 1.1 Hz), 7.67 d.d (1H,
H8, J 1.5, 8.71 Hz), 8.20 d (1H, H6, J 1.0 Hz), 8.51 d (1H,
H9, J 8.56 Hz), 9.02 d.d (1H, H1, J 6.86, 1.5 Hz). Mass
spectrum, m/z (Irel, %): 250 (100) [M]+, 181 (25), 170
(8), 125 (16), 77 (14), 69 (24), 51 (22), 39 (29). Found,
%: С 62.29; H 3.52; N 11.26. С13H9F3N2. Calculated, %:
C 62.40; H 3.63; N 11.19. M 250.23.
Pyrido[1,2-a]benzimidazol-7-amine (IIIl). Yield
1
0.59 g (97%), mp 180–182°C. Н NMR spectrum, δ,
Ethyl pyrido[1,2-a]benzimidazole-7-carboxylate
1
(IIIg). Yield 0.69 g (88%), mp 179–182°C Н NMR
ppm: 5.1 s (2H, NH2), 6.7 d.d (1H, H8, J 10, 2.0 Hz),
6.82 d (1H, H6, J 1.5 Hz), 6.85 t (1H, H2, J 7.0 Hz),
7.38 t (1H, H3, J 7.5 Hz), 7.47 d (1H, H4, J 10.0 Hz),
7.9 d (1H, H9, J 9.5 Hz), 8.82 d (1H, H1, J 7.0 Hz). Mass
spectrum, m/z (Irel, %): 183 (100) [M]+, 166 (4), 155 (15),
78 (12). Found, %: С 71.98; H 4.63; N 23.15. С11H9N3.
Calculated, %: C 72.13; H 4.92; N 22.95. M 183.21.
spectrum, δ, ppm: 1.38 m (3Н, СН3), 4.35 m (2Н, СН2),
7.02 t (1Н, Н2, J 7.5 Hz), 7.57 t (1Н, Н3, J 8.5 Hz), 7.67 d
(1Н, Н4, J 8.5 Hz), 7.95 d.d (1Н, Н8, J 1.5, 8.0 Hz), 8.35 d
(1Н, Н9, J 8.0 Hz), 8.38 (1Н, Н6, J 1.0 Hz), 9.07 (1Н, Н1,
J 8.0 Hz). Mass spectrum, m/z (Irel, %): 240 (100) [M]+,
195 (58), 167 (56), 140 (26), 78 (41), 63 (32), 51 (34), 39
(26). Found, %: С 69.85; H 4.98; N 11.72. С14H12N2О2.
Calculated, %: C 69.98; H 5.02; N 11.66. M 240.26.
1Н NMR spectra were registered on a spectrometer
Bruker DRX-500 SF (500 MHz) in DMSO-d6–CCl4, in-
ternal reference TMS. Mass spectra were recorded on an
instrument Finnigan MAT INCOS 50, ionizing electrons
energy 70 eV. Elemental analysis was carried out on an
analyzer CHN-1.
Pyrido[1,2-a]benzimidazole-7,8-dicarbonitrile
(IIIh). Yield 0.69 g (96%), mp >300°C. 1Н NMR spec-
trum, δ, ppm: 7.25 m (1Н, Н2), 7.83 m (2Н, Н3,4), 8.61 m
(1Н, Н6), 9.21 d (1Н, Н1, J 8.5 Hz), 9.24 s (1Н, Н9). Mass
spectrum, m/z (Irel, %): 218 (100) [M]+, 164 (8), 140 (6),
78 (10), 63 (12), 51 (19), 39 (35). Found, %: С 71.38; H
2.69; N 25.74. С13H6N4. Calculated, %: C 71.56; H 2.76;
N 25.69. M 218.22.
ACKNOWLEDGMENTS
The study was carried out under the financial support
of the Ministry of Education and Science of the Russian
Federation (Federal targeted program “Scientific and
2,4-Dimethylpyrido[1,2-a]benzimidazole-7-
carbonitrile (IIIi). Yield 0.63 g (86%), mp 213–219°C.
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BEGUNOV et al.
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