Simple synthesis of substituted benzo[4,5]imidazo[1,2-a]pyridines

Full text of DOI:10.1007/s11178-005-0082-5

Russian Journal of Organic Chemistry, Vol. 40, No. 11, 2004, pp. 1694 -1696. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 11,
2
004, pp. 1740-1742.
Original Russian Text Copyright Ó 2004 by Begunov, Ryzvanovich, Firgang.
SHORT
COMMUNICATIONS
Simple Synthesis of Substituted Benzo[4,5]imidazo[1,2-a]pyridines
1
1
2
R.S. Begunov , G.A.Ryzvanovich , and S.I.Firgang
1Demidov Yaroslavl' State University, Yaroslavl',150000 Russia
e-mail: begunov@bio.uniyar.ac.ru
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow
2
Received December 12, 2003
Pyridine series compounds attract traditionally great
interest. Their application field is extremely wide: dyes
manufacturing, agriculture, veterinary medicine,
pharmacology [1–3]. A special place take here the fused
pyridine derivatives. A large number of drugs belongs to
this class: quinine, desoxypeganine, enteroseptol,
echinopsin etc. [4]. Therefore a development of new
highly selective procedures for fused puridine derivatives
preparation is an urgent task.
synthesis of substituted benzo[4,5]imidazo-[1,2-a]-
pyridines consists in condensation of benzene 1-chloro-
2-nitro derivatives with 2-aminopyridine [5].
The reaction proceeds under relatively stringent
conditions (190°C, 2–3 h) unsuitable for the synthesis of
medicinals [12].
The procedure based on reductive cyclization of
N-(2,4-dinitrophenyl)pyridine chloride was not widely
used because of low yield of the final products and side
processes.Application of Pt/C or Pd/C as reducing agents
resulted in formation of 8-amino-1,2,3,4-tetrahydro-
benzo[4,5]-imidazo[1,2-a]pyridine [13].
Benzo[4,5]imidazo[1,2-a]pyridines were obtained at
the use of phenylhydrazine as cyclizing agent (boiling in
acetic acid for 2 h). However the reaction under the
mentioned conditions was accompanied with side
processes giving a considerable amount of products and
consequently reducing the yield of the target compounds
(29–53%) [13].
Aiming at development of a new highly selective
procedure for preparation of substituted benzo[4,5]-
imidazo[1,2-a]pyridines we carried out a search for a
convenient cyclizing agent. Its role was played by tin(II)
chloride in the presence of 3% HCl. We had preliminary
prepared N-(2-nitro-4R-phenyl)pyridines (Ia–c) by
reaction of pyridine with o-nitrohaloarenes. The nitro
group in the o-position of the pyridine ring in the
compounds obtained was converted by reduction into an
amino group, and then a cyclization occurred resulting
from a nucleophilic attack of the amino group on the a-
carbon in the pyridine ring. Thanks to the use of tin(II)
chloride as reductant the cyclization occurred at room
temperature within 5–10 min. Yields of the final reaction
In [5–7] various methods are described for preparation
of substituted benzo[4,5]imidazo[1,2-a]-pyridines
possessing a biological activity [8, 9] and fluorescence
properties [10, 11]. However the existing procedures have
significant disadvantages: application of expensive
reagents, high temperature of the process, a low yield of
the final products. The most common procedure of the
1070-4280/04/4011-1694Ó2004 MAIK “Nauka/Interperiodica”

SIMPLE SYNTHESIS OF SUBSTITUTED BENZO[4,5]IMIDAZO[1,2-À]PYRIDINES
1695
products attained 91–98%. Inasmuch as in the N-(2,4-
Compounds IIb, c were obtained in a similar way.
dinitrophenyl)-pyridine chloride molecule two nitro groups
were present, at careful dosage of the reducing agent
we succeeded in preparation both of 8-nitro- and 8-
aminobenzo[4,5]imidazo[1,2-a]-pyridines (IIb, d). The
primary reduction of the nitro group located in the o-
position is due to assistance of a positively charged
substituent [14].
8
-Nitrobenzo[4,5]imidazo[1,2-a]pyridine (IIb).
1
Yield 3.44 g (91%), mp 290–292°C. H, d, ppm: 9.13 d
1H, H , J 7 Hz), 8.64 d (1H, H , J 1.5 Hz), 8.50 d (1H,
H , J 8.5 Hz), 8.20 d.d (1H, H , J 8.5, 2 Hz), 7.78 d (1H,
H , J 9 Hz), 7.67 t (1H, H , J 7.5 Hz), 7.11 t (1H, H ,
J 7 Hz). Mass spectrum, m/z (I , %): 213 (100) [M] ,
83 (4), 167 (91), 155 (14), 140 (28), 78 (12). Found, %:
4
9
(
6
7
1
2
3
+
rel
1
C 61.6; H 3.1; N 20.0. C H N O . Calculated, %:
C 62.0; H 3.3; N 19.7.
1
1
7
3
2
&
O
1
ꢀ&O
5
1
5
8
-Cyanobenzo[4,5]imidazo[1,2-a]pyridine (IIc).
1
Yield 3.54 g (96%), mp 242–244°C. H, d, ppm: 9.15 d
1H, H , J 6.5 Hz), 8.51 d.d (1H, H , J 8.5, 2 Hz), 8.35 d
(1H, H , J 1.5 Hz), 7.75 d (1H, H , J 8.5 Hz), 7.74 d (1H,
H , J 9.5 Hz), 7.67 t (1H, H , J 7 Hz), 7.10 t (1H, H ,
2
1
2
1
4
7
(
2
2
9
6
B
,DꢁꢁꢁF
1
2
3
+
J 6.5 Hz). Mass spectrum, m/z (I , %): 193 (100) [M] ,
rel
6
Q&O
167 (4), 165 (4), 154 (4), 139 (4). Found, %: C 74.7;
H 3.6; N 22.0. C H N . Calculated, %: C 74.6; H 3.6;
1
1
2
7
3
1
5
N 21.8.
-Aminobenzo[4,5]imidazo[1,2-a]pyridine (IId).
To a solution of 24 g (0.107 mol) of SnCl ·2H O in 20 ml
8
B
,
,DꢁꢁꢁG
2
2
of 3% hydrochloric acid was added at stirring a solution
g (0.0178 mol) of N-(2,4-dinitrophenyl)pyridinium
5
Hence the application of tin(II) chloride as reducing
agent ensured an easy and fast procedure for preparation
of substituted benzo[4,5]-imidazo[1,2-a]pyridines in high
yields.
chloride in 20 ml of ethanol. In 10 min the reaction mixture
was alkalinized with 25% aqueous ammonia till pH 7–8,
and the reaction product was extracted with several
portions of chloroform (200 ml). On removing the
chloroform we obtained 3.16 g (97%) of 8-amino-
The composition and structure of compounds obtained
1
were proved by elemental analysis, H NMR and mass
1
benzo[4,5]-imidazo[1,2-a]pyridine, mp 180–182°C. H,
spectra.
4
6
d, ppm: 8.82 d (1H, H , J 7 Hz), 7.9 d (1H, H , J 9.5
Compounds Ia–c were obtained by published method
1
2
Hz), 7.47 d (1H, H , J 10 Hz), 7.38 t (1H, H , J 7.5
Hz), 6.85 t (1H, H , J 7 Hz), 6.82 d (1H, H , J 1.5
Hz), 6.7 d.d (1H, H , J 10, 2 Hz), 5.1 s (2H, NH ). Mass
spectrum, m/z (I , %): 183 (100) [M] , 166 (4), 155 (15),
[15].
3
9
8
-(Trifluoromethyl)benzo[4,5]imidazo[1,2-a]-
7
2
pyridine (IIa). Into a flask at vigorous stirring were
charged simultaneously a solution of 5 g (0.016 mol) of
N-(2-nitro-4-trifluoromethylphenyl)-pyridinium chloride in
+
rel
78 (12). Found, %: C 71.9; H 4.5; N 23.3. C H N .
1
1
9
3
Calculated, %: C 72.1; H 4.9; N 23.0.
1H NMR spectra were registered on spectrometer
Bruker DRX-500 at operating frequency 500 MHz from
2
0 ml of ethanol and a solution of 11.13 g (0.048 mol) of
SnCl ·2H O in 20 ml of 3% hydrochloric acid. In 10 min
2
2
the reaction mixture was alkalinized with 25% aqueous
ammonia till pH 7–8, and the reaction product was
extracted with several portions of chloroform (200 ml).
On removing the chloroform we obtained 3.7 g (98%) of
solutions in DMSO-d . Mass spectra were measured on
6
MKh-1310 device. The elemental analyses were carried
out on a CHN-1 analyzer.
1
compound IIa, mp 233–235°C. H, d, ppm: 9.15 d (1H,
REFERENCES
4
7
H , J 7.5 Hz), 8.53 d.d (1H, H , J 8, 2 Hz), 8.16 d (1H,
9
1
6
1. Comprehensive Organic Chemistry, Barton, D. and Ollis,
W.D., Eds., Oxford: Pergamon, 1979, vol. 8, p. 752. Translated
under the title Obshchaya organicheskaya khimiya,
Moscow: Khimiya, 1985, vol. 8, p. 752.
H , J 1.5 Hz), 7.75 d (1H, H , J 9 Hz), 7.68 d (1H, H , J
2
3
8
Hz), 7.66 t (1H, H , J 8 Hz), 7.09 t (1H, H , J 7 Hz).
Mass spectrum, m/z (I , %): 236 (100) [M] , 217 (20),
+
rel
186 (12), 118 (5), 69 (5). Found, %: C 60.7; H 3.3; N 12.0.
C H N F . Calculated, %: C 61.0; H 3.0; N 11.9.
2. Gilchrist, T.L., Heterocyclic Chemistry, Harlow: Longman
1
2
7
2 3
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

1
696
Scientific & Technical, 1992, 2nd ed.
BEGUNOV et al.
9. Maryanoff, B.E., Ho, W., McComsey, D.F., Reitz, A.B.,
Grous, P.P., Nortey, S.O., Shank, R.P., Dubinsky, B., Taylor,
R.J., and Gardocki, J.F., J. Med. Chem., 1995, vol. 38, p. 16.
10. Dhamnaskar, S.V. and Rangnekar, D.W., Dyes and Pigm.,
1988, vol. 9, p. 467.
11. Sabnis, R.W. and Rangnekar, D.W., J. Heterocyclic Chem.,
1990, vol. 27, p. 417.
12. Kost, A.A., Khim. Geterotsikl. Soed., 1980, p. 1200.
13. Osterheld, K., Prajsnar, B., and Hauser, H.J., Chem. Ztg.,
1979, vol. 103, p. 190.
3
. Heterocyclic Compounds, Elderfield, R.C., Ed., New York:
Wiley, 1957, vol. 6. Translated under the title Geterotsikliche-
skie soedineniya, Moscow: Inostr. Lit., 1960, vol. 1, p. 556.
. Mashkovskii, PPM, Medodcones, Moscow: Izd. “Novaya
Volna”, 2000, vol. 1, p. 540, vol. 2, p. 608.
4
5
6
. Morgan, S.G. and Stewart, J., J. Chem. Soc., 1938, p. 1057.
. Volovenko, Yu.M. and Ivanov, V.V., Khim Geterotsikl. Soed.,
1997, p. 1280.
7
. Ramesh, Babu, V.N.S., Narahari, Babu, A., Anand, V., and
Hanumanthu, P., Synth. Commun., 1998, vol. 28, p. 4439.
. Badawey, E. and Kappe, T., Eur. J. Med. Chem., 1995, vol. 30,
p. 327.
14. Uskov, S.I., Bil’kis, I.I., and Shteingarts, V.D., Zh. Org. Khim.,
1991, vol. 27, p. 36.
15. Lipke, Bodo, Z. Chem., 1970, vol. 10, p. 463.
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