Synthesis of 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1H-imidazo-[4,5-b]pyridin-5- yl)-5-oxopyrrolidine-3-carboxylic acids

Article abstract of DOI:10.1134/S1070428007110206

Nitration of 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one gave its 5-nitro derivative which was subjected to alkylation with dimethyl sulfate, diethyl sulfate, and benzyl(dimethyl)phenylammonium chloride. The resulting 1,3-dimethyl-, 1,3-diethyl-, and 1,3-d

Full text of DOI:10.1134/S1070428007110206

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 11, pp. 1706–1709. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © N.N. Smolyar, N.N. Troyan, A.B. Vasilechko, D.A. Lomov, Yu.M. Yutilov, 2007, published in Zhurnal Organicheskoi Khimii, 2007,
Vol. 43, No. 11, pp. 1706–1708.
Synthesis of 1-(1,3-Dialkyl-2-oxo-2,3-dihydro-1H-imidazo-
[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic Acids
N. N. Smolyar, N. N. Troyan, A. B. Vasilechko, D. A. Lomov, and Yu. M. Yutilov†
Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
ul. R. Lyuksemburg 70, Donetsk, 83114 Ukraine
e-mail: smolyar@skif.net
Received September 10, 2006
Abstract—Nitration of 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one gave its 5-nitro derivative which was
subjected to alkylation with dimethyl sulfate, diethyl sulfate, and benzyl(dimethyl)phenylammonium chloride.
The resulting 1,3-dimethyl-, 1,3-diethyl-, and 1,3-dibenzyl-5-nitro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-
ones were reduced to the corresponding 1,3-dialkyl-5-amino-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones,
and the latter reacted with itaconic acid to produce 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-
5-yl)-5-oxopyrrolidine-3-carboxylic acids. 1-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrroli-
dine-3-carboxylic acid was obtained by analogous reaction with 5-amino-2,3-dihydro-1H-imidazo[4,5-b]-
pyridin-2-one.
DOI: 10.1134/S1070428007110206
pounds with a view to study their pharmacological
properties and develop medical agents and drug com-
positions based thereon.
1-Substituted 5-oxopyrrolidine-3-carboxylic acids
were synthesized previously from various aryl(aryl-
alkyl)amines and itaconic acid [2]. We believe it to be
reasonable to examine the reaction of itaconic acid
with heterocyclic amines, in particular with 1,3-dial-
kyl-5-amino-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-
In the recent years, derivatives of imidazo[4,5-b]-
pyridine, which can be regarded as a purine analog,
attract increasing interest. Some of these compounds
were found to exhibit antiviral, cytostatic, antimicro-
bial, fungicide, cardiovascular, and antisecretory activ-
ity, as well as properties of angiotensin II antagonists
[1]. Versatile and pronounced biological activity of
imidazo[4,5-b]pyridine derivatives has stimulated
search for new methods of synthesis of these com-
Scheme 1.
R
H
H
N
N
N
HNO3/H2SO4
RX
O
O
O
N
N
H
N
N
O2N
N
O2N
N
H
R
Ia
Ib–Id
R
R
N
N
O
N2H4 ·H2O
HOCOC(=CH2)CH2COOH
O
O
Ia–Id
N
N
N
N
H2N
N
R
HO
R
O
IIa–IId
IIIa–IIId
R = H (a), Me (b), Et (c), Bzl (d).
†
Deceased.
1706

SYNTHESIS OF 1-(1,3-DIALKYL-2-OXO-2,3-DIHYDRO-1H-IMIDAZO-...
1707
ones and their 1,3-unsubstituted analog. New com-
pounds obtained in such a way could attract interest
from the viewpoint of biological activity, for their
molecules contain both imidazo[4,5-b]pyridin-2-one
and 5-oxopyrrolidine-3-carboxylic acid fragments; the
latter may be regarded as cyclic amino acids. This
assumption was based on the fact that some medical
agents whose molecules contain pyrrolidine, 2-oxopyr-
rolidine, and pyrrolidinecarboxylic acid fragments are
effective antibiotics; in addition, they possess other
useful properties [3].
treatment with iodine vapor and by UV irradiation.
2,3-Dihydro-1H-imidazo[4,5-b]pyridin-2-one was syn-
thesized according to the procedure described in [4].
5-Nitro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-
one (Ia). A solution of 13.5 g (10 mmol) of 2,3-di-
hydro-1H-imidazo[4,5-b]pyridin-2-one in 9 ml of con-
centrated sulfuric acid was cooled to 0°C, and 0.55 ml
(12.5 mmol) of concentrated nitric acid (d = 1.5 g/cm3)
was added dropwise under stirring at such a rate that
the temperature did not exceed 5°C. The mixture was
stirred for 1 h, allowed to warm up to 15°C, kept for
2 h at that temperature, and poured onto ice, and the
precipitate was filtered off, washed with cold water
until neutral washings, dried, and recrystallized from
water. Yield 1.47 g (82%), mp 350–353°C; published
As starting compound for the synthesis of 1,3-di-
alkyl-5-nitro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-
ones we used 5-nitro-2,3-dihydro-1H-imidazo[4,5-b]-
pyridin-2-one (Ia) which was prepared in 82% yield by
direct nitration of 2,3-dihydro-1H-imidazo[4,5-b]pyri-
din-2-one with a mixture of concentrated nitric and
sulfuric acids. 1,3-Dialkyl derivatives Ib–Id were ob-
tained by alkylation of nitro compound Ia with dimeth-
yl sulfate, diethyl sulfate, and benzyl(dimethyl)phenyl-
ammonium chloride (Scheme 1). The yields of Ib–Id
1
data [6]: mp 338–339°C. H NMR spectrum
(DMSO-d6), δ, ppm: 7.51 d (1H, 7-H, J = 8.3 Hz),
8.06 d (1H, 6-H, J = 8.3 Hz). Found, %: C 39.78;
H 2.19; N 30.86. C6H4N4O3. Calculated, %: C 40.01;
H 2.24; N 31.04.
1
1,3-Dimethyl-5-nitro-2,3-dihydro-1H-imidazo-
[4,5-b]pyridin-2-one (Ib). Compound Ia, 18 g
(10 mmol), was added under vigorous stirring to
a solution of 8.8 g (0.22 mol) of sodium hydroxide in
180 ml of water, and 21 ml (0.22 mol) of dimethyl
sulfate was then slowly added at room temperature.
After 2 h, the light yellow precipitate was filtered off,
washed with cold water and ethanol–diethyl ether
(1:1), and recrystallized from ethanol. Yield 8.2 g
were 51–81%. Their H NMR spectra contained dou-
blets from the vicinal 6-H (δ 8.04– 8.16 ppm) and 7-H
protons (δ 7.17–7.75 ppm) and signals from the
methyl, ethyl, and benzyl groups on N1 and N3 in the
imidazole ring.
Nitro compounds Ia–Id were reduced to the corre-
sponding 5-amino derivatives IIa–IId by heating in
boiling hydrazine hydrate for 10–14 h. The yields of
IIa–IId were fairly high (74–82%). Compounds IIa–
IId displayed in the 1H NMR spectra doublets from the
vicinal 6-H and 7-H protons, signals from protons in
the alkyl groups on N1 and N3, and a signal at δ 4.26–
5.67 ppm from the amino group.
1
(81%), light yellow solid, mp 277–279°C. H NMR
spectrum (CDCl3), δ, ppm: 3.48 d (6H, 1-CH3, 2-CH3),
7.75 d (1H, 7-H, J = 8.3 Hz), 8.15 d (1H, 6-H, J =
8.3 Hz). Found, %: C 46.00; H 3.79; N 26.75.
C8H8N4O3. Calculated, %: C 46.16; H 3.87; N 26.91.
Aminoimidazo[4,5-b]pyridin-2-ones IIa–IId react-
ed with itaconic acid at 120–125°C (2–3 h) to give 45–
55% of 1-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyri-
din-5-yl)-5-oxopyrrolidine-3-carboxylic (IIIa) and
1-(1,3-dialkyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]-
pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids
IIIb–IIId. The H NMR spectra of IIIa–IIId lacked
signals from NH2 protons, but those belonging to CH2
protons in the pyrrolidine fragment appeared.
1,3-Diethyl-5-nitro-2,3-dihydro-1H-imidazo-
[4,5-b]pyridin-2-one (Ic). Potassium carbonate, 33.2 g
(335 mmol), was added to a solution of 20 g
(133 mmol) of 5-nitro-2,3-dihydro-1H-imidazo[4,5-b]-
pyridin-2-one (Ia) in 150 ml of DMF. The mixture was
stirred for 0.5 h, 40 ml (305 mmol) of diethyl sulfate
was added in portions over a period of 1 h under
vigorous stirring at room temperature, and the mixture
was heated for 14 h at 90–95°C and evaporated under
reduced pressure on a water bath. The dry residue was
extracted with benzene, and the solvent was distilled
off from the extract. Yield 13.5 g (51%), orange solid,
1
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
1
Gemini-200 spectrometer (200 MHz). The purity of
the products was checked by TLC on Silufol UV-254
plates using ethanol as eluent; spots were detected by
mp 117–119°C. H NMR spectrum (CDCl3), δ, ppm:
1.44 t (3H, 1-CH2CH3), 1.47 t (3H, 3-CH2CH3), 4.06 q
(2H, 1-CH2), 4.16 q (2H, 3-CH2), 7.39 d (1H, 7-H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

SMOLYAR et al.
1708
J = 8.3 Hz), 8.16 d (1H, 6-H, J = 8.3 Hz). Found, %:
C 50.68; H 5.06; N 23.55. C10H12N4O3. Calculated, %:
C 50.84; H 5.12; N 23.72.
H 6.78; N 27.01. C10H14N4O. Calculated, %: C 58.24;
H 6.84; N 27.16.
5-Amino-1,3-dibenzyl-2,3-dihydro-1H-imidazo-
[4,5-b]pyridin-2-one (IId). Yield 74%, mp 173–175°C
1,3-Dibenzyl-5-nitro-2,3-dihydro-1H-imidazo-
[4,5-b]pyridin-2-one (Id). A solution of 14.5 g
(58.5 mmol) of benzyl(dimethyl)phenylammonium
chloride in 15 ml of water was added under stirring at
room temperature to a solution of 4.5 g (25 mmol) of
compound Ia in 20% aqueous sodium hydroxide. The
mixture was heated for 7 h at the boiling point and
subjected to steam distillation to remove N,N-dimeth-
ylaniline. After cooling, the orange precipitate was
filtered off, washed with cold water, dried, and treated
with hexane. Yield 7.2 g (80%), mp 178–179°C.
1H NMR spectrum (CDCl3), δ, ppm: 5.17 s (2H,
1-CH2), 5.30 s (2H, 3-CH2), 7.17 d (1H, 7-H, J =
8.3 Hz), 7.37 s (5H, 1-CH2Ph), 7.39 s (5H, 3-CH2Ph),
8.04 d (1H, 6-H, J = 8.3 Hz). Found, %: C 66.45;
H 4.39; N 15.40. C20H16N4O3. Calculated, %: C 66.66;
H 4.47; N 15.55.
1
(from propan-2-ol). H NMR spectrum (CDCl3), δ,
ppm: 4.26 br.s (2H, NH2), 5.04 s (2H, 1-CH2), 5.14 s
(2H, 3-CH2), 6.11 d (1H, 7-H, J = 8.2 Hz), 6.83 d (1H,
6-H, J = 8.2 Hz), 7.30 s (5H, 1-CH2Ph), 7.32 s (5H,
3-CH2Ph). Found, %: C 72.54; H 5.45; N 16.79.
C20H18N4O. Calculated, %: C 72.71; H 5.49; N 16.96.
1-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-
5-yl)-5-oxopyrrolidine-3-carboxylic acids IIIa–IIId
(general procedure). A mixture of 10 mmol of com-
pound IIa–IId and 10 mmol of itaconic acid was
heated for 2–3 h at 120–125°C. The resulting melt was
dissolved in alcohol, the solution was cooled, and the
precipitate was filtered off, dried, and recrystallized
from appropriate solvent.
5-Oxo-1-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]-
pyridin-5-yl)pyrrolidine-3-carboxylic acid (IIIa).
1
Yield 46%, mp > 250°C (from propan-1-ol). H NMR
5-Amino-2,3-dihydro-1H-imidazo[4,5-b]pyridin-
2-ones IIa–IId (general procedure). A mixture of
25 mmol of nitro compound Ia–Id and 30 ml of
hydrazine hydrate was heated for 14 h at 115–120°C in
a stream of argon. Excess hydrazine hydrate was dis-
tilled off, the residue was dissolved in water, the solu-
tion was cooled, and the precipitate was filtered off
and recrystallized from appropriate solvent.
spectrum (CD3COOD), δ, ppm: 2.13 s (2H, 4-H),
3.30–3.45 m (1H, 3-H), 4.31 q (2H, 2-H), 7.47 d (1H,
7′-H, J = 8.6 Hz), 7.93 d (1H, 6′-H, J = 8.6 Hz).
Found, %: C 50.20; H 3.76; N 21.23. C11H10N4O4. Cal-
culated, %: C 50.38; H 3.84; N 21.38.
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo-
[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic
acid (IIIb). Yield 55%, mp 212–214°C (from propan-
2-ol). 1H NMR spectrum (CDCl3), δ, ppm: 2.16 s (2H,
4-H), 3.20–3.31 m (1H, 3-H), 3.42 s (6H, 1′-CH3,
3′-CH3), 4.40 q (2H, 2-H), 7.24 d (1H, 7′-H, J =
8.5 Hz), 8.11 d (1H, 6′-H, J = 8.5 Hz). Found, %:
C 53.51; H 4.79; N 19.12. C13H14N4O4. Calculated, %:
C 53.79; H 4.86; N 19.30.
5-Amino-2,3-dihydro-1H-imidazo[4,5-b]pyridin-
2-one (IIa). Yield 80%, mp 312–314°C (from water).
1H NMR spectrum (DMSO-d6), δ, ppm: 4.32 br.s (2H,
NH2), 6.13 d (1H, 7-H, J = 8.1 Hz), 6.99 d (1H, 6-H,
J = 8.1 Hz). Found, %: C 47.79; H 3.99; N 37.14.
C6H6N4O. Calculated, %: C 48.00; H 4.03; N 37.32.
5-Amino-1,3-dimethyl-2,3-dihydro-1H-imidazo-
[4,5-b]pyridin-2-one (IIb). Yield 83%, mp 233–235°C
(from propan-2-ol); published data [7]: mp 233–
234°C. 1H NMR spectrum (DMSO-d6), δ, ppm: 3.29 d
(6H, 1-CH3, 3-CH3), 6.19 d (1H, 7-H, J = 8.2 Hz),
7.24 d (1H, 6-H, J = 8.2 Hz). Found, %: C 53.71;
H 5.59; N.23. C8H10N4O. Calculated, %: C 53.92;
H 5.66; N 31.44.
1-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-imidazo-
[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic
acid (IIIc). Yield 49%, mp 135–137°C (from propan-
1
2-ol). H NMR spectrum (CDCl)3, δ, ppm: 1.37 t (6H,
1′-CH2CH3, 3′-CH2CH3), 2.15 s (2H, 4-H), 3.22–
3.35 m (1H, 3-H), 3.95 q (4H, 1′-CH2, 3′-CH2), 4.35 q
(2H, 2-H), 6.26 d (1H, 7′-H, J = 8.0 Hz), 7.08 d (1H,
6′-H, J = 8.0 Hz). Found, %: C 56.41; H 5.66; N 17.44.
C15H18N4O4. Calculated, %: C 56.60; H 5.70; N 17.60.
5-Amino-1,3-diethyl-2,3-dihydro-1H-imidazo-
[4,5-b]pyridin-2-one (IIc). Yield 77%, mp 135–137°C
1-(1,3-Dibenzyl-2-oxo-2,3-dihydro-1H-imidazo-
[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic
acid (IIId). Yield 45%, mp 213–215°C (from ethanol).
1H NMR spectrum (CDCl3), δ, ppm: 2.17 t (2H, 4-H),
3.30–3.45 m (1H, 3-H), 4.38 q (2H, 2-H), 5.10 t (2H,
1′-CH2), 5.17 t (2H, 3′-CH2), 7.06 d (1H, 7′-H, J =
1
(from benzene–heptane, 1:1). H NMR spectrum
(CDCl3), δ, ppm: 1.35 t (3H, 1-CH2CH3), 1.39 t (3H,
3-CH2CH3), 3.91 q (2H, 1-CH2), 3.99 q (2H, 3-CH2),
4.31 br.s (2H, NH2), 6.24 d (1H, 7-H, J = 8.3 Hz),
7.06 d (1H, 6-H, J = 8.3 Hz). Found, %: C 58.05;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

SYNTHESIS OF 1-(1,3-DIALKYL-2-OXO-2,3-DIHYDRO-1H-IMIDAZO-...
1709
3. Mashkovskii, M.D., Lekarstvennnye sredstva (Drugs),
Moscow: Novaya Volna, 2004, vol. 1, pp. 41, 73, 111,
249, 280, 421, 437; vol. 2, pp. 22, 133, 369.
8.4 Hz), 7.32–7.52 m (10H, Harom), 8.00 d (1H, 6′-H,
J = 8.4 Hz). Found, %: C 67.69; H 4.94; N 12.48.
C25H22N4O4. Calculated, %: C 67.86; H 5.01; N 12.66.
4. Yutilov, Yu.M. and Svertilova, I.A., Khim. Geterotsikl.
Soedin., 1976, p. 1277.
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