Reactions of 1,3-Dialkyl-5-amino-1,3-dihydro-2H-imidazo-[4,5-b]pyridin-2- ones with acetylacetone and ethyl acetoacetate

Article abstract of DOI:10.1134/S1070428009030129

1,3-Dialkyl-5-amino-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones reacted with acetylacetone to give the corresponding 4-(1,3-dialkyl-2-oxo-1,3-dihydro- 2H-imidazo[4,5-b]pyridin-5-ylamino)pent-3-en-2-ones which underwent intramolecular cyclization to 1,3-di

Full text of DOI:10.1134/S1070428009030129

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 3, pp. 421–424. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © N.N. Smolyar, D.A. Lomov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 3, pp. 431–434.
Reactions of 1,3-Dialkyl-5-amino-1,3-dihydro-2H-imidazo-
[4,5-b]pyridin-2-ones with Acetylacetone and Ethyl Acetoacetate
N. N. Smolyar and D. A. Lomov
Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
ul. R. Lyuksemburg 70, Donetsk, 83114 Ukraine
e-mail: smolyar_nik@mail.ru
Received April 23, 2008
Abstract—1,3-Dialkyl-5-amino-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones reacted with acetylacetone to
give the corresponding 4-(1,3-dialkyl-2-oxo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-5-ylamino)pent-3-en-2-
ones which underwent intramolecular cyclization to 1,3-dialkyl-5,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]-
[1,8]naphthyridin-2-ones on heating in polyphosphoric acid or diphenyl ether. Analogous reaction of 1,3-di-
alkyl-5-amino-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones with ethyl acetoacetate led to the formation of
ethyl 3-(1,3-dialkyl-2-oxo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-5-ylamino)but-2-enoates whose cyclization
afforded 1,3-dialkyl-8-hydroxy-7-methyl-1,3-dihydro-2H-imidazo[5,4-b][1,8]naphthyridin-2-ones.
DOI: 10.1134/S1070428009030129
Imidazo[4,5-b]pyridines are the closest structural
analogs of purine which displays diverse biological
activity [1]. Structural analogy between purine and
imidazo[4,5-b]pyridine is also reflected in chemical
and biological properties of the latter. Some imidazo-
[4,5-b]pyridine derivatives were found to possess
a broad spectrum of biological properties, including
herbicidal, bacteriostatic, antiviral, antitumor, and
other kinds of activity [2]. The recent discovery of
antihypertensive agents among compounds of the
imidazo[4,5-b]pyridine series [3] has stimulated again
interest in this heterocyclic system, and efforts have
been made to search for new more effective and selec-
tive medical agents for the treatment of severe hyper-
tension in humans.
[1,2,4]triazolo[4,3-a]pyridine derivatives, which were
found to exhibit analgesic, antiinflammatory, spasmo-
lytic, and morphine-like activity [4]. With a view to
build up new tricyclic heterocyclic systems on the
basis of amino-substituted 1,3-dialkyl-2H-imidazo-
[4,5-b]pyridin-2-ones it seemed worthwhile to study
reactions of the latter with acetylacetone and ethyl
acetoacetate under the Combes and Conrad–Limpach
conditions [5]. These reactions were successfully
applied to the synthesis of derivatives of quinoline,
thienopyridine, thienonaphthyridine, benzothienopyri-
dine, thienopyridopyrimidine, and other heterocyclic
compounds that can be used for the preparation of
potential biologically active substances [6].
The reactions of 1,3-dialkyl-5-amino-2H-imidazo-
[4,5-b]pyridin-2-ones Ia–Ic with acetylacetone at 150–
155°C resulted in the formation of 81–92% of the cor-
responding 4-(1,3-dialkyl-2-oxo-2H-imidazo[4,5-b]pyr-
We previously described tricyclic systems contain-
ing an imidazo[4,5-c]pyridine fragment, namely di-
imidazo[1,2-a:4,5-c]pyridin-2-one and imidazo[4,5-c]-
Scheme 1.
Me
N
R
R
R
Me
O
O
O
N
N
N
+
O
O
O
Me
Me
N
N
N
H2N
N
N
Me
N
N
H
Me
R
R
R
Ia–Ic
IIa–IIc
IIIa–IIIc
R = Me (a), Et (b), PhCH2 (c).
421

SMOLYAR, LOMOV
422
Scheme 2.
OH
N
R
R
EtO
Me
O
O
O
N
N
Ia–Ic
+
O
O
Me
OEt
N
N
N
Me
N
N
H
R
R
IVa–IVc
Va–Vc
R = Me (a), Et (b), PhCH2 (c).
EXPERIMENTAL
idin-5-ylamino)pent-3-en-2-ones IIa–IIc (Scheme 1).
In the H NMR spectra of enamino ketones IIa–IIc,
1
1
The H NMR spectra were recorded on a Varian
Gemini 200 spectrometer at 200 MHz. The purity of
the products was checked by TLC on Silufol UV-254
plates using ethanol as eluent; spots were visualized
under UV light or by treatment with iodine vapor.
Initial 1,3-dialkyl-5-amino-1,3-dihydro-2H-imidazo-
[4,5-b]pyridin-2-ones Ia–Ic were synthesized accord-
ing to the procedure described in [8].
olefinic proton in the side-chain resonated as a singlet
at δ 5.18–5.27 ppm, and the NH signal was located in
the region δ 12.27–13.02 ppm. Heating of enamino
ketones IIa–IIc in polyphosphoric acid at 130–140°C
or in diphenyl ether at 250°C promoted their intra-
molecular cyclization to 1,3-dialkyl-5,7-dimethyl-2-
oxo-2H-imidazo[5,4-b][1,8]naphthyridines IIIa–IIIc
in 47–70% yield. Compounds IIIa–IIIc displayed in
1
4-(1,3-Dialkyl-2-oxo-1,3-dihydro-2H-imidazo-
[4,5-b]pyridin-5-ylamino)pent-3-en-2-ones IIa–IIc
(general procedure). A mixture of 5.76 mmol of com-
pound Ia–Ic and 17 ml (166 mmol) of acetylacetone
was heated for 6–7 h at 150–155°C. Excess acetyl-
acetone was distilled off, and the residue was purified
by recrystallization from appropriate solvent.
the H NMR spectra signals from the methyl group on
C6, alkyl groups on the nitrogen atoms, and protons in
positions 7 and 9 of the imidazonaphthyridine frag-
ment (δ 7.62–7.69 and 8.16–8.19 ppm, respectively).
Likewise, 1,3-dialkyl-5-amino-2H-imidazo[4,5-b]-
pyridin-2-ones Ia–Ic reacted with ethyl acetoacetate at
130–140°C to afford ethyl 3-(1,3-dialkyl-2-oxo-2H-
imidazo[4,5-b]pyridin-5-ylamino)but-2-enoates IVa–
4-(1,3-Dimethyl-2-oxo-1,3-dihydro-2H-imidazo-
[4,5-b]pyridin-5-ylamino)pent-3-en-2-one (IIa).
1
IVc in 61–73% yield (Scheme 2). The H NMR spec-
1
Yield 92%, mp 130–132°C (from decane). H NMR
tra of IVa–IVc contained signals from the side-chain
olefinic proton at δ 4.74–4.75 ppm, and the NH proton
resonated at δ 10.97 ppm. Like ketones IIa–IIc, esters
IVa–IVc underwent intramolecular cyclization on
heating in polyphosphoric acid at 130–140°C or in
diphenyl ether at 250°C. The cyclization was accom-
panied by elimination of ethanol molecule, and the
products were 8-hydroxy-1,3-dialkyl-7-methyl-2H-
imidazo[5,4-b][1,8]naphthyridin-2-ones Va–Vc (yield
spectrum (CDCl3), δ, ppm: 2.16 s (3H, CH3), 2.46 s
(3H, CH3), 3.45 s (3H, 1-CH3), 3.47 s (3H, 3-CH3),
5.27 s (1H, CH), 6.64 d (1H, 7-H, J = 8.3 Hz), 7.17 d
(1H, 6-H, J = 8.3 Hz), 13.02 s (1H, NH). Found, %:
C 59.72; H 6.20; N 21.43. C13H16N4O2. Calculated, %:
C 59.98; H 6.19; N 21.52.
4-(1,3-Diethyl-2-oxo-1,3-dihydro-2H-imidazo-
[4,5-b]pyridin-5-ylamino)pent-3-en-2-one (IIb).
Yield 88%, mp 114–116°C (from petroleum ether).
1H NMR spectrum (CDCl3), δ, ppm: 1.34 t (6H,
CH2CH3), 2.10 s (3H, CH3), 2.41 s (3H, CH3), 3.94 q
(4H, CH2CH3), 5.21 s (1H, CH), 6.60 d (1H, 7-H,
J = 8.1 Hz), 7.13 d (1H, 6-H, J = 8.1 Hz), 12.92 s
(1H, NH). Found, %: C 62.31; H 7.03; N 19.32.
C15H20N4O2. Calculated, %: C 62.47; H 6.99; N 19.42.
1
35–70%). In the H NMR spectra of Va–Vc we ob-
served signals from the C-methyl and N-alkyl groups
and singlets from protons in positions 7 and 9 of the
imidazonaphthyridine fragment at δ 7.97–8.33 and
5.93–6.63 ppm, respectively.
Compounds IIIa–IIIc and Va–Vc contain a naph-
thyridine fragment fused to imidazole ring, and they
attract interest as pharmacologically active substances,
taking into account that some naphthyridine deriva-
tives were found to exhibit diverse biological activity,
including bactericidal, antioxidant, hypotensive, anti-
tuberculous, and other properties [7].
4-(1,3-Dibenzyl-2-oxo-1,3-dihydro-2H-imidazo-
[4,5-b]pyridin-5-ylamino)pent-3-en-2-one (IIc).
Yield 81%, mp 137–138°C (from petroleum ether).
1H NMR spectrum (CDCl3), δ, ppm: 2.09 s (3H, CH3),
2.31 s (3H, CH3), 5.04 s (2H, 1-CH2), 5.11 s (2H,
2-CH2), 5.18 s (1H, CH), 6.48 d (1H, 7-H, J = 8.2 Hz),
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REACTIONS OF 1,3-DIALKYL-5-AMINO-1,3-DIHYDRO-2H-IMIDAZO-...
423
6.93 d (1H, 6-H, J = 8.2 Hz), 7.30 br.s (10H, C6H5),
12.99 s (1H, CH). Found, %: C 72.60; H 5.03;
N 13.42. C25H24N4O2. Calculated, %: C 72.79; H 5.86;
N 13.58.
1H NMR spectrum (CDCl3), δ, ppm: 1.30 t (3H,
OCH2CH3), 2.42 s (3H, CH3), 3.42 s (6H, NCH3),
4.17 q (1H, CH), 6.57 d (1H, 7-H, J = 8.2 Hz), 7.11 d
(1H, 6-H, J = 8.2 Hz), 10.97 s (1H, NH). Found, %:
C 57.79; H 6.21; N 19.15. C14H18N4O3. Calculated, %:
C 57.92; H 6.25; N 19.30.
1,3-Dialkyl-5,7-dimethyl-2-oxo-1,3-dihydro-2H-
imidazo[5,4-b][1,8]naphthyridines IIIa and IIIb
(general procedure). A mixture of 6.29 mmol of
enamino ketone IIa or IIb in 9–10 ml of polyphos-
phoric acid was heated for 3 h 130–140°C. The
resulting dark solution was poured into 40–50 ml of
water and neutralized with ammonium carbonate. The
precipitate was filtered off, washed with a small
amount of cold water, dried, and recrystallized from
appropriate solvent.
Ethyl 3-(1,3-diethyl-2-oxo-1,3-dihydro-2H-imid-
azo[4,5-b]pyridin-5-ylamino)but-2-enoate (IVb).
1
Yield 67%, mp 90–92°C (from heptane). H NMR
spectrum (CDCl3), δ, ppm: 1.32 t (6H, NCH2CH3),
1.36 t (3H, OCH2CH3), 2.42 s (3H, CH3), 3.93 q (4H,
NCH2), 4.21 q (2H, OCH2), 4.75 s (1H, CH), 6.55 d
(1H, 7-H, J = 8.2 Hz), 7.13 d (1H, 6-H, J = 8.2 Hz),
10.67 s (1H, NH). Found, %: C 60.22; H 6.89;
N 17.50. C16H22N4O3. Calculated, %: C 60.35; H 6.97;
N 17.60.
1,3,6,8-Tetramethyl-2-oxo-1,3-dihydro-2H-
imidazo[5,4-b][1,8]naphthyridine (IIIa). Yield 70%,
1
mp >230°C (from water). H NMR spectrum
Ethyl 3-(1,3-dibenzyl-2-oxo-1,3-dihydro-2H-
imidazo[4,5-b]pyridin-5-ylamino)but-2-enoate
(IVc). Yield 73%, mp 80–82°C (from heptane).
1H NMR spectrum (CDCl3), δ, ppm: 1.31 t (3H,
OCH2CH3), 2.36 s (3H, CH3), 4.17 q (2H, OCH2),
4.74 s (1H, CH), 5.08 s (2H, 1-CH2), 5.15 s (2H,
3-CH2), 6.45 d (1H, 7-H, J = 8.2 Hz), 6.95 d (1H, 6-H,
J = 8.2 Hz), 7.35 s (10H, C6H5), 10.97 s (1H, NH).
(CD3COOD), δ, ppm: 2.95 s (6H, 6-CH3, 8-CH3),
3.57 s (6H, 1-CH3, 3-CH3), 7.63 s (1H, 7-H), 8.16 s
(1H, 9-H). Found, %: C 64.30; H 5.80; N 23.00.
C13H14N4O. Calculated, %: C 64,44; H 5.82; N 23.13.
1,3-Diethyl-6,8-dimethyl-2-oxo-1,3-dihydro-2H-
imidazo[5,4-b][1,8]naphthyridine (IIIb). Yield 45%,
1
mp 112–115°C (from water). H NMR spectrum
(CD3COOD), δ, ppm: 1.47 s (6H, CH3), 3.00 s (6H,
6-CH3, 8-CH3), 4.20 q (4H, NCH2), 7.69 s (1H, 7-H),
8.19 s (1H, 9-H). Found, %: C 66.52; H 6.65; N 20.58.
C15H18N4O. Calculated, %: C 64.64; H 6.71; N 20.72.
8-Hydroxy-1,3,6-trimethyl-1,3-dihydro-2H-imid-
azo[5,4-b][1,8]naphthyridin-2-one (Va) was synthe-
sized as described above for compound IIIa from
6.29 mmol of enamino ester IVa in 9–10 ml of poly-
phosphoric acid. Yield 70%, mp 256–257°C (from
1,3-Dibenzyl-6,8-dimethyl-2-oxo-1,3-dihydro-
2H-imidazo[5,4-b][1,8]naphthyridine (IIIc). A mix-
ture of 7 ml of diphenyl ether and 2.4 mmol of en-
amino ketone IIc was heated for 30 min at 250–255°C.
The mixture was cooled, 50–60 ml of petroleum ether
(bp 60–80°C) was added, and the precipitate was fil-
tered off, dried, and recrystallized from toluene. Yield
65%, mp 130–132°C. 1H NMR spectrum (CD3COOD),
δ, ppm: 2.92 s (6H, 6-CH3, 8-CH3), 5.27 s (4H, NCH2),
7.34 s (10H, C6H5), 7.62 s (1H, 7-H), 8.17 s (1H, 9-H).
Found, %: C 76.01; H 5.58; N 14.04. C25H22N4O. Cal-
culated, %: C 76.11; H 5.62; N 14.20.
1
water). H NMR spectrum (CD3COOD), δ, ppm:
2.58 s (3H, CH3), 3.40 s (3H, 1-CH3), 3.52 s (3H,
3-CH3), 6.63 s (1H, 9-H), 8.25 s (1H, 7-H). Found, %:
C 59.82; H 4.90; N 22.80. C12H12N4O2. Calculated, %:
C 59.01; H 4.95; N 22.94.
1,3-Diethyl-8-hydroxy-6-methyl-1,3-dihydro-2H-
imidazo[5,4-b][1,8]naphthyridin-2-one (Vb) was
synthesized in a similar way from 6.29 mmol of
enamino ester IVb in 9–10 ml of polyphosphoric acid.
1
Yield 35%, mp 294–296°C (from water). H NMR
spectrum (CD3COOD), δ, ppm: 1.40 t (6H,
NCH2CH3), 2.58 s (3H, CH3), 4.09 q (4H, NCH2),
6.61 s (1H, 9-H), 8.33 s (1H, 7-H). Found, %: C 61.60;
H 5.86; N 20.42. C14H16N4O2. Calculated, %: C 61.75;
H 5.92; N 20.58.
Ethyl 3-(1,3-dialkyl-2-oxo-1,3-dihydro-2H-imid-
azo[4,5-b]pyridin-5-ylamino)but-2-enoates IVa–IVc
(general procedure). A mixture of 5.62 mmol of com-
pound Ia–Ic and 7–8 ml of ethyl acetoacetate was
heated for 6–7 h at 140–150°C. Excess ethyl aceto-
acetate was distilled off under reduced pressure, and
the residue was purified by recrystallization.
1,3-Dibenzyl-8-hydroxy-7-methyl-1,3-dihydro-
2H-imidazo[5,4-b][1,8]naphthyridin-2-one (Vc) was
synthesized as described above for compound IIIb
from 2.4 mmol of enamino ester IVc in 7 ml of di-
phenyl ether. Yield 66%, mp >300°C (from decane).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.60 s (3H,
Ethyl 3-(1,3-dimethyl-2-oxo-1,3-dihydro-2H-
imidazo[4,5-b]pyridin-5-ylamino)but-2-enoate
(IVa). Yield 61%, mp 149–151°C (from heptane).
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SMOLYAR, LOMOV
424
4. Yutilov, Yu.M. and Khabarov, K.M., USSR Inventor’s
Certificate no. 891671, 1981; Byull. Izobret., 1981,
no. 47; Yutilov, Yu.M., Khabarov, K.M., and Svertilo-
va, I.A., USSR Inventor’s Certificate no. 1123270, 1984;
Byull. Izobret., 1997, no. 7; Khabarov, K.M., Yuti-
lov, Yu.M., Filippov, I.T., Komissarov, I.V., and Sverti-
lova, I.A., USSR Inventor’s Certificate no. 1094303,
1987; Byull. Izobret., 1987, no. 48; Yutilov, Yu.M.,
Komissarov, I.V., Khabarov, K.M., and Filippov, I.T.,
USSR Inventor’s Certificate no. 1010846, 1982; Byull.
Izobret., 1987, no. 34.
CH3), 5.10 s (4H, NCH2), 5.93 s (1H, 9-H), 7.35 s
(10H, C6H5), 7.97 s (1H, 7-H), 11.86 s (1H, NH).
Found, %: C 72.60; H 5.03; N 14.00. C24H20N4O2. Cal-
culated, %: C 72.71; H 5.09; N 14.13.
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