Synthesis of 2-hetarylimidazo[4,5-d]pyridazine derivatives

Article abstract of DOI:10.1134/S1070428007060164

2-Chloropyridine-3,4-diamine reacted with hetarenecarboxylic acids (pyridine-2-, pyridine-3-, and pyridine-4-carboxylic acids and 6-oxo-1,6-dihydropyridazine-3-carboxylic acid) in polyphosphoric acid at 160-170°C to give the corresponding 2-hetarylimidazo[4,5-c]pyridin-4-ones. Nitration of the latter with a mixture of concentrated nitric and sulfuric acids led to the formation of 2-hetaryl-7-nitroimidazo[4,5-c]pyridin-4-ones which were converted into 2-hetaryl-7-methylimidazo[4,5-d]pyridazin-4-ones by the action of hydrazine hydrate at 140-150°C.

Full text of DOI:10.1134/S1070428007060164

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 6, pp. 897–900. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © N.N. Smolyar, D.A. Lomov, Yu.M. Yutilov, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 6, pp. 898–901.
Synthesis of 2-Hetarylimidazo[4,5-d]pyridazine Derivatives
N. N. Smolyar, 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 June 27, 2005
Abstract—2-Chloropyridine-3,4-diamine reacted with hetarenecarboxylic acids (pyridine-2-, pyridine-3-, and
pyridine-4-carboxylic acids and 6-oxo-1,6-dihydropyridazine-3-carboxylic acid) in polyphosphoric acid at
160–170°C to give the corresponding 2-hetarylimidazo[4,5-c]pyridin-4-ones. Nitration of the latter with a mix-
ture of concentrated nitric and sulfuric acids led to the formation of 2-hetaryl-7-nitroimidazo[4,5-c]pyridin-4-
ones which were converted into 2-hetaryl-7-methylimidazo[4,5-d]pyridazin-4-ones by the action of hydrazine
hydrate at 140–150°C.
DOI: 10.1134/S1070428007060164
Some imidazo[4,5-d]pyridazine derivatives were
found to exhibit strong antithrombotic, cardiotonic,
and antioxidant activity [1–3]. The existing methods
for the synthesis of imidazo[4,5-d]pyridazines are
based on cyclizations of 4,5-diaminopyridazines with
formic acid, formamide, and triethyl orthoformate
[4, 5]. Substituted imidazo[4,5-d]pyridazines were also
obtained by reaction of 4,5-diaminopyridazines with
aromatic aldehydes in nitrobenzene or with arenecar-
boxylic acids in polyphosphoric acid (PPA) [2, 3, 6].
Cyclization of 2-substituted diethylimidazo[4,5-d]-
pyridazines with aromatic aldehydes or compounds
having an activated methyl group in the presence of
elemental sulfur was reported to lead to analogous
results [7].
While continuing our studies in the field of syn-
thesis of substituted imidazo[4,5-d]pyridazines [7], we
tried to obtain 2-hetarylimidazo[4,5-d]pyridazine
derivatives by analogy with the transformation of
fused 5-nitropyridin-2-ones by the action of hydrazine
hydrate, which was revealed by us previously [8]. The
corresponding fused 5-nitropyridin-2-ones were syn-
thesized from 2-chloropyridine-3,4-diamine (I) and
pyridine-2-, pyridine-3-, and pyridine-4-carboxylic and
6-oxo-1,6-dihydropyridazine-3-carboxylic acids IIa–
IId, followed by nitration with a mixture of concen-
Scheme 1.
NO2
H
N
H
N
NH2
PPA, Δ
HNO3
Ht
Ht
+
Ht–COOH
N
HN
HN
N
N
NH2
Cl
O
O
IVa–IVd
I
IIa–IId
IIIa–IIId
Me
H
N
N
N2H4 ·H2O, Δ
Ht
HN
N
O
Va–Vd
Ht = 2-pyridyl (a), 3-pyridyl (b), 4-pyridyl (c), 6-oxo-1,6-dihydropyridazin-3-yl (d).
†
Deceased.
897

SMOLYAR et al.
898
Scheme 2.
NH2
H
N
H
N
N2H4 ·H2O, Δ
O
O
HN
HN
N
N
N
NH
N
NH
O
O
IIId
VI
trated sulfuric and nitric acids (Scheme 1). The reac-
tion of 2-chloropyridine-3,4-diamine (I) with hetarene-
carboxylic acids IIa–IId in polyphosphoric acid at
160–170°C (4 h) led to closure of imidazole ring and
was accompanied by acid hydrolysis with replacement
of the chlorine atom by oxo group. The 1H NMR spec-
tra of 2-hetarylimidazo[4,5-c]pyridin-4-ones IIIa–IIId
thus formed contained two doublets from the vicinal
6-H and 7-H protons in the pyridine fragment and
signals from protons in the hetaryl substituent. Com-
pounds IIIa–IIId showed in IR spectra carbonyl ab-
sorption at 1650–1670 cm–1.
EXPERIMENTAL
1
The H NMR spectra were recorded from solutions
in DMSO-d6, CD3COOD, and pyridine-d5 on a Varian
Gemini-200 spectrometer (200 MHz) using hexa-
methyldisiloxane as internal reference. The IR spectra
were obtained on a UR-20 spectrometer from samples
dispersed in mineral oil and on a Specord 75 IR instru-
ment from samples prepared as KBr pellets. The purity
of the products was checked by TLC on Silufol UV-
254 plates using alcohol and chloroform as eluents;
spots were visualized under UV light or by treatment
with iodine vapor. 2-Chloropyridine-3,4-diamine (I)
was synthesized according to the procedure reported in
[12]. The synthesis of 6-oxo-1,6-dihydropyridazine-3-
carboxylic acid (II) was described in [13].
Oxoimidazopyridines IIIa–IIId were subjected to
nitration with a mixture of concentrated nitric and sul-
furic acids according to the procedure reported in [9].
1
The H NMR spectra of the nitration products, 2-het-
2-Hetarylimidazo[4,5-c]pyridin-4-ones IIIa–IIId
(general procedure). Polyphosphoric acid, 6 ml, was
added to a mixture of 5.0 mmol of compound I and
5 mmol of acid IIa–IId, and the mixture was heated
for 4 h at 160–170°C, cooled, diluted with 15–20 ml of
water, and neutralized with ammonium carbonate. The
precipitate was filtered off, dried, and recrystallized
from appropriate solvent.
aryl-7-nitroimidazo[4,5-c]pyridin-4-ones IVa–IVd,
displayed a singlet from the 6-H proton at δ 8.58–
9.01 ppm and signals from protons in the hetaryl
substituent. In the IR spectra of IVa–IVd, absorption
bands due to stretching vibrations of the carbonyl and
nitro groups were present.
Nitro compounds IVa–IVd underwent recycliza-
tion into 7-methyl-2-hetarylimidazo[4,5-d]pyridazin-4-
one derivatives Va–Vd on heating with excess hydra-
zine hydrate for 3–4 h at 140–150°C. In the reaction
with compound IVd, the transformation of the pyridine
fragment into pyridazine was accompanied by intro-
duction of an amino group into the 4-position of the
pyridazine fragment attached to the imidazole ring.
Analogous amination (cf. [10]) occurred when com-
pound IIId was heated with hydrazine hydrate; as a re-
sult, 2-(5-amino-6-oxo-1,6-dihydropyridazin-3-yl)imid-
azo[4,5-c]pyridin-4-one (VI) was formed (Scheme 2).
The structure of compounds III–VI was confirmed
by the 1H NMR and IR spectra and elemental analyses.
2-Hetarylimidazo[4,5-d]pyridazine derivatives IVa–
IVd attract interest as potential pharmacologically
active compounds [11]. The procedure described in the
present communication may be regarded as a prepara-
tive method of synthesis of imidazo[4,5-d]pyridazines,
which supplements the existing procedures and ex-
tends their potential.
2-(2-Pyridyl)imidazo[4,5-c]pyridin-4-one (IIIa).
Yield 65%, mp >250°C (decomp., from water). IR
1
spectrum, ν, cm–1: 1650 (C=O). H NMR spectrum
(DMSO-d6), δ, ppm: 6.51 d (1H, 7-H, J = 6.0 Hz),
7.15 t (1H, 5′-H), 7.52 d (1H, 6-H, J = 6.0 Hz), 8.01 t
(1H, 4′-H), 8.26 d (1H, 3′-H, J = 7.0 Hz), 8.72 d (1H,
6-H, J = 7.0 Hz), 11.30 br.s (1H, NH). Found, %:
C 62.08; H 3.74; N 26.25. C11H8N4O. Calculated, %:
C 62.26; H 3.80; N 26.40.
2-(3-Pyridyl)imidazo[4,5-c]pyridin-4-one (IIIb).
Yield 87%, mp >250°C (decomp., from water). IR
1
spectrum, ν, cm–1: 1665 (C=O). H NMR spectrum
(CD3COOD), δ, ppm: 7.08 d (1H, 6-H, J = 6.0 Hz),
7.44 t (1H, 5′-H), 7.77 d (1H, 7-H, J = 6.0 Hz), 8.74 d
(1H, 6′-H, J = 6.0 Hz), 8.83 d (1H, 4′-H, J = 6.0 Hz),
9.41 s (1H, 2′-H). Found, %: C 62.10; H 3.72; N 26.28.
C11H8N4O. Calculated, %: C 62.26; H 3.80; N 26.40.
2-(4-Pyridyl)imidazo[4,5-c]pyridin-4-one (IIIc).
Yield 61%, mp >250°C (decomp., from water). IR
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SYNTHESIS OF 2-HETARYLIMIDAZO[4,5-d]PYRIDAZINE DERIVATIVES
899
1
spectrum, ν, cm–1: 1670 (C=O). H NMR spectrum
(DMSO-d6), δ, ppm: 6.70 d (1H, 7-H, J = 6.0 Hz),
7.30 d (1H, 6-H, J = 6.0 Hz), 8.15 d (2H, 2′-H, 6′-H,
J = 7.0 Hz), 8.81 d (2H, 3′-H, 5′-H, J = 7.0 Hz),
11.45 br.s (1H, NH). Found, %: C 62.12; H 3.75;
N 26.22. C11H8N4O. Calculated, %: C 62.26; H 3.80;
N 26.40.
7-Nitro-2-(4-pyridyl)imidazo[4,5-c]pyridin-4-one
(IVc). Yield 48%, mp >250°C (decomp., from water).
IR spectrum, ν, cm–1: 1660 (C=O), 1535 (NO2, sym.),
1
1355 (NO2, asym.). H NMR spectrum (pyridine-d5),
δ, ppm: 8.20 d (2H, 2′-H, 6′-H, J = 7.0 Hz), 8.85 d
(2H, 3′-H, 5′-H, J = 7.0 Hz), 9.01 s (1H, 6-H). Found,
%: C 51.23; H 2.70; N 27.06. C11H7N5O3. Calculated,
%: C 51.39; H 2.74; N 27.24.
2-(6-Oxo-1,6-dihydropyridazin-3-yl)imidazo-
[4,5-c]pyridin-4-one (IIId). Yield 72%, mp >300°C
(decomp., from water). IR spectrum, ν, cm–1: 1650–
7-Nitro-2-(6-oxo-1,6-dihydropyridazin-3-yl)-
imidazo[4,5-c]pyridin-4-one (IVd). Yield 63%,
mp >300°C (decomp., from water). IR spectrum, ν,
cm–1: 1660 (C=O), 1535 (NO2, sym.), 1355 (NO2,
asym.). 1H NMR spectrum (DMSO-d6), δ, ppm: 7.05 d
(1H, 4′-H, J = 9.9 Hz), 8.16 d (1H, 5′-H, J = 9.9 Hz),
8.58 s (1H, 6-H), 12.41 br.s (1H, 5-H), 13.48 br.s (1H,
1′-H). Found, %: C 43.62; H 2.15; N 30.51. C10H6N6O4.
Calculated, %: C 43.80; H 2.21; N 30.65.
1
1660 (C=O). H NMR spectrum (DMSO-d6), δ, ppm:
6.51 d (1H, 7-H, J = 6.3 Hz), 7.12 d (1H, 4′-H, J =
9.6 Hz), 7.25 d (1H, 6-H, J = 6.3 Hz), 8.19 d (1H,
5′-H, J = 9.6 Hz), 11.28 br.s (1H, 5-H), 13.31 br.s
(1H, 1′-H), 13.55 br.s (1H, 1-H). Found, %: C 52.24;
H 3.03; N 30.41. C10H7N5O2. Calculated, %: C 52.40;
H 3.08; N 30.56.
2-Hetaryl-7-methylimidazo[4,5-d]pyridazin-4-
ones Va–Vd (general procedure). A mixture of
1.2 mmol of nitro compound IVa–IVd and 24 mmol
of hydrazine hydrate was heated for 3–4 h at 140–
150°C. Excess hydrazine hydrate was distilled off
together with water, and traces of the latter were
removed by azeotrope distillation with benzene or
toluene. The solid residue was recrystallized from ap-
propriate solvent.
2-Hetaryl-7-nitroimidazo[4,5-c]pyridin-4-ones
IVa–IVd (general procedure). Compound IIIa–IIId,
1.5 mmol, was dissolved on cooling (~10°C) in 3.6 ml
of concentrated sulfuric acid, the solution was cooled
to 5°C, and a solution of 0.75 ml of concentrated nitric
acid (d = 1.5 g/cm3) in 0.5 ml of concentrated sulfuric
acid was added dropwise. After 0.5–1.0 h, the mixture
was gradually warmed up to 50–60°C, kept for 2 h at
that temperature, cooled, and poured onto ice. The
precipitate (compound IVc) was filtered off, washed
with a small amount of cold water until neutral
washings, and dried. Compound IVa separated when
the solution was adjusted to pH 3–4. Nitro compounds
IVb and IVd were isolated by neutralization of the
solution with ammonium carbonate. Compounds IVa–
IVd were purified by recrystallization from water.
7-Methyl-2-(2-pyridyl)imidazo[4,5-d]pyridazin-
4-one (Va). Yield 55%, mp >250°C (decomp., from
propan-1-ol). IR spectrum, ν, cm–1: 1665 (C=O).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.57 s (3H,
CH3), 7.56 t (1H, 5′-H), 8.05 t (1H, 4′-H), 8.29 d (1H,
3′-H, J = 7.0 Hz), 8.79 d (1H, 6′-H, J = 7.0 Hz),
12.45 br.s (1H, 5-H). Found, %: C 58.01; H 3.93;
N 30.65. C11H9N5O. Calculated, %: C 58.15; H 4.00;
N 30.82.
7-Nitro-2-(2-pyridyl)imidazo[4,5-c]pyridin-4-one
(IVa). Yield 51%, mp 180–182°C (from water). IR
spectrum, ν, cm–1: 1660 (C=O), 1530 (NO2, sym.),
7-Methyl-2-(3-pyridyl)imidazo[4,5-d]pyridazin-
4-one (Vb). Yield 50%, mp >250°C (decomp., from
1
1355 (NO2, asym.). H NMR spectrum (DMSO-d6), δ,
1
ethanol). IR spectrum, ν, cm–1: 1665 (C=O). H NMR
ppm: 7.25 t (1H, 5′-H), 8.10 t (1H, 4′-H), 8.58 d (1H,
3′-H, J = 7.0 Hz), 8.62 d (1H, 6′-H, J = 7.0 Hz), 8.92 s
(1H, 6-H). Found, %: C 51.27; H 2.69; N 27.09.
C11H7N5O3. Calculated, %: C 51.39; H 2.74; N 27.24.
spectrum (DMSO-d6), δ, ppm: 2.57 s (3H, CH3), 7.55 d
(1H, 5′-H, J = 8.0 Hz), 8.60 d (1H, 4′-H, J = 8.0 Hz),
8.72 d (1H, 6′-H, J = 8.0 Hz), 9.40 s (1H, 2′-H),
12.45 br.s (1H, 5-H). Found, %: C 57.98; H 3.95;
N 30.67. C11H9N5O. Calculated, %: C 58.15; H 4.00;
N 30.82.
7-Nitro-2-(3-pyridyl)imidazo[4,5-c]pyridin-4-one
(IVb). Yield 46%, mp >250°C (decomp., from water).
IR spectrum, ν, cm–1: 1660 (C=O), 1535 (NO2, sym.),
1
1355 (NO2, asym.). H NMR spectrum (pyridine-d5),
7-Methyl-2-(4-pyridyl)imidazo[4,5-d]pyridazin-
4-one (Vc). Yield 77%, mp >250°C (decomp., from
propan-2-ol). IR spectrum, ν, cm–1: 1665 (C=O).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.55 s (3H,
CH3), 8.16 d (2H, 2′-H, 6′-H, J = 7.0 Hz), 8.72 d (2H,
δ, ppm: 7.65 t (1H, 4′-H), 8.64 s (1H, 6-H), 8.70 d (1H,
5′-H, J = 7.0 Hz), 8.76 d (1H, 6′-H, J = 7.0 Hz), 9.47 s
(1H, 2′-H). Found, %: C 51.25; H 2.67; N 27.11.
C11H7N5O3. Calculated, %: C 51.39; H 2.74; N 27.24.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 6 2007

SMOLYAR et al.
900
4. Itai, T. and Suzuki, S., Chem. Pharm. Bull., 1960,
3′-H, 5′-H, J = 7.0 Hz), 12.50 br.s (1H, 5-H). Found,
%: C 57.96; H 3.94; N 30.69. C11H9N5O. Calculated,
%: C 58.15; H 4.00; N 30.82.
vol. 8, p. 999.
5. Yanai, M., Kinoshita, T., Takeda, O., Sadaki, H., and
Watanabe, H., Chem. Pharm. Bull., 1970, vol. 18,
p. 1685.
6. Kenji, K., Hiromu, N., Yusho, O., Keizo, T., and Hiro-
hisa, O., J. Heterocycl. Chem., 1984, vol. 21, p. 1249.
7. Gres’ko, S.V., Smolyar, N.N., and Yutilov, Yu.M.,
Russ. J. Org. Chem., 2001, vol. 37, p. 1026.
8. Yutilov, Yu.M. and Svertilova, I.A., Khim. Geterotsikl.
Soedin., 1982, p. 705; Yutilov, Yu.M. and Smo-
lyar, N.N., Khim. Geterotsikl. Soedin., 1984, p. 132;
Yutilov, Yu.M. and Smolyar, N.N., Zh. Org. Khim.,
1986, vol. 22, p. 1793; Yutilov, Yu.M., Smolyar, N.N.,
and Gres’ko, S.V., Russ. J. Org. Chem., 1995, vol. 31,
p. 273; Yutilov, Yu.M. and Svertilova, I.A., Russ. J.
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2004, vol. 40, p. 1015.
2-(5-Amino-6-oxo-1,6-dihydropyridazin-3-yl)-7-
methylimidazo[4,5-d]pyridazin-4-one (Vd). Yield
53%, mp >300°C (decomp., from water). IR spectrum,
1
ν, cm–1: 1660 (C=O). H NMR spectrum (DMSO-d6),
δ, ppm: 2.61 s (3H, CH3), 7.57 br.s (2H, NH2), 7.79 s
(1H, 3′-H), 11.19 br.s (1H, 5-H), 12.71 br.s (1H, 1′-H).
Found, %: C 46.2; H 3.43; N 37.67. C10H9N7O2. Cal-
culated, %: C 46.33; H 3.50; N 37.82.
2-(5-Amino-6-oxo-1,6-dihydropyridazin-3-yl)-
imidazo[4,5-d]pyridin-4-one (VI). Yield 70%,
mp >300°C (decomp., from water). IR spectrum,
1
ν, cm–1: 1650–1660 (C=O). H NMR spectrum
(DMSO-d6), δ, ppm: 6.45 d (1H, 7-H, J = 6.0 Hz),
6.53 s (1H, 4′-H), 7.21 d (1H, 6-H, J = 6.0 Hz),
11.11 br.s (1H, 5-H), 12.85 br.s (2H, 1-H, 1′-H).
Found, %: C 49.03; H 3.25; N 34.28. C10H8N6O2. Cal-
culated, %: C 49.18; H 3.30; N 34.41.
9. Yutilov, Yu.M. and Svertilova, I.A., Russ. J. Org.
Chem., 1999, vol. 35, p. 451.
10. Sing, B., Heterocycles, 1984, vol. 22, p. 1801.
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