Ring transformation of 7-nitro-1-(4-nitrophenyl)-4,5-dihydro-1H-imidazo- and -[1,2,3]triazolo[4,5-c]pyridin-4-ones

Article abstract of DOI:10.1023/B:RUJO.0000045196.50576.d1

Nitration of 1-phenyl-4,5-dihydroimidazo- and -1,2,3-triazolo[4,5-c] pyridin-4-ones initially occurs at the para position of the phenyl ring, and the subsequent nitration yields the corresponding 7-nitro-1-(4-nitrophenyl) derivatives. Treatment of the lat

Full text of DOI:10.1023/B:RUJO.0000045196.50576.d1

Russian Journal of Organic Chemistry, Vol. 40, No. 7, 2004, pp. 1015–1017. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 7, 2004,
pp. 1056–1058.
Original Russian Text Copyright © 2004 by Yutilov, Smolyar, Eres’ko, Gres’ko.
Ring Transformation of 7-Nitro-1-(4-nitrophenyl)-4,5-dihydro-
1H-imidazo- and -[1,2,3]triazolo[4,5-c]pyridin-4-ones
Yu. M. Yutilov, N. N. Smolyar, A. B. Eres’ko, and S. V. Gres’ko
Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
ul. R. Lyuksemburg 70, Donetsk, 83114 Ukraine
e-mail: yutilov@skif.net
Received November 19, 2002
Abstract—Nitration of 1-phenyl-4,5-dihydroimidazo- and -1,2,3-triazolo[4,5-c]pyridin-4-ones initially occurs at the
para position of the phenyl ring, and the subsequent nitration yields the corresponding 7-nitro-1-(4-nitrophenyl)
derivatives. Treatment of the latter with hydrazine hydrate leads to formation of 1-(4-aminophenyl)-7-methyl-4,5-
dihydroimidazo- and -1,2,3-triazolo[4,5-d]pyridazin-4-ones.
It seemed to be interesting to examine the behavior
of the nitration products of 1-phenyl-4,5-dihydro-
imidazo- and -[1,2,3]triazolo[4,5-c]pyridin-4-ones Ia
and Ib in the reaction with hydrazine hydrate. Initial
compounds Ia and Ib were prepared by acid hydrolysis
of 4-chloro-1-phenyl-4,5-dihydroimidazo- and -[1,2,3]-
triazolo[4,5 c]pyridines according to the procedure
described in [6]. However, it remained unclear whether
the nitration of compounds Ia and Ib will occur
initially at position 7 of the pyridine fragment or at
the N1-phenyl group.
We previously reported on a new ring transforma-
tion of fused 5-nitropyridin-2-ones under conditions
of profound hydrazinolysis. For example, the reaction
with 7-nitro-4,5-dihydroimidazo[4,5-c]pyridin-4-one
leads to formation of pyridazine derivative [1, 2]. The
general character of this transformation was demon-
strated with a series of bicyclic 5-nitropyridin-2-ones
having fused imidazole, triazole, benzene, pyridine,
and thiophene rings [2–5]. Apart from high yields of
pyridazine derivatives, a specific feature of this reac-
tion is reduction of one CH group of the pyridine
fragment to methyl. On the basis of experimental data,
a probable mechanism of the ring transformation was
proposed [4]. The discovered reaction considerably
extends preparative potential of the synthesis of dif-
ficultly accessible pyridazine derivatives, e.g., substi-
tuted 1-phenyl-4,5-dihydroimidazo- and -[1,2,3]tri-
azolo[4,5-d]pyridazines.
We have found that treatment of compounds Ia and
Ib with excess nitrating mixture under mild conditions
initially leads to introduction of a nitro group into the
para position of the phenyl ring to give compounds IIa
and IIb; the subsequent nitration of mononitro deriva-
tives IIa and IIb afforded 7-nitro-1-(4-nitrophenyl)-
4,5-dihydroimidazo- and -[1,2,3]triazolo[4,5-c]pyridin-
Scheme 1.
NO2
NO2
NH2
NO2
CH3
N
N
N
N
N
N
N
N
HNO3
HNO3
N2H4 ·H2O
N
X
X
X
X
HN
HN
HN
HN
O
O
O
O
Ia, Ib
IIa, IIb
IIIa, IIIb
IVa, IVb
X = CH (a), N (b).
1070-4280/04/4007-1015 © 2004 MAIK “Nauka/Interperiodica”

YUTILOV et al.
1016
4-ones IIIa and IIIb. The latter products can also be
obtained in fairly high yields by prolonged treatment
of Ia and Ib with excess nitrating mixture. The struc-
ture of the products was confirmed by the IR and
1H NMR spectra.
C12H9N3O·HCl. Calculated, %: C 58.19; H 4.07;
N 16.96.
1-Phenyl-4,5-dihydro[1,2,3]triazolo[4,5-c]pyri-
din-4-one hydrochloride (Ib) was synthesized in
a similar way from 4-chloro-1-phenyl-4,5-dihydro-
[1,2,3]triazolo[4,5-c]pyridine [11]. Yield 98%, mp 267–
Hydrazinolysis of compounds IIIa and IIIb under
conditions analogous to those described in [2] gave
new products which were identified as 1-(4-amino-
phenyl)-7-methyl-4,5-dihydroimidazo- and -[1,2,3]tri-
azolo[4,5 d]pyridazin-4-ones IVa and IVb. Their
1H NMR spectra contain signals from protons of the
C-methyl groups (δ 2.50–2.52 ppm), aromatic protons
of the p-phenylene fragment, and NH protons (δ 5.66–
5.68 ppm). The presence of an aromatic amino group
was confirmed by a distinct color test with sodium
hypobromite and by the absence in the IR spectrum
of absorption bands typical of stretching vibrations of
nitro group.
1
270°C. IR spectrum, ν, cm–1: 1665 (C=O). H NMR
spectrum (CF3COOH), δ, ppm: 7.33 s (5H, 1-Ph),
7.83 d (1H, 7-H, J = 7.0 Hz), 8.28 (1H, 6-H, J =
7.0 Hz). Found, %: C 52.99; H 3.61; N 22.34.
C11H8N4O·HCl. Calculated, %: C 53.13; H 3.65;
N 22.53.
1-(4-Nitrophenyl)-4,5-dihydroimidazo[4,5-c]pyr-
idin-4-one (IIa). Hydrochloride Ia, 1.4 g (5.65 mmol),
was dissolved on stirring and cooling to –5 to 0°C
in 12 ml of concentrated sulfuric acid, 1.12 g
(11.09 mmol) of potassium nitrate was added, and the
mixture was stirred for 2 h at that temperature, allowed
to slowly warm up to room temperature, and poured
onto ice. The precipitate was filtered off, washed with
2-propanol, and dried. Yield 1.0 g (69%), light yellow
crystals, mp > 300ºC. IR spectrum, ν, cm–1: 1355
(NO2, sym.), 1530 (NO2, asym.), 1700 (C=O).
1H NMR spectrum (DMSO-d6), δ, ppm: 6.61 d (1H,
7-H, J = 7.0 Hz), 7.30 d (1H, 6-H, J = 7.0 Hz), 7.91 d
(2H, 2'-H, 6'-H, J = 8.0 Hz), 8.44 d (2H, 3'-H, 5'-H, J =
8.0 Hz), 8.47 s (1H, 2-H), 11.51 s (1H, 5-H). Found,
%: C 56.09; H 3.10; N 21.79. C12H8N4O3. Calculated,
%: C 56.25; H 3.15; N 21.87.
Ring transformation products IVa and IVb attract
interest for pharmacological screening, since some
imidazo[4,5-d]pyridazine derivatives were found to
exhibit clearly pronounced cardiotonic, antithrombotic,
antioxidant, and mycostatic activity [7–10].
EXPERIMENTAL
The 1H NMR spectra were recorded on a Telsa BS-
467C spectrometer (80 MHz) in CF3COOH, as well as
on a Gemini-200 instrument (200 MHz), in acetone-d6
and DMSO-d6, using HMDS as internal reference. The
IR spectra were measured on a UR-20 spectrometer
from samples dispersed in mineral oil. The purity of
the products was checked by TLC on Silufol UV-254
plates using alcohol as eluent; spots were visualized
under UV light or by treatment with iodine vapor.
1-(4-Nitrophenyl)-4,5-dihydro[1,2,3]triazolo-
[4,5-c]pyridin-4-one (IIb) was synthesized from
hydrochloride Ib as described above for compound
1
IIa. Yield 81%, mp > 300°C (from DMSO). H NMR
spectrum (CF3COOH), δ, ppm: 6.91 d (1H, 7-H, J =
7.0 Hz), 7.30 d (1H, 6-H, J = 7.0 Hz), 7.64 d (2H, 2'-H,
6'-H, J = 8.0 Hz), 8.19 d (2H, 3'-H, 5'-H, J = 8.0 Hz).
Found, %: C 51.21; H 2.70; N 27.08. C11H7N5O3. Cal-
culated, %: C 51.37; H 2.74; N 27.23.
1-Phenyl-4,5-dihydroimidazo[4,5-c]pyridin-4-one
hydrochloride (Ia). A mixture of 1.5 g (6.35 mmol) of
4-chloro-1-phenyl-4,5-dihydroimidazo[4,5-c]pyridine
[11] and 15 ml of 85% of formic aid was heated for
2 h under reflux. Formic acid was distilled off, 10 ml
of concentrated hydrochloric acid was added to the
residue, and the resulting solution was heated for 1 h
and evaporated to dryness. The residue was ground
with 5 ml of 2-propanol, and the precipitate was
filtered off and recrystallized from alcohol. Yield 1.6 g
(99%), colorless substance, mp 260–263°C. IR spec-
7-Nitro-1-(4-nitrophenyl)-4,5-dihydroimidazo-
[4,5-c]pyridin-4-one (IIIa). a. Potassium nitrate, 1.5 g
(14.85 mmol), was added under stirring and cooling to
0–5°C to a solution of 1.3 g (5.08 mmol) of compound
IIa in 13 ml of concentrated sulfuric acid, and the
mixture was stirred for 2 h at that temperature. It was
then allowed to warm up to room temperature, heated
for 2 h at 60–65°C, cooled, and poured onto ice.
The precipitate was filtered off, washed with cold
water and 2-propanol, and dried. Yield 0.92 g
(60%), mp > 300ºC. 1H NMR spectrum (DMSO-d6), δ,
ppm: 7.78 d (2H, 2'-H, 6'-H, J = 8.5 Hz), 8.36 d (2H,
1
trum, ν, cm–1: 1660 (C=O). H NMR spectrum
(acetone-d6), δ, ppm: 6.80 d (1H, 7-H, J = 7.3 Hz),
7.63 d (1H, 6-H, J = 7.3 Hz), 7.67–7.70 m (5H, 1-Ph),
9.55 s (1H, 2-H). Found, %: C 58.02; H 4.05; N 16.72.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 7 2004

RING TRANSFORMATION OF 7-NITRO-1-(4-NITROPHENYL)-...
1017
3'-H, 5'-H, J = 8.5 Hz), 8.39 s (1H, 6-H), 8.53 s
(1H, 2-H), 11.30 s (1H, 5-H). Found, %: C 47.71;
H 2.30; N 23.12. C12H7N5O5. Calculated, %: C 47.85;
H 2.34; N 23.25.
(62%), snow-white crystals, mp > 300°C. IR spectrum,
1
ν, cm–1: 1675 (C=O). H NMR spectrum(DMSO-d6),
δ, ppm: 2.50 s (3H, CH3), 5.68 s (2H, NH2), 6.66 d
(2H, 2'-H, 6'-H, J = 8.0 Hz), 7.18 d (2H, 3'-H, 5'-H, J =
8.0 Hz), 8.23 s (1H, 2-H), 12.52 s (1H, 5-H). Found,
%: C 59.60; H 4.57; N 28.88. C12H11N5O. Calculated,
%: C 59.74; H 4.60; N 29.03.
b. Compound Ia, 1.4 g (5.65 mmol), was dissolved
in 14 ml of concentrated sulfuric acid, 2.3 g
(22.77 mmol) of potassium nitrate was added in
portions under stirring and cooling (–5 to 0°C), and
the mixture was stirred for 2 h at –5 to 0°C, allowed
to warm up to room temperature, stirred for 48 h,
poured onto ice, and treated as described above in a.
1-(4-Aminophenyl)-7-methyl-4,5-dihydro[1,2,3]-
triazolo[4,5-d]pyridazin-4-one (IVb) was synthesized
as described above for compound IVa from tri-
azolopyridine IIIb. Yield 67%, snow-white crystals,
mp > 300°C. IR spectrum, ν, cm–1: 1680 (C=O).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.52 s (3H,
CH3), 5.66 s (2H, NH2), 6.77 d (2H, 2'-H, 6'-H, J =
8.0 Hz), 7.37 d (2H, 3'-H, 5'-H, J = 8.0 Hz), 12.55 s
(1H, 5-H).
1
Yield 1.1 g (65%), mp > 300°C. H NMR spectrum
(DMSO-d6), δ, ppm: 7.79 d (2H, 2'-H, 6'-H, J =
8.5 Hz), 8.36 d (2H, 3'-H, 5'-H, J = 8.5 Hz), 8.38 s
(1H, 6-H), 8.53 s (1H, 2-H), 11.29 s (1H, 5-H). Found,
%: C 47.63; H 2.29; N 23.07. C12H7N5O5. Calculated,
%: C 47.85; H 2.34; N 23.25.
REFERENCES
7-Nitro-1-(4-nitrophenyl)-4,5-dihydro[1,2,3]tri-
azolo[4,5-c]pyridin-4-one (IIIb) was synthesized as
described above for compound IIIa (method a) using
IIb as starting compound. Yield 50%, light yellow
1. Yutilov, Yu.M. and Svertilova, I.A., Khim. Geterotsikl.
Soedin., 1982, p. 705.
2. Yutilov, Yu.M. and Svertilova, I.A., Russ. J. Org.
Chem., 1999, vol. 35, p. 583.
1
crystals, mp > 300°C. H NMR spectrum (DMSO-d6),
δ, ppm: 7.78 d (2H, 2'-H, 6'-H, J = 8.0 Hz), 8.16 d (2H,
3'-H, 5'-H, J = 8.0 Hz), 8.80 d (1H, 6-H). Found, %:
C 43.52; H 1.96; N 27.65. C11H6N6O5. Calculated, %:
C 43.72; H 2.00; N 27.81.
3. Yutilov, Yu.M. and Smolyar, N.N., Khim. Geterotsikl.
Soedin., 1984, p. 132.
4. Yutilov, Yu.M. and Smolyar, N.N., Zh. Org. Khim.,
1986, vol. 22, p. 1793.
5. Yutilov, Yu.M., Smolyar, N.N., and Gres’ko, S.V., Russ.
J. Org. Chem., 1995, vol. 31, p. 273.
6. Temple, C., Smith, B.H., and Montgomery, J.A., J. Org.
Chem., 1972, vol. 37, p. 3601.
7. FRG Patent Appl. no. 3347290, 1985; Ref. Zh., Khim.,
1986, no. 13O79P.
8. FRG Patent Appl. no. 3445299, 1986; Ref. Zh., Khim.,
1987, no. 3O147P.
Compound IIIb was also synthesized from hydro-
chloride Ib following the procedure described for IIIa
(method b). Yield 60%, mp > 300ºC. H NMR spec-
trum (DMSO-d6), δ, ppm: 7.76 d (2H, 2'-H, 6'-H, J =
8.0 Hz), 8.17 d (2H, 3'-H, 5'-H, J = 8.0 Hz), 8.82 s
(1H, 6-H). Found, %: C 43.49; H 1.93; N 27.60.
C11H6N6O5. Calculated, %: C 43.72; H 2.00; N 27.81.
1
1-(4-Aminophenyl)-7-methyl-4,5-dihydroimid-
azo[4,5-d]pyridazin-4-one (IVa). A mixture of 0.8 g
(2.66 mmol) of compound IIIa and 12 ml of hydrazine
hydrate was heated for 3–5 h at 135–140°C. Excess
hydrazine hydrate was distilled off, the residue was
ground with cold water, and the precipitate was filtered
off, washed with 2-propanol, and dried. Yield 0.4 g
9. Gerhardt, G.A., Aldous, D.L., and Castle, R.N.,
J. Heterocycl. Chem., 1965, vol. 2, p. 247.
10. Yutilov, Yu.M., Svertilova, I.A., Kirichenko, V.V.,
and Afanas’ev, B.E., USSR Inventor’s Certificate
no. 1187438, 1983; Byull. Izobret., 1997, no. 29.
11. Svertilova, I.A., Smolyar, N.N., and Yutilov, Yu.M., Ukr.
Khim. Zh., 1996, vol. 62, nos. 3–4, p. 64.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 7 2004