Cyclization of substituted 3,4-diaminopyridines into 1H-[1,2,3]triazolo[4, 5-c]pyridine 2-oxide derivatives during the nitration process

Article abstract of DOI:10.1134/S1070428010080178

The nitration of pyridine-3,4-diamine, its N,N'-diacetyl derivative, and N⁴-alkylpyridine-3,4-di- amines with excess nitric acid in concentrated sulfuric acid at 60°C was accompanied by cyclization with formation of the corresponding 1-substitu

Full text of DOI:10.1134/S1070428010080178

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 8, pp. 1219–1222. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © N.N. Smolyar, A.B. Vasilechko, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 8, pp. 1217–1220.
Cyclization of Substituted 3,4-Diaminopyridines
into 1H-[1,2,3]Triazolo[4,5-c]pyridine 2-Oxide Derivatives
during the Nitration Process
N. N. Smolyar and A. B. Vasilechko
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 December 4, 2009
Abstract—The nitration of pyridine-3,4-diamine, its N,N′-diacetyl derivative, and N4-alkylpyridine-3,4-di-
amines with excess nitric acid in concentrated sulfuric acid at 60°C was accompanied by cyclization with
formation of the corresponding 1-substituted 4-nitro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxides. 4-Chloro-1H-
[1,2,3]triazolo[4,5-c]pyridine 2-oxide derivatives were obtained under analogous conditions from 2-chloropyri-
dine-3,4-diamine, its N,N′-diacetyl derivative, and 2-chloro-N4-methylpyridine-3,4-diamine. The nitration of
these compounds at 80–90°C gave 4-chloro-7-nitro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxides.
DOI: 10.1134/S1070428010080178
We showed previously that nitration of 3,4-bis-
(formylamino)pyridine (I) with a mixture of nitric and
sulfuric acids leads to the formation of 4-nitro-1H-
[1,2,3]triazolo[4,5-c]pyridine 2-oxide (II) [1]. In the
present work we performed a more detailed study on
this reaction, using various substituted 3,4-diamino-
pyridine derivatives as substrates. We found that the
reactions of 3,4-bis(acetylamino)pyridine (III) and
3,4-diaminopyridine (IV) with excess nitric acid (d =
1.5 g/cm3) in concentrated sulfuric acid at 60°C [1]
afforded the same product which decomposed with
explosion on heating above 225°C. The presence of
strong absorption bands at 1310, 1365, and 1540 cm–1
in the IR spectrum of this compound indicated that its
molecule contains a nitro group and an N-oxide
ular weight of the product was M 181, according to the
mass spectral data. Its elemental composition was
C5H3N5O3. The above findings led us to assign the
structure of 4-nitro-1H-[1,2,3]triazolo[4,5-c]pyridine
2-oxide (II) to the obtained compound. Tautomeric
N-hydroxy structure IIa is also possible (Scheme 1).
Analysis of the mass spectrum of compound II showed
that its fragmentation under electron impact involved
successive elimination of the nitro and hydroxy groups
(Scheme 2), in keeping with the data of [2].
The reduction of nitro compound II with iron in
acetic acid under the conditions described in [3] gave
1H-[1,2,3]triazolo[4,5-c]pyridin-4-amine (V) whose
1
IR and H NMR spectra were identical to those of
an authentic sample of V prepared from 4-chloro-1H-
1
[1,2,3]triazolo[4,5-c]pyridine [4].
moiety. In the H NMR spectrum of the product we
observed signals in the aromatic region from two
vicinal protons in the pyridine fragment as two dou-
blets at δ 7.72 and 8.04 ppm (3J = 6.0 Hz). The molec-
The nitration of 3-amino-4-(methylamino)pyridine
(VIa) and 3-amino-4-(cyclohexylamino)pyridine
(VIb) followed the same pattern as in the nitration of
Scheme 1.
H
N
H
NHR
NHR
N
N
N
HNO3, H2SO4, 60°C
[H]
N
O
N
OH
N
N
N
N
N
N
N
NO2
NO2
NH2
III, IV
II
IIa
V
III, R = MeCO; IV. R = H.
1219

SMOLYAR, VASILECHKO
1220
Scheme 2.
Scheme 4.
+·
H
N
H
N
N
HNO3, H2SO4, 60°C
III, IV
N
O
N
O
N
O
·
N
–NO2
N
N
N
N
N
A
NO2
m/z 181 (Irel = 64%)
135 (100%)
H
N
HNO3, H2SO4, 60°C
118 (24%)
N
O
·
–HO
N
N
NO2
compounds III and IV. The reaction involved forma-
tion of 1,2,3-triazole ring with an N-oxide group in the
2-position and introduction of a nitro group into posi-
tion 4 of the triazolopyridine system (at the carbon
atom neighboring to the pyridine nitrogen atom). The
yields of 1-methyl- and 1-cyclohexyl-4-nitro-1H-
[1,2,3]triazolo[4,5-c]pyridine 2-oxides VIIa and VIIb
thus formed were 87 and 70%, respectively (Scheme 3).
The structure of compounds VIIa and VIIb was con-
II
derivatives having a substituent, e.g., chlorine atom, in
position 2. As substrates we selected 2-chloropyridine-
3,4-diamine (VIIIa), its N,N′-diacetyl derivative
VIIIb, and 2-chloro-N4-methylpyridine-3,4-diamine
(VIIIc). We found that the reactions of compounds
VIIIa–VIIIc with excess nitric acid (d = 1.5 g/cm3) in
concentrated sulfuric acid resulted only in the forma-
tion of fused 1,2,3-triazole 2-oxide fragment: the prod-
ucts were 4-chloro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-
oxide (IXa) and its 1-methyl-substituted analog IXc,
which were isolated in high yields. (Scheme 5). The
product structure was confirmed by elemental analyses
1
firmed by elemental analyses and H NMR spectra.
1
Compounds VIIa and VIIb displayed in the H NMR
spectra signals from methyl or cyclopropyl group, and
vicinal protons in positions 7 and 6 of the pyridine
fragment resonated as two doublets at δ 7.99–8.04 and
8.21–8.26 ppm with coupling constants J of 7.6 and
8.04 Hz, respectively.
1
and H NMR spectra. Taking into account that the
chlorine atom in position 4 of molecules IXa and IXc
exerts para-orienting effect in electrophilic substitu-
tion reactions, we anticipated introduction of a nitro
group into position 7 of the pyridine fragment as the
temperature increases from 60 do 80–90°C, as was ob-
served previously in the synthesis of 4-chloro-7-nitro-
2H-imidazo[4,5-c]pyridine [7]. In fact, by heating
compounds VIIIa–VIIIc with excess nitric acid (d =
1.5 g/cm3) in concentrated sulfuric acid at 80–90°C we
obtained 4-chloro-7-nitro-1H-[1,2,3]triazolo[4,5-c]-
pyridine 2-oxides Xa and Xc in 76 and 86% yield,
respectively. The structure of compounds Xa and Xc
was confirmed by elemental analyses and 1H NMR and
Scheme 3.
R
NHR
N
HNO3, H2SO4, 60°C
N
O
N
N
N
NH2
NO2
VIIa, VIIb
VIa, VIb
R = Me (a), cyclohexyl (b).
A probable mechanism of the process was proposed
in [5] with compounds III and IV as examples. The
initial step is likely to be formation of 1,2,3-triazole
2-oxide fragment in intermediate 1H-[1,2,3]triazolo-
[4,5-c]pyridine 2-oxide A (Scheme 4). The N2-oxide
group in A, as well as the oxo group in 1,3-dihydro-
2H-imidazo[4,5-c]pyridin-2-one [6], enhances the re-
activity of that intermediate toward nitration. The
formation of 4-nitro derivative II in the examined
reaction may be regarded as the first example of
introduction of a nitro group into the 4-position of
1H-[1,2,3]triazolo[4,5-c]pyridine molecule.
1
mass spectra. Their H NMR spectra contained a sin-
glet at δ 8.46–8.49 ppm belonging to the 6-H proton in
the pyridine fragment.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Gemini 200 spectrometer at 200 MHz using hexameth-
yldisiloxane as internal reference. The IR spectra were
measured in KBr on a Specord 75IR spectrometer. The
molecular weights were determined from the mass
spectra which were obtained on a Varian MAT-112
Our results prompted us to study the behavior under
analogous nitration conditions of pyridine-3,4-diamine
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 8 2010

CYCLIZATION OF SUBSTITUTED 3,4-DIAMINOPYRIDINES
1221
Scheme 5.
R
N
HNO3, H2SO4, 60°C
N
O
O
N
N
N
NHR
Cl
IXa, IXc
N
NHR'
NO2
R
Cl
VIIIa–VIIIc
N
HNO3, H2SO4, 80–90°C
N
N
Cl
Xa, Xc
R = R′ = H (a), MeCO (b); R = Me, R′ = H (c).
mass spectrometer with direct sample admission into
the ion source (electron impact, 70 eV). The purity of
the isolated compounds was checked by TLC on
Silufol UV-254 plates using ethanol or chloroform as
eluent; spots were visualized by UV irradiation or
treatment with iodine vapor. Compounds III, IV, VIa,
VIb, and VIIIa–VIIIc were synthesized according to
the procedures reported in [8].
δ, ppm: 7.79 d (1H, 7-H, J = 5.2 Hz), 8.20 d (1H, 6-H,
J = 5.2 Hz). Samples of II prepared according to
methods a and b showed no depression of the melting
point.
1H-[1,2,3]Triazolo[4,5-c]pyridine-4-amine (V).
A mixture of 1.0 g (5.5 mmol) of 4-nitro-1H-[1,2,3]-
triazolo[4,5-c]pyridine 2-oxide (II) and 2.5 g of iron in
35 ml of glacial acetic acid was heated for 3–4 h. The
mixture was cooled, the precipitate was filtered off, the
filtrate was evaporated to dryness, the residue was
treated with 25% aqueous ammonia, and the solution
was evaporated to dryness. The dry residue was ex-
tracted with alcohol. The extract was evaporated, and
the residue was recrystallized from alcohol. Yield 0.55 g
(74%), mp >325°C (decomp.). IR spectrum, ν, cm–1:
4-Nitro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxide
(II). a. 3,4-Bis(acetylamino)pyridine (III), 10 mmol,
was dissolved in 15 ml of cold concentrated sulfuric
acid, 2 ml (48 mmol) of concentrated nitric acid (d =
1.5 g/cm3) was added in portions under stirring and
cooling (0–5°C), and the mixture was stirred for 1 h at
0–5°C, heated to 60°C, and kept for 2 h at that tem-
perature. The mixture was cooled, poured onto ice,
neutralized to pH ~7 with ammonium carbonate, and
evaporated to dryness. The dry residue was extracted
with dimethylformamide. The solvent was distilled off
under reduced pressure, and the residue was recrystal-
lized from dimethyl sulfoxide. Yield 74%, mp >225°C
(decomposes with explosion). IR spectrum, ν, cm–1:
1540 (NO2, asym.), 1365 (NO2, sym.), 1310 (N→O).
1H NMR spectrum (pyridine-d5), δ, ppm: 7.80 d (1H,
7-H, J = 5.2 Hz), 8.21 d (1H, 6-H, J = 5.2 Hz). Mass
spectrum, m/z (Irel, %): 181 (64) [M]+, 135 (100), 118
(24). Found, %: C 33.05; H 1.64; N 38.16. C5H3N5O3.
Calculated, %: C.16; H 1.67; N 38.67. M 181.11.
1
1690, 1650, 1625. H NMR spectrum (DMSO-d6), δ,
ppm: 6.84 d (1H, 7-H, J = 6.0 Hz), 7.36 br.s (2H,
NH2), 7.68 d (1H, 6-H, J = 6.0 Hz), 12.05 s (1H, NH).
Found, %: C 44.27; H 3.69; N 51.63. C5H3N5. Calcu-
lated, %: C 44.44; H 3.75; N 51.73.
1-Methyl-4-nitro-1H-[1,2,3]triazolo[4,5-c]pyri-
dine 2-oxide (VIIa) was synthesized from 10 mmol of
3-amino-4-methylaminopyridine (VIa) as described
above for compound II (method a). Yield 87%,
1
mp >250°C (from DMSO). H NMR spectrum (pyri-
dine-d5), δ, ppm: 4.11 s (3H, CH3), 7.99 d (1H, 7-H,
J = 7.6 Hz), 8.21 d (1H, 6-H, J = 7.6 Hz). Found, %:
C 36.81; H 2.54; N 35.78. C6H5N5O3. Calculated, %:
C 36.93; H 2.58; N 35.89.
b. Compound II was synthesized in a similar way
from 10 mmol of 3,4-diaminopyridine (IV). Yield
75%, mp >225°C (decomposes with explosion). IR
spectrum, ν, cm–1: 1540 (NO2, asym.), 1365 (NO2,
1-Cyclohexyl-4-nitro-1H-[1,2,3]triazolo[4,5-c]-
pyridine 2-oxide (VIIb) was synthesized from
10 mmol of 3-amino-4-cyclohexylaminopyridine (VIb)
as described above for compound II (method a). Yield
1
sym.), 1310 (N→O). H NMR spectrum (pyridine-d5),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 8 2010

SMOLYAR, VASILECHKO
1222
1
70%, mp >250°C (from DMSO). H NMR spectrum
(pyridine-d5), δ, ppm: 1.24 m (10H, CH2), 2.81 s (1H,
NCH), 8.02 d (1H, 7-H, J = 8.04 Hz), 8.26 d (1H, 6-H,
J = 8.04 Hz). Found, %: C 49.70; H 5.68; N 26.93.
C11H13N5O3. Calculated, %: C 49.81; H 5.70; N 26.40.
from 2-chloropyridine-3,4-diamine (VIIIa). Yield
1
86%, mp >250°C (from DMSO). H NMR spectrum
(pyridine-d5): δ 8.46 ppm, s (1H, 6-H). Mass spectrum,
m/z (Irel, %): 215.8 [M]+ (20), 213.8 (90). Found, %:
C 27.77; H 0.91; Cl 16.13; N 32.38. C5H2ClN5O3.
Calculated, %: C 27.86; H 0.94; Cl 16.45; N 32.49.
M 215.56.
4-Chloro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-ox-
ide (IXa). a. Compound IXa was synthesized from
10 mmol of 2-chloropyridine-3,4-diamine (VIIIa) as
described above for compound II (method a). Yield
b. Compound Xa was synthesized from 3,4-bis-
(acetylamino)-2-chloropyridine (VIIIb). Yield 83%,
1
1
92%, mp >250°C (from DMSO). H NMR spectrum
mp >250°C (from DMSO). H NMR spectrum (pyri-
(pyridine-d5), δ, ppm: 7.52 d (1H, 7-H, J = 5.66 Hz),
8.15 d (1H, 6-H, J = 5.66 Hz). Found, %: C 35.12;
H 1.75; Cl 20.79; N 32.74. C5H3ClN4O. Calculated, %:
C 35.21; H 1.77; Cl 20.79; N 32.85.
dine-d5): δ 8.45 ppm, s (1H, 6-H). Samples of Xa
prepared according to methods a and b showed no
depression of the melting point on mixing.
4-Chloro-1-methyl-7-nitro-1H-[1,2,3]triazolo-
[4,5-c]pyridine 2-oxide (Xc) was synthesized from
3-amino-2-chloro-4-methylaminopyridine (VIIIc).
Yield 87%, mp >250°C (from DMSO). 1H NMR spec-
trum (pyridine-d5), δ, ppm: 4.27 s (3H, CH3), 8.49 s
(1H, 6-H). Found, %: C 31.28; H 1.73; Cl 15.43;
N 30.39. C6H4ClN5O3. Calculated, %: C 31.39; H 1.76;
Cl 15.44; N 30.50.
b. Compound IXa was synthesized from 10 mmol
of 3,4-bis(acetylamino)-2-chloropyridine (VIIIb) as
described above for compound II (method a). Yield
1
90%, mp >250°C (from DMSO). H NMR spectrum
(pyridine-d5), δ, ppm: 7.53 d (1H, 7-H, J = 5.66 Hz),
8.16 d (1H, 6-H, J = 5.66 Hz). Found, %: C 35.10;
H 1.73; Cl 20.78; N 32.70. C5H3ClN4O. Calculated,
%: C 35.21; H 1.77; Cl 20.79; N 32.85.
REFERENCES
4-Chloro-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyri-
dine 2-oxide (IXc) was synthesized from 10 mmol of
3-amino-2-chloro-4-methylaminopyridine (VIIIc) as
described above for compound II (method a). Yield
1. Yutilov, Yu.M. and Smolyar, N.N., Russ. J. Org. Chem.,
2004, vol. 40, p. 1526.
1
2. Terent’ev, P.B. and Stankyavichus, A.P., Mass-spektro-
skopicheskii analiz biologicheski aktivnykh soedinenii
(Mass Spectrometric Analysis of Biologically Active
Compounds), Vil’nyus: Mosklas, 1987, p. 140.
85%, mp >250°C (from DMSO). H NMR spectrum
(pyridine-d5), δ, ppm: 4.38 s (3H, CH3), 7.81 d (1H,
7-H, J = 5.6 Hz), 8.81 d (1H, 6-H, J = 5.6 Hz). Mass
spectrum, m/z (Irel, %): 185 [M]+ (100), 187 (30), 155.8
(10). Found, %: C 38.93; H 2.70; Cl 19.19; N 30.24.
C6H5ClN4O. Calculated, %: C 39.04; H 2.73; Cl 19.21;
N 30.35.
3. Hertog, H.J. and Overhoff, A.F.J., Recl. Trav. Chim.
Pays–Bas, 1950, vol. 69, p. 468.
4. Temple, C., Smith, B., and Montgomery, J., J. Org.
Chem., 1972, vol. 37, p. 3601.
4-Chloro-7-nitro-1H-[1,2,3]triazolo[4,5-c]pyri-
dine 2-oxides Xa and Xc (general procedure). Com-
pound VIIIa, VIIIb, or VIIIc, 10 mmol, was dis-
solved in 15 ml of cold concentrated sulfuric acid, 2 ml
(48 mmol) of concentrated nitric acid (d = 1.5 g/cm3)
was added in portions under stirring and cooling (0–
5°C), and the mixture was stirred for 1 h at 0–5°C. The
mixture was then heated to 80–90°C, kept for 2 h at
that temperature, cooled, poured onto ice, neutralized
to pH ~7 with ammonium carbonate, and evaporated to
dryness. The dry residue was extracted with dimethyl-
formamide. The solvent was distilled off under re-
duced pressure, and the residue was recrystallized from
appropriate solvent.
5. Vasilechko, A.B., Trudy konferentsii “Sovremennye ten-
dentsii v organicheskom sinteze i problemy khimiche-
skogo obrazovaniya” (Proc. Conf. “Current Trends in
Organic Synthesis and Chemical Education Problems”),
St. Petersburg, 2005, p. 54.
6. Yutilov, Yu.M. and Svertilova, I.A., Khim. Geterotsikl.
Soedin., 1973, p. 138; Yutilov, Yu.M. and Svertilova, I.A.,
Khim. Geterotsikl. Soedin., 1986, p. 97.
7. Yutilov, Yu.M., Adv. Heterocycl. Chem., 2005, vol. 89,
p. 169.
8. Bremer, O., Justus Liebigs Ann. Chem., 1935, vol. 515,
p. 274; Weidenhagen, R. and Weeden, U., Chem. Ber.,
1938, vol. 71, p. 2347; Kovaleva, L.I. and Yutilov, Yu.M.,
Reakt. Osobo Chist. Veshch., 1977, vol. 31, no. 1, p. 4;
Misuno, Y., Iton, T., and Saito, K., Chem. Pharm. Bull.,
1964, vol. 12, p. 866; Stetsenko, A.V. and Miroshnichen-
ko, N.S., Ukr. Khim. Zh., 1973, vol. 39, p. 703.
4-Chloro-7-nitro-1H-[1,2,3]triazolo[4,5-c]pyri-
dine 2-oxide (Xa). a. Compound Xa was synthesized
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 8 2010