Synthesis of new azolo[5,1-d][1,2,3,5]tetrazin-4-ones–analogs of antitumor agent temozolomide

Article abstract of DOI:10.1007/s11172-016-1522-9

Reactivity of 5-diazoimidazoles and 5-diazopyrazoles in the reactions with alkyland aryl isocyanates was studied. A number of new imidazo-and pyrazolo[5,1-d][1,2,3,5]tetrazin-4 ones were synthesized, which are analogs of temozolomide. It was shown that diazoazoles do not react with isothiocyanates under similar conditions.

Full text of DOI:10.1007/s11172-016-1522-9

Russian Chemical Bulletin, International Edition, Vol. 65, No. 7, pp. 1867—1872, July, 2016
1867
Synthesis of new azolo[5,1ꢀd][1,2,3,5]tetrazinꢀ4ꢀones –
analogs of antitumor agent temozolomide*
E. V. Sadchikova
Ural Federal University named after the first President of Russia B. N. Yeltsin,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Telephone: +7 (343) 375 9789. Eꢀmail: e.v.sadchikova@urfu.ru
Reactivity of 5ꢀdiazoimidazoles and 5ꢀdiazopyrazoles in the reactions with alkylꢀ and aryl
isocyanates was studied. A number of new imidazoꢀ and pyrazolo[5,1ꢀd][1,2,3,5]tetrazinꢀ4ꢀ
ones were synthesized, which are analogs of temozolomide. It was shown that diazoazoles do
not react with isothiocyanates under similar conditions.
Key words: diazoimidazole, diazopyrazole, isocyanate, isothiocyanate, imidazotetrazinone,
pyrazolotetrazinone, temozolomide.
Scheme 1
The main reason of continuous interest to the studies
of approaches to the synthesis and chemical behavior of
polynitrogenꢀcontaining fused heterocyclic systems is the
presence among them of considerable amount of biologiꢀ
cally active compounds. Thus, in 1980s a high antitumor
activity was revealed in imidazotetrazinone derivatives,
such as mitozolomide and temozolomide. The latter, startꢀ
ing from 2000 is widely used in clinical practice under the
commercial brand Temodal® in Europe and Temodar® in
the USA for treatment of some brain tumors,1,2 as well as
for the enhancement of therapeutical effect of a number of
agents in the combined antitumor therapy.3 An original
synthesis of these compounds includes transformation of
commercially available 5ꢀaminoimidazoleꢀ4ꢀcarboxamide
(1a) to unstable 5ꢀdiazoimidazoleꢀ4ꢀcarboxamide (2a) and
its subsequent reaction with 2ꢀchloroethyl isocyanate4 or
methyl isocyanate,5 respectively (Scheme 1).
Earlier, the issue concerning alternative approaches to
the synthesis of these agents was studied,6 which would
allow one to exclude from the chemical scheme of the
process, on the one hand, unstable and explosive 5ꢀdiazoꢀ
imidazoleꢀ4ꢀcarboxamide and, on the other hand, very
toxic and volatile methyl isocyanate. This way gave a numꢀ
ber of positive results, however, an initially suggested method
for the synthesis of azolotetrazinones is still considered as
the most convenient. At the present time, efforts are diꢀ
rected on the studies of the mechainism of this transforꢀ
mation, as well as on the development of technological
conditions of its conduction providing the maximum yield
and quality of the final product.7
3a,b, 4a—g,
5a—h, 6a—g,
7a,b,d,e, 8a—g
Compound 1 and 2
1a, 2a
1b, 2b
1c, 2c
1d, 2d
R
NH2
NHMe
Morpholino
Piperidino
Pyrrolidino
OEt
Product
3a,b
4a—g
5a—h
6a—g
1e, 2e
1f, 2f
7a,b,d,e
8a—g
Compound
R´
3a (mitozolomide)
3b (temozolomide)
4a—8a
CH2CH2Cl
Me
Pr
4b—8b
4c—6c, 8c
4d—8d
Cyclohexyl
CH2Ph
Ph
4e—8e
pꢀMe—C6H4
pꢀOMe—C6H4
pꢀCl—C6H4
Naphthyl
4f—6f, 8f
4g—6g, 8g
5h
Reagents and conditions: i. NaNO2, 1 M HCl.
In the present work, we study application of different
conditions for the reaction of 5ꢀdiazoazoles8,9 2b—f with
alkyl and aryl isocyanates (Schemes 1 and 2).
It is known that isocyanates under acidic or alkaline
conditions, as well as upon treatment with nucleophilic
* Based on the materials of the International Congress on the
Heterocyclic Chemistry "KOSTꢀ2015" (October 17—23, 2015,
Moscow, Russia).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1867—1872, July, 2016.
1066ꢀ5285/16/6507ꢀ1867 © 2016 Springer Science+Business Media, Inc.

1868
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Sadchikova
agents such as alcohols and water, undergo hydrolysis to
give either ureas, or the corresponding amines. Apart form
that, earlier it was shown that water nucleophilically atꢀ
tacked position 4 of the tetrazinone ring of temozolomide,
leading to the formation of 5ꢀ(3ꢀmethyltriazenꢀ1ꢀyl)ꢀ
imidazoleꢀ4ꢀcarboxamide.10
of 2200—2300 cm–1, as well as chromatographically trackꢀ
ing the disappearance of diazoazoles 2b—f, 11, and 12a—c
in the reaction mixture. It was found that the reaction
considerably accelerates when an excess of isocyanate is
used, and the experimentally found optimum ratio of reꢀ
agents is 1 : 3.
Earlier, the studies of the reaction of ethyl 5ꢀdiazoꢀ3ꢀ
methylsulfonylꢀ1Hꢀpyrazoleꢀ4ꢀcarboxylate12 and 5ꢀdiazoꢀ
3ꢀtrifluoromethylꢀ1Hꢀpyrazoleꢀ4ꢀcarboxylic acid13 with
aryl isocyanates showed that the nature of substituent in
the aromatic ring considerably influences the time required
by the process and the product yields. Thus, the reaction
with 4ꢀmethoxyphenyl isocyanate gave no product at all,
whereas the reaction with phenyl isocyanate required
10 days to proceed.
Scheme 2
In the course of our studies, we did not find that draꢀ
matic influence of substituents in the aryl part of isocyanꢀ
ate on the rate of the reaction with 5ꢀdiazoimidazoles
2b—f and 5ꢀdiazopyrazoles 11 and 12a—c and the formaꢀ
tion of the target reaction products, imidazoꢀ (4a—g, 5a—h,
6a—g, 7a,b,d,e, 8a—g) and pyrazolo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinones (13a—c, 14a—h). However, we found that
the reaction is the fastest for pꢀchlorophenyl and phenyl
isocyanates (3—5 h), it is the slowest for pꢀtolyl and
pꢀmethoxyphenyl isocyanates (10—15 h). The longest time
is required by the reaction with cyclohexyl and nꢀpropyl
isocyanates (up to 48 h), whereas pꢀtolylsulfonyl isocyanꢀ
ate does not give this reaction at all. The structure of the
starting diazoazole, in contrast to the structure of isocyanꢀ
ate used, has no any noticeable influence on the process,
except 5ꢀdiazoimidazoleꢀ4ꢀNꢀmethylcarboxamide (2b),
which can undergo intramolecular cyclization. In the reꢀ
actions with alkyl isocyanates involving this diazoimidꢀ
azole, the formation of an insignificant amount of the side
product of intramolecular cyclization, 3ꢀmethylꢀ3,7ꢀdiꢀ
hydroimidazo[4,5ꢀd]ꢀ1,2,3ꢀtriazinꢀ4ꢀone, was observed.8
The structure of all the synthesized compounds was
confirmed by modern physicochemical methods of study
of organic compound. In the process of the detailed studꢀ
ies of 1H NMR spectra of imidazo[5,1ꢀd][1,2,3,5]tetrazinꢀ
4ꢀones 4a—g, 5a—h, 6a—g, 7a,b,d,e, 8a—g, it was found
that this heterocyclic system is very unstable in solutions
of polar solvents. Thus, new signals appeared in the
1H NMR spectra of these compounds upon their standing
in dimethyl sulfoxide during 2–3 h, whereas one half of
a compound decomposed over 7 days. The analysis of the
spectral picture allows us to draw a conclusion that prodꢀ
ucts of decomposition of the imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4ꢀone structure of 4a—g, 5a—h, 6a—g, 7a,b,d,e,
8a—g are the starting 5ꢀdiazoimidazole and symmetric
N,N´ꢀdisubstituted urea.
Compound
9, 11, 13
10, 12, 14
R
H
R´
COOEt
H
Compound
10a, 12a
10b, 12b
10c, 12c
R´´´
H
Me
OMe
pꢀR´´´—C6H4
Compound
13a
R´´
Ph
13b
13c
C6H4—OMeꢀp
C6H4—Clꢀp
Compound
R´´
cyclohexyl
R´´´
H
H
Me
Me
14a
14b
14c
14d
14e
14f
Ph
cyclohexyl
Ph
pꢀOMeꢀC6H4
cyclohexyl
Ph
Me
OMe
OMe
OMe
14g
14h
pꢀOMeꢀC6H4
Reagents and conditions: i. NaNO2, 1 M HCl.
In order to avoid the prototropic transformations of
diazoazoles8,11 and the transformations of isocyanates
mentioned above, as well as to make the products more
stable, the reaction was carried out in anhydrous aprotic
solvents: acetonitrile, ethyl acetate, dichloromethane, and
chloroform. It was found that the optimum solvent was
anhydrous ethyl acetate, since it provided homogeneous
conditions for the reaction, a high degree of dissolution of
the starting compounds and a low dissolution of the reacꢀ
tion products. This allowed us in the case of involvement
in the reaction of aryl isocyanates to isolate reaction prodꢀ
ucts virtually in analytically pure form.
The reaction under study is exothermic, therefore, to
avoid overheating of the reaction mixture and possible
thermal decomposition of formed products, the solution
of the starting diazo compound in ethyl acetate and isoꢀ
cyanate should be cooled before mixing. The reaction
progress was monitored by IR spectroscopy, tracking the
disappearance of the absorption bands of the starting diazoꢀ
azole at 2160—2190 cm–1 and the isocyanate in the region
In order to synthesize thio analogs of temozolomide,
we investigated reactions of diazoazoles 2b—f, 11, and
12a—c with methyl and phenyl isothiocyanates under the
same conditions, which were selected for the reaction with
the corresponding isocyanates, as well as upon prolonged

Synthesis of azolo[5,1ꢀd][1,2,3,5]tetrazinones
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1869
(d, 3 H, NHCH3, J = 4.82 Hz); 4.25 (t, 2 H, N—CH2—CH2—CH3,
J = 7.02 Hz); 8.45 (q, 1 H, NHCH3, J = 4.82 Hz); 8.83 (s, 1 H,
H(6)). Found (%): C, 45.64; H, 5.17; N, 35.64. C9H12N6O2.
Calculated (%): C, 45.76; H, 5.12; N, 35.57.
3ꢀCyclohexylꢀ4ꢀoxoimidazo[5,1ꢀd][1,2,3,5]tetrazinꢀ8ꢀNꢀ
methylcarboxamide (4b). The yield was 60%, m.p. 156—158 °C.
IR, ν/cm–1: 3390 (NH); 3125, 2925, 2850 (CH); 1725, 1690
(C=O); 1630 (N=N). 1H NMR (DMSOꢀd6), δ: 1.23—2.02
(m, 10 H, 5 CH2); 2.82 (d, 3 H, NHCH3, J = 4.82 Hz); 4.65 (m, 1 H,
CH); 8.43 (q, 1 H, NHCH3, J = 4.82 Hz); 8.81 (s, 1 H, H(6)).
Found (%): C, 52.09; H, 5.72; N, 30.81. C12H16N6O2. Calculatꢀ
ed (%): C, 52.17; H, 5.84; N, 30.42.
3ꢀBenzylꢀ4ꢀoxoimidazo[5,1ꢀd][1,2,3,5]tetrazinꢀ8ꢀNꢀmethylꢀ
carboxamide (4c). The yield was 74%, m.p. 142—144 °C. IR,
ν/cm–1: 3370 (NH); 3132, 2929 (CH); 1742, 1650 (C=O); 1581
(N=N). 1H NMR (DMSOꢀd6), δ: 2.82 (d, 3 H, NHCH3,
J = 4.82 Hz); 5.50 (s, 2 H, CH2); 7.32—7.45 (m, 5 H, C6H5);
8.47 (q, 1 H, NHCH3, J = 4.82 Hz); 8.84 (s, 1 H, H(6)).
13C NMR (DMSOꢀd6), δ: 26.66, 52.69, 128.75, 128.81, 129.39,
129.91, 131.87, 134.93, 136.47, 140.04, 160.95. Found (%):
C, 54.97; H, 4.31; N, 29.62. C13H12N6O2. Calculated (%): C, 54.93;
H, 4.25; N, 29.56.
4ꢀOxoꢀ3ꢀphenylimidazo[5,1ꢀd][1,2,3,5]tetrazinꢀ8ꢀNꢀmethylꢀ
carboxamide (4d). The yield was 81%, m.p. 130—132 °C. IR,
ν/cm–1: 3390 (NH); 3125, 2860 (CH); 1730, 1655 (C=O); 1630
(N=N). 1H NMR (DMSOꢀd6), δ: 2.85 (d, 3 H, NHCH3,
J = 4.66 Hz); 7.55—7.67 (m, 5 H, C6H5); 8.55 (q, 1 H, NHCH3,
J = 4.66 Hz); 8.97 (s, 1 H, H(6)). Found (%): C, 53.38; H, 3.65;
N, 31.28. C12H10N6O2. Calculated (%): C, 53.33; H, 3.73;
N, 31.10.
4ꢀOxoꢀ3ꢀ(pꢀtolyl)imidazo[5,1ꢀd][1,2,3,5]tetrazinꢀ8ꢀNꢀmeꢀ
thylcarboxamide (4e). The yield was 70%, m.p. 139—141 °C. IR,
ν/cm–1: 3360 (NH); 3075, 2920 (CH); 1730, 1640 (C=O); 1600
(N=N). 1H NMR (DMSOꢀd6), δ: 2.42 (s, 3 H, CH3); 2.84 (d, 3 H,
NHCH3, J = 4.82 Hz); 7.41 (d, 2 H, H(3´), H(5´), J = 8.30 Hz);
7.52 (d, 2 H, H(2´), H(6´), J = 8.30 Hz); 8.53 (q, 1 H, NHCH3,
J = 4.82 Hz); 8.95 (s, 1 H, H(6)). Found (%): C, 55.08; H, 4.31;
N, 29.34. C13H12N6O2. Calculated (%): C, 54.93; H, 4.25; N, 29.56.
3ꢀ(pꢀMethoxyphenyl)ꢀ4ꢀoxoimidazo[5,1ꢀd][1,2,3,5]tetrꢀ
azinꢀ8ꢀNꢀmethylcarboxamide (4f). The yield was 83%, m.p.
131—133 °C. IR, ν/cm–1: 3350 (NH); 3102, 2935, 2835 (CH);
1748, 1650 (C=O); 1582 (N=N). 1H NMR (DMSOꢀd6), δ: 2.84
(d, 3 H, NHCH3, J = 4.82 Hz); 3.85 (s, 3 H, OCH3); 7.15 (d, 2 H,
H(2´), H(6´), J = 8.80 Hz); 7.55 (d, 2 H, H(3´), H(5´), J = 8.80 Hz);
8.51 (q, 1 H, NHCH3, J = 4.82 Hz); 8.93 (s, 1 H, H(6)).
13C NMR (DMSOꢀd6), δ: 26.67, 56.40, 115.18, 129.04, 130.26,
130.74, 131.99, 134.61, 139.94, 160.63, 160.92. Found (%): C,
51.86; H, 3.96; N, 28.12. C13H12N6O3. Calculated (%): C, 52.00;
H, 4.03; N, 27.99.
heating of the reaction mixture at different temperatures
in the range from 60 to 100 °C. It was found that the
diazoazoles 2b—f, 11, and 12a—c did not react with
isothiocyanates, since in a number of cases the corresponding
diazoazoles were recovered from the reaction mixtures in
the unchanged form, or their resinification was observed.
In conclusion, the best result in the synthesis of azoloꢀ
[5,1ꢀd][1,2,3,5]tetrazinꢀ4ꢀones 4a—g, 5a—h, 6a—g,
7a,b,d,e, 8a—g, 13a—c, and 14a—h was reached when the
reaction was carried out in anhydrous ethyl acetate with
a threeꢀfold excess of isocyanate at –10 °C in the initial step
with subsequent gradual increase in temperature to ambiꢀ
ent. This reaction involving isothiocyanate cannot be used
for the preparation of thio analogs of temozolomide, i.e.,
azolo[5,1ꢀd][1,2,3,5]tetrazinꢀ4ꢀthiones.
Experimental
Spectral studies were carried out for analytically and chroꢀ
matographically pure samples. IR spectra of the synthesized comꢀ
pounds were recorded on Specord IRꢀ75 and Perkin Elmer 1600,
1
Series FTIR spectrometers (in KBr pellets). H and 13C NMR
spectra were recorded on a Brucker WRꢀ300 spectrometer
(300 MHz for 1H and 75 MHz for 13C) in DMSOꢀd6 (δ scale, an
internal standard SiMe4). Melting points were determined using
a Stuart SMP30 heating stage and were not corrected. Reaction
progress and purity of compounds obtained were monitored by
TLC on Silufol UVꢀ254 plates (using silica gel CTXhꢀ1A as
a sorbent) in the following solvent systems: hexane — ethyl
acetate, 1 : 1 (A); hexane — ethyl acetate, 2 : 1 (B); chloroform —
ethanol, 3 : 1 (C); chloroform — ethanol, 10 : 1 (D).
The starting 5ꢀdiazoimidazoles8 and 5ꢀdiazopyrazoles9 were
synthesized according to the procedures described earlier, alkylꢀ
and aryl isocyanates are commercially available compounds.
Synthesis of azolo[5,1ꢀd][1,2,3,5]tetrazinꢀ4(3H)ꢀones (4a—g,
5a—h, 6a—g, 7a,b,d,e, 8a—g, 13a—c, 14a—h) (general proceꢀ
dure). A corresponding isocyanate (0.9 mmol) was added dropꢀ
wise to a cooled and protected from light solution of diazoazole
2b—f, 11, 12a—c (0.3 mmol) in anhydrous ethyl acetate (5 mL)
at –10 °C and with stirring. The temperature of the reaction
mixture was raised to ambient and the mixture was allowed to
stand under these conditions until an absorption band of the
starting diazoazole in the region of 2170—2190 cm–1 disappeared
from the IR spectra. In the reactions with aryl isocyanates,
a precipitate formed was collected by filtration, washed with
diethyl ether, and recrystallized from ethyl acetate to obtain an
analytically pure sample. In the reactions with alkyl isocyanates,
a precipitate either was not formed at all, or the product precipꢀ
itated in insignificant amounts. To isolate the main amount of
the product, activated charcoal was added to the reaction mixꢀ
ture or filtrate, then stirred for 15 min, and filtered. The filtrate
was concentrated in vacuo at a temperature below 40 °C. The
residue was treated with diethyl ether or hexane, a precipitate
formed was collected by filtration and purified by flashꢀchromaꢀ
tography, using a mixture of solvents CH3COOC2H5—CH2Cl2.
4ꢀOxoꢀ3ꢀnꢀpropylimidazo[5,1ꢀd][1,2,3,5]tetrazinꢀ8ꢀNꢀmethꢀ
ylcarboxamide (4a). The yield was 56%, m.p. 172—174 °C. IR,
ν/cm–1: 3380 (NH); 3110, 2960 (CH); 1730, 1685 (C=O); 1630
(N=N). 1H NMR (DMSOꢀd6), δ: 0.96 (t, 3 H, N—CH2—CH2—
CH3, J = 7.02 Hz); 1.83 (m, 2 H, N—CH2—CH2—CH3); 2.82
3ꢀ(pꢀChlorophenyl)ꢀ4ꢀoxoimidazo[5,1ꢀd][1,2,3,5]tetrazinꢀ
8ꢀNꢀmethylcarboxamide (4g). The yield was 83%, m.p. 136—138 °C.
IR, ν/cm–1: 3345 (NH); 3100, 2925, 2830 (CH); 1735, 1645
1
(C=O); 1580 (N=N). H NMR (DMSOꢀd6), δ: 2.83 (d, 3 H,
NHCH3, J = 4.82 Hz); 7.57 (d, 2 H, H(2´), H(6´), J = 9.0 Hz);
7.75 (d, 2 H, H(3´), H(5´), J = 9.0 Hz); 8.48 (q, 1 H, NHCH3,
J = 4.82 Hz); 8.95 (s, 1 H, H(6)). Found (%): C, 47.37; H, 3.04;
Cl, 11.64; N, 27.51. C12H9ClN6O2. Calculated (%): C, 47.30;
H, 2.98; Cl, 11.64; N, 27.58.
8ꢀ(Morpholinocarbonyl)ꢀ3ꢀnꢀpropylimidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (5a). The yield was 61%, m.p. 84—85 °C.
IR, ν/cm–1: 3090, 3020, 2985, 2970, 2860 (CH); 1730, 1625
1
(C=O); 1600 (N=N). H NMR (DMSOꢀd6), δ: 0.96 (t, 3 H,

1870
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Sadchikova
N—CH2—CH2—CH3, J = 7.32 Hz); 1.79—1.88 (m, 2 H,
N—CH2—CH2—CH3); 3.60 (m, 4 H, 2 CH2); 3.69 (m, 4 H, 2 CH2);
4.24 (t, 2 H, N—CH2—CH2—CH3, J = 7.02 Hz); 8.80 (s, 1 H,
H(6)). Found (%): C, 49.34; H, 5.46; N, 28.81. C12H16N6O3.
Calculated (%): C, 49.31; H, 5.52; N, 28.75.
7.73 (dd, 1 H, J1 = 7.32 Hz, J2 = 8.05 Hz); 7.84 (d, 1 H, J = 7.32 Hz);
8.07 (d, 1 H, J = 8.42 Hz); 8.12 (d, 1 H, J = 8.42 Hz); 8.21 (d, 1 H,
J = 8.42 Hz); 9.00 (s, 1 H, H(6)). Found (%): C, 60.67; H, 4.26;
N, 22.43. C19H16N6O3. Calculated (%): C, 60.63; H, 4.28; N, 22.33.
8ꢀ(Piperidinocarbonyl)ꢀ3ꢀnꢀpropylimidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (6a). The yield was 65%, m.p. 95—97 °C.
IR, ν/cm–1: 3100, 2940, 2855 (CH); 1735, 1620 (C=O); 1560
(N=N). 1H NMR (DMSOꢀd6), δ: 0.96 (t, 3 H, N—CH2—CH2—
CH3, J = 7.32); 1.50—1.65 (m, 6 H, 3 CH2); 1.78—1,87 (m, 2 H,
N—CH2—CH2—CH3); 3.46—3.49 (m, 2 H, CH2); 3.63—3.66
(m, 2 H, CH2); 4.22 (t, 2 H, N—CH2—CH2—CH3, J = 7.02 Hz);
8.80 (s, 1 H, H(6)). Found (%): C, 53.70; H, 6.13; N, 29.11.
C13H18N6O2. Calculated (%): C, 53.78; H, 6.25; N, 28.95.
3ꢀCyclohexylꢀ8ꢀ(piperidinocarbonyl)imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (6b). The yield was 63%, m.p. 152—154 °C.
IR, ν/cm–1: 3100, 2990, 2975, 2935, 2860 (CH); 1740, 1630
(C=O); 1550 (N=N). 1H NMR (DMSOꢀd6), δ: 1.26—2.00
(m, 16 H, 5 CH2 + 3 CH2); 3.51 (m, 2 H, CH2); 3.67 (m, 2 H, CH2);
4.59—4.70 (m, 1 H, CH); 8.60 (s, 1 H, H(6)). Found (%): C, 58.02;
H, 6.82; N, 25.58. C16H22N6O2. Calculated (%): C, 58.17; H, 6.71;
N, 25.44.
3ꢀCyclohexylꢀ8ꢀ(morpholinocarbonyl)imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (5b). The yield was 63%, m.p. 138—140°C.
IR, ν/cm–1: 3090, 3020, 2980, 2960, 2945, 2860 (CH); 1720,
1620 (C=O); 1605 (N=N). 1H NMR (DMSOꢀd6), δ: 1.09—2.02
(m, 10 H, 5 CH2); 3.55—3.68 (m, 8 H, 4 CH2); 4.37 (m, 1 H,
CH); 8.78 (s, 1 H, H(6)). Found (%): C, 54.13; H, 6.11; N, 25.41.
C15H20N6O3. Calculated (%): C, 54.21; H, 6.07; N, 25.29.
3ꢀBenzylꢀ8ꢀ(morpholinocarbonyl)imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (5c). The yield was 61%, m.p. 134—136 °C.
IR, ν/cm–1: 3089, 2967, 2923, 2866 (CH); 1742, 1628 (C=O);
1
1566 (N=N). H NMR (DMSOꢀd6), δ: 3.58 (m, 4 H, 2 CH2);
3.68 (m, 4 H, 2 CH2); 5.48 (s, 2 H, CH2); 7.32—7.45 (m, 5 H,
C6H5); 8.84 (s, 1 H, H(6)). 13C NMR (DMSOꢀd6), δ: 43.05,
47.92, 52.70, 66.96, 67.32, 128.76, 128.87, 129.40, 130.17, 132.42,
134.70, 136.50, 140.00, 161.27. Found (%): C, 56.51; H, 4.80;
N, 24.49. C16H16N6O3. Calculated (%): C, 56.47; H, 4.74; N, 24.69.
8ꢀ(Morpholinocarbonyl)ꢀ3ꢀphenylimidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (5d). The yield was 75%, m.p. 125—127 °C.
IR, ν/cm–1: 3125, 3060, 2950, 2900, 2850 (CH); 1750, 1620
(C=O); 1595, 1560 (N=N). 1H NMR (DMSOꢀd6), δ: 3.63 (m, 4 H,
2 CH2); 3.71 (m, 4 H, 2 CH2); 7.57—7.64 (m, 5 H, C6H5); 8.96
(s, 1 H, H(6)). Found (%): C, 55.35; H, 4.40; N, 25.61.
C15H14N6O3. Calculated (%): C, 55.21; H, 4.32; N, 25.75.
8ꢀ(Morpholinocarbonyl)ꢀ3ꢀ(pꢀtolyl)imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (5e). The yield was 62%, m.p. 135—137 °C.
IR, ν/cm–1: 3110, 3060, 3035, 2960, 2910, 2860 (CH); 1725,
1630 (C=O); 1595 (N=N). 1H NMR (DMSOꢀd6),δ: 2.41 (s, 3 H,
CH3); 3.63 (m, 4 H, 2 CH2); 3.71 (m, 4 H, 2 CH2); 7.40 (d, 2 H,
H(3´), H(5´), J = 8.24 Hz); 7.50 (d, 2 H, H(2´), H(6´), J = 8.24 Hz);
8.91 (s, 1 H, H(6)). Found (%): C, 56.38; H, 4.78; N, 24.53.
C16H16N6O3. Calculated (%): C, 56.47; H, 4.74; N, 24.69.
3ꢀ(pꢀMethoxyphenyl)ꢀ8ꢀ(morpholinocarbonyl)imidazo[5,1ꢀd]ꢀ
[1,2,3,5]tetrazinꢀ4(3H)ꢀone (5f). The yield was 87%, m.p.
130—132 °C. IR, ν/cm–1: 3124, 2970, 2930, 2843 (CH); 1735,
1633 (C=O); 1570 (N=N). 1H NMR (DMSOꢀd6), δ: 3.63 (m, 4 H,
2 CH2); 3.71 (m, 4 H, 2 CH2); 3.84 (s, 3 H, OCH3); 7.14 (d, 2 H,
H(2´), H(6´), J = 8.8 Hz); 7.53 (d, 2 H, H(3´), H(5´), J = 8.8 Hz);
8.94 (s, 1 H, H(6)). 13C NMR (DMSOꢀd6), δ: 42.15, 47.03,
55.47, 66.04, 66.37, 114.27, 114.78, 128.10, 129.56, 129.81,
131.69, 138.96, 159.71, 160.29. Found (%): C, 53.98; H, 4.55;
N, 23.79. C16H16N6O4. Calculated (%): C, 53.93; H, 4.53; N, 23.58.
3ꢀ(pꢀChlorophenyl)ꢀ8ꢀ(morpholinocarbonyl)imidazo[5,1ꢀd]ꢀ
[1,2,3,5]tetrazinꢀ4(3H)ꢀone (5g). The yield was 80%, m.p.
137—139 °C. IR, ν/cm–1: 3119, 2978, 2922, 2864 (CH); 1761,
1639 (C=O); 1542 (N=N). 1H NMR (DMSOꢀd6), δ: 3.63 (m, 4 H,
2 CH2); 3.71 (m, 4 H, 2 CH2); 7.66 (d, 2 H, H(2´), H(6´),
J = 9.0 Hz); 7.70 (d, 2 H, H(3´), H(5´), J = 9.0 Hz); 8.99 (s, 1 H,
H(6)). 13C NMR (DMSOꢀd6), δ: 43.08, 47.20, 66.97, 67.27,
116.00, 129.34, 129.42; 129.48, 130.15, 130.85, 134.81, 136.87,
161.10. Found (%): C, 50.07; H, 3.64; Cl, 9.64; N, 23.41.
C15H13ClN6O3. Calculated (%): C, 49.94; H, 3.63; Cl, 9.83;
N, 23.30.
3ꢀBenzylꢀ8ꢀ(piperidinocarbonyl)imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (6c). The yield was 52%, m.p. 142—144 °C.
IR, ν/cm–1: 3124, 3004, 2934, 2855 (CH); 1749, 1622 (C=O);
1
1549 (N=N). H NMR (DMSOꢀd6), δ: 1.49—1.64 (m, 6 H,
3 CH2); 3.45—3.48 (m, 2 H, CH2); 3.63—3.66 (m, 2 H, CH2);
5.47 (s, 2 H, CH2); 7.32—7.45 (m, 3 H, H(3´), H(4´), H(5´));
7.54 (d, 2 H, H(2´), H(6´), J = 9.0 Hz); 8.81 (s, 1 H, H(6)).
13C NMR (DMSOꢀd6), δ: 24.83, 26.23, 27.16, 43.29, 48.25, 52.46,
128.73, 128.86, 129.39, 130.10, 133.47, 134.19, 136.56, 140.07,
161.11. Found (%): C, 60.46; H, 5.41; N, 24.67. C17H18N6O2.
Calculated (%): C, 60.34; H, 5.36; N, 24.84.
3ꢀPhenylꢀ8ꢀ(piperidinocarbonyl)imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (6d). The yield was 77%, m.p. 111—113 °C.
IR, ν/cm–1: 3105, 3065, 2930, 2845 (CH); 1715, 1625 (C=O);
1
1580 (N=N). H NMR (DMSOꢀd6), δ: 1.53—1.66 (m, 6 H,
3 CH2); 3.50—3.53 (m, 2 H, CH2); 3.66—3.69 (m, 2 H, CH2);
7.54—7.65 (m, 5 H, C6H5); 8.93 (s, 1 H, H(6)). Found (%):
C, 59.34; H, 5.02; N, 26.02. C16H16N6O2. Calculated (%): C, 59.25;
H, 4.97; N, 25.91.
8ꢀ(Piperidinocarbonyl)ꢀ3ꢀ(pꢀtolyl)imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (6e). The yield was 88%, m.p. 140—141 °C.
IR, ν/cm–1: 3105, 2980, 2940, 2840 (CH); 1730, 1620 (C=O);
1
1550 (N=N). H NMR (DMSOꢀd6), δ: 1.53—1.63 (m, 6 H,
3 CH2); 2.41 (s, 3 H, CH3); 3.49—3.52 (m, 2 H, CH2); 3.66—3.69
(m, 2 H, CH2); 7.39 (d, 2 H, H(3´), H(5´), J = 8.24 Hz); 7.50
(d, 2 H, H(2´), H(6´), J = 8.24 Hz); 8.88 (s, 1 H, H(6)). Found (%):
C, 60.37; H, 5.35; N, 24.76. C17H18N6O2. Calculated (%): C, 60.34;
H, 5.36; N, 24.84.
3ꢀ(pꢀMethoxyphenyl)ꢀ8ꢀ(piperidinocarbonyl)imidazo[5,1ꢀd]ꢀ
[1,2,3,5]tetrazinꢀ4(3H)ꢀone (6f). The yield was 83%, m.p.
148—150 °C. IR, ν/cm–1: 3120, 3000, 2932, 2851 (CH); 1731,
1627 (C=O); 1570 (N=N). 1H NMR (DMSOꢀd6), δ: 1.53—1.65
(m, 6 H, 3 CH2); 3.49—3.53 (m, 2 H, CH2); 3.67—3.69 (m, 2 H,
CH2); 3.84 (s, 3 H, OCH3); 7.14 (d, 2 H, H(2´), H(6´), J = 9.0 Hz);
7.54 (d, 2 H, H(3´), H(5´), J = 9.0 Hz); 8.91 (s, 1 H, H(6)).
13C NMR (DMSOꢀd6), δ: 23.89, 25.28, 26.24, 42.39, 47.36, 55.46,
114.24, 128.14, 129.50, 129.88, 132.74, 132.97, 138.99, 159.66,
160.16. Found (%): C, 57.68; H, 5.19; N, 23.85. C17H18N6O3.
Calculated (%): C, 57.62; H, 5.12; N, 23.72.
8ꢀ(Morpholinocarbonyl)ꢀ3ꢀ(1´ꢀnaphthyl)imidazo[5,1ꢀd]ꢀ
[1,2,3,5]tetrazinꢀ4(3H)ꢀone (5h). The yield was 82%, m.p.
184—186 °C. IR, ν/cm–1: 3110, 2990, 2940, 2900, 2860 (CH);
1750, 1630 (C=O); 1550 (N=N). 1H NMR (DMSOꢀd6), δ: 3.70
(m, 4 H, 2 CH2); 3.74 (m, 4 H, 2 CH2); 7.59—7.69 (m, 2 H);
3ꢀ(pꢀChlorophenyl)ꢀ8ꢀ(piperidinocarbonyl)imidazo[5,1ꢀd]ꢀ
[1,2,3,5]tetrazinꢀ4(3H)ꢀone (6g). The yield was 76%, m.p.

Synthesis of azolo[5,1ꢀd][1,2,3,5]tetrazinones
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
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143—145 °C. IR, ν/cm–1: 3117, 2983, 2948, 2858 (CH); 1754,
1639 (C=O); 1570 (N=N). 1H NMR (DMSOꢀd6), δ: 1.52—1.65
(m, 6 H, 3 CH2); 3.49—3.52 (m, 2 H, CH2); 3.66—3.69 (m, 2 H,
CH2); 7.68 (s, 4 H, H(2´), H(3´), H(5´), H(6´)); 8.96 (s, 1 H,
H(6)). 13C NMR (DMSOꢀd6), δ: 24.83, 26.23, 27.17, 43.32,
48.30, 129.43, 130.12, 130.80, 133.81, 133.99, 134.75, 136.93,
139.81, 160.98. Found (%): C, 53.67; H, 4.28; Cl, 9.67; N, 23.51.
C16H15ClN6O2. Calculated (%): C, 53.56; H, 4.21; Cl, 9.88;
N, 23.42.
8ꢀ(Pyrrolidinocarbonyl)ꢀ3ꢀnꢀpropylimidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (7a). The yield was 42%, m.p. 85—87 °C.
IR, ν/cm–1: 3120, 2960, 2950, 2870 (CH); 1725, 1615 (C=O);
1540 (N=N). 1H NMR (DMSOꢀd6), δ: 0.96 (t, 3 H, N—CH2—
ν/cm–1: 3117, 2976, 2928 (CH); 1729, 1633 (C=O); 1564 (N=N).
1H NMR (DMSOꢀd6), δ: 1.34 (t, 3 H, OCH2CH3, J = 7.02 Hz);
4.39 (q, 2 H, OCH2CH3, J = 7.02 Hz); 5.52 (s, 2 H, CH2);
7.32—7.46 (m, 5 H, C6H5); 8.85 (s, 1 H, H(6)). 13C NMR
(DMSOꢀd6), δ: 15.07, 52.96, 61.72, 127.97, 128.81, 128.92, 129.39,
130.73, 136.23, 137.34, 139.78, 161.27. Found (%): C, 56.23;
H, 4.44; N, 23.29. C14H13N5O3. Calculated (%): C, 56.18; H, 4.38;
N, 23.40.
Ethyl 4ꢀoxoꢀ3ꢀphenylimidazo[5,1ꢀd][1,2,3,5]tetrazineꢀ8ꢀ
carboxylate (8d). The yield was 85%, m.p. 121—123 °C. IR,
ν/cm–1: 3115, 2980 (CH); 1725, 1710 (C=O); 1550 (N=N).
1H NMR (DMSOꢀd6), δ: 1.36 (t, 3 H, OCH2CH3, J = 7.04 Hz);
4.43 (q, 2 H, OCH2CH3, J = 7.04 Hz); 7.58—7.66 (m, 5 H,
C6H5); 8.98 (s, 1 H, H(6)). Found (%): C, 54.63; H, 3.85; N, 24.71.
C13H11N5O3. Calculated (%): C, 54.74; H, 3.89; N, 24.55.
Ethyl 4ꢀoxoꢀ3ꢀ(pꢀtolyl)imidazo[5,1ꢀd][1,2,3,5]tetrazineꢀ8ꢀ
carboxylate (8e). The yield was 70%, m.p. 129—131 °C. IR,
ν/cm–1: 3120, 2980, 2920 (CH); 1730, 1710 (C=O); 1560 (N=N).
1H NMR (DMSOꢀd6), δ: 1.36 (t, 3 H, OCH2CH3, J = 7.02 Hz);
2.42 (s, 3 H, CH3); 4.42 (q, 2 H, OCH2CH3, J = 7.02 Hz); 7.42
(d, 2 H, H(2´), H(6´), J = 8.18 Hz); 7.52 (d, 2 H, H(3´), H(5´),
J = 8.33 Hz); 8.95 (s, 1H, H(6)). Found (%): C, 56.15; H, 4.34;
N, 23.45. C14H13N5O3. Calculated (%): C, 56.18; H, 4.38; N, 23.40.
Ethyl 3ꢀ(pꢀmethoxyphenyl)ꢀ4ꢀoxoimidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazineꢀ8ꢀcarboxylate (8f). The yield was 81%, m.p. 126—128 °C.
IR, ν/cm–1: 3118, 2930, 2838 (CH); 1733, 1648 (C=O); 1606,
1566 (N=N). 1H NMR (DMSOꢀd6), δ: 1.36 (t, 3 H, OCH2CH3,
J = 7.02 Hz); 3.85 (s, 3 H, OCH3); 4.42 (q, 2 H, OCH2CH3,
J = 7.02 Hz); 7.16 (d, 2 H, H(2´), H(6´), J = 8.8 Hz); 7.55
(d, 2 H, H(3´), H(5´), J = 8.8 Hz); 8.95 (s, 1 H, H(6)). 13C NMR
(DMSOꢀd6), δ: 15.08, 56.42, 61.81, 115.23, 128.12, 128.96,
130.62, 131.11, 136.97, 139.69, 160.73, 161.25. Found (%):
C, 53.30; H, 4.15; N, 22.18. C14H13N5O4. Calculated (%): C, 53.33;
H, 4.16; N, 22.21.
CH2—CH3, J = 7.33 Hz); 1.79—1,88 (m, 6 H, 2 CH2
+
+ N—CH2—CH2—CH3); 3.51—3.56 (m, 2 H, CH2); 3.61—3.66
(m, 2 H, CH2); 4.24 (t, 2 H, N—CH2—CH2—CH3, J = 7.33 Hz);
8.78 (s, 1 H, H(6)). Found (%): C, 52.32; H, 5.95; N, 30.19.
C12H16N6O2. Calculated (%): C, 52.17; H,5.84; N, 30.42.
3ꢀCyclohexylꢀ8ꢀ(pyrrolidinocarbonyl)imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (7b). The yield was 49%, m.p. 162—164 °C.
IR, ν/cm–1: 3110, 2960, 2930, 2880, 2860 (CH); 1720, 1625
(C=O); 1545 (N=N). 1H NMR (DMSOꢀd6), δ: 1.21—2.02
(m, 14 H, 5 CH2 + 2 CH2); 3.51—3.56 (m, 2 H, CH2); 3.61—3.66
(m, 2 H, CH2); 4.60—4.69 (m, 1 H, CH); 8.75 (s, 1 H, H(6)).
Found (%): C, 57.11; H, 6.45; N, 26.31. C15H20N6O2. Calculatꢀ
ed (%): C, 56.95; H, 6.37; N, 26.56.
3ꢀPhenylꢀ8ꢀ(pyrrolidinocarbonyl)imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (7d). The yield was 63%, m.p. 126—127 °C.
IR, ν/cm–1: 3135, 3080, 2975, 2890 (CH); 1750, 1625 (C=O);
1600, 1560 (N=N). 1H NMR (DMSOꢀd6), δ: 1.87—1.93 (m, 4 H,
2 CH2); 3.51—3.59 (m, 2 H, CH2); 3.65—3.70 (m, 2 H, CH2);
7.66—7.57 (m, 5 H, C6H5); 8.91 (s, 1 H, H(6)). Found (%): C, 58.18;
H, 4.64; N, 26.89. C15H14N6O2. Calculated (%): C, 58.06;
H, 4.55; N, 27.08.
8ꢀ(Pyrrolidinocarbonyl)ꢀ3ꢀ(pꢀtolyl)imidazo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (7e). The yield was 66%, m.p. 128—130 °C.
IR, ν/cm–1: 3115, 2980, 2950, 2880 (CH); 1740, 1620 (C=O);
1555, 1515 (N=N). 1H NMR (DMSOꢀd6), δ: 1.93—1.87 (m, 4 H,
2 CH2); 2.41 (s, 3 H, CH3); 3.59—3.53 (m, 2 H, CH2); 3.70—3.65
(m, 2 H, CH2); 7.40 (d, 2 H, H(3´), H(5´), J = 8.24 Hz); 7.51
(d, 2 H, H(2´), H(6´), J = 8.24 Hz); 8.88 (s, 1 H, H(6)). Found (%):
C, 59.31; H, 5.04; N, 25.77. C16H16N6O2. Calculated (%):
C, 59.25; H, 4.97; N, 25.91.
Ethyl 4ꢀoxoꢀ3ꢀnꢀpropylimidazo[5,1ꢀd][1,2,3,5]tetrazineꢀ8ꢀ
carboxylate (8a). The yield was 51%, m.p. 110—111 °C. IR,
ν/cm–1: 3115, 2960, 2935, 2880 (CH); 1720, 1700 (C=O); 1550
(N=N). 1H NMR (DMSOꢀd6), δ: 0.97 (t, 3 H, N—CH2—CH2—
CH3, J = 7.32 Hz); 1.35 (t, 3 H, OCH2CH3, J = 7.02 Hz);
1.78—1.92 (m, 2 H, N—CH2—CH2—CH3); 4.27 (t, 2 H,
N—CH2—CH2—CH3, J = 7.02 Hz); 4.39 (q, 2 H, OCH2CH3,
J = 7.02 Hz); 8.80 (s, 1 H, H(6)). Found (%): C, 47.89; H, 5.16;
N, 28.81. C10H13N5O3. Calculated (%): C, 47.81; H, 5.22; N, 27.87.
Ethyl 3ꢀcyclohexylꢀ4ꢀoxoimidazo[5,1ꢀd][1,2,3,5]tetrazineꢀ
8ꢀcarboxylate (8b). The yield was 60%, m.p. 121—122 °C. IR,
ν/cm–1: 3120, 2940, 2935, 2860 (CH); 1720, 1700 (C=O); 1560
(N=N). 1H NMR (DMSOꢀd6), δ: 1.22—2.04 (m, 10 H, 5 CH2);
1.34 (t, 3 H, OCH2CH3, J = 7.02 Hz); 4.39 (q, 2 H, OCH2CH3,
J = 7.02 Hz); 4.71—4.34 (m, 1 H, CH); 8.78 (s, 1 H, H(6)).
Found (%): C, 53.71; H, 5.92; N, 23.89. C13H17N5O3. Calculatꢀ
ed (%): C, 53.60; H, 5.88; N, 24.04.
Ethyl 3ꢀ(pꢀchlorophenyl)ꢀ4ꢀoxoimidazo[5,1ꢀd][1,2,3,5]tetrꢀ
azineꢀ8ꢀcarboxylate (8g). The yield was 73%, m.p. 123—125 °C.
IR, ν/cm–1: 3115, 2970, 2930 (CH); 1730, 1710 (C=O); 1560
(N=N). 1H NMR (DMSOꢀd6), δ: 1.36 (t, 3 H, OCH2CH3,
J = 7.02 Hz); 4.42 (q, 2 H, OCH2CH3, J = 7.02 Hz); 7.69 (s, 4 H,
H(2´), H(3´), H(5´), H(6´)); 8.96 (s, 1 H, H(6)). Found (%):
C, 48.92; H, 3.19; Cl, 11.17; N, 21.95. C13H10ClN5O3. Calcuꢀ
lated (%): C, 48.84; H, 3.15; Cl, 11.09; N, 21.91.
Ethyl 4ꢀoxoꢀ3ꢀphenylpyrazolo[5,1ꢀd][1,2,3,5]tetrazineꢀ8ꢀ
carboxylate (13a). The yield was 70%, m.p. 158—159 °C. IR,
ν/cm–1: 3106, 3058, 2986 (CH); 1761, 1712 (C=O); 1576 (N=N).
1H NMR (DMSOꢀd6), δ: 1.36 (t, 3 H, OCH2CH3, J = 7.02 Hz);
4.40 (q, 2 H, OCH2CH3, J = 7.02 Hz); 7.60—7.70 (m, 5 H,
H(2´), H(3´), H(4´), H(5´), H(6´)); 8.73 (s, 1 H, H(7)). 13C NMR
(DMSOꢀd6), δ: 15.07, 61.85, 109.82, 127.62, 130.09, 130.69, 138.13,
140.01, 145.21, 147.67, 161.11. Found (%): C, 54.78; H, 3.93;
N, 24.48. C13H11N5O3. Calculated (%): C, 54.74; H, 3.89; N, 24.55.
Ethyl 3ꢀ(pꢀmethoxyphenyl)ꢀ4ꢀoxopyrazolo[5,1ꢀd][1,2,3,5]ꢀ
tetrazineꢀ8ꢀcarboxylate (13b). The yield was 78%, m.p.
159—160 °C. IR, ν/cm–1: 3117, 2977, 2931, 2841 (CH); 1754,
1713 (C=O); 1583 (N=N). 1H NMR (DMSOꢀd6), δ: 1.36 (t, 3 H,
OCH2CH3, J = 7.02 Hz); 3.86 (s, 3 H, OCH3); 4.40 (q, 2 H,
OCH2CH3, J = 7.02 Hz); 7.17 (d, 2 H, H(3´), H(5´), J = 9.0 Hz);
7.59 (d, 2 H, H(2´), H(6´), J = 9.0 Hz); 8.71 (s, 1 H, H(7)).
13C NMR (DMSOꢀd6), δ: 15.07, 56.43, 61.84, 109.66, 115.21,
128.99, 130.85, 141.13, 145.24, 147.63, 160.90, 161.15.
Found (%): C, 53.31; H, 4.14; N, 22.28. C14H13N5O4. Calculatꢀ
ed (%): C, 53.33; H, 4.16; N, 22.21.
Ethyl 3ꢀbenzylꢀ4ꢀoxoimidazo[5,1ꢀd][1,2,3,5]tetrazineꢀ8ꢀ
carboxylate (8c). The yield was 92%, m.p. 117—119 °C. IR,

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Sadchikova
Ethyl 3ꢀ(pꢀchlorophenyl)ꢀ4ꢀoxopyrazolo[5,1ꢀd][1,2,3,5]ꢀ
tetrazineꢀ8ꢀcarboxylate (13c). The yield was 85%, m.p. 161—162 °C.
IR, ν/cm–1: 3093, 2979, 2930 (CH); 1762, 1708 (C=O); 1584
(N=N). 1H NMR (DMSOꢀd6), δ: 1.36 (t, 3 H, OCH2CH3,
J = 7.02 Hz); 4.40 (q, 2 H, OCH2CH3, J = 7.02 Hz); 7.72 (s, 4 H,
H(2´), H(3´), H(5´), H(6´)); 8.74 (s, 1 H, H(7)). 13C NMR
(DMSOꢀd6), δ: 15.05, 61.92, 110.02, 129.42, 130.23, 135.31,
136.90, 140.93, 145.14, 147.74, 161.04. Found (%): C, 48.88;
H, 3.17; Cl, 11.03; N, 21.86. C13H10ClN5O3. Calculated (%):
C, 48.84; H, 3.15; Cl, 11.09; N, 21.91.
IR, ν/cm–1: 3145, 3060, 2950, 2840 (CH); 1755 (C=O); 1600
(N=N). H NMR (DMSOꢀd6), δ: 3.86 (s, 3 H, OCH3); 7.04
1
(d, 2 H, H(3´), H(5´), J = 8.85 Hz); 7.56—7.70 (m, 5 H, H(2´´),
H(3´´), H(4´´), H(5´´), H(6´´)); 7.66 (s, 1 H, H(8)); 8.02 (d, 2 H,
H(2´), H(6´), J = 8.85 Hz). Found (%): C, 63.87; H, 4.04; N, 22.11.
C17H13N5O2. Calculated (%): C, 63.94; H, 4.10; N, 21.93.
3,7ꢀDi(pꢀmethoxyphenyl)pyrazolo[5,1ꢀd][1,2,3,5]tetrazinꢀ
4(3H)ꢀone (14h). The yield was 91%, m.p. 180—182 °C. IR,
ν/cm–1: 3185, 2950, 2830 (CH); 1750 (C=O); 1600 (N=N).
1H NMR (DMSOꢀd6), δ: 3.85 (s, 3 H, OCH3); 3.87 (s, 3 H, OCH3);
7.03 (d, 2 H, H(3´), H(5´), J = 8.85 Hz); 7.09 (d, 2 H, H(3´´),
H(5´´), J = 9.0 Hz); 7.56 (d, 2 H, H(2´´), H(6´´), J = 9.0 Hz);
7.66 (s, 1 H, H(8)); 8.01 (d, 2 H, H(2´), H(6´), J = 8.85 Hz).
Found (%): C, 61.91; H, 4.24; N, 20.22. C18H15N5O3. Calculatꢀ
ed (%): C, 61.89; H, 4.33; N, 20.05.
3ꢀCyclohexylꢀ7ꢀphenylpyrazolo[5,1ꢀd][1,2,3,5]tetrazinꢀ4(3H)ꢀ
one (14a). The yield was 78%, m.p. 148—150 °C. IR, ν/cm–1
:
1
3150, 2925, 2850 (CH); 1725 (C=O); 1540 (N=N). H NMR
(DMSOꢀd6), δ: 1.19—2.09 (m, 10 H, 5 CH2); 4.74 (m, 1 H,
CH); 7.49 (m, 3 H, H(3´), H(4´), H(5´)); 7.67 (s, 1 H, H(8));
8.06 (d, 2 H, H(2´), H(6´), J = 7.75 Hz). Found (%): C, 65.18;
H, 5.84; N, 23.62. C16H17N5O. Calculated (%): C, 65.07; H, 5.80;
N, 23.71.
This work was financially supported by the Ministry of
Education and Science of the Russian Federation (State
Assignment No. 4.1626.2014/K) and the Russian Founꢀ
dation for Basic Research (Project No. 14ꢀ03ꢀ01033).
3,7ꢀDiphenylpyrazolo[5,1ꢀd][1,2,3,5]tetrazinꢀ4(3H)ꢀone
(14b). The yield was 94%, m.p. 198—200 °C. IR, ν/cm–1: 3150,
1
3055 (CH); 1750 (C=O); 1550 (N=N). H NMR (DMSOꢀd6),
δ: 7.04 (d, 2 H, H(2´´), H(6´´), J = 7.75 Hz); 7.49—7.76 (m, 8 H,
H(2´), H(3´), H(4´), H(5´), H(6´), H(3´´), H(4´´), H(5´´)); 7.78
(s, 1 H, H(8)). Found (%): C, 66.41; H, 3.84; N, 24.24.
C16H11N5O. Calculated (%): C, 66.43; H, 3.83; N, 24.21.
3ꢀCyclohexylꢀ7ꢀ(pꢀtolyl)pyrazolo[5,1ꢀd][1,2,3,5]tetrazinꢀ
4(3H)ꢀone (14c). The yield was 64%, m.p. 166—168 °C. IR,
ν/cm–1: 3140, 2925, 2855 (CH); 1725 (C=O); 1540 (N=N).
1H NMR (DMSOꢀd6), δ: 1.03—2.08 (m, 10 H, 5 CH2); 2.38 (s, 3 H,
CH3); 4.72 (m, 1 H, CH); 7.35 (d, 2 H, H(3´), H(5´), J = 8.0 Hz);
7.75 (s, 1 H, H(8)); 7.97 (d, 2 H, H(2´), H(6´), J = 8.0 Hz).
Found (%): C, 65.89; H, 6.26; N, 22.73. C17H19N5O. Calculatꢀ
ed (%): C, 66.00; H, 6.19; N, 22.64.
References
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3ꢀPhenylꢀ7ꢀ(pꢀtolyl)pyrazolo[5,1ꢀd][1,2,3,5]tetrazinꢀ4(3H)ꢀ
one (14d). The yield was 72%, m.p. 200—202 °C. IR, ν/cm–1
:
1
3140, 3060, 2940 (CH); 1735 (C=O); 1550 (N=N). H NMR
(DMSOꢀd6), δ: 2.39 (s, 3 H, CH3); 7.37 (d, 2 H, H(3´), H(5´),
J = 8.0 Hz); 7.59—7.64 (m, 3 H, H(3´´), H(4´´), H(5´´)); 7.69
(d, 2 H, H(2´´), H(6´´), J = 8.0 Hz); 7.90 (s, 1 H, H(8)); 8.32
(d, 2 H, H(2´), H(6´), J = 8.0 Hz). Found (%): C, 67.37; H, 4.34;
N, 23.05. C17H13N5O. Calculated (%): C, 67.32; H, 4.32; N, 23.09.
3ꢀ(pꢀMethoxyphenyl)ꢀ7ꢀ(pꢀtolyl)pyrazolo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (14e). The yield was 77%, m.p. 207—208 °C.
IR, ν/cm–1: 3145, 3050, 2930 (CH); 1730 (C=O); 1560 (N=N).
1H NMR (DMSOꢀd6), δ: 2.39 (s, 3 H, CH3); 3.85 (s, 3 H,
OCH3); 7.15 (d, 2 H, H(2´´), H(6´´), J = 8.9 Hz); 7.37 (d, 2 H,
H(3´), H(5´), J = 8.0 Hz); 7.60 (d, 2 H, H(3´´), H(5´´), J = 8.9 Hz);
7.88 (s, 1 H, H(8)); 8.00 (d, 2 H, H(2´), H(6´), J = 8.0 Hz).
Found (%): C, 64.77; H, 4.54; N, 21.04. C18H15N5O2. Calculatꢀ
ed (%): C, 64.86; H, 4.54; N, 21.01.
3ꢀCyclohexylꢀ7ꢀ(pꢀmethoxyphenyl)pyrazolo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (14f). The yield was 88%, m.p. 150—152 °C.
IR, ν/cm–1: 3145, 2925, 2850 (CH); 1725 (C=O); 1595 (N=N).
1H NMR (DMSOꢀd6 ), δ: 1.22—2.09 (m, 10 H, 5 CH2); 3.85
(s, 3 H, OCH3); 4.73 (m, 1 H, CH); 7.01 (d, 2 H, H(3´), H(5´),
J = 8.85 Hz); 7.51 (s, 1 H, H(8)); 7.97 (d, 2 H, H(2´), H(6´),
J = 8.85 Hz). Found (%): C, 62.82; H, 5.84; N, 21.47. C17H19N5O2.
Calculated (%): C, 62.76; H, 5.89; N, 21.52.
12. Y.ꢀC. Wu, X.ꢀM. Zou, F.ꢀZ. Hu, H.ꢀZ. Yang, J. Heterocycl.
Chem., 2005, 42, 609.
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Yang, J. Fluorine Chem., 2006, 127, 409.
7ꢀ(pꢀMethoxyphenyl)ꢀ3ꢀphenylpyrazolo[5,1ꢀd][1,2,3,5]ꢀ
tetrazinꢀ4(3H)ꢀone (14g). The yield was 90%, m.p. 176—178 °C.
Received January 21, 2016;
in revised form April 21, 2016