Cyclization of (1,2,4,5-tetrazin-3-yl)hydrazones to 3,7-dihydro-1,2,4- triazolo[4,3-b]-1,2,4,5-tetrazines

Article abstract of DOI:10.1007/s11172-009-0168-2

The intramolecular cyclization of (6-R-1,2,4,5-tetrazin-3-yl)hydrazones of ketones (R is 3,5-dimethylpyrazol-1-yl, 4-methylimidazol-1-yl, or 2-alkylidenehydrazino) giving rise to the previously unknown ,7-dihydro-1,2,4-triazolo[4,3-b]-1,2,4,5-tetrazines, including spiro com-pounds, was studied. The reactivity and the yields of the reaction products depend on the structure of the alkylidene fragment and the nature of the substituent in the tetrazine ring. ; 2009 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s11172-009-0168-2

Russian Chemical Bulletin, International Edition, Vol. 58, No. 6, pp. 1281—1290, June, 2009
1281
Cyclization of (1,2,4,5ꢀtetrazinꢀ3ꢀyl)hydrazones
to 3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazines*
S. G. Tolshchina, A. G. Vyakhireva, N. K. Ignatenko, R. I. Ishmetova, I. N. Ganebnykh,
P. A. Slepukhin, and G. L. Rusinov
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 1189. Eꢀmail: rusinov@ios.uran.ru
The intramolecular cyclization of (6ꢀRꢀ1,2,4,5ꢀtetrazinꢀ3ꢀyl)hydrazones of ketones (R is
3,5ꢀdimethylpyrazolꢀ1ꢀyl, 4ꢀmethylimidazolꢀ1ꢀyl, or 2ꢀalkylidenehydrazino) giving rise to the
previously unknown 3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazines, including spiro comꢀ
pounds, was studied. The reactivity and the yields of the reaction products depend on the
structure of the alkylidene fragment and the nature of the substituent in the tetrazine ring.
Key words: 3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazines, 3,6ꢀdisubstituted
1,2,4,5ꢀtetrazines, hydrazones, cyclization, ringꢀchain isomerism, nucleophilic substitution,
alkylation.
The cyclization of hydrazones has found wide use
for the construction of various heterocyclic systems.1,2
In particular, hetarylhydrazones of aldehydes, including
1,2,4,5ꢀtetrazinylhydrazones, are oxidized to give triazoleꢀ
annulated azines3—7 (Scheme 1). Attempts to isolate
dihydrotriazoloazines failed.
The IR spectra of the hydrazones show absorption
bands at 1560—1543 cm–1 (an intense band) and 1481—
1374 cm–1 (a broad band with several maxima) characterꢀ
istic of the pyrazole moiety, as well as stretching bands of
the tetrazine ring at 1088—1076, 1040—1036, 1023—987,
and 976—950 cm–1. The electronic absorption spectra
of compounds 2a—f contain two peaks with maxima at
443—457 and 510—536 nm in the visible region.
Scheme 1
The heating of hydrazones 2a—f containing aliphatic
substituents in acetonitrile affords isomeric 3,7ꢀdihydroꢀ
1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazines 3a—f, including
spiro compounds 3a—d, in 70—85% yields (see Scheme 2).
Cyclization products 3a—f are stable crystalline comꢀ
1
pounds with m.p. > 100 °C. In the H NMR spectra of
triazolotetrazines 3, the signals for all protons are slightly
(by 0.15—0.20 ppm) shifted upfield with respect to those
of the starting hydrazones (Table 2). The chemical shift of
the carbon atom of the hydrazone group in the 13C NMR
spectra of cyclic isomers 3a—f is shifted from 167 to
104—114 ppm (Table 3). The IR spectra of triazolotetrꢀ
azines are characterized by the appearance of two intense
absorption bands at 1680—1640 cm–1. The electronic
absorption spectra of compounds 3a—f show one band
with a maximum at 435—480 nm.
The elemental analysis and LCꢀmass spectrometric
data confirmed that the cyclization is not accompanied
by changes in the elemental composition of the moleꢀ
cules. The mass spectra of hydrazones and triazoloꢀ
tetrazines (APCI, atmospheric pressure chemical ionizaꢀ
tion) have molecular ion peaks [MH]+ or [M]+ in the case
of triazolotetrazines. However, in the spectra of the cyclic
In the present study, we showed that 6ꢀsubstituted
(1,2,4,5ꢀtetrazinꢀ3ꢀyl)hydrazones of ketones prepared
from hydrazine 1 can undergo the isomerization upon
heating to give the previously unknown 3,7ꢀdihydroꢀ1,2,4ꢀ
triazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazines. To study the reactivity
depending on the structure of the compounds, we consiꢀ
dered a series of tetrazinylhydrazones 2a—n containing
alkyl, aryl, or hetaryl fragments (Scheme 2).
[6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ
3ꢀyl]hydrazones 2a—n were synthesized according to the
procedure described previously8 starting from 3ꢀhydrazinoꢀ
6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazine and
ketones (see Scheme 2, Table 1).
* Dedicated to Academician O. N. Chupakhin on the occasion
of his 75th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1245—1254, June, 2009.
1066ꢀ5285/09/5806ꢀ1281 © 2009 Springer Science+Business Media, Inc.

1282
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
Tolshchina et al.
Scheme 2
isomers, the molecular ion peak [MH – N2]+ is, as a rule,
more intense. In the reversedꢀphase column chromatoꢀ
graphy, hydrazones 2a—f are retained more weakly than
the corresponding triazolotetrazines.
The structures of the hydrazones and dihydrotriazoloꢀ
tetrazines were confirmed by the Xꢀray diffraction data
for compounds 2b and 3b (Figs 1 and 2, respectively).
The geometry of the pyrazolyltetrazine moiety in
hydrazone 2b is substantially distorted. The deviation of
the C(1) and C(2) atoms from the mean plane of the
tetrazine ring is 0.09 Å. Nevertheless, the bond conjugaꢀ
tion in the ring is retained; the bond lengths are equalized
Table 1. Reaction times and yields of compounds 2a—n, 3a—n,
9a,b, 10a,b, 12a—c, and 13a—c
Comꢀ
pound
τ* /h
Yield
(%)
Comꢀ
pound
τ* /h
Yield
(%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
9a
9b
12a
12b
12c
0.5
0.25
0.25
0.5
1
1
2
2
2
8
8
8
8
8
1
1
92
85
91
74
92
84
78
79
84
80
86
75
93
94
76
79
59
—
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
10a
10b
13a
13b
13c
5
1
3
1.5
4
82
84
74
85
77
76
16
5
23
22
21
18
Traces
Traces
86
42
57
5
10
10
10
10
10
10
10
10
1
4
4
2
4
N(4)
N(3)
N(6)
C(1)
С(7)
С(6)
С(5)
N(7)
C(8)
N(5)
C(13)
C(12)
C(11)
C(10)
C(2)
N(8)
N(1)
C(9)
N(2)
С(4)
С(3)
0.5
—
0.5
63
52
88
Fig. 1. Molecular structure of 2b in the crystal structure.
* The reaction time.

Cyclization of (1,2,4,5ꢀtetrazinyl)hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1283
1
Table 2. H NMR spectra (CDCl3) of compounds 2a—n, 3a—n, 4a,b, 5, 7a,b, 8a,b, 9a,b, 10a,b, 12a,c, and 13a—c
Comꢀ
pound
δ (J/Hz)
2a
2b
2c
2d
1.83—1.90, 1.95—2.02, 2.44—2.47, 2.62—2.66 (all m, 2 Н each, 4 СН2); 2.37 (s, 3 Н, C(3)Me); 2.59 (s, 3 Н, (5)Me); 6.12
(s, 1 Н, Н(4)); 8.41 (br.s, 1 Н, NH)
1.70—1.82 (m, 6 Н, 3 СН2); 2.37 (s, 3 Н, C(3)Me); 2.46—2.59 (m, 4 Н, 2 СН2); 2.59 (s, 3 Н, C(5)Me); 6.12 (s, 1 Н, Н(4));
8.66 (br.s, 1 Н, NH)
1.65 (m, 4 Н, 2 СН2); 1.73, 1.85, 2.58, 2.69 (all m, 2 Н each, 4 СН2); 2.37 (s, 3 Н, C(3)Me); 2.59 (s, 3 Н, C(5)Me); 6.12 (s,
1 Н, Н(4)); 8.61 (br.s, 1 Н, NH)
1.86—2.10 (m, 12 Н, 2 СН, 5 СН2); 2.37 (s, 3 Н, C(3)Me); 2.59 (s, 3 Н, C(5)Me); 2.92, 3.25 (both br.s, 1 Н each, 2 СН); 6.12 (s,
1 Н, Н(4)); 8.72 (br.s, 1 Н, NH)
2e
2f
2.09, 2.21 (both s, 3 H each, 2 Ме); 2.37 (s, 3 Н, C(3)Me); 2.60 (s, 3 Н, C(5)Me); 6.12 (s, 1 Н, Н(4)); 8.57 (br.s, 1 Н, NH)
1.21 (t, 3Н, СН2Ме, J = 7.5); 2.06 (s, 3 Н, Ме); 2.37 (s, 3 Н, C(3)Me); 2.50 (q, 2 Н, СН2Ме, J = 7.5); 2.60 (s, 3 Н, C(5)Me);
6.12 (s, 1 Н, Н(4)); 8.52 (br.s, 1 Н, NH)
2g
2h
2.37 (s, 3 Н, C(3)Me); 2.46 (s, 3 H, Ме); 2.62 (s, 3 Н, C(5)Me); 6.13 (s, 1 Н, Н(4)); 7.50 (m, 5 H, Ph); 8.97 (br.s, 1 H, NH)
2.38 (s, 3 Н, C(3)Me); 2.40 (s, 3 H, Ме); 2.63 (s, 3 Н, C(5)Me); 6.14 (s, 1 Н, Н(4)); 7.54, 7.76 (both m, 2 H each, Ar); 8.97
(br.s, 1 H, NH)
2i
2.38 (s, 3 Н, C(3)Me); 2.42 (s, 3 H, Ме); 2.63 (s, 3 Н, C(5)Me); 3.86 (s, 3 Н, ОМе); 6.14 (s, 1 Н, Н(4)); 6.94, 7.85 (both m,
2 H each, Ar); 8.83 (br.s, 1 H, NH)
2j*
2k
2l
2.25 (s, 3 Н, C(3)Me); 2.41 (s, 3 H, Ме); 2.46 (s, 3 Н, C(5)Me); 6.23 (s, 1 Н, Н(4)); 6.82, 7.75 (both m, 2 H each, Ar); 9.79
(s, 1 Н, ОН); 11.45 (br.s, 1 H, NH)
1.47 (m, 18 Н, 2 But); 2.38 (s, 3 Н, C(3)Me); 2.43 (s, 3 Н, Ме); 2.63 (s, 3 Н, C(5)Me); 5.46 (br.s, 1 H, OH); 6.13 (s, 1 Н, Н(4));
7.69 (s, 2 Н, Ar); 8.78 (br.s, 1 Н, NH)
2.39 (s, 3 Н, C(3)Me); 2.60 (s, 3 H, Ме); 2.65 (s, 3 Н, C(5)Me); 6.15 (s, 1 Н, Н(4)); 7.29, 7.75, 8.32, 8.63 (all m, 1 H each, py);
8.99 (br.s, 1 H, NH)
2m
2n
3a
3b
2.38 (s, 3 Н, C(3)Me); 2.47 (s, 3 H, Ме); 2.63 (s, 3 Н, C(5)Me); 6.14 (s, 1 Н, Н(4)); 7.07, 7.40 (both m, 1 Н и 2 Н,
2ꢀthienyl); 8.81 (br.s, 1 Н, NH)
2.38 (s, 3 Н, C(3)Me); 2.43 (s, 3 H, Ме); 2.63 (s, 3 Н, C(5)Me); 6.14 (s, 1 Н, Н(4)); 7.34, 7.62, 7.73 (all m, 1 Н each,
3ꢀthienyl); 8.79 (br.s, 1 Н, NH)
1.94—2.08, 2.17—2.20 (both m, 4 Н each, 4 СН2); 2.23 (s, 3 Н, C(3)Me); 2.45 (s, 3 Н, C(5)Me); 5.99 (s, 1 Н, Н(4));
8.44 (br.s, 1 Н, NH)
1.58, 2.01 (both m, 2 Н each, 2 СН2); 1.76—1.89 (m, 6 Н, 3 СН2); 2.23 (s, 3 Н, C(3)Me); 2.45 (s, 3 Н, C(5)Me); 5.99
(s, 1 Н, Н(4)); 8.46 (br.s, 1 Н, NH)
3c
3d
1.72—2.04 (m, 12 Н, 6 СН2); 2.23 (s, 3 Н, C(3)Me); 2.46 (s, 3 Н, C(5)Me); 5.99 (s, 1 Н, Н(4)); 8.41 (br.s, 1 Н, NH)
1.77—1.80, 2.47—2.50, 2.80—2.83 (all m, 2 Н each, 3 СН2); 1.87 (m, 6 Н, 2 СН, 2 СН2); 2.01, 2.20 (both br.s, 1 Н each, 2 СН);
2.23 (s, 3 Н, C(3)Me); 2.44 (s, 3 Н, C(5)Me); 5.99 (s, 1 Н, Н(4)); 8.55 (br.s, 1 Н, NH)
1.62 (s, 6 H, 2 Ме); 2.23 (s, 3 Н, C(3)Me); 2.45 (s, 3 Н, C(5)Me); 5.99 (s, 1 Н, Н(4)); 8.47 (br.s, 1 Н, NH)
0.95 (t, 3 Н, СН2Ме, J = 7.5); 1.54 (s, 3 Н, Ме); 2.09 (q, 2 Н, СН2Ме, J = 7.5); 2.23 (s, 3 Н, C(3)Me); 2.44 (s, 3 Н,
C(5)Me); 5.99 (s, 1 Н, Н(4)); 8.41 (br.s, 1 Н, NH)
3e
3f
3g
1.84 (s, 3 H, Ме); 2.24 (s, 3 Н, C(3)Me); 2.43 (s, 3 Н, C(5)Me); 6.00 (s, 1 Н, Н(4)); 7.36—7.46 (m, 3 H, Ph); 7.66 (m, 2 H,
Ph); 8.55 (br.s, 1 H, NH)
3h
3i
1.81 (s, 3 H, Ме); 2.24 (s, 3 Н, C(3)Me); 2.43 (s, 3 Н, C(5)Me); 6.01 (s, 1 Н, Н(4)); 7.55 (m, 4 H, Ar); 8.59 (br.s, 1 H, NH)
1.82 (s, 3 H, Ме); 2.24 (s, 3 Н, C(3)Me); 2.42 (s, 3 Н, C(5)Me); 3.82 (s, 3 Н, ОМе); 5.99 (s, 1 Н, Н(4)); 6.95, 7.55 (both m,
2 H each, Ar); 8.53 (br.s, 1 H, NH)
3j
1.81 (s, 3 H, Ме); 2.24 (s, 3 Н, C(3)Me); 2.42 (s, 3 Н, C(5)Me); 5.37 (s, 1 Н, ОН); 5.99 (s, 1 Н, Н(4)); 6.88, 7.50 (both m,
2 H each, Ar); 8.53 (br.s, 1 H, NH)
3k
3l
1.45 (m, 18 Н, 2 But); 1.81 (s, 3 Н, Ме); 2.24 (s, 3 Н, C(3)Me); 2.43 (s, 3 Н, C(5)Me); 5.31 (br.s, 1 H, OH); 6.00 (s, 1 Н,
Н(4)); 7.44 (s, 2 Н, Ar); 8.49 (br.s, 1 Н, NH)
2.00 (s, 3 H, Ме); 2.23 (s, 3 Н, C(3)Me); 2.35 (s, 3 Н, C(5)Me); 5.97 (s, 1 Н, Н(4)); 7.30, 7.50, 7.73, 8.73 (all m, 1 H each,
py); 8.58 (br.s, 1 H, NH)
3m
3n
1.92 (s, 3 H, Ме); 2.23 (s, 3 Н, C(3)Me); 2.42 (s, 3 Н, C(5)Me); 5.98 (s, 1 Н, Н(4)); 7.14, 7.61 (both m, 1 Н and 2 Н,
2ꢀthienyl); 8.23 (br.s, 1Н, NH)
1.86 (s, 3 H, Ме); 2.23 (s, 3 Н, C(3)Me); 2.40 (s, 3 Н, C(5)Me); 5.98 (s, 1 Н, Н(4)); 7.22, 7.38, 7.45 (all m, 1 Н each,
3ꢀthienyl); 8.59 (br.s, 1 Н, NH)
(to be continued)

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
Tolshchina et al.
Table 2. (continued)
Comꢀ
pound
δ (J/Hz)
4a
4b
5*
1.54—1.96 (m, 10 Н, 5 СН2); 2.24 (s, 3 Н, C(3)Me); 2.29 (s, 3 Н, C(5)Me); 3.01 (s, 3 Н, N—Ме); 5.94 (s, 1 Н, Н(4))
1.59 (s, 6Н, 2 Ме); 2.24 (s, 3 Н, C(3)Me); 2.28 (s, 3 Н, C(5)Me); 2.98 (s, 3Н, NMe); 5.94 (s, 1 Н, Н(4))
2.16 (s, 3 Н, C(3)Me); 2.20 (s, 3 Н, C(5)Me); 6.03 (s, 1 Н, Н(4))
7a
7.45, 7.68, 7.89, 8.72, 8.52 (all m, 2 Н each, 2 indazolyls)
7b
2.37 (s, 6 Н, 2 С(4)Ме); 7.71 (s, 2 Н, 2 Н(5)); 8.65 (s, 2 Н, 2 Н(2))
8a*
8b*
9a
4.68 (br.s, 2 Н, NH2); 7.38, 7.61, 7.96, 8.25, 8.57 (all m, 1 Н each, indazolyl); 9.68 (br.s, 1 Н, NH)
2.21 (s, 3 Н, С(4)Ме); 4.63 (br.s, 2 Н, NH2); 7.65 (s, 1 Н, Н(5)); 8.41 (s, 1 Н, Н(2)); 9.68 (br.s, 1 Н, NH)
1.70—1.84 (m, 6 Н, 3 СН2); 2.49—2.57 (m, 4 Н, 2 СН2); 7.38, 7.60, 7.85, 8.41, 8.56 (all m, 1 Н each, indazolyl);
8.68 (br.s, 1 Н, NH)
9b
1.69—1.84 (m, 6 Н, 3 СН2); 2.33 (s, 3 Н, С(4)Ме); 2.47—2.54 (m, 4 Н, 2 СН2); 7.62 (s, 1 Н, Н(5)); 8.53 (s, 1 Н, Н(2));
8.71 (br.s, 1 Н, NH)
10a
10b
12a
12с
13a
13b
13c
1.87—2.15 (m, 10 Н, 5 СН2); 7.35, 7.57, 7.78, 8.14, 8.18 (all m, 1 Н each, indazolyl); 8.51 (br.s, 1 Н, NH)
1.55—2.03 (m, 10 Н, 5 СН2); 2.26 (s, 3 Н, С(4)Ме); 7.01 (s, 1 Н, Н(5)); 7.49 (br.s, 1 Н, NH); 7.93 (s, 1 Н, Н(2))
1.79—1.86, 1.91—1.98, 2.40, 2.60 (all m, 4 Н each, 8 СН2); 7.99 (br.s, 2 Н, 2 NH)
2.02, 2.17 (both s, 6 Н each, 4 Ме); 8.11 (br.s, 2 Н, 2 NH)
1.73—1.80, 1.84—1.91, 2.17, 2.40 (all m, 2 Н each, 4 СН2); 1.90—2.15 (m, 8 Н, 4 СН2); 7.12, 7.84 (both br.s, 1 Н each, 2 NH)
1.60—1.75 (m, 10 Н, 5 СН2); 1.83—2.06 (m, 6 Н, 3 СН2); 2.17—2.29 (m, 4 Н, 2 СН2); 7.39, 7.93 (both br.s, 1 Н each, 2 NH)
1.56 (s, 6 Н, 2 Ме); 1.81, 1.99 (both s, 3 Н each, 2 Ме); 7.18, 7.91 (both br.s, 1 Н each, 2 NH)
* DMSOꢀd6.
Table 3. 13C NMR spectra (CDCl3) of compounds 2a and 3a—f
Comꢀ
δ
pound
1, 2
13.7
14.0, 13.4
14.1, 13.5
14.2, 13.4
14.1, 13.5
3
4
5
6
7
8
R, R´
2а
3a
3b
3c
3d
152.5
150.6
150.6
150.5
150.6
110.1
110.4
110.4
110.4
110.4
142.4
142.3
142.3
142.3
142.1
158.5
141.9
142.0
142.0
142.4
160.0
162.1
162.3
161.9
162.6
167.3
114.1
106.5
110.2
110.7
24.7, 24.8, 27.7, 33.6 (4 CH2)
25.1, 34.1 (4 CH2)
22.7, 24.9, 33.3 (5 CH2)
23.2, 30.5, 34.9 (6 CH2)
26.6, 27.9, 33.4, 35.1, 37.4,
37.7 (adamantane)
3e
3f
14.0, 13.5
14.0, 13.5
150.6
150.6
110.4
110.4
142.5
142.5
142.0
141.9
162.2
162.5
104.8
107.3
22.9 (2 Ме)
20.1, 30.4, 7.7 (Ме, Еt)
С(9)
C(5)
C(4)
С(8)
C(3)
С(7)
С(10)
N(5)
N(7)
C(2)
C(1)
С(6)
С(11)
N(1)
H
N(6)
C(13)
3a—f
N(8)
R + R´ = (CH2)4 (a), (CH2)5 (b), (CH2)6 (c), 2ꢀadamantane (d),
R = R´ = Me (e), R = Me, R´ = Et (f)
C(12)
N(4)
N(2)
N(3)
As can be seen from Table 4, the H(7) atom is forꢀ
mally involved in intermolecular hydrogen bonds with
both the N(6) atom of the pyrazole ring and the N(3) atom
of the tetrazine ring. However, the geometry of the interꢀ
molecular hydrogen bonds indicates that the bond with
the pyrazole nitrogen atom plays a decisive role, whereas
the intermolecular hydrogen bond with the tetrazine ring
Fig. 2. Molecular structure of 3b in the crystal structure.
and are, on the average, 1.33(1) Å. The pyrazolyl subꢀ
stituent is not in the plane of the tetrazine ring (the angle
between the mean planes of the rings is 24.68°) and is
involved in intermolecular hydrogen bonds (Table 4).

Cyclization of (1,2,4,5ꢀtetrazinyl)hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1285
Table 4. Intermolecular hydrogen bonds in the crystal structures of compounds 2b, 3b, and 3i
Comꢀ
pound
D—H
d(D—H) d(H..A)
<DHA
/deg
d(D...A)
/Å
A
[symmetry code]
Å
2b
2b
3b
3i
N(7)—H(7)
N(7)—H(7)
N(4)—H(4)
N(2)—H(2)
1.030
1.030
0.93(1)
0.97(1)
2.064
2.551
2.24(1)
2.23(1)
154.78
132.95
137(1)
137(1)
3.027
3.339
2.996(2)
3.009(2)
N(6) [–x + 2, y – 1/2, –z + 1/2]
N(3) [–x + 2, y – 1/2, –z + 1/2]
N(3) [–x + 1, –y + 1, –z + 1]
N(1) [–x, –y, –z + 2]
is much closer to the usual polar contact than to the
standard hydrogen bond. The presence of a system of
intermolecular hydrogen bonds and the nonpolar cycloꢀ
hexyl fragments determines the molecular packing. The
polar parts of the molecules are linked through intermoꢀ
lecular hydrogen bonds to form zigzag chains, which are
separated by layers formed by the cyclohexyl rings.
Unlike compound 2b, the aromaticity of compound
3b is disturbed. The tetrazine ring of compound 3b adopts
a pseudoꢀboat conformation with the hydrogen atom at
the N(4) atom being in the equatorial orientation. The
N(6) and N(4) atoms are sp3ꢀhybridized, as is evident
from the geometry of the bonds that form a trigonal
pyramid with the nitrogen atom at the vertex. The
N(5)=C(13) fragment is in the plane with the pyrazolyl
substituent (the N(5)C(13)N(7)N(8) torsion angle is
–172.67°), which is indicative of the involvement of this
fragment in the conjugation system of the pyrazole ring.
In the crystals, spiro compound 3b forms hydrogenꢀ
bonded dimers (see Table 4).
Unlike aromatic 1,2,4,5ꢀtetrazines8,9 and 1,2,4ꢀtriꢀ
azolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazines,10 the 3,5ꢀdimethylpyrazolyl
group in dihydrotriazolotetrazines 3a—f is not replaced
by amines. According to the TLC data, triazolotetrazines
3b,e remained intact after refluxing in acetonitrile with
heptylamine or piperidine for 2 h. In DMSO, compounds
3b,e form brightꢀblue salts with potassium hydroxide, and
these salts give the methylation products at the nitrogen
C(11)
N(2)
C(1)
N(1)
N(8)
N(5)
C(6)
C(2)
C(7)
N(6)
C(8)
N(7)
C(4)
N(4)
C(5)
N(3)
C(9)
C(10)
C(3)
Fig. 3. Molecular structure of 4b in the crystal structure.
atom in position 7 (4a,b) in 60—65% yields (Scheme 3),
1
which is confirmed by H NMR spectroscopy, elemental
analysis, and the Xꢀray diffraction study of 4b (see Fig. 3).
According to the Xꢀray diffraction data, compound 4b
crystallizes in the chiral monoclinic space group P21.
The geometry of 4b is similar to that of product 3b. The
essential difference is that the pyrazolyl substituent is not
conjugated to the N(3)=C(2) fragment (the N(3)C(2)ꢀ
N(7)N(8) torsion angle is –119.65°) due to the steric
effect of the alkyl substituent.
In acetonitrile and alcohols, triazolotetrazines are hyꢀ
drolyzed under the action of KOH to give the potassium
salt of 3ꢀhydroxyꢀ6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀ
tetrazine 5 (see Scheme 3).
Scheme 3
4a,b
R—R´ = (CH2)5 (3b, 4a); R = R´ = Me (3e, 4b)

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Tolshchina et al.
According to the TLC, LCꢀmass spectrometric, and
1H and 13C NMR spectroscopic data in solution, the
reverse transformation of cyclic isomers 3a—f into
the chain isomers was not observed. It was shown that
triazolotetrazine 3b did not give the corresponding hydrꢀ
azone 2b after refluxing in acetonitrile for 10 h.
The introduction of aromatic substituents into the
alkylidene fragment leads to a substantial decrease in
the ability of tetrazinylhydrazones 2g—n to form cyclic
3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazines (see
Table 1). Thus, according to the 1H NMR data, the conꢀ
tent of cyclic isomers 3g—n in the reaction mixture after
refluxing of hydrazones 2g—n in acetonitrile for 10 h
was no higher than 45%. The yields of 3ꢀArꢀ3ꢀmethylꢀ
3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazines 3g—l
decrease from 23 to 5% in the following series: 4ꢀROC6H4
(i, j), 4ꢀOHꢀC6H2(But)2 (k) > 4ꢀC5H4N (l) > Ph (g) >
4ꢀВrC6H4 (h). In the presence of thienyl substituents in
the alkylidene fragment of hydrazones, cyclization prodꢀ
ucts 3m,n were formed in trace amounts (2—3% accordꢀ
3b,i, 4b
R″ = H (3), Me (4), R +R´ = (CH2)5 (3b, 4b), R = Me, R´= 4ꢀMeOC6H4 (3i)
Table 5. Selected bond lengths (d) and bond angles (ω) in molꢀ
ecules 3b,i and 4b
Parameter
Bond
3b
3i
4b
d/Å
N(1)—N(2)
N(2)—C(3)
C(3)—N(4)
N(4)—C(9)
N(1)—C(9)
N(4)—N(5)
N(5)—C(6)
C(6)—N(7)
N(7)—N(8)
N(8)—C(9)
1.260(2)
1.489(2)
1.471(2)
1.378(2)
1.419(2)
1.442(2)
1.271(2)
1.383(2)
1.419(2)
1.269(2)
1.261(2)
1.512(3)
1.472(3)
1.391(2)
1.414(3)
1.446(2)
1.276(2)
1.384(3)
1.419(2)
1.265(3)
1.252(3)
1.494(4)
1.459(3)
1.387(3)
1.427(3)
1.440(2)
1.279(3)
1.377(3)
1.419(3)
1.261(3)
1
ing to the H NMR data for the reaction mixtures) and
were not isolated.
Triazolotetrazines 3g—n containing aromatic subꢀ
stituents can be transformed into the starting hydrazones
2g—n. Thus, after refluxing of product 3g in acetonitrile
for 10 h, the ratio of isomers 2g and 3g in the reaction
mixture was 1 : 3 (1H NMR data). In addition, the 1H NMR
spectrum of the reaction mixture shows signals assigned
to degradation products of triazolotetrazine 3g, which were
formed in amounts comparable to those of the ringꢀcleavꢀ
age product.
Therefore, triazolotetrazines containing aromatic subꢀ
stituents are less stable than the products containing alkyl
groups and can undergo the reverse tautomeric transforꢀ
mation to the corresponding hydrazones and also can be
decomposed with the elimination of nitrogen, as evidenced
by the massꢀspectrometric data. Apparently, this is
responsible for the low yields of aromatic derivatives
of triazolotetrazines 3g—n.
The different stability of the cyclization products canꢀ
not be unambiguously attributed to the structural features
of the molecules. As exemplified by compound 3i (Fig. 3,
Table 5), the structural features of triazolotetrazines
containing aromatic substituents are similar to the correꢀ
sponding characteristics of stable molecules 3b and 4b
containing aliphatic fragments (see Table 5). Like comꢀ
pound 3b, product 3i forms dimers in the crystals with a
similar geometry of intermolecular hydrogen bonds (see
Table 4). The structure of compound 3i is characterized
by an increase in the torsion angle between the planes of
the pyrazolyl substituent and the C(2)N(3) fragment by 10°
compared to that observed in 3b (N(3)C(2)N(7)N(8) =
= –161.33°)
Angle
ω/deg
N(2)—C(3)—N(4) 101.3(2)
C(3)—N(4)—C(9) 105.9(2)
102.0(2)
105.5(2)
110.6(2)
108.8(2)
111.8(2)
125.6(2)
109.8(2)
113.7(2)
124.8(2)
109.7(2)
111.6(2)
102.7(2)
106.0(2)
110.0(2)
108.6(3)
112.2(2)
125.5(2)
108.8(2)
113.6(2)
123.7(2)
109.3(2)
110.0(2)
N(4)—C(9)—N(1) 109.8(2)
C(9)—N(1)—N(2) 108.3(2)
N(1)—N(2)—C(3) 112.4(2)
N(4)—C(9)—N(8) 125.4(2)
C(9)—N(8)—N(7) 109.8(2)
C(6)—N(7)—N(8) 114.5(2)
N(5)—C(6)—N(7) 124.7(2)
N(4)—N(5)—C(6) 109.7(2)
C(9)—N(4)—N(5) 112.9(2)
(Scheme 4) does not lead to a change in the reactivity in
the cyclization reaction, and the corresponding triazoloꢀ
tetrazine 10a is produced in 86% yield. On the contrary,
product 10b is formed from hydrazone 9b containing the
4ꢀmethylimidazolyl substituent more slowly and in lower
N(6)
N(5)
C(9)
C(11)
C(3)
C(1)
C(12)
N(1)
N(2)
C(10)
N(4)
C(15)
C(13)
C(2)
N(3)
O(1)
C(5)
N(7)
C(6)
N(8)
C(7)
C(14)
C(16)
C(4)
C(8)
The replacement of the 3,5ꢀdimethylpyrazolyl subꢀ
stituent by the indazolꢀ1ꢀyl group in hydrazone 9a
Fig. 4. Molecular structure of 3i in the crystal structure.

Cyclization of (1,2,4,5ꢀtetrazinyl)hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1287
Scheme 4
R =
(a),
(b)
Scheme 5
R—R = (CH2)4 (a), (CH2)5 (b); R = Me (c)
yield (42%) compared to 10a. Apparently, the cyclic form
is stabilized by an intramolecular hydrogen bond with the
involvement of the hydrogen atom in position 7 of
triazolotetrazine and the nitrogen atom in position 2 of
the substituent.
In the case of dihydrazones 12a—c synthesized from
3,6ꢀdihydrazinoꢀ1,2,4,5ꢀtetrazine (11), only one hydrꢀ
azone group was involved in the cyclization, and the
tricyclic system was not formed (Scheme 5).
Experimental
The NMR spectra were recorded on a Bruker Avance
DRXꢀ400 instrument operating at 400 MHz with Me4Si as the
internal standard. The chemical shifts are given on the δ scale
in ppm. The IR spectra were measured on a Perkin Elmer
Spectrum One Fourierꢀtransform IR spectrometer equipped with
a diffuse reflectance attachment. The diffuse reflectance UV
spectra were recorded on a Shimadzu UVꢀ2401 PC spectrophoꢀ
tometer using an integrating sphere assembly (barium sulfate
as the reference pellet). The mass spectra were obtained after
the chromatographic separation on a Shimadzu LCMSꢀ2010
LCꢀmass spectrometer (Supelcosil LCꢀ18 column, 250Ѕ4.6 mm,
5 μm; MeCN—H2O mobile phase, 65 : 35; the flow rate was
1 mL min–1; the temperature of the column was 60 °C; the
APCI ionization mode; the temperature of the ion source was
400 °C; the rate of the gas flow was 2.5 L min–1; the other
parameters of the mass spectrometer were specified according to
the auto tuning procedure). The melting points were determined
on a Boetius hot stage. The elemental analysis was carried out
on an automated Perkin—Elmer PEꢀ2400 analyzer. The course
of the reactions was monitored and the purity of the reaction
products was checked by TLC on plates with a fixed Sorbfil layer
using 1 : 1 benzene—acetonitrile and 2 : 4 : 1 hexane—benzene—
acetonitrile mixtures as the eluents.
Attempts to isolate dihydrazone 12b containing the
cyclohexanone moiety failed because it easily undergoes
cyclization to give compound 13b.
To sum up, we discovered for the first time the isomerꢀ
ization of tetrazinylhydrazones of ketones giving rise to
the previously unknown 3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀ
b]ꢀ1,2,4,5ꢀtetrazines. It was shown that aliphatic substituꢀ
ents in the alkylidene fragment promote the transformaꢀ
tion, whereas the presence of aromatic and heteroaromatic
groups leads to a decrease in the ability of hydrazones to
undergo cyclization, as well as in the yields and stability
of the reaction products. In addition, the cyclization of
tetrazinylhydrazones is influenced by the substituent in
position 6 of the tetrazine ring.

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Tolshchina et al.
Compounds 1 and 11 have been described previously.9,11
3ꢀHydrazinoꢀ6ꢀRꢀ1,2,4,5ꢀtetrazines 8a,b were synthesized
analogously to compound 1.9 Compounds 2a—n, 9a,b, 12a,c,
and 13b were synthesized for the first time according to a proceꢀ
dure described previously.8
2ꢀCyclopentylideneꢀ1ꢀ[6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀ
tetrazinꢀ3ꢀyl]hydrazine (2a), m.p. 123—125 °C. Found (%):
C, 52.87; H, 6.20; N, 41.16. C12H16N8. Calculated (%):
C, 52.93; H, 5.92; N, 41.15. IR, ν/cm–1: 1644, 1631, 1555,
1475, 1412, 1358, 1088, 1039, 1023, 967. UV (λmax/nm (А)):
446 (0.559), 510 (0.500). MS, m/z (I (%)): 273 (100) [MH]+,
the retention time RT 2.9 min.
2ꢀCyclohexylideneꢀ1ꢀ[6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀ
tetrazinꢀ3ꢀyl]hydrazine (2b), m.p. 140—141 °C. Found (%):
C, 54.66; H, 6.25; N, 39.00. C13H18N8. Calculated (%):
C, 54.53; H, 6.34; N, 39.13. IR, ν/cm–1: 1630, 1556, 1478,
1462, 1411, 1364, 1085, 1039, 1023, 976, 965. UV (λmax/nm (А)):
451 (0.339), 514 (0.321). MS, m/z (I (%)): 287 (89) [MH]+, 259
(100) [MH – N2]+, RT 3.1 min.
Found (%): C, 55.44; H, 4.88; N, 34.46. C15H16N8O. Calcuꢀ
lated (%): C, 55.55; H, 4.97; N, 34.55.
1ꢀ[1ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ethylidene]ꢀ2ꢀ
[6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ3ꢀyl]hydrazine
(2k), m.p. 182—184 °C. Found (%): C, 63,31; H, 7.62;
N, 25.82. C23H32N8O. Calculated (%): C, 63.28; H, 7.39;
N, 25.67.
1ꢀ[6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ3ꢀyl]ꢀ
2ꢀ[1ꢀ(2ꢀpyridyl)ethylidene]hydrazine (2l), m.p. 198—200 °C.
Found (%): C, 54.35; H, 4.86; N, 40.93. C14H15N9. Calcuꢀ
lated (%): C, 54.36; H, 4.89; N, 40.75.
1ꢀ[6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ3ꢀyl]ꢀ
2ꢀ[1ꢀ(2ꢀthienyl)ethylidene]hydrazine (2m), m.p. 191—193 °C.
Found (%): C, 49.24; H, 4.43; N, 35.62. C13H14N8S. Calcuꢀ
lated (%): C, 49.67; H, 4.49; N, 35.64.
1ꢀ[6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ3ꢀyl]ꢀ
2ꢀ[1ꢀ(3ꢀthienyl)ethylidene]hydrazine (2n), m.p. 173—175 °C.
Found (%): C, 49.71; H, 4.43; N, 35.68. C13H14N8S. Calcuꢀ
lated (%): C, 49.67; H, 4.49; N, 35.64.
2ꢀCycloheptylideneꢀ1ꢀ[6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀ
tetrazinꢀ3ꢀyl]hydrazine (2c), m.p. 124—126 °C. Found (%):
C, 56.23; H, 6.76; N, 37.35. C14H20N8. Calculated (%):
C, 55.98; H, 6.71; N, 37.31. IR, ν/cm–1: 1624, 1569, 1536,
1466, 1450, 1420, 1408, 1378, 1365, 1342, 1063, 1039, 1022,
971, 957. UV (λmax/nm (А)): 456 (0.446), 536 (0.373). MS, m/z
(I (%)): 301 (96) [MH]+, 273 (48) [MH – N2]+, RT 2.8 min.
1ꢀAdamantanylideneꢀ2ꢀ[6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀ
tetrazinꢀ3ꢀyl]hydrazine (2d), m.p. 176—178 °C. Found (%):
C, 60.54; H, 6.80; N, 33.19. C17H22N8. Calculated (%): C, 60.34;
H, 6.55; N, 33.11. IR, ν/cm–1: 1644, 1563, 1484, 1450, 1416,
1381, 1350, 1328, 1086, 1042, 1023, 967, 950. UV (λmax/nm (А)):
457 (0.542), 522 (0.500). MS, m/z (I (%)): 339 (100) [MH]+,
RT 3.8 min.
1ꢀ[6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ3ꢀyl]ꢀ
2ꢀ(propꢀ2ꢀylidene)hydrazine (2e), m.p. 151—153 °C. Found (%):
C, 48.93; H, 5.34; N, 45.79. C10H14N8. Calculated (%):
C, 48.77; H, 5.73; N, 45.50. IR, ν/cm–1: 1666, 1635, 1568,
1543, 1481, 1418, 1374, 1076, 1036, 987, 960. UV (λmax/nm (А)):
443 (0.332), 528 (0.306). MS, m/z (I (%)): 247 (100) [MH]+,
219 (94) [MH – N2]+, RT 2.7 min.
1ꢀ(Butꢀ2ꢀylidene)ꢀ2ꢀ[6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀ
tetrazinꢀ3ꢀyl]hydrazine (2f), m.p. 120—123 °C. Found (%):
C, 50.76; H, 6.19; N, 43.04. C11H16N8. Calculated (%): C, 50.76;
H, 6.20; N, 43.05. IR, ν/cm–1: 1630, 1562, 1479, 1409, 1373,
1328, 1080, 1038, 1023, 976. UV (λmax/nm (А)): 445 (0.459),
510 (0.450). MS, m/z (I (%)): 261 (100) [MH]+, 233 (36)
[MH – N2]+, RT 2.9 min.
1ꢀ[6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ3ꢀyl]ꢀ
2ꢀ(1ꢀphenylethylidene)hydrazine (2g). M.p. 175—177 °C.
Found (%): C, 58.61; H, 5.34; N, 36.42. C15H16N8. Calculꢀ
ated (%): C, 58.43; H, 5.23; N, 36.34.
Synthesis of 3ꢀRꢀ3ꢀR´ꢀ6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ
3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazines 3a—l
(general method). A solution of hydrazone 2a—l (1 mmol) in
acetonitrile (7 mL) was refluxed for 1—10 h. The solvent was
evaporated. In the synthesis of 3a—f, the residue was washed
with ethanol and filtered off. Compounds 3g—l were isolated by
column chromatography on silica gel Lancaster 0.040—0.063 mm
(230—400 mesh) using
a hexane—benzene—acetonitrile
mixture (2 : 4 : 1) as the eluent (Rf = 0.85).
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ3ꢀspirocyclopentaneꢀ3,7ꢀdiꢀ
hydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (3a), m.p. 105—
107 °C. Found (%): C, 52.86; H, 5.94; N, 41.21. C12H16N8.
Calculated (%): C, 52.93; H, 5.92; N, 41.15. IR, ν/cm–1: 1678,
1643, 1576, 1486, 1449, 1423, 1361, 1324, 1078, 1048, 996, 975,
949, 924. UV, (λmax/nm (А)): 461 (0.465). MS, m/z (I (%)): 273
(25) [MH]+, 245 (100) [MH – N2]+, RT 6.0 min.
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ3ꢀspirocyclohexaneꢀ3,7ꢀdiꢀ
hydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (3b), m.p. 125—
126 °C. Found (%): C, 54.21; H, 6.45; N, 38.87. C13H18N8.
Calculated (%): C, 54.53; H, 6.34; N, 39.13. IR, ν/cm–1: 1672,
1648, 1578, 1489, 1451, 1423, 1384, 1364, 1070, 1045, 1031,
1010, 976, 955. UV, (λmax/nm (А)): 480 (0.271). MS, m/z
(I (%)): 286 (40) [M]+, 259 (100) [MH – N2]+, RT 7.1 min.
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ3ꢀspirocycloheptaneꢀ3,7ꢀdiꢀ
hydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (3c), m.p. 98—99 °C.
Found (%): C, 56.04; H, 6.91; N, 37.39. C14H20N8. Calculꢀ
ated (%): C, 55.98; H, 6.71; N, 37.31. IR, ν/cm–1: 1675, 1653,
1570, 1484, 1456, 1421, 1362, 1085, 1055, 1011, 968, 925. UV
(λmax/nm (А)): 435 (0.490). MS, m/z (I (%)): 301 (12) [MH]+,
273 (100) [MH – N2]+, RT 8.8 min.
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ3ꢀspiroꢀ2´ꢀadamantaneꢀ3,7ꢀdiꢀ
hydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (3d), m.p. 161—
163 °C. Found (%): C, 60.13; H, 6.79; N, 33.22. C17H22N8.
Calculated (%): C, 60.34; H, 6.55; N, 33.11. IR, ν/cm–1: 1651,
1571, 1482, 1442, 1422, 1377, 1364, 1052, 1039, 1015, 996, 969.
UV (λmax/nm (А)): 367 (0.395); 441 (0.423). MS, m/z (I (%)):
339 (53) [MH]+, 311 (80) [MH – N2]+, RT 13.7 min.
3,3ꢀDimethylꢀ6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ3,7ꢀdihydroꢀ
1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (3e), m.p. 125—127 °C.
Found (%): C, 48.79; H, 5.80; N, 45.78. C10H14N8. Calculꢀ
ated (%): C, 48.77; H, 5.73; N, 45.50. IR, ν/cm–1: 1681, 1644,
1486, 1448, 1423, 1384, 1361, 1078, 1043, 1029, 976, 958, 927.
1ꢀ[1ꢀ(4ꢀBromophenyl)ethylidene]ꢀ2ꢀ[6ꢀ(3,5ꢀdimethylpyrazolꢀ
1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ3ꢀyl]hydrazine (2h), m.p. 190—192 °C.
Found (%): C, 46.45; H, 3.80; N, 28.95. C15H15N8Br. Calculꢀ
ated (%): C, 46.52; H, 3.90; N, 28.94.
1ꢀ[6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ3ꢀyl]ꢀ2ꢀ
[1ꢀ(4ꢀmethoxyphenyl)ethylidene]hydrazine (2i), m.p. 152—153 °C.
Found (%): C, 56.66; H, 5.25; N, 32.92. C16H18N8O. Calculꢀ
ated (%): C, 56.79; H, 5.36; N, 33.12.
2ꢀ[6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ1ꢀ[1ꢀ(4ꢀhydroxyphenyl)ꢀ
ethylidene]ꢀ1,2,4,5ꢀtetrazinꢀ3ꢀyl]hydrazine (2j), m.p. 212—213 °C.

Cyclization of (1,2,4,5ꢀtetrazinyl)hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1289
UV (λmax/nm (А)): 464 (0.341). MS, m/z (I (%)): 246 (19)
[M]+, 219 (92) [MH – N2]+, 260 (100) [MH – N2 + CH3CN]+,
RT 4.5 min.
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ3ꢀethylꢀ3ꢀmethylꢀ3,7ꢀdihydroꢀ
1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (3f), m.p. 120—122 °C.
Found (%): C, 50.74; H, 6.22; N, 43.27. C11H16N8. Calculꢀ
ated (%): C, 50.76; H, 6.20; N, 43.05. IR, ν/cm–1: 1681, 1642,
1576, 1487, 1448, 1421, 1381, 1361, 1077, 1053, 1031, 1005,
975. UV (λmax/nm (А)): 459 (0.347). MS, m/z (I (%)): 260 (100)
[M]+, 233 (88) [MH – N2]+, RT 5.4 min.
residue was washed with isopropanol and filtered off. The yield
was 158 mg (69%), m.p. 297—299 °C. Found (%): C, 36.39;
H, 3.25; N, 36.57. C7H7KN6O. Calculated (%): C, 36.51;
H, 3.06; N, 36.50.
3,6ꢀDiindazolꢀ1ꢀylꢀ1,2,4,5ꢀtetrazine (7a). A mixture of
3,6ꢀbis(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazine (540 mg,
2 mmol) and indazole (500 mg, 4.24 mmol) was triturated in a
crucible and then kept in the molten state at 170 °C for 40 min.
The reaction mixture was cooled, successively washed with
hexane and acetonitrile, and filtered off. The yield was 506 mg
(81%), m.p. 274—275 °C. Found (%): C, 61.23; H, 3.14;
N, 36.02. C16H10N8. Calculated (%): C, 61.14; H, 3.21; N, 35.75.
3,6ꢀDi(4ꢀmethylimidazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazine (7b). A mixꢀ
ture of 3,6ꢀbis(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazine
(1080 mg, 4 mmol) was dissolved with heating in acetonitrile
(20 mL). Then 4ꢀmethylimidazole (984 mg, 12 mmol) was added.
The reaction mixture was stirred at room temperature for 20 min
and cooled on ice. The precipitate that formed was filtered off.
The yield was 650 mg (67%), m.p. 208—209 °C. Found (%):
C, 49.66; H, 4.00; N, 46.54. C10H10N8. Calculated (%): C, 49.58;
H, 4.16; N, 46.26.
3ꢀHydrazinoꢀ6ꢀ(indazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazine (8a). The
yield was 75%, m.p. 169—172 °C. Found (%): C, 47.40; H, 3.34;
N, 48.97. C9H8N8. Calculated (%): C, 47.37; H, 3.53; N, 49.10.
3ꢀHydrazinoꢀ6ꢀ(4ꢀmethylimidazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazine
(8b). The yield was 87%, m.p. 175—176 °C. Found (%):
C, 37.27; H, 4.54; N, 57.96. C6H8N8. Calculated (%): C, 37.50;
H, 4.20; N, 58.31.
2ꢀCyclohexylideneꢀ1ꢀ[6ꢀ(indazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ
3ꢀyl]hydrazine (9a), m.p. 88—90 °C. Found (%): C, 58.59;
H, 5.47; N, 36.14. C15H16N8. Calculated (%): C, 58.43; H, 5.23;
N, 36.34.
2ꢀCyclohexylideneꢀ1ꢀ[6ꢀ(4ꢀmethylimidazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀ
tetrazinꢀ3ꢀyl]hydrazine (9b), m.p. 160—161 °C. Found (%):
C, 49.84; H, 6.37; N, 38.53. C12H16N8•H2O. Calculated (%):
C, 49.64; H, 6.25; N, 38.60.
6ꢀ(Indazolꢀ1ꢀyl)ꢀ3ꢀspirocyclohexaneꢀ3,7ꢀdihydroꢀ1,2,4ꢀtriꢀ
azolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (10a) was synthesized analogously
to compounds 3a—n, m.p. 154—157 °C. Found (%): C, 58.09;
H, 5.30; N, 35.97. C15H16N8. Calculated (%): C, 58.43; H, 5.23;
N, 36.34.
6ꢀ(4ꢀMethylimidazolꢀ1ꢀyl)ꢀ3ꢀspirocyclohexaneꢀ3,7ꢀdihydroꢀ
1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (10b) was synthesized
analogously to compounds 3a—n. M.p. 146—148 °C. Found (%):
C, 53.07; H, 6.03; N, 39.86. C12H16N8. Calculated (%): C, 52.93;
H, 5.92; N, 41.15.
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ3ꢀphenylꢀ3,7ꢀdiꢀ
hydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (3g), m.p. 118—
120 °C. Found (%): C, 58.57; H, 5.24; N, 36.28. C15H16N8.
Calculated (%): C, 58.43; H, 5.23; N, 36.34.
3ꢀ(4ꢀBromophenyl)ꢀ6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ
3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine
(3h),
m.p. 158—161 °C. MS, m/z (I (%)): 387 (10) [M]+, 359 (73)
[M – N2]+, RT 10.0 min.
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ
3ꢀmethylꢀ3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine
(3i), m.p. 154—156 °C. MS, m/z (I (%)): 339 (42) [MH]+, 311
(100) [MH – N2]+, RT 6.2 min.
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ3ꢀ(4ꢀhydroxyphenyl)ꢀ
3ꢀmethylꢀ3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine
(3j), m.p. 203—204 °C. MS, m/z (I (%)): 324 (45) [M]+, 296
(67) [M – N2]+, RT 3.6 min.
3ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ꢀ6ꢀ(3,5ꢀdimethylpyraꢀ
zolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀ
tetrazine (3k), m.p. 122—125 °C. MS, m/z (I (%)): 436 (33)
[M]+, 407 (100) [M – H – N2]+, RT 20.4 min.
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ3ꢀ(2ꢀpyridyl)ꢀ
3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine
(3l),
m.p. 101—104 °C. MS, m/z (I (%)): 310 (12) [MH]+, 282 (100)
[MH – N2]+, RT 4.4 min.
Synthesis of 3ꢀRꢀ3ꢀR´ꢀ6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ
3ꢀmethylꢀ3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazines
4a,b (general procedure). Dihydrotriazolotetrazine 3b,e (1 mmol)
was added with stirring to a suspension of KOH (224 mg,
4 mmol) in DMSO (15 mL). The reaction mixture was kept at
room temperature for 40 min and then placed in a bath with
cold water. Iodomethane (0.13 mL, 2 mmol) was added to the
reaction mixture. The mixture was stirred for 1 h, extracted with
Et2O, washed with water, and dried with anhydrous CaCl2. The
solvent was distilled off. The residue was recrystallized from
ethanol.
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ7ꢀmethylꢀ3ꢀspirocyclohexaneꢀ
3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine
(4a).
3,6ꢀDi(2ꢀcyclopentylidenehydrazino)ꢀ1,2,4,5ꢀtetrazine (12a),
m.p. 204—206 °C. Found (%): C, 50.95; H, 6.80; N, 39.55.
The yield was 63%, m.p. 109—110 °C. Found (%): C, 56.06;
H, 6.76; N, 37.73. C14H20N8. Calculated (%): C, 55.98;
H, 6.71; N, 37.31. MS, m/z (I (%)): 301 (4) [MH]+, 273 (100)
[MH – N2]+, RT 6.2 min.
6ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ3,3,7ꢀtrimethylꢀ3,7ꢀdihydroꢀ
1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (4b). The yield was 65%,
m.p. 62—64 °C. Found (%): C, 51.07; H, 6.52; N, 42.89.
C
12H18N8•0.5 H2O. Calculated (%): C, 50.87; H, 6.76; N, 39.55.
3,6ꢀDi(2ꢀpropꢀ2ꢀylidenehydrazino)ꢀ1,2,4,5ꢀtetrazine (12C),
m.p. 215—216 °C. Found (%): C, 43.13; H, 6.36; N, 50.69.
C8H14N8. Calculated (%): C, 43.23; H, 6.35; N, 50.42.
6ꢀ(2ꢀCyclopentylidenehydrazino)ꢀ3ꢀspirocyclopentaneꢀ
3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (13a) was
synthesized analogously to compounds 3a—n, m.p. 146—148 °C.
Found (%): C, 52.43; H, 6.65; N, 40.66. C12H18N8. Calculꢀ
ated (%): C, 52.54; H, 6.61; N, 40.85.
6ꢀ(2ꢀCyclohexylidenehydrazino)ꢀ3ꢀspirocyclohexaneꢀ
3,7ꢀdihydroꢀ1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (13b),
m.p. 153—155 °C. Found (%): C, 55.78; H, 7.40; N, 36.85.
C
11H16N8. Calculated (%): C, 50.76; H, 6.20; N, 43.05. MS,
m/z (I (%)): 261 (2) [MH]+, 233 (100) [MH – N2]+, RT 4.1 min.
Potassium 6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazinꢀ
3ꢀolate (5). Dihydrotriazolotetrazine 3b (286 mg, 1 mmol) was
added with stirring to a suspension of KOH (224 mg, 4 mmol) in
MeCN (or MeOH) (15 mL). The reaction mixture was kept at
room temperature for 30 min. The solvent was evaporated. The
C
14H22N8. Calculated (%): C, 55.61; H, 7.33; N, 37.06.

1290
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
Tolshchina et al.
Table 6. Crystallographic parameters and the Xꢀray data collection and structure refinement statistics
Compound
2b
3b
3i
4e
Molecular formula
Molecular weight
С13Н18N8
286.35
С13Н18N8
286.35
C16H18N8O
338.38
C11H16N8
260.32
Crystal system
Monoclinic
Space group
a/Å
b/Å
c/Å
P2(1)/c
12.885(4)
7.2229(18)
16.0562(16)
90
P2(1)/c
13.7484(5)
9.2622(4)
12.5604(5)
90.00
P2(1)/c
8.7946(8)
16.3833(15)
11.781(2)
90.00
P2(1)
8.3842(10)
8.6399(12)
9.661(3)
90.00
α/deg
β/deg
99.893(15)
90
1472.1(6)
4
112.529(4)
90.00
1477.39(10)
4
97.173(11)
90.00
1684.2(4)
4
1.335
0.091
97.546(15)
90.00
693.7(2)
2
1.246
0.085
γ/deg
V/Å3
Z
dcalc/g cm–3
1.292
0.086
1.287
0.086
μ/mm–1
Scanning range
Number of measured reflections
Rint
Number of reflections with I > 2σ(I)
Number of refined parameters
R1 (based on reflections with I > 2σ(I))
wR2 (based on reflections with I >2σ(I))
R1 (based on all reflections)
wR2 (based on all reflections)
26.39 > θ > 3.18
2940
30.52 > θ > 2.81
4335
26.37 > θ > 2.64
3324
26.39 > θ > 3.18
1511
0.0502
1190
198
0.0477
0.0795
0.1402
0.0873
0.0275
2133
262
0.0452
0.0996
0.0986
0.0916
0.0456
1447
230
0.0443
0.0935
0.1283
0.1033
0.0263
948
176
0.0353
0.0754
0.0638
0.0754
3,3ꢀDimethylꢀ6ꢀ[2ꢀ(propꢀ2ꢀylidene)hydrazino]ꢀ3,7ꢀdihydroꢀ
1,2,4ꢀtriazolo[4,3ꢀb]ꢀ1,2,4,5ꢀtetrazine (13c) was synthesized
analogously to compounds 3a—n, m.p. 153—156 °C. Found (%):
C, 43.06; H, 6.33; N, 50.39. C8H14N8. Calculated (%): C, 43.23;
H, 6.35; N, 50.42.
References
1. Yu. P. Kitaev, B. I. Buzykin, Gidrazony [Hydrazones], Nauka,
Moscow, 1974, pp. 415 (in Russian).
2. K. N. Zelenin, V. V. Alekseev, Khim. Geterotsikl. Soedin.,
1988, 3 [Chem. Heterocycl. Compd. (Engl. Transl.), 1988, 24,
No. 1].
3. H. A. Zaher, R. M. AbdelꢀRahman, A. M. AbdelꢀHalim,
Ind. J. Chem., Sect. B, 1987, 26, 110.
4. J. Daunis, R. Jacquier, P. Viallefont, Bull. Soc. Chim. Fr.,
1969, 2492.
5. A. S. Shawali, H. M. Hassaneen, N. K. Shurrab, Heteroꢀ
cycles, 2008, 75, 1479.
6. G. L. Rusinov, I. N. Ganebnykh, O. N. Chupakhin, Zh. Org.
Khim., 1999, 35, 1379 [Russ. J. Org. Chem. (Engl. Transl.),
1999, 35, 1350].
7. A. S. Shawali, S. M. Elsheikh, J. Heterocycl. Chem., 2001,
38, 541.
8. G. L. Rusinov, N. I. Latosh, I. N. Ganebnykh, R. I.
Ishmetova, N. K. Ignatenko, O. N. Chupakhin, Zh. Org.
Khim., 2006, 42, 772 [Russ. J. Org. Chem. (Engl. Transl.),
2006, 42, 757].
Xꢀray diffraction study of compounds 2b, 3b, 3i, and 4b. Single
crystals of compounds 2b, 3b, 3i, and 4b were grown by crystalliꢀ
zation from MeOH, MeCN, MeOH, and hexane, respectively.
The Xꢀray diffraction data sets were collected on a Xcalibur 3
diffractometer equipped with a CCD detector (λ(MoꢀKα) =
= 0.71073, graphite monochromator, ωꢀ and ϕꢀscanning techꢀ
nique, T = 295 K). The structures were solved by direct methods
with the use of the SHELXS97 program package and refined
using the SHELXL97 program package. The positional and therꢀ
mal parameters of nonhydrogen atoms were refined by the fullꢀ
matrix leastꢀsquares method first isotropically and then anisoꢀ
tropically. The hydrogen atoms were located in difference elecꢀ
tron density maps and refined using a riding model. The Xꢀray
data collection and structure refinement statistics are given in
Table 6. The results of the Xꢀray diffraction studies of comꢀ
pounds 2b, 3b, 3i, and 4b were deposited with the Cambridge
Crystallographic Data Centre (CCDC 730344—730347 for comꢀ
pounds 2b, 3b, 3i, and 4b, respectively).**
9. N. I. Latosh, G. L. Rusinov, I. N. Ganebnykh, O. N.
Chupakhin, Zh. Org. Khim., 1999, 35, 1392 [Russ. J. Org.
Chem. (Engl. Transl.), 1999, 35, 1363].
10. I. N. Ganebnykh, Ph. D. (Chem.) Thesis, I. Ya. Postovsky
Institute of Organic Synthesis of the Ural Branch of the
Russian Academy of Sciences, Ekaterinburg, 2003, pp. 229
(in Russian).
This study was financially supported by the Russian
Foundation for Basic Research (Project Nos 07ꢀ03ꢀ96112ꢀ
r_Ural_a and 07ꢀ03ꢀ96113ꢀr_Ural_a) and the Council
on Grants of the President of the Russian Federation
(Program for State Support of Leading Scientific Schools
of the Russian Federation, Grant NShꢀ3758.2008.3).
11. D. E. Chavez, M. A. Hiskey, J. Heterocycl. Chem., 1998, 35,
1329.
** These data can be obtained, free of charge, on application to
www.ccdc.cam.ac.uk/data_request/cif.
Received June 27, 2008;
in revised form December 22, 2008