Synthesis of monosubstituted 1,2,4,5-tetrazines –3-amino-1,2,4,5-tetrazines

Article abstract of DOI:10.1007/s10593-017-2127-4

The substitution of pyrazolyl moiety in 3-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine with N-nucleophiles provided a series of highnitrogen tetrazine derivatives, including 2-nitro-1-(1,2,4,5-tetrazin-3-yl)guanidine, N-(1H-tetrazol-5-yl)-1,2,4,5-tetrazin-3-amine, N-(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazin-3-amine, N,N'-di(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazine-3,6-diamine, N-(1,2,4,5-tetrazin-3-yl)- [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-amine, and tritetrazinylamine. The thermal stability of these new compounds was evaluated by differential scanning calorimetry and their energetic characteristics were calculated.

Full text of DOI:10.1007/s10593-017-2127-4

DOI 10.1007/s10593-017-2127-4
Chemistry of Heterocyclic Compounds 2017, 53(6/7), 802–810
Synthesis of monosubstituted 1,2,4,5-tetrazines –
3-amino-1,2,4,5-tetrazines
Gennady F. Rudakov1*, Yurii A. Moiseenko1, Natal'ya А. Spesivtseva1
1 D. I. Mendeleev University of Chemical Technology of Russia,
9 Miusskaya Sq., Moscow 125047, Russia; е-mail: rudakov@rctu.ru
Submitted January 27, 2017
Accepted after revision May 22, 2017
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(6/7), 802–810
The substitution of pyrazolyl moiety in 3-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine with N-nucleophiles provided a series of high-
nitrogen tetrazine derivatives, including 2-nitro-1-(1,2,4,5-tetrazin-3-yl)guanidine, N-(1H-tetrazol-5-yl)-1,2,4,5-tetrazin-3-amine,
N-(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazin-3-amine, N,N'-di(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazine-3,6-diamine, N-(1,2,4,5-tetrazin-3-yl)-
[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-amine, and tritetrazinylamine. The thermal stability of these new compounds was evaluated by
differential scanning calorimetry and their energetic characteristics were calculated.
Keywords: ditetrazinylamines, N,N-di(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazin-3-amine, nitroguanidine, 1,2,4,5-tetrazine, 1H-tetrazol-
5-amine, 1H-1,2,4-triazol-5-amine, nucleophilic substitution.
The chemistry of symmetrical tetrazines has been
studied for more than a hundred years, but their synthesis
and reactivity are still the topics of active research efforts.
The steady growth in the number of scientific publications
in this field points to the great importance of compounds
belonging to this class and the practical interest of
researchers in 1,2,4,5-tetrazine derivatives.1 Their high
enthalpies of formation,2 as well as the good density and
thermal stability characteristics are the reasons why
tetrazines are promising candidates for such practical
applications as components of propellants, explosives, and
pyrotechnic compositions. Currently a large number of
symmetrically and unsymmetrically substituted 1,2,4,5-
tetrazines are known, which contain various substituents at
positions 3 and 6, including explosophoric groups.3 On the
other hand, very limited information is available on the
synthesis and practical applications of monosubstituted
1,2,4,5-tetrazines. The available data are not sufficient for
predicting the properties of new compounds in this series.
Monosubstituted 1,2,4,5-tetrazines are of interest as
starting materials for the synthesis of heterocyclic
compounds4 and are used in the role of biologically active
agents,5 energetic materials,3v,6 and reagents for bio-
orthogonal chemistry.7 The synthesis of monosubstituted
tetrazines has been performed by condensation of nitriles
and their derivatives with formamidine acetate in the
presence of hydrazine,8 by oxidation of substituted
hydrazinyltetrazines,6a,9 or by reduction of halotetrazines.10
The synthetic method selected in each particular case
depends on the availability and reactivity of the starting
materials.
A convenient approach for the preparation of 3-amino-
1,2,4,5-tetrazines is nucleophilic substitution of dimethyl-
pyrazolyl (DMP) group in 3-(3,5-dimethyl-1H-pyrazol-1-yl)-
1,2,4,5-tetrazine (1).3v,6a In order to evaluate the preparative
potential of this reaction, we studied the reactivity of tetra-
zine 1 toward various N-nucleophiles. The reactions were
performed in MeCN at various temperatures (20–80°С) in
the presence or absence of K2CO3. Among the selected
N-nucleophiles were some strong bases (ammonia,
methylamine, hydrazine, and guanidine), as well as weak
bases (nitroguanidine, C-aminoazoles, and 3-amino-1,2,4,5-
tetrazines). The reaction was controlled by methods of thin-
layer chromatography (TLC) and high-performance liquid
chromatography – mass spectrometry (LC/MS). It was
established that the strongly basic nucleophiles in the
0009-3122/17/53(6/7)-0802©2017 Springer Science+Business Media New York
802

Chemistry of Heterocyclic Compounds 2017, 53(6/7), 802–810
Scheme 1
studied series quickly (15–30 min) and efficiently
substituted the dimethylpyrazolyl moiety when the reaction
proceeded in MeCN at room temperature. In the case of
ammonia, methylamine, and hydrazine, it was shown that
the use of nucleophiles in the form of their aqueous
solutions practically did not reduce the yields of the target
compounds 2–4 (Scheme 1). For comparison, the isolation
of product 2 in 81% yield has been reported in the
literature,3v but in our study the achieved yield was as high
as 90%. The synthesis of 3-guanidino-1,2,4,5-tetrazine (5)
was performed by using guanidine hydrochloride and
tetrazine 1 in the presence of K2CO3 at an equimolar ratio
of reagents and moderate heating (40°С).
amounts in DMF solution (90°С, 10 h) did not result in
complete consumption of the starting materials. The
reaction could be brought to completion only by using a
twofold excess of 5-АT. According to 13С NMR
spectroscopy data, product 7 in that case was isolated as a
mixture with 5-AT in ~1:1 molar ratio, and re-
crystallization from alcohols (MeOH, EtOH) or MeCN did
not result in the isolation of pure N-(1H-tetrazol-5-yl)-
1,2,4,5-tetrazin-3-amine (7). Heating of tetrazine 1 and 5-АТ
in acetonitrile in the presence of K2CO3 enabled us to
prepare the target compound 7 in 63% yield (Scheme 1)
even when the reagents were used in equimolar ratio.
Taking into account the successfully performed
nucleophilic substitution of DMP group with nitro-
guanidine and azolylamines, we decided to study the
possibility of involving a series of 1,2,4,5-tetrazin-3-amines
in this reaction. We found that the direction of the
substitution reaction was determined by the structure of
nucleophilic reagent. Both 1,2,4,5-tetrazin-3-amine (2) and
1,2,4,5-tetrazine-3,6-diamine (9) readily substituted the
DMP group in the molecule of tetrazine 1 (Scheme 1). This
reaction produced satisfactory yields of N-(1,2,4,5-tetrazin-
3-yl)-1,2,4,5-tetrazin-3-amine (11) and N,N'-di(1,2,4,5-
tetrazin-3-yl)-1,2,4,5-tetrazine-3,6-diamine (12), respectively.
It is necessary to note that during the synthesis of tetrazine
12 we were unable to detect the intermediate product –
N-(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazine-3,6-diamine by
LC/MS analysis. Performing the reaction with an
equimolar ratio (1:1) of reagents only decreased the yield
of tetrazine 12 (18%). Apparently, the rate-limiting step of
this process was the introduction of the first tetrazine
moiety, that is, the rate of target product 12 formation was
The reaction of tetrazine
1 with weakly basic
nucleophiles was performed by refluxing in MeCN solution
in the presence of K2CO3 (molar ratio 1:1:1). The examples
of nitroguanidine, 1H-tetrazol-5-amine (5-AT), and 1H-
1,2,4-triazol-5-amine demonstrated the general applicability
of this reaction (Scheme 1). The substitution of DMP group
occurred under heterogeneous reaction conditions with the
formation of intermediate compounds – potassium salts of
3-amino-substituted 1,2,4,5-tetrazines, which were not
isolated. The nature of the nucleophile had only a minor
effect on the reaction rate (reaction time ~3 h, control by
TLC), while the yields of the target compounds 6–8 were
largely affected by their solubility in dilute hydrochloric
acid. The reaction of nitroguanidine and 1H-tetrazol-
5-amine with tetrazine 1 proceeded analogously to the
reaction with 3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-
1,2,4,5-tetrazine.11,12 Thus, a nucleophilic substitution
reaction of 5-АT was difficult to accomplish in the absence
of a base. Prolonged heating of reagents at equimolar
803

Chemistry of Heterocyclic Compounds 2017, 53(6/7), 802–810
Scheme 2
substantially faster than the rate of intermediate product
formation.
The use of 6-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-
tetrazin-3-amine (10) in this reaction led to the formation
of two compounds. Along with the expected 6-(3,5-di-
methyl-1H-pyrazol-1-yl)-N-(1,2,4,5-tetrazin-3-yl)-1,2,4,5-
tetrazin-3-amine (13) we also were able to isolate 6-(3,5-
dimethyl-1H-pyrazol-1-yl)-N-[6-(3,5-dimethyl-1H-pyrazol-
1-yl)-1,2,4,5-tetrazin-3-yl]-1,2,4,5-tetrazin-3-amine (14)
(Scheme 1). The ratio of products 13 and 14, calculated
from the results of 1Н NMR spectroscopy, was equal to 5:1.
The process optimization by variation of the reagent ratio
did not offer substantial improvements of selectivity.
The formation of by-product 14 in the reaction of
tetrazines 1 and 10 points to nucleophilic substitution of
hydrogen atom13 at position 6 of tetrazine 1 or trans-
amination of 6-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-
tetrazin-3-amine (10). Mechanistic studies by using LC/MS
analysis showed that tetrazine 10 in the presence of K2CO3
in MeCN medium was transformed into at least four
compounds (Scheme 2). Heating for 4 h at 80°С resulted in
a mixture containing the starting compound 10 (retention
time (RT) 1.59 min, m/z 192 [M+H]+) along with tetrazine 14
(RT 1.88 min, m/z 366 [M+H]+), 6-(3,5-dimethyl-1H-pyra-
zol-1-yl)-1,2,4,5-tetrazin-3-ol (15) (RT 1.48 min, m/z 193
[M+H]+), 3,6-diamino-1,2,4,5-tetrazine (9) (RT 0.34 min,
m/z 113 [M+H]+), and N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-
1,2,4,5-tetrazin-3-yl]-1,2,4,5-tetrazine-3,6-diamine (16)
(RT 1.62 min, m/z 287 [M+H]+). All products except for
diaminotetrazine 9 gave clear mass spectral signals both as
positive ([M+H]+) and negative ions ([M−H]−), enabling
reliable determination of their molecular mass values.
Scheme 2 illustrates the transformations of amino-
tetrazine 10, showing that both the dimethylpyrazolyl and
amino groups were involved in nucleophilic substitution
reactions. The appearance of ammonia in the reaction
mixture led to the formation of tetrazine 9. Ditetrazinyl-
amine 16 can be formed from both the starting compound
10 and by partial ammonolysis of tetrazine 14. Thus, it
can be concluded that the most likely reason for the
formation of ditetrazinylamine 14 is the transamination of
nucleophile 10 in alkaline medium. At the same time, the
rate of this transformation was approximately 5 times
slower than the rate of nucleophilic substitution of DMP
group in tetrazine 1.
Tetrazines 13 and 14 were obtained in high yields by
reactions of 3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-
tetrazine (17) with aminotetrazines 2 and 1014 (Scheme 3).
These results indicate that the dimethylpyrazolyl substituent
had only a minor effect on the nucleophilicity of 3-amino-
1,2,4,5-tetrazine and the DMP group in tetrazine 17 was a
better nucleofuge compared to tetrazine 1.
The use of N,N'-dialkyl-1,2,4,5-tetrazine-3,6-diamines
as nucleophiles in the reaction with tetrazine 1 led to an
unusual result. Heating of N,N'-dimethyl-1,2,4,5-tetrazine-
3,6-diamine (18) and tetrazine 1 in MeCN medium in the
presence of K2CO3 did not yield N,N'-dimethyl-N-1,2,4,5-
tetrazin-3-yl-1,2,4,5-tetrazine-3,6-diamine (19), but rather
a mixture of N-methyl-1,2,4,5-tetrazin-3-amine (4) and
6-(3,5-dimethyl-1H-pyrazol-1-yl)-N-methyl-1,2,4,5-tetrazin-
3-amine (20) (Scheme 4). The product yields after
chromatographic separation were 42 and 17%, respectively.
It should be noted that N,N'-diisopropyl-1,2,4,5-tetrazine-
3,6-diamine did not react under analogous conditions.
The obtained result can be explained by deamination of
tetrazine 18 in alkaline medium with subsequent
substitution of both DMP group and hydrogen atom in
tetrazine 1 with a MeNH group.13 However, as indicated by
Scheme 3
Scheme 4
804

Chemistry of Heterocyclic Compounds 2017, 53(6/7), 802–810
Scheme 5
Scheme 6
LC/MS analysis, tetrazine 1 reacted with tetrazine 18
selectively, without the formation of by-products, while
directed synthesis of tetrazine 4 was accomplished in a
high yield (Scheme 1) and was not accompanied by the
formation of tetrazine 20. We previously observed a
substantial difference in the reactivity of N,N'-dialkyl-
1,2,4,5-tetrazine-3,6-diamines in the case of their nitration
reactions with dilute HNO3.15 The use of N,N'-diisopropyl-
1,2,4,5-tetrazine-3,6-diamine, which tends to form radical
cation, led to mononitroamine, while tetrazine 18 was left
unchanged under analogous conditions. The results
obtained here show that the redox properties of substituted
tetrazines must be also taken into account when performing
reactions under nucleophilic substitution conditions.
Apparently, tetrazine 18 in alkaline medium has a stronger
tendency to form a radical anion that attacks tetrazine 1 at
position 6 of heterocycle. The mechanism of this trans-
formation is probably analogous to the mechanism of
vicarious nucleophilic substitution of hydrogen atom in
aromatic compounds.16 The tetrazine ring of the attacking
nucleophile in this case unexpectedly plays the role of a
leaving group.
The DMP group in 3-(3,5-dimethyl-1H-pyrazol-1-yl)-
[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (21) can be substi-
tuted by various N-nucleophiles.6a,17 However, the use of
triazolotetrazine 22 as N-nucleophile has been described
only in a few examples.17,18 We have established that both
triazolotetrazines 21 and 22 can be used equally
successfully for the synthesis of monosubstituted tetrazine
23 (Scheme 5).
The use of dihetarylamines in the synthesis of tri-
hetarylamines has been known for a long time.19 Some
compounds of this class may be of interest as energetic
materials20 and effective reagents for complex formation.21
There is no information available in the literature about the
synthesis and properties of tritetrazinylamines. The attempt
to synthesize N,N-di(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazin-
3-amine (25) by substitution of DMP group in tetrazine 1
with ditetrazinylamine 11 in the presence of K2CO3 did not
produce positive results. However, tritetrazinylamine 25
could be obtained by heating the sodium salt of
ditetrazinylamine 11 with 3-chloro-1,2,4,5-tetrazine (24) in
THF (Scheme 6).
the range from 8.36 (for compound 4) to 10.79 ppm (for
compound 25), depending on the electron donor-acceptor
properties of the substituent at position 3.
All of the monosubstituted aminotetrazines except for
the tritetrazinylamine 25 were efficiently ionized under
LC/MS conditions both as positive ([M+H]+) and negative
ions ([M−H]−). Electron impact ionization (MS, GC/MS,
70 eV) of N-substituted 1,2,4,5-tetrazin-3-amines showed a
similar type of fragmentation (Scheme 7). Mass spectra of
compounds 2, 4, 5, 8, 11, 12, 23, 25 besides molecular ions
(Irel 9–52%) showed also the more stable ions (Irel 80–
100%) of the respective cyanamide derivatives (compound
2, m/z 42): methylcyanamide (compound 4, m/z 56),
N-cyanoguanidine (compound 5, m/z 84), 1,2,4-triazol-
5-ylcyanamide (compound 8, m/z 109), cyanocyanamide
(compounds 11, 12, 23, m/z 67), and dicyanocyanamide
(compound 25, m/z 92). The presence of a tetrazole moiety
in the side chain (compound 7) resulted in the appearance
of a N-cyanoimidoformamide ion in the mass spectrum
(m/z 69 (Irel 100%)), while 3,5-dimethyl-1Н-pyrazole-
1-carbonitrile ion (m/z 121 (Irel 100%)) was detected in the
case of a dimethylpyrazolyl substituent (compound 13).23
The thermal stability of compounds 6–8, 11, 12, 23, 25
was evaluated by method of differential scanning
calorimetry (DSC). The results showed that all tetrazines
except for N-(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazin-3-amine
(11) (mp 190–195°С) decomposed without melting at
temperatures above 210°С (Table 1). The highest thermal
stability was found in the case of the linear polytetrazine 12
(decomp. temp. 279–283°С). When comparing the
decomposition temperature of tetrazine 7 and its 3,6-
disubstituted analog – (N,N'-di(1H-tetrazol-5-yl)-1,2,4,5-
tetrazine-3,6-diamine (BTATz)3j), a significant decrease of
thermal stability was observed, which was associated with
changes in the symmetry (degree of substitution) in the
tetrazine ring.
All of the obtained 1,2,4,5-tetrazines were colored
crystalline compounds (λmax(MeCN) 515–539 nm). Their
IR spectra contained an absorption band in the range of
3035–3123 cm−1, which was characteristic for С–Н bond
vibrations.22 The proton at position 6 of the tetrazine ring
Tetrazines 6–8, 11, 12, 23 have acidic properties and can
be used for the preparation of energetic salts with inorganic
and nitrogen-containing organic bases. 1-(1,2,4,5-Tetrazin-
3-yl)guanidine (5) is a suitable base for obtaining salts with
1
gave Н NMR signal (in DMSO-d6 solution) observed in
805

Chemistry of Heterocyclic Compounds 2017, 53(6/7), 802–810
Scheme 7
R1
R2
N
N
R1 = H
H
R2
H
R1 = H
N
N
R2 = Tz, TrTz, TzATz
N
N
N
N
N
N
R2NCN
–2N2
–2HCN
–N2
–HCN
–H
R2 = H, Me, HN=CNH2,
R
1 = R2 = Tz
N
N
1,2,4-triazol-5-yl
N
N
–3N2
–3HCN
Tz =
N
N
N
N
N
N
N
N
TrTz =
N
NCNCN
–CN
N
N
N
N
N
TzATz =
N
N
N
N
N
H
Experimental
Table 1. The energetic characteristics of monosubstituted 1,2,4,5-
tetrazines 6–8, 11, 12, 23, 25, and BTATz
IR spectra were recorded on a Thermo Nicolet 360 FTIR
spectrometer in KBr pellets. Electronic absorption spectra
were recorded on a PF-6100UF spectrophotometer for
MeCN solutions over the wavelength range of 360–660 nm.
1Н and 13С NMR spectra were acquired on a Varian
Mercury Plus instrument (400 and 100 MHz, respectively)
for solutions in CDCl3 (compound 24) or in DMSO-d6 (the
rest of the compounds) at 50°С (13С NMR spectrum of
tetrazine 8 was acquired at 125°С). Residual solvent
Com-
pound
Тonset,*
°С
d,**
ΔHf°,***
kJ/mol
D,*4
m/s
P,*5
GPa
Q
expl,*6
kJ/kg
g/cm3
232
257
268
210
279
240
231
309
1.83
1.65
1.59
1.63
1.69
1.64
1.88
1.88
499
555
529
616
956
838
987
918
9175
8181
7818
7861
8110
7885
9067
8809
33.3
23.0
20.1
21.0
22.9
21.5
30.5
30.1
5334
3688
3640
3778
3782
4104
4067
4002
6
7
8
11
12
1
signals were used as internal standard for Н and 13С NMR
23
25
spectra (2.50 and 39.5 ppm, respectively for DMSO, 7.26
and 77.2 ppm – for CDCl3). LC/MS analysis was
performed on a Thermo Finnigan Surveyor MSQ instrument
under gradient elution conditions, using chemical ionization
at atmospheric pressure with simultaneous recording of
positively and negatively charged ions. The following
chromatography conditions were used: Onyx Monolithic
C18 column (25×4.6 mm), mobile phase – (H2O + MeCN)+
0.1 vol % HCOOH, elution flow rate – 1.5 ml·min–1, room
temperature (20°С). GC/MS analysis was performed on a
Thermo Scientific Trace 1310/ISQ LT instrument equipped
with a TG-SQC capillary column (15 m, 0.25 mm, 0.25 µm).
Mass spectra of tetrazines 7, 8, 11–14, 23, 25 were
recorded by using direct introduction of sample into the
ionization chamber of the mass spectrometer (ISQ-LT).
The mass spectra (GC/MS and MS) were recorded in the
m/z range of 40–650 at ionization energy of 70 eV and the
ion source temperature equal to 200°С. High-resolution
mass spectra were recorded on a Bruker МicrOTOF II
instrument with electrospray ionization. Elemental analysis
was performed on a PerkinElmer 2400 Series II CHN-
analyzer. Melting points were determined on a Boetius hot
stage. Decomposition temperatures were determined by
method of differential scanning calorimetry on a Mettler
Toledo DSC 822e instrument at the heating rate of 10°С/min
over the temperature range of 20–350°С. The decomposi-
tion process was characterized by interval Тonset–Тmax. The
reaction progress was controlled by TLC method using
BTATz*7
* Тonset – temperature of the start of vigorous decomposition (DSC).
** d – density, calculated by the group contribution method.25
*** ΔHf° – enthalpy of formation, according to quantum-chemical
calculations (functional 6-31+G(2df,p)).
*4 D – velocity of detonation.24
*5 P – pressure of detonation.24
*6 Qexpl – heat of explosion.24
*7 Previously published results.26
HNO3 and HClO4. The calculation of energetic
characteristics has shown24 that tetrazines 6 and 25 have
superior values of the velocity of detonation and heat of
explosion, compared to BTATz (Table 1), and therefore are
of interest as components for high-energy compositions.
Thus, we have established that 3-(3,5-dimethyl-1H-
pyrazol-1-yl)-1,2,4,5-tetrazine participates in nucleophilic
substitution reactions with weakly basic N-nucleophiles.
The direction and selectivity of such reactions with 1,2,4,5-
tetrazin-3-amine derivatives are determined by the degree
of substitution at the nucleophilic site and the stability of
the nucleophile in alkaline medium. This reaction was used
to synthesize the first representative of tritetrazinylamines.
It was shown that monosubstituted ditetrazinylamines can
be used as intermediate products for the synthesis of new
high-nitrogen heterocyclic systems.
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Chemistry of Heterocyclic Compounds 2017, 53(6/7), 802–810
Sorbfil PTSKh-AF-А-UF plates. The obtained compounds
H 4.61; N 62.87. C3H5N5. Calculated, %: С 32.43; H 4.54;
N 63.03.
2-Nitro-1-(1,2,4,5-tetrazin-3-yl)guanidine (6). Yield
were purified by column chromatography on Durasil Н 40–
63 µm silica gel.
3,6-Bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine (17),27
N,N'-diisopropyl-1,2,4,5-tetrazine-3,6-diamine,15 as well as
compounds 1,6a 9,27 10,15 18,15 21,6a 226a were synthesized
according to published procedures.
295 mg (80%, method II), orange crystals, decomp. temp.
232–235°С (MeCN). Rf 0.61 (EtOAc). IR spectrum, ν, cm−1:
1253, 1584 (NO2), 1613 (C=N), 2867–3019 (NH···N), 3093
(C–H Het), 3206, 3371 (N–H). UV spectrum, λmax, nm (ε):
1
Preparation of monosubstituted 1,2,4,5-tetrazines 2–4,
6–8, 11, 23 (General method). Method I. A solution of 3-(3,5-
dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine (1) (352 mg,
2 mmol) in MeCN (20 ml) was treated with the appropriate
amine (4 mmol) in the form of aqueous solution (NH3 –
25% (272 mg), MeNH2 – 40% (310 mg)) or 100%
hydrazine hydrate (100 mg, 2 mmol) and the mixture was
stirred at 18–20°С until the reaction was complete (control
by TLC method, reaction time 30 min). The solvent was
removed by evaporation at reduced pressure and the
residue was washed with PhMe (compound 2), Et2O
(compound 3), or crystallized from a suitable solvent.
Method II. A mixture of tetrazine 1 (352 mg, 2 mmol),
of the appropriate N-nucleophile (2 mmol) (208 mg of
nitroguanidine, 170 mg of 5-aminotetrazole, 168 mg of
3-amino-1,2,4-triazole, 194 mg of aminotetrazine 2, or
274 mg of aminotetrazine 22), and K2CO3 (276 mg,
2 mmol) in MeCN (20 ml) was stirred at the reflux
temperature for 2–3 h (TLC). The solvent was removed by
evaporation at reduced pressure. The residue was dissolved
in H2O (4 ml), acidified with 10% HCl to рН 2, and stirred
until achieving complete precipitation of the product (1–2 h).
The product was filtered off, washed with H2O, PhMe, and
purified when necessary by the method of silica gel column
chromatography.
517 (513). H NMR spectrum, δ, ppm: 9.62 (2H, s, NH2);
10.34 (1H, s, H-6); 12.13 (1H, br. s, NH). 13C NMR spectrum,
δ, ppm: 155.5; 157.2; 162.4. Mass spectrum (LC/MS), m/z
(Irel, %): 185 [M+H]+ (100). Found, m/z: 207.0351.
C3H4N8NaO2. Calculated, m/z: 207.0355. Found, %:
С 19.44; H 2.32; N 60.77. C3H4N8O2. Calculated, %:
С 19.57; H 2.19; N 60.86.
N-(1H-Tetrazol-5-yl)-1,2,4,5-tetrazin-3-amine
(7).
Yield 208 mg (63%, method II), orange-red crystals,
decomp. temp. 257–260°С (MeCN). Rf 0.51 (MeCN–AcOH,
30:1). IR spectrum, ν, cm−1: 1636 (C=N), 2660–2989
(NH···N), 3077 (C–H Het), 3180 (N–H). UV spectrum,
1
λmax, nm (ε): 516 (475). H NMR spectrum, δ, ppm: 10.22
(1H, s, H-6); 13.60 (2H, br. s, 2NH). 13C NMR spectrum,
δ, ppm: 150.5; 155.0; 160.9. Mass spectrum (MS), m/z (Irel, %):
165 [M]+ (69), 137 (15), 109 (20), 82 (35), 69 (100), 53
(36). Mass spectrum (LC/MS), m/z (Irel, %): 166 [M+H]+
(100). Found, %: С 21.93; H 1.91; N 76.20. C3H3N9.
Calculated, %: С 21.82; H 1.83; N 76.35.
N-(1H-1,2,4-Triazol-5-yl)-1,2,4,5-tetrazin-3-amine (8).
Yield 191 mg (58%, method II), dark-orange crystals,
decomp. temp. 268–275°С. Rf 0.57 (MeCN–AcOH, 30:1).
IR spectrum, ν, cm−1: 1641 (C=N), 2620–2923 (NH···N),
3118 (С–H Het), 3148 (N–H). UV spectrum, λmax, nm (ε):
518 (420). 1H NMR spectrum, δ, ppm: 8.21 (1H, s,
H triazole); 10.02 (1H, s, H tetrazine); 12.59 (2H, br. s,
2NH). 13C NMR spectrum, δ, ppm: 144.9; 152.0; 153.7;
161.8. Mass spectrum (MS), m/z (Irel, %): 164 [M]+ (52),
109 (100), 68 (40), 54 (27), 53 (21), 42 (66). Mass
spectrum (LC/MS), m/z (Irel, %): 165 [M+H]+ (100).
Found, m/z: 187.0504. C4H4N8Na. Calculated, m/z:
187.0456. Found, %: С 29.24; H 2.57; N 68.18. C4H4N8.
Calculated, %: С 29.27; H 2.46; N 68.27.
N-(1,2,4,5-Tetrazin-3-yl)-1,2,4,5-tetrazin-3-amine (11).
Yield 195 mg (55%, method II), dark-pink crystals, mp 190–
195°С, decomp. temp. 210–230°С (MeCN). Rf 0.32 (CCl4–
MeCN, 3:1). IR spectrum, ν, cm−1: 1588 (C=N), 2878–
3028 (NH···N), 3079 (С–H Het), 3200 (N–H). UV spectrum,
λmax, nm (ε): 520 (1042). 1H NMR spectrum, δ, ppm: 10.30
(2H, s, H-6,6'); 12.78 (1H, br. s, NH). 13C NMR spectrum,
δ, ppm: 155.7; 161.9. Mass spectrum (MS), m/z (Irel, %):
177 [M]+ (23), 67 (100). Mass spectrum (LC/MS), m/z (Irel,
%): 178 [M+H]+ (100). Found, m/z: 200.0413. C4H3N9Na.
Calculated, m/z: 200.0409. Found, %: С 27.23; H 1.68;
N 71.08. C4H3N9. Calculated, %: С 27.12; H 1.71; N 71.17.
N-(1,2,4,5-Tetrazin-3-yl)[1,2,4]triazolo[4,3-b][1,2,4,5]tetra-
zine-6-amine (23). Yield 71% (method II, refluxing for 2 h).
Method III. A mixture of tetrazine 2 (223 mg, 2.3 mmol),
triazolotetrazine 21 (497 mg, 2.3 mmol), and K2CO3 (317 mg,
2.3 mmol) in MeCN (15 ml) was stirred at reflux
temperature for 3 h. The reaction mixture was cooled, the
precipitate was filtered off and washed with MeCN. The
1,2,4,5-Tetrazin-3-amine (2). Yield 175 mg (90%,
method I), red crystals, mp 176–178°С (МеОН) (mp 176–
177°С3v). Rf 0.35 (EtOAc–hexane, 1:1). IR spectrum, ν, cm−1:
1521, 1640 (C=N), 3078 (C–H Het), 3127, 3318 (N–H).
1
UV spectrum, λmax, nm (ε): 526 (570). H NMR spectrum,
δ, ppm: 7.89 (2H, s, NH2); 9.70 (1H, s, Н-6). 13C NMR
spectrum, δ, ppm: 152.9; 164.5. Mass spectrum (GC/MS),
m/z (Irel, %): 97 [M]+ (28), 42 (100), 41 (17). Mass spectrum
(LC/MS), m/z (Irel, %): 98 [M+H]+ (100).
3-Hydrazinyl-1,2,4,5-tetrazine (3). Yield 181 mg
(81%, method I), orange crystals, mp 84–87°С (decomp.,
CH2Cl2) (mp 88°С6a). Rf 0.35 (EtOAc–hexane, 2:1).
IR spectrum, ν, cm−1: 1559, 1633 (C=N), 3084 (C–H Het),
3230, 3326 (N–H). 1H NMR spectrum, δ, ppm: 4.56 (2H, s,
NH2); 9.48 (1H, br. s, NH); 9.71 (1H, s, H-6). 13C NMR
spectrum, δ, ppm: 152.8; 164.1. Mass spectrum (LC/MS),
m/z (Irel, %): 113 [M+H]+ (100).
N-Methyl-1,2,4,5-tetrazin-3-amine (4). Yield 155 mg
(70%, method I), red crystals, mp 109–110°С (i-PrOH).
Rf 0.54 (EtOAc–heptane, 1:1). IR spectrum, ν, cm−1: 1605
(C=N); 2932 (С–H), 3081 (С–H Het), 3158, 3249 (N–H).
1
UV spectrum, λmax, nm (ε): 527 (547). H NMR spectrum,
δ, ppm (J, Hz): 2.97 (3H, d, 3J = 4.9, CH3NH); 8.36 (1H, s,
H-6); 9.69 (1H, br. s, NH). 13C NMR spectrum, δ, ppm:
26.9; 152.4; 162.8. Mass spectrum (GC/MS), m/z (Irel, %):
111 [M]+ (42), 56 (80), 55 (100). Mass spectrum (LC/MS),
m/z (Irel, %): 112 [M+H]+ (100). Found, %: С 32.47;
807

Chemistry of Heterocyclic Compounds 2017, 53(6/7), 802–810
product was transferred into H2O (5 ml), acidified with
reflux temperature for 2 h. The reaction mixture was
evaporated at reduced pressure. The residue was dissolved
in H2O (5 ml) and acidified with 10% HCl to рН 2. The
precipitate that formed was filtered off, washed with H2O
and PhMe, and dried. Yield 185 mg (92%), pink crystals,
mp 212–214°С (MeCN). Rf 0.56 (CCl4–MeCN, 1:1).
IR spectrum, ν, cm−1: 1570, 1581 (C=N), 2851–2957
(NH···N, C–H), 3035 (C–H Het), 3145 (N–H). UV spectrum,
10% HCl to рН 2, and stirred for 1 h. The precipitate was
filtered off, washed with H2O, and dried. Yield 400 mg
(80%), orange crystals, decomp. temp. 240–246°С (MeCN–
H2O). Rf 0.26 (CCl4–MeCN, 1:1). IR spectrum, ν, cm−1: 1566,
1590 (C=N), 2803–3016 (NH···N), 3093, 3123 (C–H Het),
3192, 3361 (N–H). UV spectrum, λmax, nm (ε): 430 sh.
(~500), 523 (494). 1H NMR spectrum, δ, ppm: 9.82 (1H, s,
H triazole); 10.34 (1H, s, H tetrazine); 13.20 (1H, br. s,
NH). 13C NMR spectrum, δ, ppm: 137.2; 149.6; 151.5;
155.6; 161.7. Mass spectrum (MS), m/z (Irel, %): 217 [M]+
(43), 162 (34), 107 (30), 95 (27), 67 (100), 53 (26). Mass
spectrum (LC/MS), m/z (Irel, %): 218 [M+H]+ (100).
Found, m/z: 240.0472. C5H3N11Na. Calculated, m/z:
240.0470. Found, %: С 27.58; H 1.41; N 70.84. C9H9N11.
Calculated, %: С 27.66; H 1.39; N 70.95.
1
λmax, nm (ε): 521 (787). H NMR spectrum, δ, ppm: 2.27
(3H, s, CH3); 2.57 (3H, s, CH3); 6.29 (1H, s, H pyrazole);
10.31 (1H, s, H tetrazine); 12.91 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 13.1; 13.2; 110.1; 142.5; 151.7; 155.7;
158.0; 159.6; 161.8. Mass spectrum (MS), m/z (Irel, %):
271 [M]+ (42), 121 (100), 106 (25), 94 (7), 80 (15), 67 (23),
53 (26). Mass spectrum (LC/MS), m/z (Irel, %): 272 [M+H]+
(100). Found, m/z: 294.0935. C9H9N11Na. Calculated, m/z:
294.0940. Found, %: С 39.83; H 3.41; N 56.78. C9H9N11.
Calculated, %: С 39.85; H 3.34; N 56.80.
1-(1,2,4,5-Tetrazin-3-yl)guanidine (5). A mixture of
tetrazine 1 (300 mg, 1.7 mmol) and guanidine hydro-
chloride (163 mg, 1.7 mmol) in MeCN (20 ml) at 40°С was
treated by the addition of K2CO3 (235 mg, 1.7 mmol) and
stirred for 3 h. The precipitate was filtered off, washed first
with MeCN and then with H2O, and dried. Yield 140 mg
(59%), dark-red crystals, decomp. temp. 196–203°С
(MeCN). Rf 0.23 (EtOAc). IR spectrum, ν, cm−1: 1612,
1659 (C=N), 3120 (С–H Het), 3352, 3441 (N–H). UV
spectrum, λmax, nm (ε): 369 sh. (~1200), 539 (463). 1H NMR
spectrum, δ, ppm: 7.24 (4H, br. s, 2NH, NH2); 9.64 (1H, s,
CH). 13C NMR spectrum, δ, ppm: 151.2; 159.8; 166.9. Mass
spectrum (MS), m/z (Irel, %): 139 [M]+ (9), 84 (100), 68 (25),
43 (63). Mass spectrum (LC/MS), m/z (Irel, %): 140 [M+H]+
(100). Found, m/z: 162.0492. C3H5N7Na. Calculated, m/z:
162.0504. Found, %: С 25.84; H 3.71; N 70.17. C3H5N7.
Calculated, %: С 25.90; H 3.62; N 70.48.
The reaction of 3-(3,5-dimethyl-1H-pyrazol-1-yl)-
1,2,4,5-tetrazine (1) and 6-(3,5-dimethyl-1H-pyrazol-1-yl)-
1,2,4,5-tetrazin-3-amine (10). A mixture of tetrazine 1
(176 mg, 1 mmol), tetrazine 10 (191 mg, 1 mmol), and
K2CO3 (138 mg, 1 mmol) in MeCN (10 ml) was stirred at
reflux temperature for 3 h. The solvent was removed by
evaporation at reduced pressure. The residue was dissolved
in H2O (5 ml), acidified with 10% HCl, and extracted with
EtOAc (5×3 ml). The combined organic layer was washed
with saturated NaCl solution and dried over anhydrous
Na2SO4. The solvent was removed by evaporation and red
1
crystals (210 mg) were obtained. According to Н NMR
spectral data, the product consisted of a mixture of
tetrazines 13 and 14 in 5:1 ratio. The mixture was separated
by silica gel column chromatography, using 2:1 EtOAc–
hexane system as eluent. Individual compounds 13 (150 mg,
55%) and 14 (37 mg, 10%) were obtained.
N,N'-Di(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazine-3,6-dia-
mine (12). A mixture of 1,2,4,5-tetrazine-3,6-diamine (9)
(90 mg, 0.8 mmol), tetrazine 1 (282 mg, 1.6 mmol), and
K2CO3 (221 mg, 1.6 mmol) in MeCN (20 ml) was stirred at
reflux temperature for 3 h. The reaction mixture was cooled
to room temperature, the precipitate was filtered off and
washed with MeCN. The solid residue was dissolved in
H2O and acidified with 10% HCl to pH 1. The precipitate
that formed was filtered off, washed with H2O and PhMe,
and recrystallized from MeCN in a Soxhlet apparatus.
Yield 170 mg (78%), red crystals, decomp. temp. 279–283°
С (MeCN). Rf 0.5 (CCl4–MeCN, 1:1). IR spectrum, ν, cm−1:
1585 (C=N), 2851–3008 (NH···N), 3078 (C–H Het), 3200
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-N-[6-(3,5-dimethyl-1H-
pyrazol-1-yl)-1,2,4,5-tetrazin-3-yl]-1,2,4,5-tetrazin-3-amine (14).
Orange crystals, mp 238–239°С (MeCN) (mp 239–
240°С14). Rf 0.36 (CCl4–MeCN, 1:1). IR spectrum, ν, cm−1:
1574 (C=N), 2804–2983 (NH···N, C–H), 3158, 3432 (N–H).
1H NMR spectrum, δ, ppm: 2.27 (6H, s, 2CH3); 2.56 (6H, s,
2CH3); 6.30 (2H, s, H pyrazole); 13.08 (1H, br. s, NH). Mass
spectrum (MS), m/z (Irel, %): 365 [M]+ (13), 216 (25), 122
(25), 121 (100), 106 (20), 94 (5), 80 (13), 67 (11), 53 (20).
Mass spectrum (LC/MS), m/z (Irel, %): 366 [M+H]+ (100).
The reaction of 3-(3,5-dimethyl-1H-pyrazol-1-yl)-
1,2,4,5-tetrazine (1) and N,N'-dimethyl-1,2,4,5-tetrazine-
3,6-diamine (18). A mixture of tetrazine 1 (352 mg,
2 mmol), tetrazine 18 (140 mg, 1 mmol), and K2CO3
(276 mg, 2 mmol) in MeCN (20 ml) was stirred at reflux
temperature for 3 h. The solvent was removed by
evaporation and the residue was separated by silica gel
column chromatography, using CHCl3 as eluent. The
isolated products were tetrazine 20 (72 mg, 17%) and
tetrazine 4 (94 mg, 42%).
1
(N–H). UV spectrum, λmax, nm (ε): 522 (1560). H NMR
spectrum, δ, ppm: 10.25 (2H, s, H-6,6'); 12.68 (2H, br. s,
2NH). 13C NMR spectrum, δ, ppm: 155.5; 158.7; 162.0.
Mass spectrum (MS), m/z (Irel, %): 272 [M]+ (18), 122 (13),
68 (36), 67 (100). Mass spectrum (LC/MS), m/z (Irel, %):
273 [M+H]+ (100). Found, m/z: 295.0630. C6H4N14Na.
Calculated, m/z: 295.0641. Found, %: С 26.32; H 1.51;
N 71.98. C6H4N14. Calculated, %: С 26.48; H 1.48; N 72.04.
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-N-(1,2,4,5-tetrazin-3-yl)-
1,2,4,5-tetrazin-3-amine (13). A mixture of 3,6-bis(3,5-
dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine (17) (200 mg,
0.74 mmol), tetrazine 2 (72 mg, 0.74 mmol), and K2CO3
(102 mg, 0.74 mmol) in MeCN (15 ml) was stirred at
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-N-methyl-1,2,4,5-
tetrazin-3-amine (20). Orange crystals, mp 196–197°С
(EtOH) (mp 194–195°С (MeOH–H2O)28). Rf 0.27 (EtOAc–
heptane, 1:1). IR spectrum, ν, cm−1: 1587 (C=N), 2864,
808

Chemistry of Heterocyclic Compounds 2017, 53(6/7), 802–810
(j) Sauer, J. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996, Vol. 6, p. 901. (k) Sauer, J. Chem.
Heterocycl. Compd. 1995, 31, 1140. [Khim. Geterotsikl.
Soedin. 1995, 1307.] (l) Neunhöffer, H. In Comprehensive
Heterocyclic Chemistry I; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon: Oxford, 1984, Vol. 3, p. 531. (m) Kovalev, E. G.;
Postovskii, I. Ya.; Rusinov, G. L.; Shegal, I. L. Chem.
Heterocycl. Compd. 1981, 17, 1063. [Khim. Geterotsikl. Soedin.
1981, 1462.] (n) Wiley, P. F. In The Chemistry of Heterocyclic
Compounds; Weissberger, A.; Taylor, E. C., Eds.; John Wiley
& Sons: New York, 1978, Vol. 33, p. 1073.
2928 (C–H), 3055 (C–H Het), 3138, 3214
1
(N–H). H NMR spectrum, δ, ppm (J, Hz): 2.22 (3Н, s,
3
СН3); 2.38 (3Н, s, СН3); 3.03 (3Н, d, J = 4.8, CH3NH);
6.17 (1H, s, H pyrazole); 8.61 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 12.2; 13.3; 27.6; 108.4; 143.3; 150.0;
157.3; 162.8. Mass spectrum (GC/MS), m/z (Irel, %): 205
[M]+ (24), 122 (41), 121 (100), 120 (32), 106 (28), 95 (10),
80 (20), 67 (18), 55 (22), 53 (35). Mass spectrum (LC/MS),
m/z (Irel, %): 206 [M+H]+ (100).
3-Chloro-1,2,4,5-tetrazine (24). Gaseous chlorine was
bubbled through a stirred solution of 3-hydrazinyl-1,2,4,5-
tetrazine (3) (0.7 g, 6.25 mmol) in MeCN (30 ml) at room
temperature for 30 min. The solvent was then removed by
evaporation at reduced pressure, with temperature not
exceeding 25°C. The residue was dissolved in CH2Cl2 and
filtered through a 2 cm thick layer of silica gel. The solvent
was removed by evaporation at room temperature. Yield
0.3 g (40%), volatile orange crystals, mp 66–68°С
(pentane). Rf 0.45 (EtOAc–heptane, 1:4). UV spectrum,
λmax, nm (ε): 515 (568). IR spectrum, ν, cm−1: 894 (C–Cl),
2. (a) Wei, T.; Zhu, W.; Zhang, X.; Li, Y.-F.; Xiao, H. J. Phys.
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1
1402, 1493 (C=N), 3090 (C–H Het). H NMR spectrum,
δ, ppm: 10.28 (1H, s, H-6). 13C NMR spectrum, δ, ppm:
157.8; 170.8. Found, %: C 20.69; H 0.95; N 47.86. C2HClN4.
Calculated, %: C 20.62; H 0.86; N 48.09.
N,N-Di(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazin-3-amine
(25). Sodium hydride (40 mg, 60% dispersion in mineral
oil, 1.0 mmol) was added to a solution of ditetrazinylamine
11 (177 mg, 1.0 mmol) in anhydrous THF (5 ml), and the
mixture was stirred for 30 min at room temperature.
Tetrazine 24 (128 mg, 1.1 mmol) was added to the obtained
suspension, and the resulting mixture was stirred at reflux
for 2 h. The reaction mixture was cooled and filtered. The
brown precipitate was transferred into 10% HCl (3 ml), the
mixture was stirred for 1 h and filtered. Yield 149 mg
(58%), red crystals, decomp. temp. 231–255°С (MeCN).
Rf 0.69 (CCl4–MeCN, 3:1). IR spectrum, ν, cm−1: 1429
(C=N), 3094 (C–H Het). UV spectrum, λmax, nm (ε): 523
1
(2330). H NMR spectrum, δ, ppm: 10.79 (3H, s, H-6,6',6'').
13C NMR spectrum, δ, ppm: 158.2; 164.6. Mass spectrum
(MS), m/z (Irel, %): 257 [M]+ (28), 92 (100), 66 (24).
Found, %: C 28.09; H 1.14; N 70.58. C6H3N13. Calculated,
%: C 28.02; H 1.18; N 70.80.
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