Synthesis of 1,2,4,5-tetrazines, symmetrically and unsymmetrically 3,6-disubstituted by N-nucleophiles

Article abstract of DOI:10.1134/S1070428006050198

6-R-3-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazines with aliphatic, cycloaliphatic, and aromatic amines, and also with NH-heterocycles undergo a nucleophilic substitution of the dimethylpyrazole moiety yielding symmetrically and unsymmetrically substitute

Full text of DOI:10.1134/S1070428006050198

ISSN 1070-4280 Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 5, pp. 757-765. Ó Pleiades Publishing, Inc. 2006.
Original Russian Text Ó G.L. Rusinov, N.I. Latosh, I.I. Ganebnykh, R.I. Ishmetova, N.K. Ignatenko, O.N. Chupakhin, 2006, published in
Zhurnal Organicheskoi Khimii, 2006, Vol. 42, No. 5, pp. 772-780.
Synthesis of 1,2,4,5-Tetrazines, Symmetrically and Unsymmetrically
3,6-Disubstituted by N-Nucleophiles
G.L. Rusinov, N.I. Latosh, I.I. Ganebnykh, R.I. Ishmetova,
N.K. Ignatenko, and O.N. Chupakhin
Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences, Yekaterinburg, 620219 Russia
e-mail: rusinov@ios.uran.ru
Received August 11, 2004
Abstract—6-R-3-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazines with aliphatic, cycloaliphatic, and aromatic amines,
and also with NH-heterocycles undergo a nucleophilic substitution of the dimethylpyrazole moiety yielding
symmetrically and unsymmetrically substituted 1,2,4,5-tetrazines. In the 3,6-diimidazolyl- and 3,6-dibenzotriazolyl
derivatives reactions of nucleophilic substitution of the heterocyclic moiety also occur. In some cases an ipso-
substitution of amino, hydrazino, and azido groups is observed.
DOI: 10.1134/S1070428006050198
3,6-Bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (I)
in reaction with aliphatic, cycloaliphatic, and aromatic
amines at room temperature is known [1–4] to undergo
a substitution of dimethylpyrazolyl moiety to furnish in
a high yield unsymmetrically substituted tetrazines II. In
these reactions as nucleophiles served aliphatic, cyclo-
aliphatic, and aromatic amines. At the same time in cer-
tain reactions of tetrazine I with the primary aliphatic
amines products of two pyrazolyl groups substitution III
were isolated. Therefore compound I is a promising syn-
thon for preparation of a large series of symmetrically
and unsymmetrically 3,6-disubstituted 1,2,4,5-tetrazines of-
ten unavailable by other synthetic methods. However the
application in this respect of 3-amino-substituted 6-(3,5-
dimethylpyrazol-1-yl)-1,2,4,5-tetrazines reactions with nu-
cleophiles is poorly investigated. In a recent article [5] re-
actions of these tetrazines with hydrazine and KOH were
considered.
In the present study we more thoroughly investigated
the prospects of synthetic applications of the nucleophilic
substitution of the dimethylpyrazolyl moiety in 6-R-3-(3,5-
dimethylpyrazol-1-yl)-1,2,4,5-tetrazines IIà–IIi with vari-
ous amines.
Scheme 1.
+ &
1 1
1 1
&+
1
1 1
1 1
1
+ &
1X
1X
1 1
1
1
1X
ꢀ+1X
+1X
1
1
1 1
,
B
&+
&+
B
,,, ꢀꢀꢀ,,,O
,, ꢀꢀꢀ,,L
&+
+1X
1X
1 1
1X
1 1
B
9,ꢀꢀꢀ9,,,
II, Nu1 = 1-indolyl (à), 5-bromoindol-3-yl (b), BnNH(c), HOCH2CH2NH (d), NH2 (e), N2H3 (f), N3 (g), 4-FC6H4NH (h), 1-adamantyl-
amino (i); III, Nu2 = BnNH (à), HOCH2CH2NH (b), CH2=CHCH2NH (c), PhCONH (d), pyrrolidino (e), morpholino (f), cyclo-
hexylamino (g), cycloheptylamino (h), 5-bromoindol-3-yl (i), 1-imidazolyl (j), 1-benzotriazolyl (k), PhNH (l); VI–VIII, Nu1 =
PhNH (à), 4-MeC6H4NH (b), 3-MeC6H4NH (c), 3,4-Me2C6H3NH (d), 4-MeOC6H4NH (e), 4-FC6H4NH (f), 4-ClC6H4NH (g),
4-BrC6H4NH (h), thiomorpholino (i), 1-adamantylamino (j); Nu3 = BnNH (VI), HOCH2CH2NH (VII), CH2=CHCH2NH (VIII).
757

RUSINOV et al.
758
We found that at boiling compound I in acetonitrile
tained over its melting point the pyrazolyl groups under-
went substitution furnishing 3,6-bis(benzotriazol-1-yl)-
1,2,4,5-tetrazine (IIIk) (yield 53%). This compound can
also be obtained in a simpler way by boiling initial tetrazine
I with benzotriazole in benzene. As a side product an-
other complex V of tetrazine IIIk with 3,5-dimethylpyr-
azole in a 1:1 ratio was isolated in an 11% yield.
the primary aliphatic amines (benzylamine, ethanolamine,
and allylamine) easily replaced both dimethyl-pyrazolyl
groups. As a result compounds IIIà–IIIc formed in high
yields (Scheme 1).
Weak nucleophiles, like acid amides, are involved into
the substitution reaction with 1,2,4,5-tetrazines only in the
presence of strong bases. For instance, it was shown re-
cently that this substitution occurred with methylsulfanyl-
tetrazines when introducing butyllithium into the reaction
mixture [6]. We carried out reaction of tetrazine I with
benzamide in the presence of potassium tert-butylate and
isolated in a 48% yield the corresponding product of
disubstitution, 3,6-dibenzamido-1,2,4,5-tetrazine (IIId) that
had been previously obtained by acylation of 3,6-diamino-
1,2,4,5-tetrazine (yield 30%) [7]. The substitution of
pyrazolyl groups is favored by high pressure. Thus the
symmetrically 3,6-disubstituted tetrazines IIIe–IIIh con-
taining pyrrolidine, morpholine, cyclohexylamine, and
cycloheptylamine rests were successfully prepared in
good yields heating for 3–4 h at 80°Ñ and a pressure of
500 MPa (at higher temperature the decomposition of
the tetrazine ring was observed). Product IIIf formed in
a low yield also at the ordinary pressure when tetrazine
IIIj was boiled in neat morpholine.
The formation of tetrazine IIIk was unambiguously
1
confirmed by the data of H NMR spectroscopy: Four
groups of nonequivalent protons were observed. If the
reaction occurred at the position N2 of the benzotriazole
in the 1H NMR spectrum should appear only two groups
of signals due to the presence of protons equivalent in
pairs.
Compounds II whose synthesis was described in [3]
by reactions with N-nucleophiles gave rise to unsym-
metrically substituted tetrazines VI–VIII.
It was established that the substitution of the dimethyl-
pyrazolyl group in compounds IIà–IIi by primary aliphatic
amines occurred at boiling for 3–12 h with a small excess
of the amine in acetonitrile. Under these conditions the
secondary aliphatic amines were not involved into the
substitution reaction.
The primary amines can substitute in compounds IIà–
IIi the pyrazolyl group as well as the earlier introduced
nucleophile. For instance, the storage of tetrazine IIc with
ethanolamine at 20°Ñ for 12 days resulted in solution con-
taining according to TLC tetrazine IIc, IId, IIIà, and
IIIb.
We established that NH-heterocyclic compounds
also could be involved into the nucleophilic substitution of
the pyrazole moieties. In particular, we studied the reac-
tions of tetrazine I with indole, 5-bromoindole, imidazole,
and benzotriazole. Tetrazine I readily reacted with indole
in acetonitrile at 20°Ñ in the presence of triethylamine
furnishing a product of substitution of a single pyrazolyl
group IIà in a 73% yield. We failed to obtain a product of
the second pyrazolyl group substitution at prolonged boil-
ing of tetrazine I in acetonitrile with excess indole; the
process was accompanied by formation of an intractable
mixture of substances. 5-Bromoindole with tetrazine I in
acetonitrile in the presence of triethylamine furnished prod-
ucts of mono- and disubstitution IIb and IIIi in 70 and
86% yields respectively. The reaction of tetrazine I with
imidazole occurred even in the absence of a base at 40°Ñ
giving 3,6-bis(imidazol-1-yl)-1,2,4,5-tetrazine (IIIj).
Therewith the yield of tetrazine IIIj at the use of anhy-
drous acetonitrile attained 93–95%.
Therefore the preparation from compound I of un-
symmetrical diamino-substituted tetrazines VI–VIII re-
quires first bringing into the reaction the aromatic or sec-
ondary aliphatic amine and then the primary aliphatic
amine.
We found that the amino group in tetrazine IIe was
the first to be replaced in reactions with primary and sec-
ondary aliphatic amines, and then the pyrazolyl group was
also substituted similarly to reactions described in [5] of
1,2,4,5-tetrazines with hydrazine hydrate or KOH. In par-
ticular, after 3 h of boiling the said tetrazine in acetonitrile
with two equiv of benzylamine a mixture of products
formed containing according to NMR data 6-benzylamino-
3-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (IIc) as the
main component and in a lesser amount 3,6-bis(benzyl-
amino)-1,2,4,5-tetrazine (IIIà) (in a ratio ~6:1). On bring-
ing into the reaction additional quantity of benzylamine
we obtained as the main product tetrazine IIIà. At heat-
ing hydrazinotetrazine IIf with benzylamine also the sub-
stitution of the hydrazine moiety was observed.
Azidotetrazine IIg obtained in its turn by nitrosation of
The reaction of tetrazine I with benzotriazole occurred
in a different fashion. Just after the dissolution in acetoni-
trile fine orange crystals of derivative IV precipitated
which were identified as a complex of compound I with
the benzotriazole in 1:2 ratio.At heating the complex ob-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

SYNTHESIS OF 1,2,4,5-TETRAZINES
759
tetrazine IIf reacted with benzylamine already at room
temperature giving in a high yield the product of azide
group substitution IIc.
Scheme 2.
1 1
&+
1
5
1+1
Thus the nucleophilic substitution of the dimethyl-
pyrazolyl group in the amino, hydrazino, and azido deriva-
tives of tetrazine by the method described is complicated
by the possibility of replacement of NH2, N2H3, and N3
groups. With hydrazine derivatives this problem can be
solved by their transformation into hydrazones. For in-
stance, in hydrazones IXà–IXc obtained like in [3] the
pyrazolyl group was substituted in the acetonitrile solu-
tion by dodecylamine and benzylamine (Scheme 2).
1
5ꢀ
1 1
+ &
B
,; ꢀꢀꢀ,;F
1 1
5
+1X
1X
1+1
1 1
5ꢀ
B
B
; ꢀꢀꢀ;Fꢁꢀ;, ꢀꢀꢀ;,F
R = H, R' = Ph (à); R= Me, R' = Ph (b); R = Me, R' =
4-ClC6H4(c); Nu = NHBn (X), NH(CH2)11CH3 (XI).
The imidazolyl and benzotriazolyl moieties in 1,2,4,5-
tetrazines IIIj and IIIk, like the pyrazolyl groups in com-
pound I, can be replaced by amines, but in compounds
IIIj and IIIk the heterocyclic substituents are more
labile. For instance, after boiling for 12 h of tetrazines I
or IIIk in neat aniline 3,6-bis(phenylamino)-1,2,4,5-
tetrazine IIIl was isolated in 42 and 54% yields respec-
tively. The departing ability of imidazole moiety in reac-
tion of tetrazine IIIj with aniline proved to be even greater:
Product IIll was isolated in a 64% yield already after 5 h
of boiling. Under less stringent conditions only one het-
erocyclic moiety was replaced. 3-(Benzotriazol-1-yl)-6-
phenylamino-1,2,4,5-tetrazine (XIIà) was obtained in the
reaction of tetrazine IIIk with exess aniline (5 equiv) in
acetonitrile.
Xà–Xc) and Bruker Avance DRX-400 (400 MHz; for all
other compounds). Chemical shifts were measured rela-
tive HMDS or TMS. Spectra of compounds IIà, IIb,
IIg, IIk, IXà, IXb, and Xà–Xc were registered in CDCl3,
all other, in DMSO-d6.
6-(3,5-Dimethylpyrazol-1-yl)-3-(indol-1-yl)-
1,2,4,5-tetrazine (IIà). To a dispersion of 0.27 g
(1.0 mmol) of tetrazine I and 0.14 g (1.2 mmol) of indole
in 10 ml of acetonitrile was added 0.1 ml of triethylamine,
the mixture was heated till it homogenized, then it was
maintained for 2 h at 18–20°Ñ, the solution was evapo-
rated, and the residue was recrystallized from ethanol.
1
Yield 73%, mp 161–163°C (from C2H5OH). H NMR
spectrum, d, ppm: 2.41 s (3Í, ÑÍ3), 2.74 s (3Í, ÑÍ3),
The use of the procedure of the nucleophilic sub-
stitution of dimethylpyrazolyl, and also benzotriazolyl and
imidazolyl groups in the derivatives of 1,2,4,5-tetrazine
considerably extends the bank of various symmetrically
and unsymmetrically substituted 1,2,4,5-tetrazines.
6.20 s (1H, H4Pz), 6.89–6.90 m (1Í, H3Ind), 7.32–7.36 m,
4,5,6,7
7.4–7.45 m, 7.67–7.71 m, 8.68–8.72 m(4Í, H
), 8.33 m
Ind
(1Í, H2Ind). Found, %: Ñ 61.87; H 4.49; N 33.88.
Ñ15Í13N7. Calculated, %: C 61.84; H 4.50; N 33.66.
3-(5-Bromoindol-1-yl)-6-(3,5-dimethylpyrazol-1-
yl)-1,2,4,5-tetrazine (IIb). From the filtrate of the
reaction mixture obtained on isolation of tetrazine IIIi
(its preparation is described below) after 0.5 h a red pre-
cipitate separated which was tetrazine IIb; it was fil-
tered off and recrystallized from acetonitrile. Yield 70%,
EXPERIMENTAL
All compounds obtained were as a rule crystalline
substances of bright color from orange to violet.
The reactions progress was monitored and the purity
of compounds obtained was checked by TLC on Silufol
plates with fixed layer, eluents chloroform–ethanol, 9:1,
or benzene-acetonitrile, 1:1.
Elemental analysis was carried out on automatic CHN-
analyzers EA1108 (Carlo Erba Instruments) and PE 2400
series (II) (Perkin Elmer). Melting points were measured
on the Boetius heating block and were reported uncor-
rected. Initial reagents and solvents were purified by stan-
dard procedures.
1
mp 199–200°C (from CH3CN). H NMR spectrum, d,
ppm: 2.41 s (3H, CH3), 2.73 s (3H, CH3), 6.21 s (1H,
H4Pz), 6.83 d, 7.81 d (2H, at H2I,n3d), 8.33 d, 8.55 d (2H,
H6I,n7d), 7.51 d.d (1H, HI4nd). Found, %: C 48.65; H 3.13;
N 26.46. C15H12BrN7. Calculated, %: C 48.67; H 3.27;
N 26.48.
Substitution of amino group in 3-amino-6-(3,5-
dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (IIe). A dis-
persion of 0.30 g (1.57 mmol) of tetrazine IIe [3] and
0.35 ml (2 equiv) of benzylamine in 5 ml of CH3CN was
boiler for 3 h (TLC monitoring), then the reaction mixture
1H NMR spectra were registered on spectrometers
Tesla BS567A (80 MHz; for compounds IIIg, IXà, IXb,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

RUSINOV et al.
760
was evaporated, the residue was washed with water and
recrystallized from methanol. Yield of tetrazine IIc
0.26 g (59%).
6-(1-Adamantylamino)-3-(3,5-dimethylpyrazol-1-
yl)-1,2,4,5-tetrazine (IIi). In 7 ml of acetonitrile was
charged 0.31 g (1.2 mmol) of tetrazine I and 0.24 g
(1.5 mmol) of 1-aminoadamantane. The mixture was
heated for 3 h at 50–60°C, then cooled to 0°C. The
separated bright-red precipitate was filtered off, washed
with cold acetonitrile and recrystallized from ethanol.Yield
Likewise the heating for 12 h of 0.300 g (1.57 mmol)
of tetrazine IIe and 0.52 ml (3 equiv) of benzylamine in
5 ml of CH3CN resulted in formation of tetrazine IIIa.
The reaction mixture was evaporated, the residue was
washed with hexane and recrystallized from methanol.
Yield 0.24 g (52%). According to NMR data the product
contained about 5% of tetrazine IIc. The analytically pure
sample identical to that synthesized from tetrazine I was
obtained after repeated recrystallization from methanol.
1
0.31 g (83%), mp 162–164°C (from C2H5OH). H NMR
spectrum, d, ppm: 1.69 m (6H, HAd), 2.13 m (9H, HAd),
2.21 s (3H, 3Pz-CH3), 2.40 s (3H, 5Pz-CH3), 6.18 s (1H,
4Pz-CH), 8.43 (1H, NH). Found, %: C 62.73; H 7.12;
N 30.08. C17H23N7. Calculated, %: C 62.75; H 7.12;
N 30.13.
3-Azido-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-
tetrazine (IIg). To a dispersion of 0.87 g (4.20 mmol) of
tetrazine IIc [3], 7 ml CH3CN, and 3 ml of acetic acid
was added at stirring 0.36 g (5.14 mmol) of sodium ni-
trite. After 3 min the slightly self-heated solution was
evaporated. The azidotetrazine obtained was extracted
from the oily residue with acetonitrile (10 ml), and the
extract was evaporated. The oily residue was washed
with a little water, then dissolved in petroleum ether at
heating. From the cooled solution on the next day precipi-
tated pure azidotetrazine IIg like crystals or oil drops; the
latter were ground in petroleum ether till crystallization.
Yield 0.71 g (78%), mp 51–52°C (from petroleum ether).
1H NMR spectrum, d, ppm: 2.38 s (3H, 3Pr-CH3 ); 2.68 d
(3H, 5Pz-CH3, J 0.8 Hz); 6.19 s (1H, 4Pz-CH). Found, %:
C 38.73; H 3.17; N 57.92. C7H7N9. Calculated, %:
C 38.71; H 3.25; N 58.04.
Symmetric disubstituted tetrazines IIIa–IIIc and
3,6-unsymmetric disubstituted 1,2,4,5-tetrazines
VI–VIII. A mixture of 1.2–1.5 mmol of 3-amino-substi-
tuted 6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine II (the
synthesis and properties of compounds II are published
in [3] save those of IIa, IIb, IIg–IIi) and 1.5–2.0 mmol
(in the synthesis of compounds VI–VIII) or 3–4 mmol
( in preparation of compounds IIIa–IIIc) of an appropri-
ate amine was boiled in CH3CN for 3–12 h (TLC moni-
toring). On cooling the reaction mixture the precipitate
was filtered off and recrystallized.
N,N'-Dibenzyl-1,2,4,5-tetrazine-3,6-diamine
(IIIa). Yield 87%, mp 154–155°C (from CH3OH).
1H NMR spectrum, d, ppm: 4.50 d (4H, 2CH2, J 6.3),
7.18–7.38 m (10H, Harom), 8.00 t (2H, NHaliph, J 6.3 Hz).
Found, %: C 65.68; H 5.44; N 28.85. C16H16N6. Calcu-
lated, %: C 65.74; H 5.52; N 28.74.
Substitution of azido group in 3-azido-6-(3,5-
dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (IIg).Toa solu-
tion of 0.06 g (0.26 mmol) of azidotetrazine IIg in 1.5 ml
of CH3CN was added at stirring 0.04 ml (0.36 mmol) of
benzylamine. Within several minutes crystalline tetrazine
IIc precipitated from the solution. After 15 min the sol-
vent was removed in air, the residue was washed with
water and recrystallized. Yield 0.05 g (63%).
3,6-Bis(hydroxyethylamino)-1,2,4,5-tetrazine
(IIIb). Yield 72%, mp 125–126°C (from C2H5OH).
1H NMR spectrum, d: ppm: 3.33–3.41 m (2H, CH2), 3.53–
3.58 m (2H, CH2), 4.2 br.s (1H, OH), 7.16 t (1H, NH,
J 5.8 Hz). Found, %: C 36.12; H 5.88; N 42.01.
C6H12N6O2. Calculated, %: C 36.00; H 6.04; N 41.98.
N,N'-Diallyl-1,2,4,5-tetrazine-3,6-diamine (IIIc).
Yield 74%, mp 116–117°C (from CH3OH–H2O) [8].
1H NMR spectrum, d, ppm: 3.92–3.95 m (2H, CH2), 5.05–
5.23 m (2H, =CH2), 5.86–5.96 m (1H, =CH), 7.39 t (1H,
NHaliph, J 6.0 Hz). Found, %: C 50.17; H 6.37; N 43.88.
C8H12N6. Calculated, %: C 49.99; H 6.29; N 43.72.
3-(3,5-Dimethylpyrazol-1-yl)-6-(p-fluorophenyl)-
amino-1,2,4,5-tetrazine (IIh). To 0.50 g (1.85 mmol)
tetrazine I in 7 ml of acetonitrile was added 0.30 ml
(2.70 mmol) of p-fluoroaniline, and the mixture was
stirred for 2 h at 40–50°C. On cooling the solution to 0°C
the precipitated dark-red needle crystals were filtered off
and recrystallized from methanol. Yield 0.47 g (88%),
N-Benzyl-N'-phenyl-1,2,4,5-tetrazine-3,6-di-
amine (VIa). Yield 58%, mp 184°C (from CH3OH).
1H NMR spectrum, d, ppm: 4.58 d (2H, CH2, J 6.5 Hz),
6.72–7.35 m (10H, Harom), 8.34 t (1H, NHaliph, J 6.5 Hz),
9.91 s (1H, NHarom). Found, %: C 65.44; H 5.26; N 29.80.
C15H14N6. Calculated, %: C 64.73; H 5.07; N 30.20.
1
mp 191–192°C (from CH3OH). H NMR spectrum, d,
ppm: 2.46 s (3H, CH3), 2.50 s (3H, CH3), 6.23 s (1H,
CH), 7.26 m (2H, CHarom), 7.71 m (2H, CHarom), 10.99 s
(1H, NH). Found, %: C 54.70; H 4.19; N 34.40.
C13H12FN7. Calculated, %: C 57.73; H 4.24; N 34.37
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

SYNTHESIS OF 1,2,4,5-TETRAZINES
761
Benzyl(6-thiomorpholino-1,2,4,5-tetrazin-3-
N-Benzyl-N'-p-tolyl-1,2,4,5-tetrazine-3,6-di-
amine (VIb). Yield 48%, mp 231°C (from C2H5OH).
1H NMR spectrum, d, ppm: 2.24 s (3H, CH3), 4.57 d
(2H, CH2, J 6.3 Hz), 7.05–7.56 m (9H, Harom), 8.31 t
(1H, NHaliph, J 6.3 Hz), 9.88 C (1H, NHarom). Found, %:
C 65.78; H 5.59; N 28.70. C16H16N6. Calculated, %:
C 65.74; H 5.51; N 28.75.
yl)amine (VIi). Yield 43%, mp 103°C (from CH3OH–
1
H2O). H NMR spectrum, d, ppm: 2.63–2.67 m (4H,
S(CH2)2), 3.97–4.01 m (4H, N(CH2)2), 4.54 d (2H, CH2,
J 6.3 Hz), 7.22–7.38 m (5H, Harom); 8.16 t (1H, NHaliph
,
J 6.3 Hz). Found, %: C 54.05; H 5.66; N 28.98.
C13H16N6S. Calculated, %: C 54.15; H 5.59; N 29.14.
[6-(1-Adamantylamino)-1,2,4,5-tetrazin-3-
N-Benzyl-N'-m-tolyl-1,2,4,5-tetrazine-3,6-di-
amine (VIc). Yield 55%, mp 237°C (from C2H5OH).
1H NMR spectrum, d, ppm: 2.27 s (3H, CH3), 4.58 d
(2H, CH2, J 6.3 Hz), 6.95–7.59 m (9H, Harom), 8.36 t
(1H, NHaliph, J 6.3 Hz), 9.98 C (1H, NHarom). Found, %:
C 65.38; H 5.28; N 28.98. C16H16N6. Calculated, %:
C 65.74; H 5.51; N 28.75.
yl]benzylamine (VIj). Yield 55%, mp 133–134°C (from
1
C2H5OH). H NMR spectrum, d, ppm: 1.68 m (6H,
Hadamantyl), 2.08 m (9H, Hadamantyl), 4.51 d (2H, CH2,
J 6.4 Hz), 6.62 C (1H, NHarom), 7.29 m (5H, Harom),
7.69 t (1H, NHaliph, J 6.4 Hz). Found, %: C 67.90;
H 7.18; N 25.22. C19H24N6. Calculated, %: C 67.83;
H 7.19; N 24.98.
N-Benzyl-N'-(3,4-dimethylphenyl)-1,2,4,5-
tetrazine-3,6-diamine (VId). Yield 43%, mp 199°C
(from CH3CN). 1H NMR spectrum, d, ppm: 2.16 s (3H,
CH3), 2.19 s (3H, CH3), 4.57 d (2H, CH2, J 6.5 Hz),
6.99–7.50 m (9H, Harom), 8.28 t (1H, NHaliph, J 6.5 Hz),
9.78 s (1H, NHarom). Found, %: C 66.68; H 5.86; N 27.53.
C17H18N6. Calculated, %: C 66.65; H 5.92; N 27.43.
2-(6-Phenylamino-1,2,4,5-tetrazin-3-ylamino)-
ethanol (VIIa). Yield: 55%, mp 213–214°C (from
1
CH3OH). H NMR spectrum, d, ppm: 3.41–3.48 m
(2H,CH2), 3.56–3.61 m (2H,CH2), 4.69 t (1H, OH,
J 5 Hz), 6.92–6.98 m (1H, Harom), 7.27–7.30 m (2H,
Harom), 7.61–7.65 m and 7.62 t (3H, 3H, 2Harom and
NHaliph), 9.90 s (1H, NHarom). Found, %: C 51.55; H 4.97;
N 36.21. C10H12N6O. Calculated, %: C 51.72; H 5.21;
N 36.19.
N-Benzyl-N'-(4-methoxyphenyl)-1,2,4,5-
tetrazine-3,6-diamine (VIe). Yield: 49%, mp 226°C
1
(from C2H5OH). H NMR spectrum, d, ppm: 3.70 s (3H,
OCH3), 4.55 d (2H, CH2, J 6.6 Hz), 6.83–7.38 m (9H,
Harom), 8.23 t (1H, NHaliph, J 6.6 Hz), 9.73 C (1H, NHarom).
Found, %: C 62.36; H 5.10; N 27.15. C16H15N6O.
Calculated, %: C 62.53; H 4.92; N 27.34.
2-(6-p-Tolylamino-1,2,4,5-tetrazin-3-ylamino)-
ethanol (VIIb). Yield: 39%, mp 244–245°C (from
CH3OH). 1H NMR spectrum, d, ppm: 2.25 s (3H, CH3),
3.40–3.47 m (2H,CH2), 3.56–3.63 m (2H,CH2), 4.69 t
(1H, OH, 5.5 Hz), 7.09–7.12 m (2H, Harom, J 8 Hz); 7.50–
7.54 m and 7.55 t (3H, 2Harom and NHaliph, J 8 Hz),
9.78 s (1H, NHarom). Found, %: C 53.57; H 5.68; N 33.98.
C11H14N6O. Calculated, %: C 53.65; H 5.73; N 34.13.
N-Benzyl-N'-(4-fluorophenyl)-1,2,4,5-tetrazine-
3,6-diamine (VIf). Yield: 46%, mp 216–217°C (from
1
C2H5OH). H NMR spectrum, d, ppm: 4.58 d (2H, CH2,
J 6.10 Hz), 7.09–7.40 m (7H, Harom), 7.60–7.66 m (2H,
Harom), 8.31 t (1H, NHaliph, J 6.1 Hz), 10.31 s (1H,
NHarom). Found, %: C 60.52; H 4.27; N 28.10. C15H13FN6.
Calculated, %: C 60.80; H 4.42; N 28.36.
2-(6-m-Tolylamino-1,2,4,5-tetrazine-3-ylamino)-
ethanol (VIIc). Yield 46%, mp 141–142°C (from
CH3OH–H2O). 1H NMR spectrum, d, ppm: 2.29 s (3H,
CH3); 3.41–3.48 m (2H,CH2), 3.57–3.69 m (2H, CH2),
4. 69 t (1H, OH, J 5.5 Hz), 6.73 d (1H, Harom); 7.14–
7.20 m (1H, Harom), 7.40–7.47 m (2H, Harom); 7.60 t (1H,
NH, J 5.5 Hz), 9.82 s (1H, NHarom). Found, %: C 53.39;
H 5.78; N 34.03. C11H14N6O. Calculated, %: C 53.65;
H 5.73; N 34.13.
N-Benzyl-N'-(4-chlorophenyl)-1,2,4,5-tetrazine-
3,6-diamine (VIg). Yield 56%, mp 229–230°C (from
C2H5OH). 1H NMR spectrum, d, ppm: 4.59 d (2H, CH2,
J 6.1 Hz), 7.16–7.94 m (9H, Harom), 8.42 t (1H, NHaliph
,
J 6.1 Hz), 10.16 s (1H, NHarom). Found, %: C 57.91;
H 4.16; N 26.92. C15H13ClN6. Calculated, %: C 57.61;
H 4.19; N 26.87.
2-[6-(4-Methoxyphenylamino)-1,2,4,5-tetrazin-3-
N-Benzyl-N'-(4-bromophenyl)-1,2,4,5-tetrazine-
3,6-diamine (VIh). Yield: 65%, mp 238°C (from
CH3OH). 1H NMR spectrum, d, ppm: 4.59 d (2H, CH2,
ylamino]ethanol (VIIe). Yield 51%, mp 227–228°C
1
(from C2H5OH). H NMR spectrum, d, ppm: 3.38–
3.46 m (2H, CH2), 3.55–3.73 m (2H, CH2), 3.73 s (3H,
J 6.3 Hz), 7.26-7.67 m (9H, Harom), 8.42 t (1H, NHaliph
,
CH3), 4.68 t (1H, OH, J 5.5 Hz), 6.86–6.92 m (2H, Harom),
J 6.3 Hz), 10.16 s (1H, NHarom). Found, %: C 50.51;
H 3.59; N 23.76. C15H13BrN6. Calculated, %: C 50.44;
H 3.67; N 23.53.
7.50–7.55 m and 7.51 t (3H, 2Harom and NHaliph
,
J 3.4 Hz), 9.68 s (1H, NHarom). Found, %: C 50.38;
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RUSINOV et al.
762
H 5.34; N 31.91. C11H14N6O2. Calculated, %: C 50.38;
H 5.38; N 32.04.
N-Allyl-N'-p-tolyl-1,2,4,5-tetrazine-3,6-diamine
(VIIIb). Yield: 66%, mp 214–215°C (from CH3CN).
1H NMR spectrum, d, ppm: 2.25 s (3H, CH3); 3.94–
4.06 m (2H, =CH2), 5.04–5.32 m (2H, NHCH2), 5.77–
6.15 m (1H, =CH), 7.05–7.14 m (2H, Harom, J 8 Hz),
2-[6-(4-Fluorophenylamino)-1,2,4,5-tetrazin-3-
ylamino]ethanol (VIIf). Yield 53%, mp 221–222°C
(from CH3COCH3). 1H, d, ppm: 3.40–3.47 t (2H, CH2,
J 5.5 Hz), 3.56–3.62 m (2H, CH2), 4.69 t (1H, OH,
J 5.5 Hz), 7.10–7.17 m (2H, Harom), 7.59–7.66 m and
7.61 t (3H, 2Harom and NHaliph), 9.92 s (1H, NHarom).
Found, %: C 48.04; H 4.40; N 33.57. C10H11FN6O.
Calculated, %: C 48.00; H 4.43; N 33.58.
7.48–7.57 m (2H, Harom, J 8 Hz), 7.90 t (1H, NHaliph
,
J 5.3 Hz), 9.86 s (1H, NHarom). Found, %: C 59.52;
H 6.02; N 34.93. C12H14N6. Calculated, %: C 59.49;
H 5.82; N 34.69.
N-Allyl-N'-m-tolyl-1,2,4,5-tetrazine-3,6-diamine
(VIIIc). Yield 39%, mp 179–180°C (from C2H5OH–
2-[6-(4-Chlorophenylamino)-1,2,4,5-tetrazin-3-
1
H2O). H NMR spectrum, d, ppm: 2.37 s (3H, CH3),
ylamino]ethanol (VIIg). Yield 73%, mp 247–248°C
1
4.11–4.26 m (2H, =CH2), 5.15–5.44 m (2H, NHCH2),
5.83–6.21 m (1H, =CH), 6.84–7.74 m (4H, Harom), 7.52 t
(1H, NHaliph), 8.31 s (1H, NHarom). C2H5OH–H2O).
Found, %: C 59.47; H 5.86; N 34.68. C12H14N6.
Calculated, %: C 59.49; H 5.82; N 34.69.
(from C2H5OH). H NMR spectrum, d, ppm: 3.41–
3.48 m (2H, CH2), 3.56–3.63 m (2H, CH2), 4.69 t (1H,
OH, J 5 Hz), 7.31–7.37 m (2H, Harom), 7.63–7.70 m and
7.67 t (3H, 2Harom and NHaliph, J 5 Hz), 10.07 s (1H,
NHarom). Found, %: C 45.16; H 4.04; N 31.43.
C10H11ClN6O. Calculated, %: C 45.04; H 4.16; N 31.51.
N-Allyl-N'-(3,4-dimethylphenyl)-1,2,4,5-
tetrazine-3,6-diamine (VIIId). Yield 37%, mp 193–
2-[6-(4-Bromophenylamino)-1,2,4,5-tetrazine-3-
1
194°C (from C2H5OH). H NMR spectrum, d, ppm:
ylamino]ethanol (VIIh). Yield 64%, mp 249–250°C
1
2.16 s (3H, CH3), 2.19 s (3H, CH3), 3.94–4.05 m (2H,
=CH2), 5.04–5.32 m (2H, NHCH2), 5.77–6.15 m (1H,
(from C2H5OH). H NMR spectrum, d, ppm: 3.41–
3.47 m (2H,CH2), 3.55–3.61 m (2H, CH2), 4.69 t (1H,
OH, J 5.5 Hz), 7.41–7.47 m (2H, Harom), 7.58–7.63 m
(2H, Harom), 7.68 t (1H, NH, J 5 Hz), 10.08 s (1H, NHarom).
Found, %: C 38.41; H 3.54; N 27.09. C10H11BrN6O.
Calculated, %: C 38.60; H 3.56; N 27.01.
=CH), 6.99–7.42 m (4H, Harom), 7.87 t (1H, NHaliph
,
J 5.7 Hz), 9.76 s (1H, NHarom). Found, %: C 61.04;
H 6.53; N 33.14.C13H16N6. Calculated, %: C 60.92;
H 6.29; N 32.79.
N-Allyl-N'-(4-methoxyphenyl)-1,2,4,5-tetrazine-
3,6-diamine (VIIIe). Yield 35%, mp 207–208°C (from
CH3CN). 1H NMR spectrum, d, ppm: 3.72 s (3H, CH3),
3.90–4.04 m (2H, =CH2), 5.04–5.32 m (2H, NHCH2),
2-[6-Morpholino-1,2,4,5-tetrazine-3-ylamino]-
ethanol (VIIi). Yield 65%, mp 80°C (from CH3OH).
1H NMR spectrum, d, ppm: 2.65–2.69 m [4H, N(CH2)2],
3.36–3.43 m (2H,CH2), 3.53–3.57 m (2H, CH2), 3.98–
4.02 m [2H, S(CH2)2], 4.65 t (1H, OH, J 5.5 Hz), 7.42 t
(1H, NH, J 5.5 Hz). Found, %: C 39.55; H 5.89; N 34.51.
C8H14N6OS. Calculated, %: C 39.66; H 5.82; N 34.68.
5.62–6.14 m (1H, =CH), 6.84–6.95 m (2H, Harom
,
J 9 Hz), 7.49–7.58 m (2H, Harom, J 9 Hz), 7.85 t (1H,
NHaliph, J 6.4 Hz), 9.79 s (1H, NHarom). Found, %:
C 55.83; H 5.42; N 32.66. C12H14N6O. Calculated, %:
C 55.80; H 5.46; N 32.54.
[6-(1-Adamantylamino)-1,2,4,5-tetrazine-3-
ylamino]ethanol (VIIj). Yield 66%, mp 158–159°C (from
1
N-Allyl-N'-(4-chlorophenyl)-1,2,4,5-tetrazine-
3,6-diamine (VIIIg). Yield 73%, mp 242–243°C (from
CH3CN). 1H NMR spectrum, d, ppm: 3.94–4.05 m (2H,
=CH2), 5.04–5.32 m (2H, NHCH2), 5.77–6.10 m (1H,
CH3OH–H2O). H NMR spectrum, d, ppm: 1.61–
1.68 m (6H, HAd); 2.05–2.08m (9H, HAd), 3.34–3.38 m
(2H,CH2), 3.54–3.57 m (2H,CH2), 4.47 br.s (1H, OH),
6.81 C (1H, NHarom), 6.89 t (1H, NH, J 6.0 Hz). Found,
%: C 57.88; H 7.50; N 28.91. C14H22N6O. Calculated,
%: C 57.91; H 7.64; N 28.94.
=CH), 7.40–7.67 m (4H, Harom), 8.03 t (1H, NHaliph
,
J 6.2 Hz), 10.15 s (1H, NHarom). Found, %: C 50.40;
H 4.05; N 32.17. C11H11ClN6. Calculated, %: C 50.29;
H 4.22; N 31.99.
N-Allyl-N'-phenyl-1,2,4,5-tetrazine-3,6-diamine
(VIIIa). Yield: 79%, mp 216–217°C (from CH3CN).
1H NMR spectrum, d, ppm: 3.94–4.06 m (2H, =CH2),
5.05–5.32 m (2H, NHCH2), 5.77–6.12 m (1H, =CH),
6.87–7.67 m (5H, Harom), 7.96 t (1H, NHaliph, J 5.5 Hz),
9.74 s (1H, NHarom). C11H12N6. Found, %: C 57.68;
H 5.35; N 36.81. Calculated, %: C 57.88; H 5.30; N 36.82.
N-Allyl-N'-(4-bromophenyl)-1,2,4,5-tetrazine-
3,6-diamine (VIIIh). Yield 77%, mp 239–240°C (from
CH3CN). 1H NMR spectrum, d, ppm: 3.95–4.05 m (2H,
=CH2), 5.05–5.32 m (2H, NHCH2), 5.77–6.15 m (1H,
=CH), 7.27–7.42 m (2H, Harom, J 8 Hz), 7.60–7.73 m
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

SYNTHESIS OF 1,2,4,5-TETRAZINES
763
(2H, Harom, J 8 Hz), 8.02 t (1H, NHaliph, 6 Hz), 10.14 s
(1H, NHarom). Found, %: C 43.27; H 3.70; N 27.39.
C11H11BrN6. Calculated, %: C 43.02; H 3.61; N 27.36.
3,6-Dimorpholino-1,2,4,5-tetrazine (IIIf). b. To
1 mmol (0.214 g) of tetrazine IIIj in 5 ml of anhydrous
acetonitrile was added 11.5 mmol (1.0 ml) of morpholine
and 5 mg of potassium tert-butylate. The mixture was
boiled for 30 h (TLC monitoring, eluent benzene–
acetonitrile, 1:1). On cooling the separated precipitate was
filtered off and recrystallized from acetonitrile. Yield
0.35 g (14%) (80% by the general procedure), mp 259–
260°C (subl.) (from C2H5OH). 1H NMR spectrum, d,
ppm: 3.64–3.66 m (8H, 4CH2); 3.73–3.76 m (8H, 4CH2).
Found, %: C 47.85; H 6.52; N 33.39. C10H16N6O2.
Calculated, %: C 47.61; H 6.39; N 33.31.
Allyl(6-morpholino-1,2,4,5-tetrazin-3-yl)-amine
(VIIIi). Yield 66%, mp 87–88°C (from C2H5OH–H2O).
1H NMR spectrum, d, ppm: 2.65–2.69 m [4H, N(CH2)2],
3.93–4.02 m [6H, S(CH2)2 and =CH2], 5.05–5.22 m (2H,
NHCH2), 5.85–6.00 m (1H, =CH), 7.74 t (1H, NHaliph
,
J 9 Hz). Found, %: C 45.49; H 5.60; N 35.18. C9H14N6S.
Calculated, %: C 45.36; H 5.92; N 35.26.
3,6-Dibenzamido-1,2,4,5-tetrazine (IIId). To
a dispersion of 0.5 g (1.85 mmol) of tetrazine I and
0.45 g (3.70 mmol) of benzamide in 8 ml of anhydrous
THF was added at stirring 0.62 g (5.52 mmol) of sodium
tert-butylate. The reaction mixture was boiled for 5 min,
cooled, 0.5 ml of trifluoroacetic acid and then 100 ml of
water was added, after 15 min the separated precipitate
was filtered off and washed with methanol. Yield 0.30 g
(48%), mp 280–282°C [7] (from DMF–CH3OH). 1H NMR
spectrum, d, ppm: 7.57–7.61 m (4H, CHm), 7.61–7.70 m
(2H, CHp), 8.08–8.10 m (4H, CH°), 12.08 s (2H, 2NH).
Found, %: C 60.17; H 3.56; N 26.55. C16H12N6O2.
Calculated, %: C 60.00; H 3.77; N 26.23.
3,6-Bis(5-bromoindol-1-yl)-1,2,4,5-tetrazine
(IIIi). In 20 ml of acetonitrile was dispersed 4 g
(2.0 mmol) of tetrazine I and 0.59 g (3.0 mmol) of
5-bromoindole, 0.2 ml of triethylamine was added, and
the mixture was heated for 2–3 min to attain homo-
genizing. On cooling within 5 min a brigh scarlet
precipitate separated, it was filtered off, twice recrystal-
lized from DMF, and dried in a vacuum.Yield 0.28 g (86%),
mp 293–294°C (from DMF). 1H NMR spectrum, d, ppm:
8.51 s, 8.53 s (2H, 4indolyl-CH); 8.00 d, 8.46 d (4H, H6,7
indolyl), 7.00 d (2H, 2indolyl-CH); 7.61 d.d (2H, 4indolyl-CH).
Found, %: C 45.93; H 2.33; N 18.24. C18H10Br2N6.
Calculated, %: C 45.98; H 2.14; N 17.88.
3,6-Symmetric disubstituted 1,2,4,5-tetrazines
IIIe–IIIh. Into a teflon ampule of 1 ml capacity was
placed 0.04 mmol of tetrazine I and 0.15 mmol of an
appropriate amine. The ampule was filled with acetoni-
trile and placed into a hydraulic press. The ampule was
maintained for 3 h at 500 MPa and 80°C, then it was
cooled under pressure. On opening the ampule the crys-
talline precipitate was filtered off and recrystallized.
3,6-Bis(1-imidazolyl)-1,2,4,5-tetrazine (IIIj). To
20 ml of acetonitrile was added 1.08 g (4 mmol) of
tetrazine I, 0.81 g (12 mmol) of imidazole, the mixture
was slightly heated for 1 min to attain homogenizing. Im-
mediately after dissolution of the initial reagents a crys-
talline orange precipitate started to form in the solution.
The precipitate was filtered off, washed with 5 ml of
acetonitrile, and dried. Yield 0.68 g (79%), mp >360°C.
1H NMR spectrum, d, ppm: 7.37 m (2H arom), 8.04 d.d
(2Harom, J 1.5 Hz), 8.78 d.d (1Harom). Found, %: C 44.69;
H 2.66; N 52.25. C8H6N8. Calculated, %: C 44.86; H 2.82;
N 52.32.
3,6-Di(pyrrolidin-1-yl)-1,2,4,5-tetrazine (IIIe).
Yield 61%, mp 183–184°C (from H2O–CH3CN) (publ.:
mp 178–179°C [9]). 1H NMR spectrum, d, ppm: 1.95–
2.00 m (8H, b-CH2), 3.49–3.54 m (8H, a-CH2). Found,
%: C 54.48; H 7.42; N 37.92. C10H16N6. Calculated, %:
C 54.52; H 7.32; N 38.15.
3,6-Bis(benzotriazol-1-yl)-1,2,4,5-tetrazine
(IIIk). In a round-bottom flask 0.25 g (0.5 mmol) of com-
plex IV was heated for 0.5 h at 170–180°C (silicon bath).
At heating the complex melted, some benzotriazole ap-
peared on the walls of the flask, and then the content of
the flask solidified. From the crystalline mass the benzo-
triazole was washed with benzene, then it was washed
with hot acetonitrile to remove tetrazine I impurity, and
the remaining tetrazine IIIk was dried. Yield 0.08 g (53%),
3,6-Bis(cyclohexylamino)-1,2,4,5-tetrazine
(IIIg). Yield 78%, mp 248–249°C (from C2H5OH).
1H NMR spectrum, d, ppm: 1.10–1.20 m, 1.72–1.93 m
(8H and 12H, 10CH2), 3.59–3.62 m (2H, 2CH), 7.12 d
(2H, 2NH, J 7.6 Hz). Found, %: C 60.78; H 8.79; N 30.26.
C14H24N6. Calculated, %: C 60.84; H 8.75; N 30.41.
3,6-Bis(cycloheptylamino)-1,2,4,5-tetrazine (IIIh).
1
Yield 84%, mp 214–216°C (from C2H5OH). H NMR
1
mp 280°C. H NMR spectrum, d, ppm: 8.61 d, 8.32 d
spectrum, d, ppm: 1.36–1.71 m, 1.86–1.95 m (24H,
12CH2), 3.80 m (2H, 2CH), 7.15 d (2H, 2NH, J 7.9 Hz).
Found, %: C 63.01; H 9.35; N 27.81. C16H28N6.
Calculated, %: C 63.12; H 9.27; N 27.61.
(4H, J 8.4 Hz), 7.84 m, 7.66 m (4Haryl). Found, %:
C 53.34; H 2.41; N 44.50. C14H8N10. Calculated, %:
C 53.16; H 2.54; N 44.29.
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RUSINOV et al.
764
3,6-Diphenylamino-1,2,4,5-tetrazine (IIIl) a.
78%, mp 175–177°C. 1H NMR spectrum, d, ppm: 2.37 s,
2.46 s, 2.62 s (3H each, 3CH3); 6.13 s (1H, H4 Pz), 7.36–
7.93 m (5H, Ph), 8.97 br.s (1H, NH–N=). Found, %:
C 58.61; H 5.34; N 36.42. C15H16N8. Calculated, %:
C 58.42; H 5.23; N 36.35.
A solution of 0.21 g (1.0 mmol) of tetrazine IIIj in 3 ml of
aniline was boiled for 5 h, and then left standing for 12 h
at room temperature. The precipitated crystals were fil-
tered off and washed with methanol. Yield 0.17 g (64%),
mp 323°C. 1H NMR spectrum, d, ppm: 6.98–7.02 m (2H,
Hp), 7.32–7.36 m (4H, Hm), 7.69–7.71 m (4H, Ho),
10.26 s (2H, 2NH). Found, %: C 63.76; H 4.30; N 32.06.
C14H12N6. Calculated, %: C 63.62; H 4.58; N 31.80.
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazin-
3-yl]-N'-[1-(4-chlorophenyl)ethylidene]hydrazine
(IXc). Yield 70%, mp 182–184°C. 1H NMR spectrum, d,
ppm: 2.40 s (6H, 2CH3), 2.63 s (3H, CH3), 7.34–7.87 m
(4H, Harom), 6.14 s (H4 Pz); 8.96 br.s (1H, NHN=). Found,
%: C 52.29; H 4.33; N 32.55. C15H15ClN8. Calculated,
%: C 52.56; H 4.41; N 32.69.
b. In a similar way 0.27 g (1.0 mmol) of tetrazine I
boiled for 12.5 h in 3 ml of aniline afforded tetrazine IIIl
in a 42% yield.
c. In a similar way 0.27 g (1.0 mmol) of tetrazine IIIk
boiled for 12 h in 3 ml of aniline afforded tetrazine IIIl in
a 54% yield.
3-Hydrazono-6-amino-substituted 1,2,4,5-
tetrazines X and XI. To 1 mmol of an appropriate hy-
drazone IXa–IXc in 10–25 ml of acetonitrile was added
at stirring 1.1–3.65 mmol of dodecylamine or benzylamine.
The reaction mixture was heated for 3 h at 50°C (for
preparation of compounds Xa–Xc and XIa) or it was
stirred at room temperature (for preparation of com-
pounds XIb and XIc). The separated precipitate was fil-
tered off (after 12 h for compounds X) and recrystallized
from acetonitrile. Yield 22–65%.
Complex of 3,6-bis(3,5-dimethylpyrazol-1-yl)-
1,2,4,5-tetrazine with benzotriazole, 1:2 (IV). A mix-
ture of 0.27 g (1 mmol) of tetrazine I and 0.24 g (2 mmol)
of benzotriazole was heated in 20 ml of acetonitrile till
dissolution (3–5 min). After several minutes fine orange
crystals precipitated, the precipitate was filtered off, and
dried. Yield 0.48 g (94%), mp 162°C. In the NMR spec-
trum (DMSO-d6) were registered signals of tetrazine I
and benzotriazole (the complex decomposed). Found, %:
C 56.83; H 4.46; N 38.71. C24H24N14. Calculated, %:
C 56.68; H 4.76; N 38.56.
Benzyl-[6-(N'-benzylidenehydrazino)-1,2,4,5-
tetrazin-3-yl]amine (Xa). Yield 22%, mp 220–223°C
(from CH3CN). 1H NMR spectrum, d, ppm: 3.48 s (1H,
N=CH), 4.60 d (2H, Ph–CH2NH), 7.33–8.39 m (11H,
2Ph, CH2NH), 11.57 br.s (1H, NHN=). Found, %: C 62.96;
H 4.78; N 32.34. C16H15N7. Calculated, %: C 62.94;
H 4.95; N 32.11.
Complex of 3,6-bis(benzotriazol-1-yl)-1,2,4,5-
tetrazine with 3,5-dimethylpyrazole, 1:2 (V). The
benzene extract from the above described synthesis of
compound IIIk consisting of a mixture of tetrazine I,
benzotriazole, and the second reaction product (Rf 0.8,
acetonitrile–benzene, 1:1) was evaporated. The residue
was treated with methanol, the insoluble orange compound
was filtered off, washed with methanol on the filter, and
dried. Yield 0.03 g (11%), mp 153–154°C. Found, %:
C 56.68; H 4.82; N 38.56. C24H24N14. Calculated, %:
C 56.68; H 4.76; N 38.56.
Benzyl-{6-[N'-(1-phenylethylidene)hydrazino]-
1,2,4,5-tetrazin-3-yl}amine (Xb). Yield 65%, mp 174–
1
175.5°C (from CH3CN). H NMR spectrum, d, ppm:
2.37 s (3H, CH3), 4.74 d (2H, PhCH2NH), 5.7 t (1H,
NHCH2Ph), 7.33–7.91 m (10H, 2 CH2NH), 5.7 t (1H,
NHCH2Ph), 7.33–7.91 m (10H, 2Ph), 8.30 br.s (1H,
NHN=). Found, %: C 63.97; H 5.31; N 30.90. C17H17N7.
Calculated, %: C 63.93; H 5.37; N 30.70.
3-Hydrazono-6-(3,5-dimethylpyrazol-1-yl)-
1,2,4,5-tetrazines IXa–IXc. To a dispersion of 2.0 g
(9.7 mmol) of tetrazine I in 20 ml of methanol was added
dropwise 9.7 mmol of aldehyde or ketone, several drops
of acetic acid was added, and the mixture was stirred for
3 h. The separated precipitate was filtered off. Yield 79–
91 %.
Benzyl(6-{N'-[1-(4-chlorophenyl)ethylidene]-
hydrazino}-1,2,4,5-tetrazin-3-yl)amine (Xc). Yield
1
24%, mp 182–183°C (from CH3CN). H NMR spec-
trum, d, ppm: 2.34 s (3H, CH3); 4.74 (d, 2H, PhCH2NH),
5.76 t (1H, NHCH2Ph), 7.28–7.88 m (9Harom), 8.33 br.s
(1H, NHN=). Found, %: C 57.72; H 4.39; N 27.59.
C17H16ClN7. Calculated, %: C 57.71; H 4.56; N 27.71.
N-Benzylidene-N'-[6-(3,5-dimethylpyrazol-1-yl)-
1,2,4,5-tetrazin-3-yl]hydrazine (IXa) was described in
[3].
[6-(N'-Benzylidenehydrazino)-1,2,4,5-tetrazin-3-
yl]dodecylamine (XIa). Yield 24%, mp 204–205°C
(from CH3CN). 1H NMR spectrum, d, ppm: 0.85 t (3H,
CH2CH3, J 7.0 Hz), 1.15–1.24 m (20H, 10CH2), 1.58 q
N-[6-(3,5-Dimethylpyrazol-1-yl)-1,2,4,5-tetrazin-
3-yl]-N'-(1-phenylethylidene)hydrazine (IXb). Yield
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

SYNTHESIS OF 1,2,4,5-TETRAZINES
765
(1H each, HBt), 8.20 d, 8.31 s (1H each, HBt, J 8.4 Hz),
11.24 br.s (1H, NH). Found, %: C 57.95; H 3.50; N 38.34.
C14H10N8. Calculated, %: C 57.93; H 3.47; N 38.60.
(2H, NH–CH2, J 7.0 Hz), 2.36 s (3H, CH3), 7.34–7.43 m
(3H, Harom), 7.80–7.84 m (3H, NHCH2, Harom), 10.45 br.s
(1H, NH–N). Found, %: C 65.51; H 8.85; N 25.54.
C21H33N7. Calculated, %: C 65.76; H 8.67; N 25.57.
The study was carried out under the financial support
of the Russian Foundation for Basic Research (grant
no. 02-03-32332a) and of the International Science and
Technology Center (grant no. 708).
Dodecyl-{6-[N'-(1-phenylethylidene)hydrazino]-
1,2,4,5-tetrazin-3-yl}amine (XIb). Yield 60%, mp
1
156°C (from CH3CN) H, d, ppm: 0.85 t (3H, CH2CH3,
J 7.0 Hz), 1.15–1.24 m [18H, (CH2)9], 1.56–1.60 m (2H,
CH2CH3), 2.36 s (3H, CH3), 3.35 m (2H, NHCH2), 7.34–
7.43 m, 7.80–7.84 m (6H, 5Harom, NH), 10.4 br.s (1H,
NH=N). Found, %: C 66.44; H 8.80; N 24.68. C22H35N7.
Calculated, %: C 66.46; H 8.87; N 24.66.
REFERENCES
1. Glidewell, C., Lightfoot, P., Royles, B.J.L., and Smith, D.M.,
J. Chem. Soc., Perkin Trans. 2, 1997, p. 1167.
2. Coburn, M.D., Buntain, G.A., Harris, B.W., Hiskey, M.A.,
Lee, K.-Y., and Ott, D.G., J. Heterocycl. Chem., 1991,
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3. Latosh, N.I., Rusinov, G.L., Ganebnykh, I.N., and Chupa-
khin, O.N., Zh. Org. Khim., 1999, vol. 35, p. 1392.
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Dodecyl(6-{N'-[1-(4-chlorophenyl)ethylidene]-
hydrazino}-1,2,4,5-tetrazin-3-yl)amine (XIc). Yield
74%, mp 165°C (from CH3CN). 1H NMR spectrum, d,
ppm: 0.85 t (3H, CH2CH3, J 7.0 Hz), 1.15–1.24 m (20H,
10CH2), 1.57–1.59 m (2H, NHCH2); 2.34 s (3H, CH3),
7.46 d (2Harom, J 7.0 Hz), 7.82–7.87 m (3H, NHCH2,
Harom), 10.53 br.s (1H, NH–N). Found, %: C 61.38;
H 7.95; N 22.71. C22H34ClN7. Calculated, %: C 61.16;
H 7.93; N 22.69.
vol. 35, p. 1329.
~
¢
¢
5. Novak, Z., Bostai, B., Csekei, M., Lorincz, K., and Ko-
tschy,A., Heterocycl., 2003, vol. 60, p. 2653.
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3-(Benzotriazol-1-yl)-6-phenylamino-1,2,4,5-
tetrazine (XIIa).Amixture of 0.32 g (1 mmol) of tetrazine
IIIk and 0.46 ml (5 mmol) of aniline in 5 ml of acetoni-
trile was heated for 5 min till homogenizing, then the mix-
ture was stirred for 2 h at room temperature,evaporated,
the residue was thoroughly washed with ethyl ether and
chloroform. Yield 80%, mp 228–229°C. 1H NMR spec-
trum, d, ppm: 7.12 t (1H, Hp, J 7.2 Hz), 7.55–7.59 m,
7.82–7.84 m (2H, 4CHPh), 7.55–7.59 m, 7.72–7.75 m
7. Kemp, G.A., Bachmann, H.J., Berkelhammer, G., and
Asato, G., UK Patent 1245443, 1971; Chem. Abstr., 1972,
vol. 77, 844t.
8. Wiley, P.F., Heterocycl. Chem., Weissberger, A. and
Taylor, E.C., Eds., NewYork: J. Wiley & Sons Intersci., 1978,
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9. Fischer, H., Muller, T., Umminger, I., Neugebauer, F., and
Symons, M., J. Chem. Soc., Perkin Trans. 2, 1988, p. 413.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006