Replacement of dimethylpyrazolyl group in 1,2,4,5-tetrazines by aliphatic alcohols and water

Article abstract of DOI:10.1134/S1070428009070197

Reactions of 3,6-bis(4-R-3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazines and 3-amino-6-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazines with aliphatic alcohols and water in the presence of a base involved replacement of the dimethylpyrazolyl group and resulted in the formation of mono- and dialkoxy-1,2,4,5-tetrazines and 6-substituted 3-hydroxy-1,2,4,5-tetrazines. Dissociation constants of the latter were determined by potentiometric titration.

Full text of DOI:10.1134/S1070428009070197

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 7, pp. 1102–1107. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © R.I. Ishmetova, N.I. Latosh, I.N. Ganebnykh, N.K. Ignatenko, S.G. Tolshchina, G.L. Rusinov, 2009, published in Zhurnal
Organicheskoi Khimii, 2009, Vol. 45, No. 7, pp. 1113–1118.
Replacement of Dimethylpyrazolyl Group in 1,2,4,5-Tetrazines
by Aliphatic Alcohols and Water
R. I. Ishmetova, N. I. Latosh, I. N. Ganebnykh, N. K. Ignatenko,
S. G. Tolshchina, and G. L. Rusinov
Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. S. Kovalevskoi/Akademicheskaya 22/20, Yekaterinburg, 620041 Russia
e-mail: rusinov@ios.uran.ru
Received February 29, 2008
Abstract—Reactions of 3,6-bis(4-R-3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazines and 3-amino-6-(3,5-di-
methyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazines with aliphatic alcohols and water in the presence of a base involved
replacement of the dimethylpyrazolyl group and resulted in the formation of mono- and dialkoxy-1,2,4,5-
tetrazines and 6-substituted 3-hydroxy-1,2,4,5-tetrazines. Dissociation constants of the latter were determined
by potentiometric titration.
DOI: 10.1134/S1070428009070197
Replacement of the dimethylpyrazolyl group in
3,6-bis(3,5-dimethyl-4-R-1H-pyrazol-1-yl)-1,2,4,5-tet-
razines Ia–Ic and their derivatives by nitrogen-cen-
tered nucleophiles has been well documented [1–4],
while reactions of the same tetrazines with oxygen-
centered nucleophiles have been studied poorly. How-
ever, 3-hydroxy-6-(3,5-dimethyl-1H-pyrazol-1-yl)-
1,2,4,5-tetrazine attracts interest as promising ligand in
the synthesis of organometallic clusters with important
magnetic properties [5–7].
zines IIIa–IIIh can also be obtained in high yields
from the corresponding potassium salts IIa–IIh that
are formed form compounds Ia–Ih in the presence of
a base (potassium hydroxide or tert-butoxide; see
table, Scheme 1).
Hydroxytetrazines IIIa–IIIh are strong organic OH
acids. They form brightly colored salts with both po-
tassium and sodium ions and aliphatic and cycloali-
phatic amines, e,g,, with benzylamine and morpholine
(salts IVa and IVb). The acid dissociation constants of
hydroxytetrazines IIIa–IIIh were determined by
potentiometric titration of their aqueous solutions at
a ionic strength μ of 0.1 (KCl) using glass and calomel
electrodes. The following pKa values were obtained:
IIIa, 3.00±0.01; IIIb, 3.01±0.02; IIIc, 3.09±0.02;
IIId, 4.38±0.01; IIIe, 5.54±0.05; IIIf, 4.48±0.03;
IIIg, 3.19±0.04; IIIh, 3.31±0.05.
Hydrolysis of 3,6-bis(3,5-dimethyl-1H-pyrazol-1-
yl)-1,2,4,5-tetrazine (Ia) in dilute hydrochloric acid
was reported to produce 6-(3,5-dimethyl-1H-pyrazol-
1-yl)-1,2,4,5-tetrazin-3-ol (IIIa) in 15% yield [8]. We
have found that the yield of tetrazine IIIa may be
increased up to almost quantitative (97%) by carrying
out the reaction in aqueous acetic acid. Hydroxytetra-
Scheme 1.
Me
N
N
N
OK
N
N
OH
N
N
O–
K+, H2O, catalyst
Me Me
BH
N
N
N
HCl
N
N
N
N
BH2
N
N
N
Me
R
R
R
N
–
R
N
NH
Ia–Ih
IIa–IIh
IIIa–IIIh
IVa, IVb
I–III, R = 3,5-dimethyl-1H-pyrazol-1-yl (a), 4-bromo-3,5-dimethyl-1H-pyrazol-1-yl (b), 4-chloro-3,5-dimethyl-1H-pyrazol-1-yl (c),
morpholino (d), thiomorpholino (e), piperidino (f), pyrrolidin-1-yl (g), 4-methylpiperazin-1-yl (h); IV, R = 3,5-dimethyl-1H-pyrazol-
1-yl, BH = PhCH2NH2 (a), morpholine (b).
1102

REPLACEMENT OF DIMETHYLPYRAZOLYL GROUP IN 1,2,4,5-TETRAZINES
1103
Yields and melting points of 6-substituted 3-hydroxy-
1,2,4,5-tetrazine potassium salts IIa–IIh
Alkoxytetrazines can be synthesized via replace-
ment of the pyrazolyl group in compounds I by alcohol
residues in the presence of a base. For example,
3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methoxy-1,2,4,5-
tetrazine (Va) was obtained in 76% yield by heating
tetrazine Ia in boiling methanol in the presence of pyr-
idine [3]. The use of triethylamine as a base ensured
smooth formation of tetrazine Va in a high yield at
room temperature, whereas the reaction performed on
heating under reflux gave 3,6-dimethoxy-1,2,4,5-tetra-
zine (VI), in contrast to the procedures described
previously [9, 10]. In the presence of potassium tert-
butoxide, compound VI was synthesized in 72% yield
at room temperature.
Compound no.
Yield, %
mp, °C (decomp.)
IIa
IIb
IIc
IId
IIe
IIf
81
88
91
79
92
82
68
72
300
316–320
320–322
292
268
254–257
298
IIg
IIh
278–280
methanol were carried out by heating under reflux over
a period of 0.5–1.5 h, and the products were methoxy-
tetrazines VIId and VIIi–VIIr. The reactions with
propan-1-ol to give compounds VIIIi–VIIIn and with
propan-2-ol to give compounds IXd, IXk, and IXl
required a longer time, 2–6 and 10–12 h, respectively,
whereas tert-butyl alcohol failed to react at all.
Replacement of the pyrazolyl substituent in tetra-
zine Ia by ethoxy group gave 81% of 6-(3,5-dimethyl-
1H-pyrazol-1-yl)-3-ethoxy-1,2,4,5-tetrazine (Vb)
when the reaction was carried out in anhydrous ethanol
in the presence of triethylamine. Tetrazine Ia also
reacted with higher alcohols. For example, by heating
compound Ia with nonan-1-ol in anhydrous dioxane in
the presence of triethylamine we obtained 3-(3,5-di-
methyl-1H-pyrazol-1-yl)-6-nonyloxy-1,2,4,5-tetrazine
(Vc) in 56% yield (Scheme 2). Likewise, unsymmet-
rically substituted 3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-
R-1,2,4,5-tetrazines Id and Ii–Ir [3, 4] reacted with
oxygen-centered nucleophiles in the presence of potas-
sium tert-butoxide to give products of replacement of
the pyrazolyl group (Scheme 3). The reactions with
Symmetric 3,6-disubstituted 1,2,4,5-tetrazines re-
acted with unsaturated alcohols according to the
scheme described in [11, 12], but triethylamine was
used as base instead of sodium hydride. In the reaction
of tetrazine Ia with but-3-yn-1-ol, a mixture of furo-
pyridazine XII and pyridazine XIII was formed at
a ratio of 5:1 (1H NMR data). Under analogous condi-
tions, 3,6-bis(1H-imidazol-1-yl)-1,2,4,5-tetrazine (X)
Scheme 2.
Me
N
N
N
N
N
OMe
N
N
ROH, B
2MeOH, B
Ia
Me
N
N
RO
MeO
N
Va–Vc
VI
V, R = Me (a), Et (b), C9H19 (c).
Scheme 3.
Me
N
N
N
N
N
OR'
Me
Me
R'OH, t-BuOK, Δ
N
N
+
Me
HN
N
N
N
R
R
N
Id, Ii–Ir
VIId, VIIi–VIIr, VIIIi–VIIIn
IXd, IXk, IXl
R = morpholino (d), PhNH (i), 4-MeOC6H4NH (j), 4-MeC6H4NH (k), 4-FC6H4NH (l), 4-ClC6H4NH (m), 4-BrC6H4NH (n), 3-Me-
C6H4NH (o), 3,4-Me2C6H3NH (p), 1-adamantylamino (q), MeC(Ph)=NNH (r); VII, R′ = Me; VIII, R′ = Pr; IX, R′ = i-Pr.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 7 2009

ISHMETOVA et al.
1104
Scheme 4.
N
R
N
N
R
O
HC
Et3N, MeCN
N
N
N
+
+
OH
N
R
N
R
R
OH
Ia, X
XI, XII
XIII
Ia, XII, XIII, R = 3,5-dimethyl-1H-pyrazol-1-yl; X, XI, R = 1H-imidazol-1-yl.
was converted in a good yield (75%) into furopyrida-
zine XI, presumably via replacement of the imidazolyl
group and subsequent intramolecular [4+2]-cyclo-
addition.
c. Tetrazine Ia, 1.00 g (3.6 mmol), was added to a
mixture of 15 ml of propan-2-ol and 0.3 g (5.4 mmol)
of potassium hydroxide, the mixture was stirred for
1 h, and the product was isolated as described above
in b. Yield 0.68 g (78%).
EXPERIMENTAL
6-Substituted 3-hydroxy-1,2,4,5-tetrazines IIIb–
IIIh were synthesized in a similar way.
1
The H NMR spectra were recorded on a Bruker
6-(4-Bromo-3,5-dimethyl-1H-pyrazol-1-yl)-
1,2,4,5-tetrazin-3-ol (IIIb). Yield 92%, mp 189°C
Avance DRX-400 instrument at 400 MHz using CDCl3
as solvent and tetramethylsilane as internal reference.
The melting points were determined on a Boetius
melting point apparatus. The progress of reactions and
the purity of products were monitored by TLC on
Silufol plates using chloroform–ethanol (9 :1) as
eluent. Flash chromatography was performed on silica
gel (5–40 μm); eluent benzene–acetonitrile. The acid
dissociation constants were determined with the aid of
a Radelkis OP-208/1 digital pH-meter.
1
(decomp.). H NMR spectrum, δ, ppm: 2.33 s (3H,
CH3), 2.63 s (3H, CH3). Found, %: C 31.08; H 2.48;
N 30.95. C7H7BrN6O. Calculated, %: C 31.00; H 2.58;
N 31.00.
6-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)-
1,2,4,5-tetrazin-3-ol (IIIc). Yield 88%, mp 178–
1
180°C (decomp.). H NMR spectrum, δ, ppm: 2.35 s
(3H, CH3), 2.68 s (3H, CH3). Found, %: C 37.01;
H 3.12; N 36.98. C7H7ClN6O. Calculated, %: C 37.09;
H 3.09; N 37.09.
3,6-Bis(1H-imidazol-1-yl)-1,2,4,5-tetrazine (X)
was synthesized as described in [4].
6-Morpholino-1,2,4,5-tetrazin-3-ol (IIId). Yield
81%, mp 152–154°C. 1H NMR spectrum, δ, ppm: 3.57 t
(4H, CH2OCH2, J = 9.2 Hz), 3.74 t (4H, CH2NCH2,
J = 9.2 Hz). Found, %: C 39.27; H 4.85; N 38.21.
C6H9N5O2. Calculated, %: C 39.34; H 4.92; N 38.25.
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetra-
zin-3-ol (IIIa). a. A suspension of 5.65 g (20.9 mmol)
of tetrazine Ia in 35 ml of glacial acetic acid was
heated to the boiling point until compound Ia dis-
solved. The solution was filtered, the filtrate was
cooled, and the orange crystals were filtered off and
washed with acetic acid. Yield 3.90 g (97%), mp 204–
6-Thiomorpholino-1,2,4,5-tetrazin-3-ol (IIIe).
1
Yield 90%, mp 130–132°C. H NMR spectrum, δ,
1
ppm: 2.69 t (4H, CH2SCH2, J = 9.6 Hz), 3.96 t (4H,
CH2NCH2, J = 9.6 Hz). Found, %: C 36.09; H 4.45;
N 35.09. C7H9N5OS. Calculated, %: C 36.18; H 4.52;
N 35.18.
206°C. H NMR spectrum, δ, ppm: 2.22 s (3H, CH3),
2.39 s (3H, CH3), 6.21 s (1H, 4′-H). Found, %:
C 43.61; H 4.19; N 43.82. C7H8N6O. Calculated, %:
C 43.75; H 4.17; N 43.75.
6-Piperidino-1,2,4,5-tetrazin-3-ol (IIIf). Yield
69%, mp 126°C (decomp.). 1H NMR spectrum, δ, ppm:
1.62 m (6H, CH2), 3.62 t (4H, CH2NCH2, J = 5.2 Hz).
Found, %: C 46.32; H 6.16; N 38.58. C7H11N5O. Cal-
culated, %: C 46.41; H 6.08; N 38.67.
b. Potassium tert-butoxide, 0.21 g (1.87 mmol),
was added in portions under stirring at room tempera-
ture to a mixture of 0.46 g (1.7 mmol) of tetrazine Ia in
6 ml of propan-2-ol. The originally red crystals gradu-
ally turned lilac. After 0.75 h, the crystals were filtered
off, washed with propan-2-ol, and dried in air. Yield of
potassium salt IIa 0.32 g (81%), mp 300°C. The prod-
uct was dissolved in 7 ml of distilled water, and 18%
hydrochloric acid was added dropwise under stirring
until pH ~2.5. The crystals (orange needles) were
filtered off, washed with water, and dried. Yield 0.21 g
(78%), mp 204–206°C.
6-(Pyrrolidin-1-yl)-1,2,4,5-tetrazin-3-ol (IIIg).
1
Yield 72%, mp 199–200°C (decomp.). H NMR spec-
trum, δ, ppm: 2.11 m (4H, CH2CH2), 3.77 m (4H,
CH2NCH2). Found, %: C 43.22; H 5.33; N 41.85.
C6H9N5O. Calculated, %: C 43.11; H 5.39; N 41.92.
6-(4-Methylpiperazin-1-yl)-1,2,4,5-tetrazin-3-ol
1
(IIIh). Yield 66%, mp 240°C (decomp.). H NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 7 2009

REPLACEMENT OF DIMETHYLPYRAZOLYL GROUP IN 1,2,4,5-TETRAZINES
1105
spectrum, δ, ppm: 2.24 s (3H, NCH3), 2.54 t (4H,
NCH2, J = 5.0 Hz), 4.02 t (4H, NCH2, J = 5.0 Hz).
Found, %: C 42.27; H 6.01; N 42.95. C7H12N6O. Cal-
culated, %: C 42.86; H 6.12; N 42.86.
C 60.32; H 8.31; N 26.29. C16H26N6O. Calculated, %:
C 60.35; H 8.23; N 26.40.
3,6-Dimethoxy-1,2,4,5-tetrazine (VI). a. Triethyl-
amine, 0.1 ml, was added to a mixture of 0.5 g
(1.85 mol) of tetrazine Ia and 20 ml of anhydrous
methanol, and the mixture was heated for 30 min under
reflux (TLC). The solvent was distilled off, the bright
red residue was dissolved in 2 ml of benzene, and the
solution was passed through a column charged with
silica gel using benzene as eluent to isolate 0.260 g
(80%) of compound VI.
Benzylammonium 6-(3,5-dimethyl-1H-pyrazol-
1-yl)-1,2,4,5-tetrazin-3-olate (IVa). Yield 78%,
mp 144–146°C. 1H NMR spectrum, δ, ppm: 2.17 s and
2.22 s (3H each, CH3), 4.06 s (2H, CH2Ph), 6.04 s (1H,
4′-H), 7.48–7.38 m (5H, Ph), 8.23 br.s (3H, H3N+).
Found, %: C 56.27; H 5.88; N 32.52. C14H17N7O. Cal-
culated, %: C 56.19; H 5.69; N 32.78.
b. Potassium tert-butoxide, ~25 mg, was added to
a mixture of 0.5 g (1.85 mol) of tetrazine Ia and 20 ml
of anhydrous methanol, and the solution was stirred for
30 min at room temperature. The product was isolated
as described above in a. Yield 0.233 g (72%),
mp 62°C. H NMR spectrum: δ 4.18 ppm, s (6H,
OCH3). Found, %: C 33.86; H 3.93; N 39.29.
C4H6N4O2. Calculated, %: C 33.80; H 4.25; N 39.42.
Morpholinium 6-(3,5-dimethyl-1H-pyrazol-1-yl)-
1,2,4,5-tetrazin-3-olate (IVb). Yield 70%, mp 147–
150°C. H NMR spectrum, δ, ppm: 2.22 s and 2.16 s
(3H each, CH3), 3.14–3.12 m (4H, CH2NCH2), 3.78–
3.76 m (4H, CH2OCH2), 6.05 s (1H, 4′-H), 8.75 br.s
(2H, H2N+). Found, %: C 47.10; H 6.13; N 34.93.
C11H16N7O2. Calculated, %: C 47.48; H 5.79; N 35.23.
1
1
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-methoxy-
1,2,4,5-tetrazine (Va). Triethylamine, ~0.1 ml, was
added to a mixture of 1.0 g (37 mmol) of tetrazine Ia
and 30 ml of methanol, and the mixture was stirred for
3 h at room temperature (the progress of the reaction
was monitored by TLC). The solvent was distilled off,
and the residue was recrystallized from methanol–
water (3:7). Yield 0.61 g (81%), dark red crystals,
mp 156–157°C. 1H NMR spectrum, δ, ppm: 2.35 s and
2.63 s (3H each, CH3), 4.33 s (3H, OCH3), 6.14 s (1H,
4′-H). Found, %: C 46.72; H 5.12; N 40.53. C8H10N6O.
Calculated, %: C 46.60; H 4.85; N 40.78.
6-Substituted 3-alkoxy-1,2,4,5-tetrazines VIId,
VIIi–VIIr, VIIIi–VIIIn, IXd, IXk, and IXl (general
procedure). A mixture of 0.01 mol of tetrazine Id or
Ii–Ir, a small amount of potassium tert-butoxide, and
30 ml of the corresponding alcohol was heated for 2–
12 h under reflux, the progress of the reaction being
monitored by TLC. The mixture was cooled, and the
precipitate was filtered off and purified by recrystal-
lization.
3-Methoxy-6-morpholino-1,2,4,5-tetrazine
1
(VIId). Yield 81%, mp 115–116°C. H NMR spec-
trum, δ, ppm: 3.86 m (8H, morpholine), 4.17 s (3H,
OCH3). Found, %: C 42.51; H 5.71; N 35.64.
C7H11N5O2. Calculated, %: C 42.69; H 5.71; N 35.53.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-ethoxy-
1,2,4,5-tetrazine (Vb). A mixture of 0.27 g (1.0 mmol)
of tetrazine Ia, 0.14 ml (1.0 mol) of triethylamine, and
10 ml of anhydrous ethanol was stirred for 45 min at
50°C. The solvent was evaporated, and the residue was
washed with a small amount of anhydrous hexane and
recrystallized from hexane. Yield 0.18 g (81%),
mp 114–116°C. 1H NMR spectrum, δ, ppm: 1.59 t (3H,
CH3, J = 7.0 Hz), 2.39 s and 2.65 s (3H each, CH3),
4.76 q (2H, CH2, J = 7.0 Hz), 6.17 s (1H, 4′-H). Found,
%: C 49.28; H 5.48; N 38.34. C9H12N6O. Calculated,
%: C 49.08; H 5.49; N 38.16.
6-Methoxy-N-phenyl-1,2,4,5-tetrazin-3-amine
(VIIi). Yield 93%, mp 199–200°C. 1H NMR spectrum,
δ, ppm: 4.10 s (3H, OCH3); 7.02 m, 7.34 m, and
7.70 m (5H, Harom); 10.48 br.s (1H, NH). Found, %:
C 53.30; H 4.45; N 34.80. C9H9N5O. Calculated, %:
C 53.20; H 4.43; N 34.48.
6-Methoxy-N-(4-methoxyphenyl)-1,2,4,5-tetra-
zin-3-amine (VIIj). Yield 85%, mp 138–139°C.
1H NMR spectrum, δ, ppm: 3.74 s and 4.09 s (3H each,
OCH3), 6.92 d and 7.58 d (2H each, Harom, J = 9.0 Hz),
10.27 br.s (1H, NH). Found, %: C 51.48; H 4.62;
N 30.06. C10H11N5O2. Calculated, %: C 51.50; H 4.72;
N 30.06.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-nonyloxy-
1,2,4,5-tetrazine (Vc) was synthesized in a similar
1
way. Yield 60%, bright red syrupy material. H NMR
spectrum, δ, ppm: 0.87 t (3H, CH3, J = 7.0 Hz), 1.2–
1.4 m (10H, CH2), 1.53 m (2H, CH2), 1.95 m (2H,
OCH2CH2), 2.37 s and 2.64 s (3H each, CH3), 4.67 t
(2H, OCH2, J = 7.0 Hz), 6.15 s (1H, 4′-H). Found, %:
6-Methoxy-N-(4-methylphenyl)-1,2,4,5-tetrazin-
3-amine (VIIk). Yield 85%, mp 166°C. 1H NMR spec-
trum, δ, ppm: 2.27 s (3H, CH3), 4.10 s (3H, OCH3),
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ISHMETOVA et al.
1106
7.09 d and 7.57 d (2H each, Harom, J = 8.5 Hz),
10.39 br.s (1H, NH). Found, %: C 55.38; H 5.15;
N 32.06. C10H11N5O. Calculated, %: C 55.30; H 5.07;
N 32.26.
ppm: 1.08 t (3H, CH3, J = 7.5 Hz); 1.88 m (2H,
CH2CH3); 4.42 t (2H, OCH2, J = 6.5 Hz); 6.97–
7.01 m, 7.28–7.32 m, and 7.68–7.71 m (5H, Harom);
10.42 s (1H, NH). Found, %: C 57.02; H 5.72;
N 30.05. C11H13N5O. Calculated, %: C 57.14; H 5.63;
N 30.30.
N-(4-Fluorophenyl)-6-methoxy-1,2,4,5-tetrazin-
3-amine (VIIl). Yield 91%, mp 232°C (sublimes).
1H NMR spectrum, δ, ppm: 4.13 s (3H, OCH3), 7.07 m
and 7.70 m (4H, Harom), 10.47 br.s (1H, NH). Found,
%: C 48.71; H 3.57; N 31.78. C9H8FN5O. Calculated,
%: C 48.88; H 3.62; N 31.67.
N-(4-Methoxyphenyl)-6-propoxy-1,2,4,5-tetra-
zin-3-amine (VIIIj). Yield 49%, mp 138–139°C.
1H NMR spectrum, δ, ppm: 1.07 t (3H, CH3, J =
7.5 Hz), 1.87 m (2H, CH2CH3), 4.39 t (2H, OCH2, J =
6.5 Hz), 6.86 m and 7.57 m (4H, Harom), 3.73 s (3H,
OCH3), 10.23 br.s (1H, NH). Found, %: C 55.34;
H 5.50; N 26.69. C12H15N5O2. Calculated, %: C 55.17;
H 5.75; N 26.82.
N-(4-Chlorophenyl)-6-methoxy-1,2,4,5-tetrazin-
3-amine (VIIm). Yield 88%, mp 218–220°C. 1H NMR
spectrum, δ, ppm: 4.10 s (3H, OCH3), 7.33–7.43 m and
7.63–7.76 m (4H, Harom), 10.64 br.s (1H, NH). Found,
%: C 45.45; H 3.21; N 29.66. C9H8ClN5O. Calculated,
%: C 45.47; H 3.37; N 29.73.
N-(4-Methylphenyl)-6-propoxy-1,2,4,5-tetrazin-
3-amine (VIIIk). Yield 59%, mp 147–148oC. 1H NMR
spectrum, δ, ppm: 1.07 t (3H, CH3, J = 7.5 Hz), 1.87 m
(2H, CH2CH3), 2.30 s (3H, CH3), 4.40 t (2H, OCH2,
J = 6.5 Hz), 7.09 d and 7.56 d (2H each, Harom, J =
8.5 Hz), 10.33 br.s (1H, NH). Found, %: C 58.92;
H 6.01; N 28.32. C12H15N5O. Calculated, %: C 58.78;
H 6.12; N 28.57.
N-(4-Bromophenyl)-6-methoxy-1,2,4,5-tetrazin-
3-amine (VIIn). Yield 88%, mp 221°C. 1H NMR spec-
trum, δ, ppm: 4.11 s (3H, OCH3), 7.73–7.47 m (4H,
H
arom), 10.67 br.s (1H, NH). Found, %: C 38.54;
H 2.71; N 24.90. C9H8BrN5O. Calculated, %: C 38.30;
H 2.84; N 24.82.
N-(4-Fluorophenyl)-6-propoxy-1,2,4,5-tetrazin-
3-amine (VIIIl). Yield 68%, mp 172–173°C. 1H NMR
spectrum, δ, ppm: 1.07 t (3H, CH3, J = 7.5 Hz), 1.88 m
(2H, CH2CH3), 4.41 t (2H, OCH2, J = 6.5 Hz), 7.07 m
and 7.70 m (4H, Harom), 10.45 br.s (1H, NH). Found,
%: C 50.95; H 4.77; N 29.98. C11H12FN5O. Calculated,
%: C 51.01; H 4.82; N 28.11.
6-Methoxy-N-(3-methylphenyl)-1,2,4,5-tetrazin-
3-amine (VIIo). Yield 58%, mp 154–155°C. 1H NMR
spectrum, δ, ppm: 2.31 s (3H, CH3), 4.10 s (3H, OCH3),
7.38 m (3H, Harom), 7.53 m (1H, Harom), 10.42 br.s (1H,
NH). Found, %: C 55.32; H 4.99; N 32.31. C10H11N5O.
Calculated, %: C 55.30; H 5.07; N 32.26.
N-(3,4-Dimethylphenyl)-6-methoxy-1,2,4,5-tetra-
1
zin-3-amine (VIIp). Yield 59%, mp 189°C. H NMR
N-(4-Chlorophenyl)-6-propoxy-1,2,4,5-tetrazin-
3-amine (VIIIm). Yield 72%, mp 201–202°C. 1H NMR
spectrum, δ, ppm: 1.07 t (3H, CH3, J = 7.5 Hz), 1.88 m
(2H, CH2CH3), 4.42 t (2H, OCH2, J = 6.5 Hz), 7.29 m
and 7.72 m (4H, Harom), 10.61 br.s (1H, NH). Found,
%: C 49.91; H 4.46; N 26.28. C11H12ClN5O. Calculat-
ed, %: C 49.72; H 4.52; N 26.37.
spectrum, δ, ppm: 2.19 s and 2.22 s (3H each, CH3),
4.09 s (3H, OCH3), 7.06–7.46 m (3H, Harom), 10.35 br.s
(1H, NH). Found, %: C 56.93; H 5.55; N 30.42.
C11H13N5O. Calculated, %: C 57.14; H 5.63; N 30.30.
N-(1-Adamantyl)-6-methoxy-1,2,4,5-tetrazin-3-
1
amine (VIIq). Yield 63%, mp 174–176°C. H NMR
spectrum, δ, ppm: 1.66 m and 2.07 m (15H, Ad), 4.02 s
(3H, OCH3), 7.72 br.s (1H, NH). Found, %: C 59.59;
H 7.36; N 26.61. C13H19N5O. Calculated, %: C 59.77;
H 7.28; N 26.82.
N-(4-Bromophenyl)-6-propoxy-1,2,4,5-tetrazin-
3-amine (VIIIn). Yield 54%, mp 136°C. H NMR
1
spectrum, δ, ppm: 1.07 t (3H, CH3, J = 7.5 Hz), 1.88 m
(2H, CH2CH3), 4.42 t (2H, OCH2, J = 6.5 Hz), 7.43 m
and 7.67 m (4H, Harom), 10.61 br.s (1H, NH). Found,
%: C 42.50; H 3.82; N 22.64 C11H12BrN5O. Calculat-
ed, %: C 42.58; H 3.87; N 22.58.
1-(6-Methoxy-1,2,4,5-tetrazin-3-yl)-2-(1-phenyl-
ethylidene)hydrazine (VIIr). Yield 76%, mp 177–
1
178°C. H NMR spectrum, δ, ppm: 2.42 s (3H, CH3),
4.24 s (3H, OCH3), 7.43–7.35 m (3H, Harom), 7.88–
7.85 m (2H, Harom), 8.66 br.s (1H, NH). Found, %:
C 53.89; H 4.86; N 34.61. C11H12N6O. Calculated, %:
C 54.08; H 4.95; N 34.41.
3-Isopropoxy-6-morpholino-1,2,4,5-tetrazine
(IXd). Yield 46%, mp 94–95°C. 1H NMR spectrum, δ,
ppm: 1.39 d (6H, CH3, J = 6.0 Hz), 3.74 m (8H, mor-
pholine), 5.22 m (1H, OCH). Found, %: C 48.09;
H 6.58; N 31.00. C9H15N5O2. Calculated, %: C 48.00;
H 6.67; N 31.11.
N-Phenyl-6-propoxy-1,2,4,5-tetrazin-3-amine
1
(VIIIi). Yield 54%, mp 136°C. H NMR spectrum, δ,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 7 2009

REPLACEMENT OF DIMETHYLPYRAZOLYL GROUP IN 1,2,4,5-TETRAZINES
1107
6-Isopropoxy-N-(4-methylphenyl)-1,2,4,5-tetra-
zin-3-amine (IXg). Yield 59%, mp 162–164°C.
1H NMR spectrum, δ, ppm: 1.44 d (6H, CH3, J =
6 Hz), 2.30 s (3H, CH3C6H4), 5.26 m (1H, OCH), 7.09 d
and 7.56 d (2H each, Harom, J = 8.5 Hz), 10.30 br.s (1H,
NH). Found, %: C 58.86; H 6.05; N 28.63. C12H15N5O.
Calculated, %: C 58.78; H 6.12; N 28.57.
2.30 s, 2.32 s, 2.42 s, and 2.75 s (3H each, CH3); 2.95 t
and 4.03 t (4H, CH2CH2, J = 5.8 Hz), 6.08 s (2H, 4′-H,
4″-H), 8.24 s (1H, 4-H).
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 07-03-96112-r_ural_a, 07-03-96113-r_ural_a) and
by the Council for Grants at the President of the
Russian Federation (Program for Support of Leading
Scientific Schools, project no. NSh-3758.2008.3).
N-(4-Fluorophenyl)-6-isopropoxy-1,2,4,5-tetra-
zin-3-amine (IXh). Yield 51%, mp 162–163°C.
1H NMR spectrum, δ, ppm: 1.48 t (6H, CH3, J = 6 Hz),
5.28 m (1H, OCH), 7.09 m and 7.70 m (4H, Harom),
10.30 br.s (1H, NH). Found, %: C 50.79; H 4.92;
N 28.22. C11H12FN5O. Calculated, %: C 51.01; H 4.82;
N 28.11.
REFERENCES
1. Coburn, M.D., Buntain, G.A., Harris, B.W.,
Hiskey, M.A., Lee, K.-Y., and Ott, D.G., J. Heterocycl.
Chem., 1991, vol. 28, p. 2049.
2. Glidewell, C., Lightfoot, P., Royles, B.J.L., and
Smith, D.M., J. Chem. Soc., Perkin Trans. 2, 1997,
p. 1167.
3. Latosh, N.I., Rusinov, G.L., Ganebnykh, I.N., and
Chupakhin, O.N., Russ. J. Org. Chem., 1999, vol. 35,
p. 1350.
4. Rusinov, G.L., Latosh, N.I., Ganebnykh, I.N., Ishme-
tova, R.I., Ignatenko, N.K., and Chupakhin, O.N., Russ.
J. Org. Chem., 2006, vol. 42, p. 757.
3-(1H-Imidazol-1-yl)-5,6-dihydrofuro[2,3-c]pyr-
idazine (XI). A mixture of 107 mg (0.5 mmol) of
tetrazine X, 0.1 ml (1.35 mmol) of but-3-yn-1-ol, and
3 drops of triethylamine in 5 ml of anhydrous aceto-
nitrile was heated for 1.5 h under reflux. The precip-
itate was filtered off, the filtrate was evaporated, and
the residue was combined with the first precipitate and
recrystallized from anhydrous acetonitrile. Yield 69 mg
1
(73%), mp 243–245°C. H NMR spectrum, δ, ppm:
3.42 t and 4.73 t (4H, CH2, J = 8.8 Hz); 7.06, 7.85, and
8.39 (3H, 2′-H, 4′-H, 5′-H), 8.04 s (1H, 4-H). Found,
%: C 57.80; H 4.24; N 30.05. C9H8N4O. Calculated,
%: C 57.44; H 4.29; N 29.77.
5. Eremenko, I.L., Malkov, A.E., Sidorov, A.A., Fomi-
na, I.G., Aleksandrov, G.G., Nefedov, S.E., Rusi-
nov, G.L., Chupakhin, O.N., Novotortsev, V.M., Ikor-
skii, V.N., and Moiseev, I.I., Inorg. Chim. Acta, 2002,
vol. 334, p. 334.
6. Malkov, A.E., Fomina, I.G., Sidorov, A.A., Aleksand-
rov, G.G., Egorov, I.M., Latosh, N.I., Chupakhin, O.N.,
Rusinov, G.L., Rakitin, Yu.V., Novotortsev, V.M., Ikor-
skii, V.N., Eremenko, I.L., and Moiseev, I.I., J. Mol.
Struct., 2003, vol. 656, p. 207.
7. Kiskin, M.A., Sidorov, A.A., Fomina, I.G. Rusi-
nov, G.L., Ishmetova, R.I., Aleksandrov, G.G., Shveden-
kov, Yu.G., Dobrokhotova, Zh.V., Novotortsev, V.M.,
Chupakhin, O.N., Eremenko, I.L., and Moiseev I.I.,
Inorg. Chem. Commun., 2005, vol. 8, p. 524.
Reaction of 3,6-bis(3,5-dimethyl-1H-pyrazol-1-
yl)-1,2,4,5-tetrazine (Ia) with but-3-yn-1-ol. A mix-
ture of 135 mg (0.5 mmol) of tetrazine Ia, 0.1 ml
(1.35 mmol) of but-3-yn-1-ol, and 3 drops of triethyl-
amine in 5 ml of anhydrous acetonitrile was heated for
3 h under reflux (until the initial tetrazine disappeared
according to the TLC data). The mixture was cooled,
the solvent was distilled off, and the residue was
recrystallized from anhydrous acetonitrile. The product
was a mixture of compounds XII and XIII at a ratio of
5:1 (according to the 1H NMR data), mp 107–112°C.
8. Scott, F.L., Angew. Chem., 1957, vol. 69, p. 506.
9. Neugebauer, F.A. and Fischer, H., Justus Liebigs Ann.
Chem., 1982, no. 3, p. 387.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5,6-dihydro-
1
furo[2,3-c]pyridazine (XII). H NMR spectrum, δ,
ppm: 2.28 s and 2.65 s (3H each, CH3), 3.35 t and
4.74 t (4H, CH2, J = 8.5 Hz), 6.01 s (1H, 4′-H), 7.96 s
(1H, 4-H).
10. Novák, Z., Bostai, B., Csékei, M., Lőrincz, K., and
Kotschy, A., Heterocycles, 2003, vol. 60, p. 2653.
11. Seitz, G., Görge, L., and Dietrich, S., Tetrahedron Lett.,
1985, vol. 26, p. 4355.
2-[3,6-Bis(3,5-dimethyl-1H-pyrazol-1-yl)pyrida-
zin-4-yl]ethanol (XIII). H NMR spectrum, δ, ppm:
1
12. Seitz, G. and Görge, L., Chem.-Ztg., 1987, vol. 111, p. 16.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 7 2009