Reactions of 1,2,4,5-tetrazines with S-nucleophiles

Article abstract of DOI:10.1007/s11172-011-0155-2

The reactions of 3,6-disubstituted and azoloannulated 1,2,4,5-tetrazines containing heterocyclic leaving groups with S-nucleophiles were studied. The methods of introduction of functionalized thiols, including thiol derivatives of 1,7- and 1,2-dicarba-clo

Full text of DOI:10.1007/s11172-011-0155-2

Russian Chemical Bulletin, International Edition, Vol. 60, No. 5, pp. 985—991, May, 2011
985
Reactions of 1,2,4,5ꢀtetrazines with Sꢀnucleophiles*
S. G. Tolshchina,a R. I. Ishmetova,a N. K. Ignatenko,a A. V. Korotina,a
I. N. Ganebnykh,a V. A. Ol´shevskaya,b V. N. Kalinin,b and G. L. Rusinova
aI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi, 620990 Ekaterinburg, Russian Federation.
Fax: +7 (343) 369 3058. Eꢀmail: rusinov@ios.uran.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 6549
The reactions of 3,6ꢀdisubstituted and azoloannulated 1,2,4,5ꢀtetrazines containing heꢀ
terocyclic leaving groups with Sꢀnucleophiles were studied. The methods of introduction of
functionalized thiols, including thiol derivatives of 1,7ꢀ and 1,2ꢀdicarbaꢀclosoꢀdodecaboranes,
into the tetrazine ring were developed. It was established for the first time that, instead of
replacement of a leaving group in the tetrazine ring, the attack of Sꢀnucleophile at the unsubstiꢀ
tuted carbon atom occurs in the case of imidazo[1,2ꢀb][1,2,4,5]tetrazines to form previously
unknown products of nucleophilic substitution of the hydrogen atom.
Key words: 1,2,4,5ꢀtetrazines, [1,2,4]triazolo[4,3ꢀb][1,2,4,5]tetrazines, imidazo[1,2ꢀb]ꢀ
[1,2,4,5]tetrazines, Sꢀnucleophiles, nucleophilic substitution.
Scheme 1
1,2,4,5ꢀTetrazines substituted by Sꢀnucleophiles are
of interest as materials possessing electrochemical activity,
luminiscence properties,1,2 ability to form molecular comꢀ
plexes with organic molecules,3 which opens prospects for
their application in sensory devices and molecular elecꢀ
tronics. The ability of 1,2,4,5ꢀtetrazines to react with thiꢀ
ols, in particular, with thio groups of amino acids as part
of proteins, can be used for labeling and analysis of biologꢀ
ical objects.4
At the present time, there are only singular examples
of introduction of Sꢀnucleophile residues into the tetraꢀ
zine ring.1,2,5 These reactions are usually carried out based
on insufficiently stable and hardly accessible halogenated
1,2,4,5ꢀtetrazine derivatives. At the same time, it is
known5—8 that the 1,2,4,5ꢀtetrazines containing heteroꢀ
cyclic leaving groups are convenient substrates for modifiꢀ
cation of the tetrazine ring in the reactions with Nꢀ and
Oꢀnucleophiles.
In the present work, we studied in detail the reactions
of 3,6ꢀdiazolylꢀ1,2,4,5ꢀtetrazines 1a—c with Sꢀnucleoꢀ
philes. A series of products of monoꢀ (2) and disubstituꢀ
tion (3) in tetrazines 1a—c by various functionalized thiols,
including thiol derivatives of oꢀ and mꢀcarboranes, was
synthesized (Scheme 1).
Compounds 2 and 3 were synthesized in acetonitrile at
room temperature in the presence of catalytic amounts of
triethylamine. Replacement of heterocyclic leaving groups
in the tetrazine ring is the main reaction pathway of
* Dedicated to Academician V. N. Charushin on the occasion of
his 60th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 961—967, May, 2011.
1066ꢀ5285/11/6005ꢀ985 © 2011 Springer Science+Business Media, Inc.

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Tolshchina et al.
3,6ꢀdiazolylꢀ1,2,4,5ꢀtetrazines with Sꢀnucleophiles. Howꢀ
ever, according to the data from TLC, the reactions mixꢀ
tures contained generally also dihydrotetrazines and diꢀ
sulfides, which are products of the side redox reactions
proceeding due to a high electrophilicity of the 1,2,4,5ꢀ
tetrazine ring. Heating of the reaction mixtures resulted in
the increase in the amount of these side products and
decrease in the yields of target substituted tetrazines.
It was established that the imidazolyl fragments are
easier substituted by Sꢀnucleophiles than the 3,5ꢀdimethylꢀ
pyrazolyl group. For example, the reactions of thiols with
compounds 1b,c afforded only the corresponding disubꢀ
stituted derivatives 3, while tetrazine 1a form mixtures of
monoꢀ and disubstitution products with predominance of
derivatives 2. The reaction of compound 1a with thioglyꢀ
colic acid is an exception, which proceeds without basic
catalysis to afford disubstituted tetrazine 3d at any reagent
ratio. The structures of the synthesized thiol derivatives
were confirmed by the Xꢀray diffraction data for 3,6ꢀdibenzylꢀ
thioꢀ1,2,4,5ꢀtetrazine (3b) (Fig. 1).
At the same time, hydrazine, which is a stronger
nucleophile, replace readily one of the alkylthio group in
tetrazines 3. In such a manner, we synthesized hydrazinoꢀ
tetrazines 5a,b (Scheme 3) containing, respectively, the
isopropylthio group and mꢀcarboranylthio fragment, which
is promising unit in the medicaments for boron neutron
capture therapy of oncological diseases. Introduction of
the hydrazine group open the way for subsequent chemiꢀ
cal modification of tetrazines 5a,b.
Scheme 3
By the example of the reaction of tetrazine 2c with
cytisine, it was shown that the 3,5ꢀdimethylpyrazolyl group
in the products 2 can be substituted further by Nꢀnucleoꢀ
philes (Scheme 2). Compound 4 containing the thiol and
amine fragments was obtained upon refluxing reagents in
acetonitrile in a yield of 55%. We failed to synthesize comꢀ
pound 4 by substitution of the alkylthio group in comꢀ
pound 3c.
Scheme 2
By the example of compounds 3a,e, it was shown that
the tetrazines containing the fragments of Sꢀnucleophiles
enter into the [4+2] cycloaddition reactions with inverted
electronic requirements similarly to diazolyltetrazines 19,
which are accompanied by release of molecular nitrogen.
Novel pyridazines 6a,b (see Scheme 3) having the carboꢀ
rane substituents and lipophilic alkyl fragments in their
structures were obtained by these transformations. Diꢀ
hydropyridazine, which formed as a result of the addition
of allylcarborane, was not isolated, since under the reacꢀ
tion conditions it was oxidized by the starting tetrazine 3a
to pyridazine 6a. The structure of pyridazine 6a was conꢀ
firmed by Xꢀray diffraction (Fig. 2).
It is known10,11 that the heterocyclic leaving group in
the tetrazine ring of [1,2,4]triazolo[4,3ꢀb]ꢀ and imidꢀ
azo[1,2ꢀb][1,2,4,5]tetrazines is readily substituted by
Nꢀ and Oꢀnucleophiles as in the unannulated derivatives.
It was established that azoloannulation causes change in
i. Cytisine.
N(2)
N(1)
S(2)
S(1)
C(12)
C(5)
C(13)
C(14)
C(11)
C(16)
C(2)
C(10)
C(1)
N(3)
C(3)
C(6)
C(7)
N(4)
C(4)
C(8)
C(9)
C(15)
Fig. 1. Molecular geometry of 3b in the crystal (the thermal
ellipsoids are shown with 50% probability).

Reactions of 1,2,4,5ꢀtetrazines with Sꢀnucleophiles
C(9)
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
987
synthesis of compound 10 from 3ꢀaminoꢀ6ꢀ(3,5ꢀdimethylꢀ
pyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazine and chloroacetaldehyde
allowed us to obtain the targeted product in a yield of
only 13%.
C(7)
C(8)
S(1)
C(12)
N(2)
C(4)
N(1)
C(6)
Scheme 5
C(3)
C(10)
C(13)
B(6)
B(10)
C(2)
C(5)
B(9)
S(2)
C(11)
B(8)
B(5)
B(4)
C(1)
B(3)
B(7)
B(2)
B(1)
Fig. 2. Molecular geometry of 6a in the crystal (the thermal
ellipsoids are shown with 50% probability).
the reactivities of tetrazines in the reactions with Sꢀnucleoꢀ
philes. For examples, in contrast to the 3,6ꢀdisubstituted
derivatives 1, [1,2,4]triazolo[4,3ꢀb][1,2,4,5]tetrazine 7 afꢀ
fords no products of replacement of the pyrazolyl group by
thiols even upon heating in the presence of triethylamine.
To synthesize the targeted triazolotetrazines 8a,b containꢀ
ing the thiol fragment in the position 6, cyclocondensaꢀ
tion of the hydrazine derivatives 5a,b with triethylorthoꢀ
formate was carried out (Scheme 4).
The reaction of imidazo[1,2ꢀb][1,2,4,5]tetrazine 10
with thiols in acetonitrile in the presence of triethylamine
affords no substitution products of the heterocyclic leavꢀ
ing group in the tetrazine ring. Previously unknown prodꢀ
ucts of nucleophilic substitution of the hydrogen atom in
the imidazole fragment 11a—c were isolated in these reacꢀ
tions. The structures of these compounds were confirmed
by the Xꢀray diffraction data for 11c (Fig. 3).
Scheme 4
Thus, 3,6ꢀdisubstituted 1,2,4,5ꢀtetrazines containing
heterocyclic leaving groups form readily the monoꢀ and
disubstitution products under the action of Sꢀnucleophiles.
Azoloannulation results in the change in the reactivities of
1,2,4,5ꢀtetrazines.
Experimental
Compound 1a—c, 7 have been described earlier.7,13—15
9ꢀMercaptoꢀoꢀ and 9ꢀmercaptoꢀmꢀcarboranes were prepared acꢀ
cording to a known procedure.16
NMR spectra were recorded on a Avance DRXꢀ400 (Brukꢀ
er) spectrometer at 400 MHz using Me4Si as the internal stanꢀ
dard. The chemical shifts are given in the δ scale in ppm. Meltꢀ
ing points were determined using a Stuart instrument. Elemental
analysis was performed on a CHN РЕ 2400 Ser. II (Perꢀ
kin—Elmer) analyzer. The course of reactions and purity of comꢀ
The influence of the annulated imidazole ring on the
reactivities of 1,2,4,5ꢀtetrazines in the reactions with
Sꢀnucleophiles was studied by the example of 3ꢀ(3,5ꢀdiꢀ
methylpyrazolꢀ1ꢀyl)imidazo[1,2ꢀb][1,2,4,5]tetrazine (10)
(Scheme 5). Compound 10 was obtained in a high yield
(86%) by cyclocondensation of tetrazine 9 containing the
aminoacetal fragment. The earlier described12 method of

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Tolshchina et al.
N(5)
N(3)
C(9)
N(1)
N(4)
N(2)
C(6)
N(7)
C(8)
C(5)
C(4)
C(7)
N(6)
C(2)
C(4S)
C(3S)
B(5)
B(6)
C(3)
S(1)
B(2)
C(5S)
C(6S)
C(2S)
B(3)
C(10)
B(10)
B(7)
C(11)
Fig. 3. Molecular geometry of 11c in the crystal (the thermal ellipsoids are shown with 50% probability).
C(1)
B(1)
B(4)
C(1S)
B(8)
B(9)
pounds obtained was monitored by TLC on Sorbfil plates, the
eluent was a benzene—acetonitrile (1 : 1) mixture. Silica gel
(Lancaster 0.040—0.063 mm, 230—400 mesh) was used for colꢀ
umn chromatography, the eluent was a benzene—acetonitrile
(1 : 1) mixture.
3ꢀAlkylthioꢀ6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazines
2a—c. To a solution of tetrazine 1a (270 mg, 1 mmol) in acetoniꢀ
trile (15 mL), alkylthiol (1 mmol) and triethylamine (50 mg,
0.5 mmol) were added with stirring. The reaction mixture was
stirred for 1—5 h at room temperature (TLC control). The solꢀ
vent was evaporated and compounds 2a—c were isolated by colꢀ
umn chromatography (Rf 0.7—0.8).
3ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ6ꢀisopropylthioꢀ1,2,4,5ꢀtetrꢀ
azine (2a). The yield was 162 mg (65%), m.p. 89—90 °C.
Found (%): C, 48.33; H, 5.60; N, 33.25. C10H14N6S. Calculatꢀ
ed (%): C, 47.98; H, 5.64; N, 33.57.
3ꢀBenzylthioꢀ6ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazine
(2b). The yield was 89 mg (30%), m.p. 90—93 °C. Found (%):
C, 56.54; H, 4.77; N, 27.92. C14H14N6S. Calculated (%):
C, 56.36; H, 4.73; N, 28.17.
3ꢀ[3ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propylthio]ꢀ6ꢀ(3,5ꢀ
dimethylpyrazolꢀ1ꢀyl)ꢀ1,2,4,5ꢀtetrazine (2c). The yield was
223 mg (49%), m.p. 98—100 °C. Found (%): C, 63.09; H, 7.58;
N, 18.43. C24H34N6OS. Calculated (%): C, 63.40; H, 7.54;
N, 18.49.
3,6ꢀDiisopropylthioꢀ1,2,4,5ꢀtetrazine (3a). To a suspension
of tetrazine 1b (214 mg, 1 mmol) in acetonitrile (10 mL), isoproꢀ
pylthiol (152 mg, 2 mmol) and triethylamine (50 mg, 0.5 mmol)
were added. The reaction mixture was stirred for 5 min at room
temperature. The solvent was evaporated, the product was exꢀ
tracted with pentane, and the crystals obtained after evaporation
of pentane were washed with water and recrystallized from pentane.
The yield was 170 mg (74%), m.p. 59 °C. Found (%): C, 41.73;
H, 6.19; N, 24.22. C8H14N4S2. Calculated (%): C, 41.71; H, 6.13;
N, 24.32.
temperature. The precipitate that formed was filtered off and
recrystallized from acetonitrile. The yield was 203 mg (62%),
m.p. 139—140 °C. Found (%): C, 59.09; H, 4.19; N, 17.17.
C16H14N4S2. Calculated (%): C, 58.87; H, 4.32; N, 17.16.
3,6ꢀDi[3ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propylthio]ꢀ
1,2,4,5ꢀtetrazine (3c). To a suspension of tetrazine 1b (214 mg,
1 mmol) in acetonitrile (10 mL), 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀ(3ꢀthiolꢀ
propyl)phenol (561 mg, 2 mmol) and triethylamine (50 mg,
0.5 mmol) were added. The reaction mixture was stirred for
5 min at room temperature. The solvent was evaporated, the
product was extracted with pentane, and the crystals obtained of
evaporation of pentane were washed with water and recrystalꢀ
lized from pentane. The yield was 249 mg (39%), m.p. 123—125 °C.
Found (%): C, 67.94; H, 8.68; N, 8.78. C36H54N4O2S2. Calcuꢀ
lated (%): C, 67.67; H, 8.52; N, 8.77.
3,6ꢀDicarboxymethylthioꢀ1,2,4,5ꢀtetrazine (3d). To a soluꢀ
tion of tetrazine 1a (270 mg, 1 mmol) in acetonitrile (10 mL),
thioglycolic acid (184 mg, 2 mmol) was added. The reaction
mixture was stirred for 15 min at room temperature. The precipꢀ
itate that formed was filtered off and washed with acetonitrile.
The yield was 215 mg (79%), m.p. 204 °C (decomp.). Found (%):
C, 26.42; H, 2.52; N, 20.70. C6H6N4O4S2•0.5H2O. Calculatꢀ
ed (%): C, 26.57; H, 2.60; N, 20.65.
3,6ꢀDi(1,7ꢀdicarbaꢀclosoꢀdodecaboranꢀ9ꢀyl)thioꢀ1,2,4,5ꢀ
tetrazine (3e). To a suspension of tetrazine 1c (242 mg, 1 mmol)
in acetonitrile (10 mL), 9ꢀmercaptoꢀmꢀcarborane (352 mg,
2 mmol) and triethylamine (50 mg, 0.5 mmol) were added. The
reaction mixture was stirred for 3 h at room temperature. The
precipitate that formed was filtered off and washed with acetoniꢀ
trile. The yield was 379 mg (88%), m.p. 241—243 °C. Found (%):
C, 17.00; H, 5.18; N, 13.08. C6H22B20N4S2. Calculated (%):
C, 16.74; H, 5.15; N, 13.01.
3,6ꢀDi(1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ9ꢀyl)thioꢀ1,2,4,5ꢀ
tetrazine (3f). To a suspension of tetrazine 1c (242 mg, 1 mmol)
in acetonitrile (10 mL), 9ꢀmercaptoꢀoꢀcarborane (352 mg,
2 mmol) and triethylamine (50 mg, 0.5 mmol) were added. The
reaction mixture was stirred for 3 h at room temperature and
then kept for 24 h at –20 °C. The precipitate that formed was
filtered off and washed with acetonitrile. The yield was 90 mg
3,6ꢀDibenzylthioꢀ1,2,4,5ꢀtetrazine (3b). To a suspension of
tetrazine 1b (214 mg, 1 mmol) in acetonitrile (10 mL), benzylꢀ
thiol (248 mg, 2 mmol) and triethylamine (50 mg, 0.5 mmol)
were added. The reaction mixture was stirred for 1 h at room

Reactions of 1,2,4,5ꢀtetrazines with Sꢀnucleophiles
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
989
(20%), m.p. 250 °C (decomp.). Found (%): C, 18.39; H, 5.51;
N, 13.58. C6H22B20N4S2•0.5CH3CN. Calculated (%): C, 18.64;
H, 5.25; N, 13.97.
0.5 mmol) in an acetonitrile—DMF (4 : 1) mixture (5 mL),
hydrazineꢀhydrate (30 mg, 0.6 mmol) was added with stirring.
The reaction mixture was stirred for 15 min at room temperaꢀ
ture. The solvent was removed under reduced pressure and prodꢀ
uct 5b was isolated by column chromatography, Rf 0.7. The yield
was 108 mg (76%), m.p. 145—146 °C. Found (%): C, 17.01;
H, 5.12; N, 29.18. C4H14B10N6S. Calculated (%): C, 16.78;
H, 4.93; N, 29.35.
3,6ꢀDiisopropylthioꢀ4ꢀ(1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ9ꢀ
yl)methylpyridazine (6a). A solution of compound 3a (230 mg,
1 mmol) and 9ꢀallylꢀoꢀcarborane (184 mg, 1 mmol) in mesityꢀ
lene (10 mL) was refluxed for 5 h. The solvent was removed
under reduced pressure and the residue was recrystallized from
acetonitrile. The yield was 173 mg (45%), m.p. 146—148 °C.
Found (%): C, 40.65; H, 7.57; N, 7.38. C13H28B10N2S2. Calcuꢀ
lated (%): C, 40.60; H, 7.34; N, 7.28.
Nꢀ{6ꢀ[3ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propylthio]ꢀ
1,2,4,5ꢀtetrazineꢀ3ꢀyl}cytisine (4). A solution of compound 2c
(227 mg, 0.5 mmol) and cytisine (95 mg, 0.5 mmol) was refluxed
for 6 h. The solvent was concentrated and product 4 was isolated
by column chromatography, Rf 0.35. The yield was 312 mg (55%),
m.p. 83—85 °C. Found (%): C, 63.81; H, 7.27; N, 14.67.
C30H40N6O2S•H2O. Calculated (%): C, 63.58; H, 7.47; N, 14.83.
3ꢀHydrazinoꢀ6ꢀisopropylthioꢀ1,2,4,5ꢀtetrazine (5a). To a soꢀ
lution of compound 3a (230 mg, 1 mmol) in acetonitrile (5 mL),
hydrazine hydrate (50 mg, 1 mmol) was added with stirring. The
reaction mixture was stirred for 15 min at room temperature.
The solvent was concentrated and product 5a was isolated by
column chromatography, Rf 0.5. The yield was 147 mg (79%),
m.p. 91—92 °C. Found (%): C, 32.27; H, 5.52; N, 45.45.
C5H10N6S. Calculated (%): C, 32.25; H, 5.41; N, 45.13.
3ꢀHydrazinoꢀ6ꢀ(1,7ꢀdicarbaꢀclosoꢀdodecaboranꢀ9ꢀyl)thioꢀ
1,2,4,5ꢀtetrazine (5b). To a suspension of compound 3e (215 mg,
1,4ꢀDi(1,7ꢀdicarbaꢀclosoꢀdodecaboranꢀ9ꢀyl)thioꢀ4aꢀ(pyrrolꢀ
idinꢀ1ꢀyl)ꢀ5,6,7,7aꢀtetrahydroꢀ4aHꢀcyclopenta[d]pyridazine (6b).
To a suspension of compound 3e (215 mg, 0.5 mmol) in acetoꢀ
nitrile (8 mL), 1ꢀpyrrolidinecyclopentene (69 mg, 0.5 mmol)
Table 1. 1H NMR spectra of compounds 2a—c, 3a—f, 4, 5a,b, 6a,b, 8a,b, 9, 10, and 11a—c in DMSOꢀd6
Comꢀ
pound
δ (J/Hz)
2aa
2ba
1.54 (d, 6 H, 2 Me (Pri), J = 6.8); 2.38, 2.68 (both s, 3 H each, 2 Ме (Pyr)); 4.17 (m, 1 H, CH (Pri)); 6.17 (s, 1 H, H(4) (Pyr))
2.38, 2.66 (both s, 3 H each, 2 Ме (Pyr)); 4.58 (s, 2 H, CH2); 6.16 (s, 1 H, H(4) (Pyr)); 7.29—7.36 (m, 3 H, Ph);
7.49 (m, 2 H, Ph)
2c
1.36 (s, 18 H, 2 But); 2.03 (m, 2 H, CH2CH2CH2); 2.26, 2.54 (both s, 3 Heach, 2 Ме (Pyr)); 2.66 (t, 2 H, CH2Ar, J = 7.7);
3.36 (t, 2 H, SCH2, J = 7.2); 6.32 (s, 1 H, H(4) (Pyr)); 6.72 (s, 1 H, ОH); 6.94 (s, 2 H, Ar)
1.50 (d, 12 H, 4 Me (2 Pri), J = 6.8); 4.09 (m, 2 H, 2 CH (2 Pri))
4.51 (s, 4 H, 2 CH2); 7.28—7.36 (m, 6 H, 2 Ph); 7.45 (m, 4 H, 2 Ph)
1.36 (s, 36 H, 4 But); 1.99 (m, 4 H, 2 CH2CH2CH2); 2.63 (t, 4 H, 2 CH2Ar, J = 7.5), 3.27 (t, 4 H, 2 SCH2, J = 7.3);
6.71 (s, 2 H, 2 ОH); 6.92 (s, 4 H, 2 Ar)
3aa
3ba
3c
3d
3eb
3f
4a
4.17 (s, 4 H, 2 CH2); 13.01 (br.s, 2 H, 2 CООH)
1.60—3.30 (m, 18 H, 18 BH); 4.21 (br.s, 4 H, 4 CH)
1.60—3.10 (m, 18 H, 18 BH); 5.09, 5.11 (both br.s, 2 H each, 4 CH)
1.43 (s, 18 H, 2 But); 2.01—2.16 (m, 4 H, 2 CH2); 2.31, 2.49 (both m, 1 H each, 2 CH); 2.68—2.73 (m, 2 H, CH2);
3.21—3.37 (m, 6 H, 3 CH2); 4.86—4.96 (m, 2 H, CH2); 5.06 (br.s, 1 H, ОH); 6.10 (dd, 1 H, H(3) of the pyridone
fragment of cytisine, J1 = 7.0, J2 = 1.2); 6.38 (dd, 1 H, H(1) of the pyridone fragment of cytisine, J1 = 9.2,
J
2 = 1.2); 7.00 (s, 2 H, Ar); 7.24 (t.d, 1 H, H(2) of the pyridone fragment of cytisine, J1 = 9.2, J2 = 7.0)
5a
5b
6aa
1.38 (d, 6 H, 2 Me (Pri), J = 6.8); 3.90 (m, 1 H, CH (Pri)); 4.54 (br.s, 2 H, NH2); 9.40 (br.s, 1 H, NH)
1.60—3.60 (m, 9 H, 9 BH); 4.15 (br.s, 2 H, 2 CH); 4.61 (br.s, 2 H, NH2); 9.54 (br.s, 1 H, NH)
0.80—3.00 (m, 9 H, 9 BH); 1.42 (d, 12 H, 4 Me (2 Pri), J = 6.8); 2.13 (s, 2 H, CH2); 3.45, 3.51 (both br.s, 1 H each, 2 CH);
4.20, 4.28 (both m, 1 H each, 2 CH (2 Pri)); 6.74 (s, 1 H, H(5) pyridazine)
1.44—3.46 (m, 25 H, 18 BH, 3 CH2, CH); 1.46—1.55 (m, 4 H, 2 CH2 pyrrolidine); 2.96 (br.s, 4 H, 4 CH);
3.02 (t, 4 H, 2 CH2 pyrrolidine, J = 7.6)
1.48 (d, 6 H, 2 Me (Pri), J = 6.8); 3.88 (m, 1 H, CH (Pri)); 9.84 (s, 1 H, CH)
1.50—3.20 (m, 9 H, 9 BH); 4.28 (br.s, 2 H, 2 CH); 9.82 (s, 1 H, CH)
2.36, 2.57 (both s, 3 H each, 2 Ме (Pyr)); 3.46 (s, 6 H, 2 МеО); 3.79 (m, 2 H, CH2); 4.60 (t, 1 H, CH, J = 5.1);
6.06 (br.s, 1 H, NH); 6.11 (s, 1 H, H(4) (Pyr))
2.39, 2.77 (both s, 3 H each, 2 Ме (Pyr)); 6.18 (s, 1 H, H(4) (Pyr)); 8.19, 8.44 (both d, 1 H each, 2 CH, J = 0.8)
2.25, 2.36 (both s, 3 H each, 2 Ме (Pyr)); 6.26 (s, 1 H, H(4) (Pyr)); 7.26—7.34 (m, 5 H, Ph); 8.79 (s, 1 H, CH)
1.40—3.20 (m, 9 H, 9 BH); 2.38, 2.73 (both s, 3 H each, 2 Ме (Pyr)); 3.58, 3.68 (both br.s, 1 H each, 2 CH of carborane);
6.16 (s, 1 H, H(4) (Pyr)); 8.41 (s, 1 H, CH)
6ba
8a
8b
9a
10a
11a
11ba
11c
1.50—3.10 (m, 9 H, 9 BH); 2.28, 2.61 (both s, 3 H each, 2 Ме (Pyr)); 4.17 (br.s, 2 H, 2 CH of carborane);
6.31 (s, 1 H, H(4) (Pyr)); 8.69 (s, 1 H, CH)
a The spectrum was recorded in CDCl3.
b The spectrum was recorded in DMFꢀd7.

990
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Tolshchina et al.
was added. The reaction mixture was stirred for 30 min at 60 °C
until completion of gas evolution and complete dissolution of
the starting substance. The product was swaged with water (3 mL),
filtered off, and recrystallized from acetonitrile. The yield was
173 mg (62%), m.p. 102—104 °C. Found (%): C, 32.30; H, 7.05;
N, 7.53. C15H37B20N3S2•H2O. Calculated (%): C, 32.70; H, 6.74;
N, 7.08.
3ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)imidazo[1,2ꢀb][1,2,4,5]tetrꢀ
azine (10). Compound 9 (0.5 mmol) was refluxed for 4 h in
CН3CООН (5 mL). The solvent was removed under reduced
pressure and the residue was washed with ethanol. The yield
was 93 mg (86%), m.p. 194—195 °C. Found (%): C, 50.29;
H, 4.21; N, 45.36. C9H9N7. Calculated (%): C, 50.23; H, 4.22;
N, 45.56.
[1,2,4]Triazolo[4,3ꢀb][1,2,4,5]tetrazines 8a,b. Compound
5 (1 mmol) was refluxed for 3—4 h (TLC control) in
a CН3CООН—CН(ОЕt)3 (1 : 3) mixture (8 mL). The solvent
was removed under reduced pressure. The residue was washed
with hexane (8a) or diethyl ether (8b).
6ꢀ(Isopropylthio)[1,2,4]triazolo[4,3ꢀb][1,2,4,5]tetrazine
(8a). The yield was 157 mg (80%), m.p. 86—88 °C. Found (%):
C, 37.00; H, 4.24; N, 42.62. C6H8N6S. Calculated (%): C, 36.72;
H, 4.11; N, 42.83.
6ꢀ(1,7ꢀDicarbaꢀclosoꢀdodecaboranꢀ9ꢀyl)thio[1,2,4]triazoloꢀ
[4,3ꢀb][1,2,4,5]tetrazine (8b). The yield was 142 mg (48%), m.p.
181—183 °C. Found (%): C, 20.44; H, 4.21; N, 28.05.
C5H12B10N6S. Calculated (%): C, 20.26; H, 4.08; N, 28.36.
6ꢀ(2,2ꢀDimethoxyethylamino)ꢀ3ꢀ(3,5ꢀdimethylpyrazolꢀ1ꢀyl)ꢀ
1,2,4,5ꢀtetrazine (9). To a suspension of tetrazine 1a (1 mmol) in
acetonitrile (6 mL), 2,2ꢀdimethoxyethylamine (110 mg, 1.05 mmol)
was added. The reaction mixture was stirred for 10 min at room
temperature. The solvent was removed under reduced pressure
and the residue was washed with hexane. The yield was 235 mg
(84%), m.p. 95—96 °C. Found (%): C, 47.33; H, 6.12; N, 35.36.
C11H17N7O2. Calculated (%): C, 47.30; H, 6.14; N, 35.10.
6ꢀSubstituted 3ꢀazolylimidazo[1,2ꢀb][1,2,4,5]tetrazines 11a—c.
To a solution of imidazo[1,2ꢀb][1,2,4,5]tetrazine 10 (0.5 mmol)
in acetonitrile (5 mL), thiol (0.6 mmol) and triethylamine (50 mg,
0.5 mmol) were added. The reaction mixture was stirred for
5—7 h at room temperature (TLC control). The solvent was
concentrated. Compounds 11a—c were isolated by column
chromatography (Rf 0.7—0.8).
3ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ6ꢀ(phenylthio)imidazo[1,2ꢀb]ꢀ
[1,2,4,5]tetrazine (11a). The yield was 61 mg (38%), m.p.
137—140 °C. Found (%): C, 55.61; H, 3.76; N, 30.31. C15H13N7S.
Calculated (%): C, 55.71; H, 4.05; N, 30.32.
6ꢀ[(1,2ꢀDicarbaꢀclosoꢀdodecaboranꢀ9ꢀyl)thio]ꢀ3ꢀ(3,5ꢀdiꢀ
methylpyrazolꢀ1ꢀyl)imidazo[1,2ꢀb][1,2,4,5]tetrazine (11b). The
yield was 60 mg (31%), m.p. 187—190 °C. Found (%): C, 34.13;
H, 5.24; N, 24.93. C11H19B10N7S. Calculated (%): C, 33.92;
H, 4.92; N, 25.17.
6ꢀ[(1,7ꢀDicarbaꢀclosoꢀdodecaboranꢀ9ꢀyl)thio]ꢀ3ꢀ(3,5ꢀdiꢀ
methylpyrazolꢀ1ꢀyl)imidazo[1,2ꢀb][1,2,4,5]tetrazine (11c). The
yield was 113 mg (58%), m.p. 170—173 °C. Found (%): C, 33.79;
H, 4.87; N, 25.16. C11H19B10N7S. Calculated (%): C, 33.92;
H, 4.92; N, 25.17.
Table 2. Principal crystallographic data for compounds 3b, 6a, and 11c
Compound
3b
6a
11c
Molecular formula
Molecular weight
Crystal system
Space group
a/Å
b/Å
c/Å
α/deg
β/deg
C16H14N4S2
326.43
C13H28B10N2S2
384.59
Monoclinic
P2(1)/n
10.9319(3)
12.0400(3)
17.3565(5)
90.00
106.621(2)
90.00
C11H19B10N7S•C6H6
467.60
Monoclinic
P2(1)/c
9.7789(12)
5.5097(6)
29.099(4)
90
95.760(10)
90
1559.9(3)
4
Triclinic
P –1
8.8455(9)
11.7839(11)
13.4495(12)
66.345(9)
88.425(8)
69.879(9)
1195.7(2)
2
γ/deg
V/Å3
2189.01(10)
4
Z
dcalc/g cm–3
μ/mm–1
1.390
0.342
1.167
0.244
1.299
0.158
Scan range in θ/deg
Number of measured
26.37 ≥ θ ≥ 2.81
9421 (0.0326)
30.51 ≥ θ ≥ 2.98
19348 (0.0162)
28.28 ≥ θ ≥ 2.76
7020 (0.0221)
reflections (Rint
)
Number of independent
reflections
Number of reflections
with I > 2σ(I)
Number of refined
parameters
3146
1719
215
6498
4056
303
5787
3776
364
R1 (over I > 2σ(I))
wR2 (over I > 2σ(I))
R1 (over all reflections)
wR2 (over all reflections)
0.0313
0.0453
0.0786
0.0486
0.0403
0.1072
0.0661
0.1123
0.0385
0.0908
0.0686
0.0962

Reactions of 1,2,4,5ꢀtetrazines with Sꢀnucleophiles
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
991
The 1H NMR spectra of compounds 2a—c, 3a—f, 4, 5a,b,
6a,b, 8a,b—10a,b, and 11a—c are given in Table 1.
3. B. J. Jordan, M. A. Pollier, L. A. Miller, C. Tiernan,
G. Clavier, P. Audebert, V. M. Rotello, Org. Lett., 2007,
9, 2835.
Xꢀray diffraction study of compounds 3b, 6a, and 11c. The
single crystals of compounds 3b and 6a were obtained by recrysꢀ
tallization from MeCN and the single crystal of compound 11c
was obtained by recrystallization from benzene. The experiment
was performed on a Xcaliburꢀ3 Xꢀray diffractometer with a CCD
detector (λ(MoꢀKα) = 0.71073 Å, graphite monochromator,
ωꢀ and ϕꢀscanning, T = 295 (3b, 6a) and 120 K (11c)). The strucꢀ
tures were solved by the direct method according to the SHELXSꢀ97
program and refined using the SHELXLꢀ97 program. The posiꢀ
tions and temperature parameters of nonꢀhydrogen atoms were
refined in the isotropic approximation and then in the anisotroꢀ
pic approximation by the fullꢀmatrix least square method. The
crystal structure of 11c contain solvate molecule of the solvent.
The hydrogen atoms were localized at the electron density maxima
and involved in the refinement in the riding model. The main
parameters of the Xꢀray diffraction experiment are given in Table 2.
The Xꢀray diffraction data are deposited in Cambridge Crysꢀ
tallographic Data Centre under the Nos 818 588—818 590
(compounds 3b, 6a, and 11c, respectively). These materials are
free accessible and can be requested at www.ccdc.cam.ac.uk/
data_request/cif.
4. M. J. Tucker, J. R. Courter, J. Chen, O. Atasoylu, A. B.
Smith, R. M. Hochstrasser, Angew. Chem., Int. Ed., 2010,
49, 3612.
5. Z. Novak, B. Bostai, M. Csekei, K. Lorincz, A. Kotschy,
Heterocycles, 2003, 60, 2653.
6. N. I. Latosh, G. L. Rusinov, I. N. Ganebnykh, O. N. Chuꢀ
pakhin, Zh. Org. Khim., 1999, 35, 1392 [Russ. J. Org. Chem.
(Engl. Transl.), 1999, 35, 1363].
7. G. L. Rusinov, N. I. Latosh, I. N. Ganebnykh, R. I. Ishmeꢀ
tova, N. K. Ignatenko, O. N. Chupakhin, Zh. Org. Khim.,
2006, 42, 772 [Russ. J. Org. Chem. (Engl. Transl.), 2006,
42, 757].
8. R. I. Ishmetova, N. I. Latosh, I. N. Ganebnykh, N. K. Igꢀ
natenko, S. G. Tolshchina, G. L. Rusinov, Zh. Org. Khim.,
2009, 45, 1113 [Russ. J. Org. Chem. (Engl. Transl.), 2009,
45, 1102].
9. G. L. Rusinov, R. I. Ishmetova, S. G. Tolshchina, N. K.
Ignatenko, I. N. Ganebnykh, P. A. Slepukhin, V. A. Ol´shevꢀ
skaya, V. N. Charushin, Izv. Akad. Nauk., Ser. Khim., 2010,
116 [Russ. Chem. Bull., Int. Ed., 2010, 59, 116].
10. G. L. Rusinov, I. N. Ganebnykh, R. I. Ishmetova, N. K.
Ignatenko, M. V. Berezin, S. G. Tolshchina, A. V. Zolottseꢀ
va, Vestn. Ural. Gos. Tekhn. Univ., Ser. Khim., 2005, 5, 158
(in Russian).
11. I. N. Ganebnykh, Ph. D. Thes. (Chem.), Inst. of Organ.
Synth., Ural Branch of the Russ. Acad. Sci., Ekaterinburg,
2003, 229 pp. (in Russian).
12. L. Pellegatti, E. Vedrenne, J.ꢀM. Leger, C. Jarry, S. Routier,
J. Comb. Chem., 2010, 12, 604.
The authors are grateful to P. A. Slepukhin for perꢀ
forming Xꢀray diffraction study.
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 08ꢀ03ꢀ99084ꢀ
r_ofi and 11ꢀ03ꢀ00545ꢀa) and the Council for Grants at
the President of the Russian Federation (State Support of
Leading Scientific Schools of the Russian Federation
(Grant NShꢀ65261.2010.3)), as well as by the Ministry of
Education and Science of the Russian Federation (State
Contract No. 02.740.11.0260).
13. M. D. Coburn, G. A. Buntain, B. W. Harris, M. A. Hiskey,
K.ꢀY. Lee, D. G. Ott, J. Heterocycl. Chem., 1991, 28, 2049.
14. G. L. Rusinov, R. I. Ishmetova, I. N. Ganebnykh, O. N.
Chupakhin, Heterocycl. Commun., 2006, 2, 99.
15. G. L. Rusinov, I. N. Ganebnykh, O. N. Chupakhin, Zh. Org.
Khim., 1999, 35, 1379 [Russ. J. Org. Chem. (Engl. Transl.),
1999, 35, 1350].
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Received January 31, 2011