Unusual expansion of the 1,2,4,5-tetrazine ring in [1,2,4]triazolo[4,3-b] [1,2,4,5]tetrazines leading to [1,2,4,6]tetrazepine systems

Article abstract of DOI:10.1002/ejoc.201001590

Expansion of the tetrazine ring has first been found to occur when [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines were allowed to react with CH-active compounds in acetonitrile in the presence of triethylamine to give the unexpected series of 8,9-dihydro-7H-[1

Full text of DOI:10.1002/ejoc.201001590

FULL PAPER
DOI: 10.1002/ejoc.201001590
Unusual Expansion of the 1,2,4,5-Tetrazine Ring in [1,2,4]Triazolo[4,3-b]-
[1,2,4,5]tetrazines Leading to [1,2,4,6]Tetrazepine Systems
Ilya N. Ganebnykh,[a] Svetlana G. Tolshchina,[a] Rashida I. Ishmetova,[a]
Nina K. Ignatenko,[a] Pavel A. Slepukhin,[a] Gennady L. Rusinov,*[a] and
Valery N. Charushin[a]
Keywords: Nitrogen heterocycles / Ring expansion / C–H activation / Nucleophilic substitution
Expansion of the tetrazine ring has first been found to occur
when [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines were allowed to
react with CH-active compounds in acetonitrile in the pres-
ence of triethylamine to give the unexpected series of 8,9-
dihydro-7H-[1,2,4]-triazolo[4,3-b][1,2,4,6]tetrazepine deriva-
tives.
in the presence of triethylamine results in the expansion of
the tetrazine ring to yield previously unknown 8,9-dihydro-
7H-[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepines 2, including
spirocyclic derivatives 2f–j (Scheme 1).
Introduction
It is well known that 1,2,4,5-tetrazines bearing leaving
groups in the 3- and 6-positions are able to undergo nucleo-
philic substitution reactions by N, O, and S nucleophiles to
give the corresponding mono- or disubstitution prod-
ucts.[1–7] Also, some carbon modifications of 1,2,4,5-tetra-
zines due to displacement reactions with anhydro bases of
quinaldinium salts[8] and heterocyclic carbenes[9] or by
cross-coupling reactions with arylboronic acids[10] and
acetylenes[11] have been reported. There are also examples
where instead of nucleophilic substitution reactions at C-3
or C-6, azaphilic addition[12,13] or [4+2]cycloaddition reac-
tions[8,14] have been observed to give rise to the correspond-
ing 1,4-dihydrotetrazines or pyridazine derivatives, respec-
tively.
The reactions of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines
with nucleophilic reagents have so far been scarcely investi-
gated. It has been reported that the 3,5-dimethylpyrazolyl
substituents in [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines can
easily be displaced with aliphatic amines or alcohols.[15]
However, the reaction of 1,2,4-triazolo[4,3-b][1,2,4,5]tetra-
zines with C nucleophiles has never been studied.
Results and Discussion
Scheme 1. Synthesis of 8,9-dihydro-7H-[1,2,4]triazolo[4,3-b]-
[1,2,4,6]tetrazepine derivatives.
In the course of this study it has been established that
treatment of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines 1 with
Compounds 2 were obtained in 40–90% yield as color-
CH-active compounds in acetonitrile at room temperature less or light-yellow crystalline products. It has been shown
that a substituent in the triazole ring of starting materials
[a] I.Ya. Postovsky Institute of Organic Synthesis of the Russian
Academy of Sciences,
1a–d has no significant effect on the reaction rates and
yields of the ring-expansion products. The formation of 2
can be rationalized through the addition of C nucleophile
at the electron-deficient nitrogen atom in the 8-position of
the triazolotetrazine system followed by ring opening and
recyclization into the seven-membered ring (Scheme 2).
S.Kovalevskoy st. 22, 620990, GSP-147, Ekaterinburg, Russian
Federation
Fax: 7-343-3741189
E-mail: rusinov@ios.uran.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001590.
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Scheme 2. The mechanism suggested for the formation of 8,9-dihy-
dro-7H-[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepines.
Although nucleophilic attack at a nitrogen atom is not
typical for the vast majority of heterocyclic compounds,
there are some examples in tetrazine chemistry where the
extremely electron-deficient tetrazine ring undergoes aza-
philic additions with methyllithium, Grignard reagents, or
organozinc compounds to give 1-alkyl- or 1-aryl-substi-
tuted 1,4-dihydrotetrazines.[12,13] These literature data can
be considered as an argument in favor of the first step of
the suggested mechanism. Moreover, according to quantum
chemical calculations the LUMO distribution in triazolote-
trazines has the maximal coefficient for the N-8 nitrogen,[16]
thus indicating that this nitrogen atom appears to be the
most plausible site for nucleophilic attack.
Scheme 3. Transformations of 8,9-dihydro-7H-[1,2,4]triazolo[4,3-
b][1,2,4,6]tetrazepines bearing a barbituric acid fragment.
having the 3,3-dimethyl-5-oxopentanic acid fragment. Com-
pound 2c is more stable than spiro derivative 2f, and it is
not transformed into 3c upon heating at reflux in acetoni-
trile. On the other hand, triazolotetrazepine 3c was ob-
tained from 2c upon continuous heating at reflux for 5 h in
aqueous acetonitrile (Scheme 4).
It has been established that 2 containing the fragments
of 1,3-dicarbonyl compounds are able to eliminate one of
the carbonyl groups upon treatment with water. Thus, com-
pounds 2i,j derived from the addition of barbituric acid
were transformed into triazolotetrazepines 2k,l upon
recrystallization from acetonitrile (Scheme 3). The forma-
tion of 2k,l can be explained by hydrolytic cleavage of the
barbituric acid fragment with subsequent decarboxylation.
Indeed, yields of 2k,l increase from 40 to 80% on transfer
from acetonitrile to a mixture of water/acetonitrile as the
solvent for recrystallization.
A similar elimination of the R1 group was observed for
the addition of ethyl acetoacetate to triazolotetrazines 1a
and 1c (Scheme 1). These reactions gave rise to 2d,e, which
instead of an acetyl group bear a hydrogen atom at the sp3
1
carbon atom in the seven-membered ring. The H NMR
spectra of 2d,e,k,l exhibit characteristic spin–spin coupling
constants between this hydrogen atom and the protons of
one (for 2d,k,l) or two (for 2e) NH groups.
Also, it has been established that compounds 2 that bear
a hydrogen atom in the 8-position (i.e., 2l) can be easily
oxidized by the oxygen present in air to afford the corre-
Scheme 4. Transformations of 8-acyl-8,9-dihydro-7H-[1,2,4]tria-
zolo[4,3-b][1,2,4,6]tetrazepines.
sponding 7H-[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepines
3
(Scheme 3). Unlike colorless 2, compounds 3 are intense
The structural data for compounds 2a,d–f and 3b, be-
yellow solids due to the system of conjugated bonds in their longing to the novel family of [1,2,4]triazolo[4,3-b][1,2,4,6]
structure. tetrazepines, was obtained by X-ray crystallography (Fig-
Cleavage of the diketonic fragment followed by aromati- ures 1 and 2). The differences in the crystal structures of
zation of triazolotetrazepines is also observed for 2c,f de- 2a,d–f are not significant, as all these compounds show sim-
rived from the addition of dimedone (2f) and acetylacetone ilar organization. Indeed, the measured bond lengths and
(2c; Scheme 4). When heated in acetonitrile, compound 2f angles proved to have expected values, whereas the crystal
is converted slowly (for 10 h) into triazolotetrazepine 3b, packings for these compounds are determined mainly by
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Unusual Expansion of the Tetrazine Ring in Triazolotetrazines
contribution of the intermolecular hydrogen bonds between sion product 3f in 50% yield, whereas compound 4c was
the NH of the dihydrotetrazepine ring and the nitrogen isolated in only 20% yield.
atom of the triazole moiety. It is quite natural that the con-
formations of the dihydrotetrazepine rings and the molecu-
lar packings vary from compound to compound, as they
are subject to the effects of the substituents in the aza-
bicyclic system.
Scheme 5. The reaction of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines
with ethyl cyanoacetate.
Evidence for the formation of diamino compounds 4a–c
was obtained by X-ray crystallographic analysis, as exem-
plified by the structure of 4c (Figure 3).
Figure 1. The X-ray structure of 8,9-dihydro-7H-[1,2,4]triazolo[4,3-
b][1,2,4,6]tetrazepine 2f.
Figure 3. Two independent units in the cell of compound 4c.
Figure 2. The X-ray structure of 7H-[1,2,4]triazolo[4,3-b][1,2,4,6]-
The interaction of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines
tetrazepine 3b.
with malononitrile proceeds unexpectedly, resulting in the
The tetrazepine ring in compound 3b is planar, and the formation of triazolo[1,5-a]pyrimidines 5 instead of tri-
maximum deviation of the atoms from the plane of the azolo[1,2,4,6]tetrazepine derivatives (Scheme 6). A plausible
azaaromatic ring is 0.03 Å. Dispersions of bond lengths in mechanism for the transformation of 1 into 5 suggests dis-
the tetrazepine ring, varying from 1.39 to 1.26 Å, are nor- placement of the cyano group in the reaction intermediate
mal for the azaaromatic compounds. The conformation of by a second molecule of malononitrile, followed by conden-
3b is determined by two types of hydrogen bonds: the intra- sation into the pyrimidine ring (Scheme 6).
molecular three-centered hydrogen bonds N4–H4···O1 and
N4–H4···N2 and the intermolecular hydrogen bond O2– ilar to 2 in these reactions failed, even though the reaction
H2···N6[–x, –y + 1, –z + 1]. temperatures and concentrations of reagents were varied.
All attempts to detect the formation of tetrazepines sim-
The nitrile group in CH-active compounds affects their Also, it is worth noting that in the reaction of 1b with ma-
reactivity. Indeed, reactions of triazolotetrazines 1 with lononitrile, besides the formation of triazolopyrimidine 5b,
ethyl cyanoacetate result in the formation of both ring-ex- nucleophilic displacement of the cyano group in 5b by ma-
pansion (i.e., 3) and ring-cleavage products (i.e., 4; lononitrile takes place, affording compound 6 (Scheme 6).
Scheme 5). Dihydrotriazolotetrazepines with cyano- and
Evidence for the structures 5 and 6 is provided by X-ray
ethoxycarbonyl fragments in the 8-position have never been crystallography (Figures 4 and 5).
obtained. For triazolotetrazines 1a,b the ratio of 3 and 4
Also, it has been found unexpectedly that triethylamine
proved to be 1:1, whereas yields of these products were only itself is capable of reacting with triazolotetrazines 1, al-
25–30%. Compound 1e was transformed into ring-expan- though it requires a higher temperature and other different
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Scheme 7. Synthesis of 7H,7ЈH-8,8Ј-bis[1,2,4]triazolo[4,3-b]-
[1,2,4,6]tetrazepine derivatives.
Compounds 7 possess rather high melting points (above
350 °C) and a low solubility in many organic solvents,
which makes it difficult to register high-resolution NMR
spectra. Therefore, the structure of 7a was established by
X-ray crystallography (Figure 6).
Scheme 6. Interaction of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines
with malononitrile.
Figure 6. The X-ray structure of 7H,7ЈH-8,8Ј-bis[1,2,4]triazolo[4,3-
b][1,2,4,6]tetrazepine 7a.
Bonds lengths and the general geometry of the tetrazep-
ine ring in 7a are in a good agreement with those for 3b.
The conformation of the molecule was determined by the
intramolecular hydrogen bond N3–H3···N8 and is stabi-
lized by strong π–π interactions; the distance between
centroids C1N2N1C4N6 and C1N2N1C4N6 [1 – x, –y, 1 –
z] is 3.235 Å.
Figure 4. The X-ray structure of [1,2,4]triazolo[1,5-a]pyrimidine 5c.
The formation of compounds 7 can possibly be explained
by interaction of triazolotetrazines 1 with diethylamino-
ethene, which is formed under the reaction conditions due
to oxidation of triethylamine. This assumption is substanti-
ated by the fact that this enamine is capable of reacting with
1,2,4,5-tetrazines to give [4+2] cycloaddition products.[17]
In order to prove or reject the opportunity of triazolo-
tetrazines 1 reacting with enamines, we studied the reac-
tions of 1 with 1-piperidinocyclopentene and 1-morpholino-
cyclopentene. These enamines are known to react with non-
Figure 5. The X-ray structure of [1,2,4]triazolo[1,5-a]pyrimidine 6.
reaction conditions. Indeed, heating compounds 1 with tri- condensed 1,2,4,5-tetrazines to give pyridazines[18] or tri-
ethylamine in acetonitrile at reflux affords derivatives of cyclic adducts.[19] The structure of triazolo[4,3-b][1,2,4,5]-
7H,7ЈH-8,8Ј-bis[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepine 7 in tetrazines does not contain a fixed cis-diene system that is
20–30% yield (Scheme 7). A similar yield of 7a was reached necessary for realization of the [4+2] cycloaddition process.
in DMSO, and the yield improved to 40% when the reac- Therefore, we expected that enamines might act as C nu-
tion was carrying out in DMF.
cleophiles to give ring-expansion products like compounds
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Unusual Expansion of the Tetrazine Ring in Triazolotetrazines
2. However, the experiments showed that the reaction of
1 with enamines stops after opening of the tetrazine ring,
affording products 8 without further cyclization (Scheme 8).
Conclusions
Transformations of [1,2,4]triazolo[4,3-b][1,2,4,5]tetra-
zines by action of C nucleophiles have been studied. It has
been established that these reactions are initiated by nucleo-
philic attack at the ring nitrogen atom, which appears to
be a rare phenomenon in heterocyclic chemistry. The ring
opening of the tetrazine ring followed by recyclization pro-
vide new opportunities for construction of [1,2,4]tri-
azolo[1,5-a]pyrimidines and [1,2,4]triazolo[4,3-b][1,2,4,6]-
tetrazepines, as representatives of a new heterocyclic
system.
Experimental Section
General: All reagents were commercially available and used without
further purification. Melting points were determined with a Stuart
melting-point apparatus. NMR spectra were recorded with a
Bruker Avance DRX-400 spectrometer using Me4Si as an internal
standard. Mass spectromeric data were obtained with a Bruker
microTOF-Q II LC-mass spectrometer and a Shimadzu LCMS-
2010 instrument operating in electrospray ionization mode. Ele-
mental analyses were carried out with an automated Perkin–Elmer
PE-2400 microanalyzer.
Scheme 8. Interaction of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines
with enamines.
The structure of compounds 8 was confirmed by X-ray
analysis (Figure 7), thus providing an additional argument
in favor of the suggested mechanism, which involves the
addition of C nucleophiles at the 8-position of the triazolo-
tetrazine system. The LC–MS analysis data showed that
compounds 8 easily undergo hydrolysis into their diamino
derivatives 4.
Synthesis of 1a-i: Compounds 1a–c,e,g–i have been described ear-
lier.[15,20] Compounds 1d,f were synthesized following the reported
procedures.[15]
3-(Cyclopentylthio)-6-(3,5-dimethylpyrazol-1-yl)[1,2,4]triazolo-
[4,3-b][1,2,4,5]tetrazine (1d): Yield: 72%. M.p. 119 °C. 1H NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 1.63–1.77 (m, 6 H, 3 CH2), 2.17
(m, 2 H, CH2), 2.29 (s, 3 H, pyrazole-CH3), 2.59 (s, 3 H, pyrazole-
CH3), 4.17 (m, 1 H, SCH), 6.38 (s, 1 H, pyrazole 4-H) ppm.
C13H16N8S (316.38): calcd. C 49.35, H 5.10, N 35.42; found C
49.47, H 5.22, N 35.32.
3-Amino-6-(benzylthio)[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (1f):
Yield: 73%. M.p. 188–189 °C. 1H NMR (400 MHz, CDCl3, 25 °C):
δ = 4.63 (s, 2 H, SCH2Ph), 5.60 (br. s. 2 H, NH2), 7.26–7.40 (m, 5
H, Ph) ppm. C10H9N7S (259.29): calcd. C 46.32, H 3.50, N 37.81;
found C 46.59, H 3.33, N 38.06.
General Procedure for the Synthesis of 8,9-Dihydro-7H-[1,2,4]-
triazolo[4,3-b][1,2,4,6]tetrazepine Derivatives 2a–j: To a stirred mix-
ture of 1 (1 mmol) and the CH-active compound (1.2 mmol) in
CH3CN (5 mL) was added TEA (1 mmol). The reaction mixture
was stirred at room temperature. Upon completion of the reaction,
as monitored by TLC, a white or pale-yellow precipitate was fil-
tered off and washed with CH3CN.
Diethyl 6-(3,5-Dimethylpyrazol-1-yl)-7H-[1,2,4]triazolo[4,3-b]-
[1,2,4,6]tetrazepine-8,8(9H)-dicarboxylate (2a): Compound 2a was
prepared from 1a and diethyl malonate (reaction time 5 min).
Yield: 207 mg (55 %). M.p. 183–184 °C. 1H NMR (400 MHz,
[D6]DMSO, 25 °C): δ = 1.16 (t, J = 7.1 Hz, 6 H, 2 OCH2CH3),
2.19 (s, 3 H, pyrazole-CH3), 2.49 (s, 3 H, pyrazole-CH3), 4.24 (m,
4 H, 2 OCH2CH3), 6.20 (s, 1 H, pyrazole 4-H), 8.28 (s, 1 H, 3-H),
8.57 (s, 1 H, NH), 8.76 (br. s, 1 H, NH) ppm. MS (ESI): m/z (%)
= 377.2 (100) [M + 1]+. C15H20N8O4 (376.37): calcd. C 47.87, H
5.36, N 29.77; found C 47.83, H 5.37, N 29.79.
Figure 7. The X-ray structure of compound 8c.
According to the X-ray data, all analyzed compounds
with the open tetrazine ring (i.e., 4c, 5c, 6, 8c) have some
general features, despite the variety of substituents. All
structures are characterized with high values for angles be-
tween the planes of the amidine moiety and the triazole
ring. In all compounds the molecular packing is determined
by a strong system of intermolecular hydrogen bonds be-
tween the NH2 groups and the nitrogen atoms of the azole
system (for 4c, 8c), the imino group (for 5c), or the cyano
groups (for 6).
Diethyl 6-(3,5-Dimethylpyrazol-1-yl)-3-(dodecylthio)-7H-[1,2,4]-
triazolo[4,3-b][1,2,4,6]tetrazepine-8,8(9H)-dicarboxylate (2b): Com-
pound 2b was prepared from 1b and diethyl malonate (reaction
time 5 min). Yield: 473 mg (82 %). M.p. 105–106 °C. 1H NMR
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(400 MHz, [D6]DMSO, 25 °C): δ = 0.85 [t, J = 7.0 Hz, 3 H, 192.57 ppm. MS (ESI): m/z (%) = 363.1 (100) [M + 1]+.
(CH2)11CH3], 1.15 (t, J = 7.1 Hz, 6 H, 2 OCH2CH3), 1.23 [m, 16 C17H14N8O2 (362.35): calcd. C 56.35, H 3.89, N 30.92; found C
H, (CH2)8], 1.36 (m, 2 H, CH2), 1.65 (m, 2 H, CH2), 2.20 (s, 3 H,
pyrazole-CH3), 2.56 (s, 3 H, pyrazole-CH3), 3.06 (t, J = 7.3 Hz, 2
H, SCH2), 4.24 (m, 4 H, 2 OCH2CH3), 6.22 (s, 1 H, pyrazole 4-
H), 8.61 (s, 1 H, NH), 8.70 (br. s, 1 H, NH) ppm. MS (ESI): m/z
(%) = 577.3 (100) [M + 1]+. C27H44N8O4S (576.75): calcd. C 56.23,
H 7.69, N 19.43; found C 56.23, H 7.64, N 19.66.
56.27, H 3.67, N 30.89.
6-(3,5-Dimethylpyrazol-1-yl)-3-dodecylthio-8,9-dihydro-7H-[1,2,4]-
triazolo[4,3-b][1,2,4,6]tetrazepine-8-spiro-2Ј-indene-1Ј,3Ј-dione (2h):
Compound 2h was prepared from 1b and indanedione (reaction
time 2 h). Yield: 259 mg (46 %). M.p. 186–187 °C. 1H NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 0.85 [t, J = 7.0 Hz, 3 H,
(CH2)11CH3], 1.24 [m, 16 H, (CH2)8], 1.39 (m, 2 H, CH2), 1.69 (m,
2 H, CH2), 2.15 (s, 3 H, pyrazole-CH3), 2.58 (s, 3 H, pyrazole-
CH3), 3.10 (t, J = 7.3 Hz, 2 H, SCH2), 6.15 (s, 1 H, pyrazole 4-H),
8.02–8.11 (m, 4 H, Ar), 8.72 (br. s, 1 H, NH), 8.91 (s, 1 H, NH)
ppm. MS (ESI): m/z (%) = 563.3 (100) [M + 1]+. C29H38N8O2S
(562.73): calcd. C 61.90, H 6.81, N 19.91; found C 61.51, H 6.53,
N 19.86.
6-(3,5-Dimethylpyrazol-1-yl)-8,8-diacetyl-8,9-dihydro-7H-[1,2,4]tri-
azolo[4,3-b][1,2,4,6]tetrazepine (2c): Compound 2c was prepared
from 1a and 2,4-pentanedione (reaction time 10 min). Yield:
221 mg (70%). M.p. 178–181 °C. 1H NMR (400 MHz, [D6]DMSO,
25 °C): δ = 2.21 (s, 3 H, pyrazole-CH3), 2.33 (s, 6 H, 2 Ac), 2.45
(s, 3 H, pyrazole-CH3), 6.17 (s, 1 H, pyrazole 4-H), 8.24 (s, 1 H, 3-
H), 8.86 (s, 1 H, NH), 9.00 (br. s, 1 H, NH) ppm. MS (ESI): m/z
(%) = 317.2 (100) [M + 1]+ C13H16N8O2 (316.32): calcd. C 49.36,
.
6-(3,5-Dimethylpyrazol-1-yl)-8,9-dihydro-7H-[1,2,4]triazolo[4,3-b]-
[1,2,4,6]tetrazepine-8-spiro-5Ј-pyrimidine-2Ј,4Ј,6Ј(1ЈH,3ЈH,5ЈH)-
trione (2i): Compound 2i was prepared from 1a and barbituric acid
(reaction time 2 h). Yield: 405 mg (91 %). M.p. 211–212 °C (de-
H 5.10, N 35.42; found C 49.37, H 5.08, N 35.31.
Ethyl 6-(3,5-Dimethylpyrazol-1-yl)-8,9-dihydro-7H-[1,2,4]triazolo-
[4,3-b][1,2,4,6]tetrazepine-8-carboxylate (2d): Compound 2d was
prepared from 1a and ethyl acetoacetate (reaction time 24 h). Yield:
180 mg (59%). M.p. 206–207 °C. 1H NMR (400 MHz, [D6]DMSO,
25 °C): δ = 1.08 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.19 (s, 3 H,
pyrazole-CH3), 2.46 (s, 3 H, pyrazole-CH3), 4.08 (m, 2 H,
OCH2CH3), 5.15 (d, J = 6.5 Hz, 1 H, 8-H), 6.14 (s, 1 H, pyrazole
4-H), 8.21 (s, 1 H, 3-H), 8.32 (s, 1 H, NH), 8.83 (d, J = 6.5 Hz, 1 H,
NH) ppm. MS (ESI): m/z (%) = 305.2 (100) [M + 1]+. C12H16N8O2
(304.31): calcd. C 47.36, H 5.30, N 36.82; found C 47.30, H 5.60,
N 36.87.
1
comp.). H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 0.96 [t, J =
7.2 Hz, 9 H, (CH3CH2)3N], 2.18 (s, 3 H, pyrazole-CH3), 2.52 [q, J
= 7.2 Hz, 6 H, (CH3CH2)3N], 2.51 (s, 3 H, pyrazole-CH3), 6.15 (s,
1 H, pyrazole 4-H), 8.33 (s, 1 H, 3-H), 9.22 (br. s, 2 H, 2 NH), 10.5
(br. s, 2 H, 2 NH) ppm. MS (ESI): m/z (%) = 345.1 (100)
[M + 1]+. C12H12N10O3·Et3N (445.48): calcd. C 48.53, H 6.11, N
34.59; found C 48.64, H 6.15, N 34.92.
3-Cyclopentylthio-6-(3,5-dimethylpyrazol-1-yl)-8,9-dihydro-7H-
[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepine-8-spiro-5Ј-pyrimidine-
2Ј,4Ј,6Ј(1ЈH,3ЈH,5ЈH)-trione (2j): Compound 2j was prepared from
1d and barbituric acid (reaction time 2 h). Yield: 406 mg (72%).
Ethyl 3-(Benzylthio)-6-(3,5-dimethylpyrazol-1-yl)-8,9-dihydro-7H-
[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepine-8-carboxylate (2e): Com-
pound 2e was prepared from 1c and ethyl acetoacetate (reaction
time 24 h). Yield: 257 mg (55 %). M.p. 164–166 °C. 1H NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 1.07 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 2.07 (s, 3 H, CH3CN), 2.19 (s, 3 H, pyrazole-CH3),
2.52 (s, 3 H, pyrazole-CH3), 4.09 (m, 2 H, OCH2CH3), 4.32 (s, 2
H, CH2Ph), 5.17 (dd, J = 6.5, 5.5 Hz, 1 H, 8-H), 6.16 (s, 1 H,
pyrazole 4-H), 7.21–7.42 (m, 5 H, Ph), 8.39 (d, J = 5.5 Hz, 1 H,
NH), 8.88 (d, J = 6.5 Hz, 1 H, NH) ppm. MS (ESI): m/z (%) =
1
M.p. 198 °C (decomp.). H NMR (400 MHz, [D6]DMSO, 25 °C):
δ = 1.03 [t, J = 7.1 Hz, 9 H, (CH3CH2)3N], 1.57 (m, 4 H, 2 CH2),
1.70 (m, 2 H, CH2), 2.07 (m, 2 H, CH2), 2.19 (s, 3 H, pyrazole-
CH3), 2.61 (s, 3 H, pyrazole-CH3), 2.70 [q, J = 7.1 Hz, 6 H,
(CH3CH2)3N], 3.79 (m, 1 H, SCH), 6.19 (s, 1 H, pyrazole 4-H),
8.75 (br. s, 1 H, NH), 9.26 (br. s, 1 H, NH), 11.0 (br. s, 2 H,
2 NH) ppm. MS (ESI): m/z (%) = 445.2 (100) [M + 1]+.
C17H20N10O3S·Et3N·H2O (563.68): calcd. C 49.01, H 6.62, N
27.33; found C 49.22, H 6.37, N 27.49.
427.1 (100) [M + H]+ C19H22N8O2S·CH3CN (467.55): calcd. C
.
53.95, H 5.39, N 26.96; found C 53.88, H 5.21, N 26.71.
General Procedure for the Synthesis of [1,2,4]Triazolo[4,3-b]-
[1,2,4,6]tetrazepine Derivatives 2k,l and 3a–c: Compound 2
(0,5 mmol) in acetonitrile or aqueous acetonitrile (3 mL) was
heated at reflux for 10 min to 10 h. After cooling to room tempera-
ture the precipitate formed was filtered off and air dried.
6-(3,5-Dimethylpyrazol-1-yl)-8,9-dihydro-7H-[1,2,4]triazolo[4,3-b]-
[1,2,4,6]tetrazepine-8-spiro-2Ј-(5Ј,5Ј-dimethylcyclohexane-1Ј,3Ј-
dione) (2f): Compound 2f was prepared from 1a and dimedone (re-
action time 2 h). Yield: 200 mg (56%). M.p. 202–204 °C. 1H NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 0.85 (s, 3 H, CH3), 1.15 (s, 3
H, CH3), 2.21 (s, 3 H, pyrazole-CH3), 2.51 (s, 3 H, pyrazole-CH3),
2.69 (d, J = 13.5 Hz, 2 H, 2 HA), 3.23 (d, J = 13.5 Hz, 2 H, 2 HB),
6.19 (s, 1 H, pyrazole 4-H), 8.33 (s, 1 H, 3-H), 8.42 (br. s, 1 H,
NH), 8.51 (s, 1 H, NH) ppm. 13C NMR (400 MHz, [D6]DMSO,
25 °C): δ = 13.36, 14.16, 26.54, 28.91, 30.77, 49.39, 80.36, 110.10,
141.78, 142.14, 143.46, 148.23, 149.38, 198.92 ppm. MS (ESI): m/z
(%) = 357.2 (100) [M + 1]+. C16H20N8O2 (356.38): calcd. C 53.92,
H 5.66, N 31.44; found C 54.01, H 5.32, N 31.49.
1-{6-(3,5-Dimethylpyrazol-1-yl)-8,9-dihydro-7H-[1,2,4]triazolo-
[4,3-b][1,2,4,6]tetrazepine-8-carbonyl}urea (2k): Compound 2k was
prepared from 2i in aqueous acetonitrile (water/CH3CN, 1:10; reac-
tion time 10 min). Yield: 133 mg (79 %). M.p. 199–200 °C. 1H
NMR (400 MHz, [D6]DMSO, 25 °C): δ = 2.19 (s, 3 H, pyrazole-
CH3), 2.46 (s, 3 H, pyrazole-CH3), 5.21 (br. s, 1 H, 8-H), 6.14 (s, 1
H, pyrazole 4-H), 7.36 (br. s, 2 H, NH2), 7.98 (s, 1 H, CONHCO),
8.22 (s, 1 H, 3-H), 8.69 (d, J = 6.1 Hz, 1 H, NH), 10.36 (br. s, 1 H,
NH) ppm. MS (ESI): m/z (%) = 319.3 (100) [M + 1]+
.
6-(3,5-Dimethylpyrazol-1-yl)-8,9-dihydro-7H-[1,2,4]triazolo[4,3-b]-
[1,2,4,6]tetrazepine-8-spiro-2Ј-indene-1Ј,3Ј-dione(2g): Compound 2g
was prepared from 1a and indanedione (reaction time 2 h). Yield:
138 mg (38%). M.p. 229–230 °C. 1H NMR (400 MHz, [D6]DMSO,
25 °C): δ = 2.14 (s, 3 H, pyrazole-CH3), 2.48 (s, 3 H, pyrazole-
CH3), 6.12 (s, 1 H, pyrazole 4-H), 8.06 (m, 4 H, Ar), 8.44 (s, 1 H,
C11H14N10O2·H2O (336.31): calcd. C 39.28, H 4.80, N 41.65; found
C 39.66, H 4.60, N 41.68.
1-{3-Cyclopentylthio-6-(3,5-dimethylpyrazol-1-yl)-8,9-dihydro-7H-
[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepine-8-carbonyl}urea (2l): Com-
pound 2l was prepared from 2j in aqueous acetonitrile (water/
3-H), 8.75 (br. s, 1 H, NH), 8.92 (s, 1 H, NH) ppm. 13C NMR CH3CN, 1:10; reaction time 10 min). Yield: 171 mg (80%). M.p.
(400 MHz, [D6]DMSO, 25 °C): δ = 13.24, 13.69, 68.36, 109.17,
124.17, 137.05, 139.42, 141.12, 141.62, 142.80, 148.75, 149.97, 4 H, 2 CH2), 1.69 (m, 2 H, CH2), 2.07 (m, 2 H, CH2), 2.19 (s, 3
181–183 °C. 1H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 1.57 (m,
2314
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2309–2318

Unusual Expansion of the Tetrazine Ring in Triazolotetrazines
H, pyrazole-CH3), 2.55 (s, 3 H, pyrazole-CH3), 3.78 (m, 1 H, CH), (t, J = 7.3 Hz, 3 H, OCH2CH3), 1.36 (m, 2 H, CH2), 1.68 (m, 2 H,
5.22 (br. s, 1 H, 8-H), 6.16 (s, 1 H, pyrazole 4-H), 7.36 (br. s, 2 H,
CH2), 2.18 (s, 3 H, pyrazole-CH3), 2.46 (s, 3 H, pyrazole-CH3), 3.11
NH2), 8.01 (s, 1 H, CONHCO), 8.73 (d, J = 6.1 Hz, 1 H, NH), (m, 2 H, SCH2), 4.31 (m, 2 H, OCH2CH3), 6.26 (s, 1 H, pyrazole 4-
10.37 (br. s, 1 H, NH) ppm. MS (ESI): m/z (%) = 419.1 (100) [M H), 10.06 (s, 1 H, NH) ppm. MS (ESI): m/z (%) = 503.3 (100) [M
+ 1]+. C16H22N10O2S·0.5H2O (427.48): calcd. C 44.95, H 5.42, N
32.77; found C 44.88, H 5.48, N 32.59.
+ 1]+. C24H38N8O2S (502.68): calcd. C 57.34, H 7.62, N 22.29;
found C 56.99, H 7.62, N 22.09.
Ethyl 6-(4-Bromo-3,5-dimethylpyrazol-1-yl)-7H-[1,2,4]triazolo[4,3-
b][1,2,4,6]tetrazepin-8-carboxylate (3f): Yield: 191 mg (50%). M.p.
218–220 °C. H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 1.33 (t,
J = 7.1 Hz, 3 H, OCH2CH3), 2.23 (s, 3 H, pyrazole-CH3), 2.51 (s,
3 H, pyrazole-CH3), 4.34 (q, J = 7.1 Hz, 2 H, OCH2CH3), 8.43 (s,
1 H, 3-H), 9.96 (s, 1 H, NH) ppm. MS (ESI): m/z (%) = 381.0 (100)
[M]+. C12H13BrN8O2 (381.19): calcd. C 37.81, H 3.44, N 29.40;
found C 37.74, H 3.48, N 29.53.
1-{3-Cyclopentylthio-6-(3,5-dimethylpyrazol-1-yl)-7H-[1,2,4]-
triazolo[4,3-b][1,2,4,6]tetrazepine-8-carbonyl}urea (3a): Compound
3a was prepared from 2j in acetonitrile (reaction time 5 h). Yield:
73 mg (35 %). M.p. 232 °C. 1H NMR (400 MHz, [D6]DMSO,
25 °C): δ = 1.61 (m, 4 H, 2 CH2), 1.71 (m, 2 H, CH2), 2.18 (m, 2
H, CH2), 2.20 (s, 3 H, pyrazole-CH3), 2.49 (s, 3 H, pyrazole-CH3),
3.91 (m, 1 H, SCH), 6.30 (s, 1 H, pyrazole 4-H), 7.39 (s, 2 H, NH2),
9.81 (s, 1 H, NH), 10.24 (s, 1 H, NH) ppm. MS (ESI): m/z (%) =
417.2 (100) [M + 1]+. C16H20N10O2S (416.46): calcd. C 46.14, H
4.84, N 33.63; found C 46.28, H 4.80, N 33.61.
1
NЈ-(3-Amino-4H-1,2,4-triazol-4-yl)-3,5-dimethylpyrazol-1-carbox-
amidine (4a): Yield: 66 mg (30 %). M.p. 230–231 °C. 1H NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 2.18 (s, 3 H, pyrazole-CH3),
2.52 (s, 3 H, pyrazole-CH3), 5.55 (s, 2 H, NH2), 6.14 (s, 1 H, pyr-
azole 4-H), 7.30 (s, 2 H, NH2), 7.87 (s, 1 H, triazole 5-H) ppm. MS
(ESI): m/z (%) = 221.1 (100) [M + 1]+. C8H12N8 (220.23): calcd. C
43.63, H 5.49, N 50.88; found C 43.66, H 5.82, N 50.71.
5-{6-(3,5-Dimethylpyrazol-1-yl)-7H-[1,2,4]triazolo[4,3-b][1,2,4,6]-
tetrazepin-8-yl}-3,3-dimethyl-5-oxopentanoic Acid (3b): Compound
3b was prepared from 2f in acetonitrile (reaction time 10 h). Yield:
1
91 mg (49%). M.p. 218–220 °C. H NMR (400 MHz, [D6]DMSO,
25 °C): δ = 1.10 (s, 6 H, 2 CH3), 2.22 (s, 3 H, pyrazole-CH3), 2.34
(s, 2 H, CH2), 2.49 (s, 3 H, pyrazole-CH3), 3.10 (s, 2 H, CH2), 6.29
(s, 1 H, pyrazole 4-H), 8.41 (s, 1 H, 3-H), 10.03 (s, 1 H, NH), 12.10
(s, 1 H, COOH) ppm. MS (ESI): m/z (%) = 373.2 (100) [M + 1]+.
C16H20N8O3 (372.38): calcd. C 51.61, H 5.41, N 30.09; found C
51.47, H 5.52, N 29.94.
NЈ-(3-Amino-5-dodecylthio-4H-1,2,4-triazol-4-yl)-3,5-dimethylpyr-
azol-1-carboxamidine (4b): Yield: 105 mg (25%). M.p. 137–139 °C.
1H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 0.85 [t, J = 7.1 Hz,
3 H, (CH2)11CH3], 1.22 [m, 16 H, (CH2)8], 1.28 (m, 2 H, CH2),
1.55 (m, 2 H, CH2), 2.18 (s, 3 H, pyrazole-CH3), 2.54 (s, 3 H,
pyrazole-CH3), 2.84 (t, J = 7.1 Hz, 2 H, SCH2), 5.65 (s, 2 H, NH2),
6.14 (s, 1 H, pyrazole 4-H), 7.36 (s, 2 H, NH2) ppm. MS (ESI): m/z
(%) = 421.3 (100) [M + 1]+. C20H36N8S (420.62): calcd. C 57.11,
H 8.63, N 26.64; found C 57.14, H 8.75, N 26.42.
8-Acetyl-6-(3,5-dimethylpyrazol-1-yl)-7H-[1,2,4]triazolo[4,3-b]-
[1,2,4,6]tetrazepine (3c): Compound 3c was prepared from 2c in
aqueous acetonitrile (water/CH3CN,1:10; reaction time 5 h). Yield:
88 mg (65%). M.p. 220 °C (decomp.). 1H NMR (400 MHz, [D6]-
DMSO, 25 °C): δ = 2.21 (s, 3 H, pyrazole-CH3), 2.47 (s, 3 H, Ac),
2.49 (s, 3 H, pyrazole-CH3), 6.29 (s, 1 H, pyrazole 4-H), 8.42 (s, 1
H, 3-H), 9.97 (s, 1 H, NH) ppm. MS (ESI): m/z (%) = 273.1 (20)
[M + 1]+. C11H12N8O (272.27): calcd. C 48.53, H 4.44, N 41.16;
found C 48.55, H 4.39, N 41.04.
NЈ-(3-Amino-4H-1,2,4-triazol-4-yl)-4-bromo-3,5-dimethylpyrazol-
1
1-carboxamidine (4c): Yield: 60 mg (20%). M.p. 236–237 °C. H
NMR (400 MHz, [D6]DMSO, 25 °C): δ = 2.22 (s, 3 H, pyrazole-
CH3), 2.54 (s, 3 H, pyrazole-CH3), 5.60 (s, 2 H, NH2), 7.51 (s, 2
H, NH2), 7.89 (s, 1 H, triazole 5-H) ppm. MS (ESI): m/z (%) =
299.0 (100) [M]+. C8H11BrN8 (299.13): calcd. C 32.12, H 3.71, N
37.46; found C 32.26, H 3.48, N 37.07.
General Procedure for the Synthesis of 7H-[1,2,4]Triazolo-
[4,3-b][1,2,4,6]tetrazepine Derivatives 3d–f and NЈ-(3-Amino-4H-
1,2,4-triazol-4-yl)-3,5-dimethylpyrazole-1-carboxamidine Derivatives
4a–c: To a stirred mixture of 1 (1 mmol) and ethyl cyanoacetate
(1.2 mmol) in CH3CN (5 mL) was added TEA (1 mmol). The reac-
tion mixture was stirred at room temperature for 20 min.
General Procedure for the Synthesis of [1,2,4]triazolo[1,5-a]pyrimid-
ine Derivatives 5a–d and 6: To a stirred mixture of 1 (1 mmol) and
malononitrile (2 mmol) in CH3CN (5 mL) was added TEA
(1 mmol). The reaction mixture was stirred at room temperature.
Upon completion of the reaction, which was monitored by TLC, a
white precipitate was filtered off and recrystallized from CH3CN.
Reactions of 1a,e with Ethyl Cyanoacetate: Compounds 4a,c were
obtained as white solid precipitates, which were filtered off and air
dried. Filtrates were evaporated and yellow residues were recrys-
tallized from EtOAc or MeCN to give 3d and 3f, respectively.
NЈ-{5,6-Dicyano-7-imino[1,2,4]triazolo[1,5-a]pyrimidin-3(7H)-yl}-
3,5-dimethylpyrazol-1-carboxamidine (5a): Compound 5a was pre-
pared from 1a (reaction time 20 min). Yield: 135 mg (42%). M.p.
Reaction of 1b with Ethyl Cyanoacetate: The yellow precipitate of
3e was filtered off and air dried. The filtrate was stayed for 8 h,
and a white precipitate of 4b was filtered off.
1
Ͼ350 °C. H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 2.22 (s, 3
H, pyrazole-CH3), 2.54 (s, 3 H, pyrazole-CH3), 6.24 (s, 1 H, pyr-
azole 4-H), 7.98 (br. s, 2 H, NH2), 8.16 (s, 1 H, triazole CH), 9.24
(s, 1 H, NH) ppm. MS (ESI): m/z (%) = 322.1 (100) [M + 1]+.
C13H11N11 (321.30): calcd. C 48.60, H 3.45, N 47.95; found C
48.70, H 3.29, N 47.88.
Ethyl 6-(3,5-Dimethylpyrazol-1-yl)-7H-[1,2,4]triazolo[4,3-b]-
[1,2,4,6]tetrazepin-8-carboxylate (3d): Yield: 91 mg (30 %). M.p.
1
207–209 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.43 (t, J =
7.1 Hz, 3 H, OCH2CH3), 2.26 (s, 3 H, pyrazole-CH3), 2.52 (s, 3 H,
pyrazole-CH3), 4.44 (q, J = 7.1 Hz, 2 H, OCH2CH3), 6.07 (s, 1 H,
pyrazole 4-H), 7.83 (s, 1 H, 3-H), 10.46 (s, 1 H, NH) ppm. MS
(ESI): m/z (%) = 303.1 (100) [M + 1]+. C12H14N8O2 (302.29): calcd.
C 47.68, H 4.67, N 37.07; found C 47.78, H 4.91, N 36.73.
NЈ-{5,6-Dicyano-2-(dodecylthio)-7-imino-[1,2,4]triazolo[1,5-a]-
pyrimidin-3(7H)-yl}-3,5-dimethylpyrazol-1-carboxamidine (5b):
Compound 5b was prepared from 1b (reaction time 30 min) and
purified by column chromatography (MeCN/benzene, 1:1; Rf =
1
0.8). Yield: 167 mg (32%). M.p. 165–166 °C. H NMR (400 MHz,
Ethyl 6-(3,5-Dimethylpyrazol-1-yl)-3-dodecylthio-7H-[1,2,4]triazolo- CDCl3, 25 °C): δ = 0.87 [t, J = 7.1 Hz, 3 H, (CH2)11CH3], 1.25 [m,
[4,3-b][1,2,4,6]tetrazepin-8-carboxylate (3e): Yield: 126 mg (25%). 16 H, (CH2)8], 1.47 (m, 2 H, CH2), 1.85 (m, 2 H, CH2), 2.25 (s, 3
1
M.p. 131–132 °C. H NMR (400 MHz, [D6]DMSO, 25 °C): δ = H, pyrazole-CH3), 2.62 (s, 3 H, pyrazole-CH3), 3.46 (t, J = 6.8 Hz,
0.85 [t, J = 7.2 Hz, 3 H, (CH2)11CH3], 1.24 [m, 16 H, (CH2)8], 1.31 2 H, SCH2), 6.05 (s, 1 H, pyrazole 4-H), 7.63 (br. s, 3 H, NH,
Eur. J. Org. Chem. 2011, 2309–2318
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2315

G. L. Rusinov et al.
NH2) ppm. MS (ESI): m/z (%) = 522.3 (100) [M + 1]+. C25H35N11S solution of 1 (1 mmol) in CH3CN (5 mL) was added the corre-
FULL PAPER
(521.68): calcd. C 57.56, H 6.76, N 29.53; found C 57.76, H 6.72,
N 29.57.
sponding enamine (1.1 mmol). The reaction mixture was stirred at
room temperature for 20–30 min. Upon completion of the reaction,
as monitored by TLC, a white or pale-yellow precipitate was fil-
tered off, washed with CH3CN, and air dried.
NЈ-{2-(Benzylthio)-5,6-dicyano-7-imino-[1,2,4]triazolo[1,5-a]-
pyrimidin-3(7H)-yl}-3,5-dimethylpyrazol-1-carboxamidine (5c):
Compound 5c was prepared from 1c (reaction time 30 min). Yield:
151 mg (34%). M.p. 197–200 °C. 1H NMR (400 MHz, [D6]DMSO,
25 °C): δ = 2.21 (s, 3 H, pyrazole-CH3), 2.52 (s, 3 H, pyrazole-
CH3), 4.58 (s, 2 H, SCH2), 6.24 (s, 1 H, pyrazole 4-H), 7.26–7.37
(m, 3 H, Ph), 7.56 (m, 2 H, Ph), 8.05 (s, 1 H, NH), 7.96–8.21 (br.
s, 2 H, NH2) ppm. MS (ESI): m/z (%) = 444.2 (100) [M + 1]+.
C20H17N11S (443.49): calcd. C 54.16, H 3.86, N 34.74; found C
54.18, H 3.96, N 34.60.
NЈ-[3-(Benzylthio)-5-(2-piperidinocyclopent-2-enylideneamino)-4H-
1,2,4-triazol-4-yl]-3,5-dimethylpyrazol-1-carboxamidine (8a): Com-
pound 8a was prepared from 1c and 1-piperidinocyclopentene.
Yield: 323 mg (66 %). M.p. 148–150 °C. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.47 (m, 6 H, 3 CH2), 2.22 (s, 3 H, pyrazole-
CH3), 2.52 (m, 2 H, CH2), 2.62 (s, 3 H, pyrazole-CH3), 3.06 (m, 6
H, 3 CH2), 4.42 (s, 2 H, SCH2), 5.97 (s, 1 H, pyrazole 4-H), 6.14
(t, J = 3.0 Hz, 1 H, C=CH), 6.76 (s, 2 H, NH2), 7.19–7.30 (m, 3 H,
Ph), 7.38 (m, 2 H, Ph) ppm. 13C NMR (400 MHz, CDCl3, 25 °C): δ
= 13.51, 15.52, 24.46, 25.41, 27.03, 33.64, 35.82, 50.61, 110.53,
127.42, 128.51, 129.05, 129.18, 131.13, 136.84, 143.38, 148.19,
150.18, 152.94, 154.83, 155.13, 180.67 ppm. MS (ESI): m/z (%) =
490.1 (100) [M + 1]+. C25H31N9S (489.64): calcd. C 61.32, H 6.38,
N 25.75; found C 60.99, H 6.22, N 25.66.
2-{2-(Benzylthio)-5,6-dicyano-7-imino[1,2,4]triazolo[1,5-a]pyrimidin-
3(7H)-yl}guanidine (5d): Compound 5d was prepared from 1f (reac-
tion time 24 h). Yield: 120 mg (33%). M.p. Ͼ350 °C. 1H NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 4.51 (s, 2 H, SCH2), 6.03 (s, 2
H, NH2), 6.18 (s, 2 H, NH2), 7.26–7.38 (m, 3 H, Ph), 7.54 (m, 2
H, Ph), 7.88 (s, 1 H, NH) ppm. MS (ESI): m/z (%) = 365.1 (100)
[M + 1]+. C15H12N10S (364.39): calcd. C 49.44, H 3.32, N 38.44;
found C 49.15, H 3.06, N 37.99.
NЈ-[3-(2-Morpholinocyclopent-2-enylideneamino)-4H-1,2,4-triazol-
4-yl]-4-bromo-3,5-dimethylpyrazol-1-carboxamidine (8b): Com-
pound 8b was prepared from 1e and 1-morpholinocyclopentene.
Yield: 399 mg (89%). M.p. 180 °C (decomp.). 1H NMR (400 MHz,
[D6]DMSO, 25 °C): δ = 2.22 (s, 3 H, pyrazole-CH3), 2.53 (s, 3 H,
pyrazole-CH3), 2.55 (m, 2 H, CH2), 3.04 (m, 6 H, 3 CH2), 3.44 (m,
4 H, 2 CH2), 6.20 (t, J = 3.0 Hz, 1 H, C=CH), 7.61 (s, 2 H, NH2),
8.41 (s, 1 H, triazole 5-H) ppm. 13C NMR (400 MHz, [D6]DMSO,
25 °C): δ = 12.23, 13.44, 26.24, 33.16, 49.01, 65.71, 98.52, 129.90,
139.83, 140.51, 147.98, 151.11, 152.62, 155.28, 178.58 ppm. MS
(ESI): m/z (%) = 448.1 (100) [M + 1]+. C17H22BrN9O (448.32):
calcd. C 45.54, H 4.95, N 28.12; found C 45.81, H 4.76, N 28.07.
NЈ-{7-Amino-6-cyano-5-(dicyanomethylene)-2-(dodecylthio)[1,2,4]-
triazolo[1,5-a]pyrimidin-3(5H)-yl}-3,5-dimethylpyrazole-1-carbox-
amidine (6): Compound 6 was prepared from 1b (reaction time
30 min) and purified by column chromatography (MeCN/benzene,
1:1; Rf = 0.2). Yield: 151 mg (27%). M.p. 232–235 °C. 1H NMR
(400 MHz, CDCl3 , 25 °C): δ = 0.85 [t, J = 7.0 Hz, 3 H,
(CH2)11CH3], 1.23 [m, 16 H, (CH2)8], 1.39 (m, 2 H, CH2), 1.75 (m,
2 H, CH2), 2.22 (s, 3 H, pyrazole-CH3), 2.54 (s, 3 H, pyrazole-
CH3), 3.26 (t, J = 7.2 Hz, 2 H, SCH2), 6.22 (s, 1 H, pyrazole 4-H),
8.04 (br. s, 2 H, NH2), 8.94 (s, 2 H, NH2) ppm. MS (ESI): m/z (%)
= 561.3 (100) [M + 1]+. C27H36N12S (560.72): calcd. C 57.83, H
6.47, N 29.98; found C 57.71, H 6.35, N 29.59.
NЈ-[3-(2-Morpholinocyclopent-2-enylideneamino)-5-phenyl-4H-
1,2,4-triazol-4-yl]-3,5-dimethylpyrazole-1-carboxamidine (8c): Com-
General Procedure for the Synthesis of 7H,7ЈH-8,8Ј-Bis[1,2,4]tri- pound 8c was prepared from 1h and 1-morpholinocyclopentene.
azolo[4,3-b][1,2,4,6]tetrazepine Derivatives 7a–d: Compound 1
Yield: 370 mg (76 %). M.p. 174–176 °C. 1H NMR (400 MHz,
(1 mmol) and TEA (1 mmol) in acetonitrile (5 mL) were heated at [D6]DMSO, 25 °C): δ = 2.07 (s, 3 H, CH3CN), 2.20 (s, 3 H, pyr-
reflux for 1 h. After cooling to room temperature a dark-yellow
precipitate was filtered off, washed with CH3CN, and air dried.
azole-CH3), 2.48 (s, 3 H, pyrazole-CH3), 2.54 (m, 2 H, CH2), 3.08
(m, 6 H, 3 CH2), 3.39 (m, 4 H, 2 CH2), 6.18 (s, 1 H, pyrazole 4-
H), 6.20 (t, J = 3.0 Hz, 1 H, C=CH), 7.41–7.51 (m, 3 H, Ph), 7.61
(s, 2 H, NH2), 7.88 (m, 2 H, Ph) ppm. 13C NMR (400 MHz,
[D6]DMSO, 25 °C): δ = 13.32, 14.55, 26.36, 33.40, 49.01, 65.70,
109.90, 126.63, 127.80, 128.37, 128.53, 129.23, 129.73, 142.37,
148.75, 149.49, 151.23, 153.85, 155.86, 178.20 ppm. MS (ESI): m/z
(%) = 446.2. (100) [M + 1]+. C23H27N9O·CH3CN (486.57): calcd.
C 61.71, H 6.21, N 28.79; found C 61.52, H 6.14, N 28.50.
6,6Ј-Bis(3,5-Dimethylpyrazol-1-yl)-7H,7ЈH-8,8Ј-bis[1,2,4]triazolo-
[4,3-b][1,2,4,6]tetrazepine (7a): Compound 7a was prepared from
1a. Yield: 76 mg (33%) [92 mg (40%) in DMF]. M.p. Ͼ350 °C. MS
(ESI): m/z (%) = 459.2 (100) [M + 1]+. C18H18N16 (458.44): calcd.
C 47.16, H 3.96, N 48.88; found C 47.08, H 3.98, N 48.76.
6,6Ј-Bis(3,5-Dimethylpyrazol-1-yl)-3,3Ј-bis(benzylthio)-7H,7ЈH-
8,8Ј-bis[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepine (7b): Compound 7b
was prepared from 1c. Yield: 88 mg (25%). M.p. 302–303 °C. MS
(ESI): m/z (%) = 703.3 (100) [M + 1]+. C32H30N16S2 (702.82): calcd.
C 54.69, H 4.30, N 31.89; found C 54.70, H 4.29, N 31.60.
NЈ-[3-Ethylthio-5-(2-piperidinocyclopent-2-enylideneamino)-4H-
1,2,4-triazol-4-yl]-3,5-dimethylpyrazol-1-carboxamidine (8d): Com-
pound 8d was prepared from 1i and 1-piperidinocyclopentene.
Yield: 321 mg (75 %). M.p. 180–182 °C. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.40 (t, J = 7.3 Hz, 3 H, SCH2CH3), 1.48 (m,
6 H, 3 CH2), 2.23 (s, 3 H, pyrazole-CH3), 2.52 (m, 2 H, CH2), 2.66
(s, 3 H, pyrazole-CH3), 3.07 (m, 6 H, 3 CH2), 3.19 (q, J = 7.3 Hz,
2 H, SCH2CH3), 5.99 (s, 1 H, pyrazole 4-H), 6.12 (t, J = 3.0 Hz, 1
H, C=CH), 6.81 (s, 2 H, NH2) ppm. 13C NMR (400 MHz, CDCl3,
25 °C): δ = 13.51, 14.75, 15.47, 24.48, 25.42, 25.74, 27.03, 33.63,
50.60, 110.50, 130.97, 143.38, 148.46, 150.16, 152.94, 154.73,
155.10, 180.51 ppm. MS (ESI): m/z (%) = 428.1 (100) [M + 1]+.
C20H29N9S (427.57): calcd. C 56.18, H 6.84, N 29.48; found C
56.29, H 6.84, N 29.35.
6,6Ј-Bis(3,5-Dimethylpyrazol-1-yl)-3,3Ј-bis(methylthio)-7H,7ЈH-
8,8Ј-bis[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepine (7c): Compound 7c
was prepared from 1g. Yield: 105 mg (38%). M.p. Ͼ350 °C. MS
(ESI): m/z (%) = 551.2 (100) [M + 1]+. C20H22N16S2 (550.63): calcd.
C 43.63, H 4.03, N 40.70; found C 43.61, H 4.08, N 41.03.
6,6Ј-Bis(3,5-dimethylpyrazol-1-yl)-3,3Ј-diphenyl-7H,7ЈH-8,8Ј-bis-
[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepine (7d): Compound 7d was
prepared from 1h. Yield: 67 mg (22%). M.p. 358–360 °C. MS (ESI):
m/z (%) = 611.26 (100) [M + 1]+. C30H26N16 (610.63): calcd. C
59.01, H 4.29, N 36.70; found C 58.73, H 4.11, N 36.39.
General Procedure for the Synthesis of NЈ-(4H-1,2,4-triazol-4-yl)-
3,5-dimethylpyrazol-1-carboxamidine Derivatives 8a–d: To a stirred
X-ray Structure Data Collection and Refinement: Single crystals
suitable for X-ray analysis were obtained by slow evaporation from
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2309–2318

Unusual Expansion of the Tetrazine Ring in Triazolotetrazines
Table 1. X-ray crystallography data for 7H-[1,2,4]triazolo[4,3-b][1,2,4,6]tetrazepine derivatives 2a, 2d–f, 3b, and 7a.
2a
2d
2e
2f
3b
7a
Crystal size [mm]
Crystal color
Empirical formula
Temperature [K]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
α [°]
β [°]
0.52ϫ0.47ϫ0.35 0.49ϫ0.35ϫ0.27 0.22ϫ0.14ϫ0.08 0.37ϫ0.23ϫ0.15 0.48ϫ0.23ϫ0.05 0.41ϫ0.34ϫ0.12
colorless
C15H20N8O4
295(2)
colorless
C12H16N8O2
295(2)
colorless
C21H25N9O2S
295(2)
colorless
C16H20N8O2
295(2)
yellow
C19H27N9O4
295(2)
orange
C24H32N18O2
135(2)
triclinic
P1
monoclinic
P21/c
triclinic
P1
monoclinic
P21/n
triclinic
P1
triclinic
P1
¯
¯
¯
¯
9.530(2)
11.0427(18)
14.5205(18)
9.9544(11)
90
111.618(13)
90
8.7474(12)
11.3138(15)
12.8395(19)
111.530(13)
101.637(12)
97.241(11)
1129.5(3), 2
0.182
7.0613(16)
13.2039(19)
18.885(2)
90
97.897(14)
90
7.1382(7)
11.0063(17)
14.5308(19)
94.685(12)
99.666(10)
93.060(10)
1119.0(3), 2
0.097
8.2080(15)
9.7675(19)
10.701(2)
65.970(19)
88.906(15)
68.323(18)
719.4(2), 1
0.099
10.4179(12)
10.5811(13)
101.539(10)
113.864(15)
102.047(14)
890.8(2), 2
0.106
γ [°]
Volume, Z
1483.9(3), 4
0.100
1744.1(5), 4
0.096
μ [mm–1]
Reflections collected
8028
10299
5235
8205
6513
5544
Independent reflections (Rint
S
)
5147 (0.0233)
1.006
4419 (0.0319)
1.000
4491 (0.0359)
1.000
3539 (0.0431)
1.010
4451 (0.0314)
1.002
3440 (0.0329)
1.004
R1 [IϾ2σ(I)]
0.0467
0.0459
0.0439
0.0382
0.0422
0.0394
wR2 [IϾ2σ(I)]
0.0955
0.0892
0.0885
0.0579
0.0655
0.0607
R1 (all data)
0.1020
0.1309
0.0858
0.1028
0.1196
0.0948
wR2 (all data)
0.1037
0.352, –0.229
97.7 (26.00)
0.0968
0.184, –0.257
97.6 (30.51)
0.0924
0.373, –0.207
97.4 (26.37)
0.0613
0.178, –0.135
99.4 (26.37)
0.0723
0.200, –0.118
97.6 (26.37)
0.0633
0.198, –0.206
96.8 (28.28)
Larg. diff. peak, hole [eÅ–3]
Completeness [%] to θ (°)
Table 2. X-ray crystallography data for the tetrazine ring opening products 4c, 5c, 6, and 8c.
4c
5c
6
8c
Crystal size [mm]
Crystal color
Empirical formula
Temperature [K]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
α [°]
β [°]
0.18ϫ0.09ϫ0.03
colorless
C8H11BrN8
295(2)
0.43ϫ0.34ϫ0.21
colorless
C22H20N12S
130(2)
monoclinic
P21/c
15.8451(16)
6.2850(6)
24.365(3)
90
94.563(9)
90
0.44ϫ0.36ϫ0.09
light brown
C27H38N12OS
295(2)
monoclinic
C2/c
46.648(9)
12.5144(5)
10.788(2)
90
98.882(2)
90
0.48ϫ0.33ϫ0.21
light brown
C25H30N10O
295(2)
triclinic
triclinic
¯
¯
P1
P1
7.2903(8)
10.2961(12)
15.881(4)
99.696(14)
95.313(14)
90.457(9)
1169.7(3), 4
3.507
8.4222(8)
9.906(2)
15.4653(15)
78.927(13)
86.020(8)
82.042(12)
1252.8(3), 2
0.085
γ [°]
Volume, Z
2418.7(4), 4
0.171
6222.2(17), 8
0.146
μ [mm–1]
Reflections collected
Independent reflections (Rint
S
R1 [IϾ2σ(I)]
wR2 [IϾ2σ(I)]
R1 (all data)
wR2 (all data)
Larg. diff. peak, hole [eÅ–3]
Completeness [%] to θ (°)
8435
4716 (0.0341)
1.012
0.0438
0.0832
0.1026
0.0890
0.535, –0.573
98.7 (26.37)
8708
4824(0.0368)
0.998
0.0418
0.0648
0.0972
0.0682
0.273, –0.281
97.6 (26.37)
13588
6318(0.0409)
1.003
0.0366
0.0518
0.0989
0.0543
0.205, –0.228
98.9 (26.38)
10824
5986 (0.0314)
1.000
0.0418
0.0758
0.1178
0.0794
0.192, –0.177
97.1 (26.00)
)
MeCN (for compounds 2a, 2d–f, 4c, 5c, 6, 8c) or from DMF (for
compounds 3b, 7a). X-ray intensity data were collected with a Xcal-
ibur CCD diffractometer using Mo-Kα (λ = 0.71069 Å) radiation.
Crystal data and data collection parameters are summarized in
Tables 1 and 2. The unit cell parameters were refined using all col-
lected spots after the integration process. With exception of 4c, the
data were not corrected for absorption, but the data collection
mode partially take into account the absorption phenomena (see
the total number of collected reflections vs. the independent
number of reflections in Tables 1 and 2). For 4c the analytical ab-
sorption data correction was used.[21] The structures were solved
by direct methods with SHELX97.[22] All structures were refined
by full-matrix least-squares on F2 using SHELX97.[22] All non-hy-
drogen atoms were refined with anisotropic temperature factors.
The hydrogen atoms of NH-group were localized by Fourier-differ-
ence synthesis, while other H atoms were calculated with AFIX.
The H atoms were included in the refinement with an isotropic
temperature factor.
CCDC-807605 (for 2a), -807604 (for 2d), -807606 (for 2e), -807609
(for 2f), -807610 (for 3b), -807607 (for 4c), -807602 (for 5c), -807614
(for 6), -807613 (for 7a), and -807603 (for 8c) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Eur. J. Org. Chem. 2011, 2309–2318
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2317

G. L. Rusinov et al.
FULL PAPER
[8] G. L. Rusinov, R. I. Ishmetova, I. N. Ganebnykh, O. N. Chu-
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[10] N. Leconte, A. Keromnes-Wuillaume, F. Suzenet, G. Guil-
laumet, Synlett 2007, 2, 204–210.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed information concerning crystal structures of com-
pounds 2a, 2d–f, 3b, 4c, 5c, 6, 7a, and 8c provided by X-ray analy-
sis.
[11] Z. Novak, A. Kotschy, Org. Lett. 2003, 5, 3495–3497.
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Acknowledgments
The work was financially supported by the Russian Academy of
Sciences (grants 09-I-3-2004, 09-P-3-2001, 09-T-3-1016), the Rus-
sian Foundation for Basic Research (grant 11-03-00545-a), the
State Contract (02.740.11.0260), and the State Program for Sup-
porting of Leading Scientific Schools of Russian Federation (grant
NSh-65261.2010.3)
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Received: November 25, 2010
Published Online: March 2, 2011
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2309–2318