Synthesis of 3,6-divinyl-1,2,4,5-tetrazine, the first member of the elusive vinyltetrazine family

Article abstract of DOI:10.1055/s-0028-1087818

The synthesis of the first vinyltetrazine derivative is described. 3,6-Divinyl-1,2,4,5-tetrazine was obtained following a methodology involving cyclization from an imidate and use of 2-phenylsulfonylethyl groups as masked vinyl entities. The first propert

Full text of DOI:10.1055/s-0028-1087818

LETTER
731
Synthesis of 3,6-Divinyl-1,2,4,5-Tetrazine, the First Member of the Elusive
Vinyltetrazine Family
Synthesis of
3
t
é
nyl-1,2,4,5-
p
Tetrazine hanie Pican,a Vincent Lapinte,a,c Jean-François Pilard,*a Eric Pasquinet,b Lionel Beller,b Laurent Fontaine,a
Didier Poullainb
a
UCO2M – Chimie des Polymères, UMR6011 CNRS, Université du Maine, Avenue O. Messiaen, 72085 Le Mans Cedex 09, France
Fax +33(0)24833754; E-mail: jean-francois.pilard@univ-lemans.fr
b
c
CEA, DAM, LE RIPAULT, 37260 Monts, France
Institut Charles Gerhardt Montpellier, UMR5253 CNRS, IAM, Université Montpellier II, Place E. Bataillon, 34095 Montpellier
Cedex 5, France
Received 17 November 2008
dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate11 was at-
tempted without success.12 The second investigated path-
way was based on a modified Stille coupling procedure13
from 3,6-bis(methylsulfanyl)-1,2,4,5-tetrazine,14 but this
attempt was also unsuccessful.
Abstract: The synthesis of the first vinyltetrazine derivative is
described. 3,6-Divinyl-1,2,4,5-tetrazine was obtained following a
methodology involving cyclization from an imidate and use of 2-
phenylsulfonylethyl groups as masked vinyl entities. The first prop-
erties of this unique compound are reported.
Key words: azo compounds, condensation, cyclizations, fused ring
systems, heterocycles
These failures led us to build the tetrazine ring rather than
start from a tetrazine compound. For this purpose, acrylo-
nitrile was first tested as a precursor since several conju-
gated nitriles were reported to undergo cyclization to di-
hydrotetrazines in the presence of hydrazine, Cu(NO3)2,
and zinc dust.15 The cyclized product was obtained in only
minor amount, standard Michael addition being the major
pathway. In order to overcome this problem, a masked vi-
nyl group was tested. Indeed, the use of appropriate phe-
nylsulfonyl groups further treated in basic media was
shown to lead to vinyl derivatives under smooth condi-
tions.16 A cyclization was attempted starting from nitrile
1.17 No reaction occurred whatever the temperature used
(from r.t. to 70 °C). This result tends to establish that the
scope of this process is limited to a few types of precur-
sors.18 In order to increase the reactivity of 1, its conver-
sion into the corresponding imidate was accomplished.
We focused on a Pinner methodology19 since the product
is usually isolated in pure form following an easy workup.
Imidate hydrochloride 2 was thus obtained in 94% yield
after ten hours at room temperature (Scheme 1).20
Polymers based on nitrogen-rich heterocycles have been
the subject of numerous studies, owing to their specific
characteristics, such as thermal stability and energetic
properties. Hence, a substantial amount of work has been
devoted to the synthesis of vinyl-substituted azahetero-
cycles. For example, 2- and 5-vinyltetrazole derivatives
have been obtained and polymerized to yield polyvinyl-
tetrazoles as energetic binding agents for jet engine fuels,
gun powders, or explosives.1 In the triazoles series, both
4(5)-vinyl-1,2,3-triazoles and 1- or 4-vinyl-1,2,4-triazoles
are known, and the resulting polymers were described.2
The same also applies to vinyl derivatives of 1,3,5-tri-
azines and polymers thereof.3 Among all this work on
high-nitrogen polymers, it appeared that tetrazine-con-
taining polymers had been largely unexplored,4 although
tetrazines are known for their ability to react in inverse de-
mand Diels–Alder reactions,5 and for their energetic,6
dye,7 insecticide,8 electrochemical,9 and biomedical10
properties. In particular, polyvinyltetrazines are missing
in the literature, most probably because, to the best of our
knowledge, vinyltetrazines are unknown. Herein, we de-
scribe the synthesis of the first derivative of this up-to-
now elusive class of compounds: 3,6-divinyl-1,2,4,5-tet-
razine (8). The properties of 8 and preliminary polymer-
ization experiments are also set forth.
PhS
EtOH (10 equiv)
PhS
HCl (g)
NH⋅HCl
r.t., 10 h
EtO
CN
94%
2
1
Scheme 1 Synthesis of imidate 2
The first synthetic approach developed to reach com-
pound 8 involved the elaboration of a functionalized tetra-
zine ring prior to further side-chain modification. In order
to target a tetrazine ring possessing either hydroxymethyl
or formyl groups as functionalities capable of further
modifications, an ester reduction of the readily available
The cyclization reaction from 2 using hydrazine hydrate
proved to be the key step of the synthesis. Our first exper-
iment using two equivalents of hydrazine hydrate at 0 °C
yielded a mixture of 4-amino-1,2,4-triazole 5 and tetra-
zine 6 (Scheme 2 and Table 1, entry 1). This result
prompted us to investigate the course of the reaction more
thoroughly. Parameters, such as temperature and quantity
of hydrazine hydrate, were varied and the products care-
fully isolated and characterized.21 As expected,22 higher
temperatures favored the formation of compound 5. It was
SYNLETT 2009, No. 5, pp 0731–0734
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087818; Art ID: D38808ST
© Georg Thieme Verlag Stuttgart · New York

732
S. Pican et al.
LETTER
quantitatively obtained after simple precipitation from cy- yields. We therefore settled for an amount of base of 1.9
clohexane when the reaction was performed at 78 °C equivalents, thus ensuring a reasonable conversion rate
(Table 1, entry 2). Using one equivalent of hydrazine hy- (the monovinyl derivative was also evidenced) without
drate at 20 °C (Table 1, entry 3), analysis of the crude formation of further byproducts. After purification, the
product revealed two other products: acyclic diamine 3 target compound 3,6-divinyl-1,2,4,5-tetrazine (8) was ob-
and 3,6-bis(2-phenylsulfanylethyl)-1,2-dihydro-1,2,4,5- tained in a 42% yield as a volatile, pink oil which solidi-
tetrazine 4. We found that the latter readily oxidized to 6 fied in the freezer (Scheme 3).25
during workup. Diamine 3 was by far the major product
when using only 0.5 equivalent of hydrazine hydrate
PhO2S
PhS
(Table 1, entry 4). These results clearly evidenced that 3
is the first intermediate in the synthesis of 6. To the best
of our knowledge, this kind of acyclic intermediate has
never been isolated in hydrazine-mediated syntheses of
tetrazines from imidates or related compounds.
KOt-Bu (1.9 equiv)
THF
N
N
N
N
MCPBA (4.1 equiv)
CH2Cl2, 0 °C, 1 h
N
N
N
N
N
N
N
N
–20 °C, 1.5 h
SO2Ph
SPh
6
7
8
quantitative
42%
PhS
PhS
Scheme 3 Oxidation of tetrazine 6 to vinyltetrazine 8
N
N
NH2
NH2
N2H4⋅H2O
NH⋅HCl
Polymerization experiments were then carried out, using
radical or anionic initiation, but without success. The fail-
ure of homopolymerization and even copolymerization
reactions suggested that 8 could act as a radical inhibitor.
However, EPR experiments did not confirm this assump-
tion. Therefore, the stability of 8 in various conditions was
checked. When 3,6-divinyl-1,2,4,5-tetrazine was reacted
under UV irradiation at –10 °C with 11 mol% of Irgacure
651 as the radical initiator, a total decomposition of the
starting material occurred as indicated by 1H NMR. Since
a further experiment performed under similar conditions
without any radical initiator led to entire recovery of 8, its
radical sensitivity was evidenced. The second investiga-
tion focused on the stability of 8 with increasing tempera-
ture. 3,6-Divinyl-1,2,4,5-tetrazine was left unchanged
after heating for five days at 40 °C (0.1 M in CDCl3), as
evidenced by 1H NMR. In contrast, when the temperature
was increased (80 °C in DMF) an insoluble material start-
ed to appear. The same solid was recovered when 8 was
allowed to stand without caution at room temperature.
Since the brownish solid was found insoluble in every sol-
vents, its characterization remained cumbersome. We an-
ticipated that this could be the homopolymer of 8, but
elemental analyses revealed that the nitrogen content of
the solid was too low (28.1% instead of the expected
41.8%). These results could be indicative of [4+2] cy-
cloadditions with loss of N2, a well-known process in the
tetrazine series,5 leading to a cross-linked polypyridazine
network.
Et3N (1.8 equiv), EtOH
EtO
SPh
3
2
N2H4⋅H2O
SPh
PhS
PhS
N
N
N
N
N
NH
NH
N
N
+
N
NH2
N
SPh
SPh
SPh
6
5
4
Scheme 2 Cyclization reaction of imidate 2
Table 1 Cyclization Reaction of Imidate 2 Using Hydrazine Hy-
drate
Entry N2H4 (equiv) Temp (°C) Time (h) 3
4
0
0
5
6
1
2
0
4
0
0
24a 30a
2
2
78
20
20
19
6
100a
0
3
1
43 26 19
78
12
7
4b
0.5
4
0
0
a Isolated product.
b In this reaction 15% of starting material were detected in the crude
mixture.
In summary, we have described the synthesis of 3,6-di-
vinyl-1,2,4,5-tetrazine, the first reported example to date
of a vinyltetrazine. Compound 8 can be seen as a tetraaza
analogue of the widely used 1,4-divinylbenzene. There-
fore, although our preliminary studies showed a limited
stability at high temperatures and in the presence of radi-
cals, 8 is believed to be a useful building block in the syn-
thesis of new tetrazine-based molecules and materials.
Moreover, 8 stands as an interesting substrate for Diels–
Alder reactions, since both the tetrazine ring and the later-
al double bonds could participate in such processes.
According to standard procedures,23 oxidation of 6 was
then performed using 4.1 equivalents of MCPBA at low
temperature, leading to disulfone 7 (Scheme 3).24 As ex-
pected, this occurred chemoselectively since no nitrogen
oxidation was observed after treatment. The subsequent
1,2-elimination of the phenylsulfonyl end chain was ex-
pected to generate vinyl groups as reported earlier.
Among the large palette of bases usually employed,16 we
focused on the use of KOt-Bu in THF for practical rea-
sons. Even a slight excess of KOt-Bu resulted in low
Synlett 2009, No. 5, 731–734 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,6-Divinyl-1,2,4,5-Tetrazine
733
(15) Lim, C. L.; Pyo, S. H.; Kim, T. Y.; Yim, E. S.; Han, B. H.
Bull. Korean Chem. Soc. 1995, 16, 374.
Acknowledgment
Authors wish to thank Dr Pierre Guenot (CRMPO, Université de
Rennes 1) for his assistance in the 3,6-divinyl-1,2,4,5-tetrazine sta-
bility investigations.
(16) (a) Simpkins, N. S. In Sulfones in Organic Synthesis, Vol.
10; Baldwin, J. E.; Magnus, P. D., Eds.; Tetrahedron Org.
Chem. Series, Pergamon Press: Oxford, 1993. (b) Julia, M.;
Arnould, D. Bull. Soc. Chim. Fr. 1973, 2, 746. (c) Colter,
A. K.; Miller, R. E. Jr. J. Org. Chem. 1971, 36, 1898.
(d) Hwang, S. H.; Kurth, M. J. Tetrahedron Lett. 2002, 43,
53. (e) Giovannini, R.; Marcantoni, E.; Pietrini, M.
Tetrahedron Lett. 1998, 39, 5827. (f) Baker-Glenn, C. A.
G.; Barrett, A. G. M.; Gray, A. A.; Procopiou, P. A.; Ruston,
M. Tetrahedron Lett. 2005, 46, 7427.
(17) Renard, M.; Ghosez, L. A. Tetrahedron 2001, 57, 2597.
(18) Sołoducho, J.; Doskocz, J.; Cabaj, J.; Roszak, S.
Tetrahedron 2003, 59, 4761.
(19) (a) Weintraub, L.; Oles, S. R.; Kalish, N. J. Org. Chem.
1968, 33, 1679. (b) Butler, R. C. M.; Chapleo, C. B.; Myers,
P. L.; Welburn, A. P. J. Heterocycl. Chem. 1985, 22, 177.
(20) Ethyl 3-Phenylsulfanylpropionimido Ester
Hydrochloride (2)
References and Notes
(1) Kizhnyaev, V. N.; Vereshchagin, L. I. Russ. Chem. Rev.
2003, 72, 143; and references cited therein.
(2) (a) Kizhnyaev, V. N.; Pokatilov, F. A.; Tsypina, N. A.;
Ratovskii, G. V.; Vereshchagin, L. I.; Smirnov, A. I. Russ. J.
Org. Chem. 2002, 38, 1056. (b) Wouters, G.; Smets, G.
Makromol. Chem. 1982, 183, 1861. (c) Attaryan, O. S.;
Asratyan, G. V.; Eliazyan, G. A.; Darbinyan, E. G.;
Matsoyan, S. G. Arm. Khim. Zh. 1986, 39, 630. (d) Toppet,
S.; Wouters, G.; Smets, G. J. Polym. Sci. Polym. Lett. 1976,
14, 389.
(3) (a) American Cyanamid Company; GB 935787, 1963.
(b) Schaefer, F. C.; Peters, G. A. US 2845422, 1958.
(c) Yuki, Y.; Kakurai, T.; Nogushi, T.; Hiramatsu, N.
Kobunshi Kugaku 1969, 26, 134. (d) Yuki, Y.; Kakurai, T.;
Nogushi, T. Kobunshi Kugaku 1969, 26, 141.
A steady stream of gaseous HCl was bubbled at r.t. for 10 h
through a stirred EtOH solution (7.3 mL, 0.125 mol) of
propionitrile 1 (2.02 g, 12.3 mmol). A white powder
gradually precipitated. The solvent was removed under
vacuum, and the crude precipitate was triturated three times
with anhyd Et2O and finally filtered leading to compound 2
as a white powder (94% yield); mp 74–75 °C. 1H NMR (400
MHz, CDCl3): d = 12.50 (s, 1 H), 11.60 (s, 1 H), 7.41–7.27
(m, 5 H), 4.56 (q, J = 6.9 Hz, 2 H), 3.30 (t, J = 6.6 Hz, 2 H),
3.06 (t, J = 6.6 Hz, 2 H), 1.44 (t, J = 6.9 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 177.0, 133.7, 130.9, 129.1, 126.4,
70.9, 33.4, 28.8, 13.4. IR (KBr): nmax = 3078, 2951, 1692,
1384, 975 cm–1. LC-MS (AP+, MeCN–H2O, 80:20): 2.67
min, 246.7 [M + 1] and 210.3 [M – Cl]. HRMS (FI): m/z
calcd for C11H15ONS [M – HCl]: 209.0874; found:
209.0875.
(e) Overberger, C. G.; Shapiro, S. L. J. Am. Chem. Soc.
1954, 76, 1061. (f) Fukui, K.; Kitano, H.; Mizuta, M.;
Osaka, T.; Kanai, K. JP 44025793, 1970.
(4) (a) Audebert, P.; Sadki, S.; Miomandre, F.; Clavier, G.
Electrochem. Commun. 2004, 6, 144. (b) Topp, K. D.;
Grote, M. React. Funct. Polym. 1996, 31, 117. (c) Zhang,
B. W.; Fischer, K.; Bieniek, D.; Kettrup, A. React. Funct.
Polym. 1994, 24, 49. (d) Stoicescu-Crivetz, L.; Mantaluta,
E.; Neamtu, G.; Zugravescu, I. J. Polym. Sci., Part C:
Polym. Symp. 1969, 22, 761. (e) Stoicescu-Crivetz, L.;
Mantaluta, E.; Neamtu, G.; Zugravescu, I. Rev. Roum. Chim.
1966, 11, 1127. (f) Konishi, K.; Kobota, J.; Kotone, A.;
Nakane, Y. JP 7234499, 1972.
(5) (a) Hamasaki, A.; Ducray, R.; Boger, D. L. J. Org. Chem.
2006, 71, 185. (b) Soenen, D. R.; Zimpleman, J. M.; Boger,
D. L. J. Org. Chem. 2003, 68, 3593. (c) Wan, Z. K.; Woo,
G. H. C.; Snyder, J. K. Tetrahedron 2001, 57, 5497.
(d) Kotschy, A.; Novák, Z.; Vincze, Z.; Smith, D. M.; Hajós,
G. Tetrahedron Lett. 1999, 40, 6313. (e)Seitz, G.; Overheu,
W. Arch. Pharm. 1977, 310, 936.
(6) (a) Chavez, D. E.; Hiskey, M. A.; Gilardi, R. D. Org. Lett.
2004, 6, 2889. (b) Talawar, M. B.; Sivabalan, R.;
Senthilkumar, N.; Prabhu, G.; Asthana, S. N. J. Hazard.
Mater. 2004, 113, 11. (c) Pagoria, P. F.; Lee, G. S.;
Mitchell, A. R.; Schmidt, R. D. Thermochim. Acta 2002,
384, 187. (d) Oxley, J. C.; Smith, J. L.; Chen, H.
Thermochim. Acta 2002, 384, 91. (e) Chavez, D. E.; Hiskey,
M. A.; Gilardi, R. D. Angew. Chem. Int. Ed. 2000, 39, 1791.
(7) Kotone, A.; Hoda, M. JP 24002, 1971.
(8) Tsuda, S.; Manabe, Y.; Tsuji, K. JP 107254, 1988.
(9) Audebert, P.; Sadki, S.; Miomandre, F.; Clavier, G.;
Vernières, M.-C.; Saoud, M.; Hapiot, P. New J. Chem. 2004,
28, 387.
(21) General Cyclization Procedure
Imidoester hydrochloride 2 (6.17 g, 25.1 mmol) was
dissolved in EtOH (0.16 M) under a nitrogen atmosphere,
and the solution was brought to –10 °C. Then, Et3N and
N2H4·H2O (2.5 mL, 51.4 mmol) were successively added to
the solution and the mixture was allowed to stir (conditions:
see Table 1). The mixture was concentrated under vacuum,
and the slightly pink crude solid obtained was further
dissolved in EtOAc and washed with H2O. The aqueous
layer was then extracted with EtOAc, and the resulting
organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated under vacuum. Depending on
reaction conditions the products could be obtained.
Compound 5 was isolated after simple precipitation from
cyclohexane, whereas 3, 4, and 6 were obtained after
chromatography over SiO2 (cyclohexane–EtOAc, 7:1).
N¢-[1-Amino-3-(phenylsulfanyl)propylid-1-ene]-3-
(phenylthio)propanehydrazonamide (3)
Mp 75 °C (white crystals). 1H NMR (400 MHz, CDCl3): d =
7.88–7.15 (m, 10 H), 5.43 and 5.09 (br s, 4 H), 3.24 (t,
J = 7.4 Hz, 4 H), 2.55 (t, J = 7.4 Hz, 4 H). 13C NMR (100
MHz, CDCl3): d = 155.8, 135.5, 129.5, 129.0, 126.3, 32.9,
30.8. IR (KBr): nmax = 3450, 3337, 3060, 2960, 1633, 1583,
1482, 1444, 1356, 1287, 910 cm–1. LC-MS (AP+, MeCN–
H2O, 80:20): 3.40 min, 358.9.
(10) (a) Rao, G. W.; Hu, W. X. Bioorg. Med. Chem. Lett. 2005,
15, 3174. (b) Hu, W. X.; Rao, G. W.; Sun, Y. Q. Bioorg.
Med. Chem. Lett. 2004, 14, 1177.
(11) Boger, D. L.; Coleman, R. S.; Panek, J. S. J. Org. Chem.
1985, 50, 5377.
3,6-Bis-(2-phenylsulfanylethyl)-1,2-dihydro-1,2,4,5-
tetrazine (4)
(12) Lithium aluminium hydride, sodium borohydride, or
diisobutylaluminium hydride led to major decomposition
regardless of the conditions used.
(13) Alphonse, F. A.; Suzenet, F.; Keromnes, A.; Lebret, B.;
Guillaumet, G. Org. Lett. 2003, 5, 803.
(14) Sandstrom, J. Acta Chem. Scand. 1961, 15, 1575.
Mp 151 °C (white crystals); 1H NMR (400 MHz, DMSO-
d6): d = 7.96 (s, 2 H), 7.37–7.26 (m, 8 H), 7.24–7.12 (m, 2
H), 3.10 (t, J = 7.6 Hz, 4 H), 2.30 (t, J = 7.6 Hz, 4 H). 13
C
NMR (100 MHz, DMSO-d6): d = 148.5, 135.7, 129.1, 128.1,
Synlett 2009, No. 5, 731–734 © Thieme Stuttgart · New York

734
S. Pican et al.
LETTER
125.7, 29.8, 28.2. IR: nmax = 3243, 3054, 1677, 1575, 1476,
1436, 1400, 1287, 1257, 1242, 1208, 1165, 1086, 1020 cm–1.
LC-MS (AP+, MeCN–H2O, 50:50): 7.15 min, 356.9.
4-Amino-3,5-bis(2-phenylsulfanylethyl)-1,2,4-triazole
(5)
mixture was successively washed with a solution of NaHSO3
(10%) and a solution of NaHCO3 (10%). The organic layer
was then washed with sat. NaCl solution, dried over MgSO4,
and filtered. Product 7 was finally obtained as a pink powder
(2.19 g, 100%) after concentration under vacuum; mp 183–
185 °C. 1H NMR (400 MHz, DMSO-d6): d = 7.92–7.88 (m,
4 H), 7.74–7.60 (m, 2 H), 7.71–7.62 (m, 4 H), 3.93 (t, J = 7.6
Hz, 4 H), 3.44 (t, J = 7.6 Hz, 4 H). 13C NMR (100 MHz,
DMSO-d6): d = 167.0, 138.2, 134.1, 129.6, 127.9, 51.9, 28.1.
IR (KBr): nmax = 3082, 2954, 1448, 1427, 1395, 1310, 1294,
1269, 1148, 1083, 1047, 1033, 996, 980, 906, 778, 745, 711
cm–1. LC-MS (AP+, MeCN–H2O, 50:50): 5.72 min, 418.9
[MH+]. Anal. Calcd for C18H18N4S2O4: C, 51.66; H, 4.34; N,
13.39. Found: C, 51.98; H, 4.40; N, 13.55. HRMS (CI): m/z
calcd for C18H19N4S2O4 [MH+]: 419.0848; found: 419.0854.
(25) 3,6-Divinyl-1,2,4,5-tetrazine (8)
Mp 80–82 °C (white crystals). 1H NMR (400 MHz, DMSO-
d6): d = 7.40–7.16 (m, 10 H), 5.63 (s, 2 H), 3.31 (t, J = 7.0
Hz, 4 H), 2.98 (t, J = 7.0 Hz, 4 H). 13C NMR (100 MHz,
CDCl3): d = 153.5, 134.9, 129.0, 128.9, 126.3, 31.4, 24.6.
IR (KBr): nmax = 3444, 3042, 2991, 1633, 1583, 1482, 1438,
1231, 1205, 790 cm–1. LC-MS (AP+, MeCN–H2O, 80:20):
2.49 min, 356.6 [MH+]. Anal Calcd for C18H20N4S2: C,
60.64; H, 5.65; N, 15.72; S, 17.93. Found: C, 60.31; H, 5.81;
N, 15.67; S, 17.71.
3,6-Bis(2-phenylsulfanylethyl)-1,2,4,5-tetrazine (6)
Mp 55 °C (pink crystals). 1H NMR (400 MHz, CDCl3): d =
7.42–7.35 (m, 4 H), 7.32–7.25 (m, 4 H), 7.24–7.17 (m, 2 H),
3.60 (t, J = 6.8 Hz, 4 H), 3.52 (t, J = 6.8 Hz, 4 H). 13C NMR
(100 MHz, CDCl3): d = 168.4, 134.5, 130.5, 129.0, 126.7,
34.7, 31.8. IR (KBr): nmax = 3023, 2406, 1520, 1425, 1356,
1218, 1048, 929 cm–1. LC-MS (AP+, MeCN–H2O, 80:20):
3.12 min, 355.2 [MH+]. HRMS (CI): m/z calcd for
C18H19N4S2 [MH+]: 355.1051; found: 355.1043.
To a stirred solution of s-tetrazine 7 (600 mg, 1.43 mmol) in
dry THF (120 mL) was added KOt-Bu (307 mg, 2.73 mmol)
at –20 °C for 1.5 h. The reaction was followed by TLC
analysis [Rf(7) = 0.45 (cyclohexane–EtOAc, 4:6);
Rf(8) = 0.95 (cyclohexane–EtOAc, 4:6)]. The solution was
finally diluted with 150 mL of cooled Et2O, filtered, and
washed with a solution of NaHCO3 (10%, 2 × 100 mL). The
organic layer was then washed with brine (150 mL), dried
over MgSO4, and further concentrated under controlled
vacuum because of its volatility. Product 8 was purified over
a SiO2 column (pentane–Et2O, 80:20; Rf = 0.96), obtained as
a dark pink oil (81 mg, 42% yield), and kept in the freezer.
1H NMR (400 MHz, CD2Cl2): d = 7.17 (dd, J = 10.8, 17.6
Hz, 2 H), 7.01 (dd, J = 1.2, 17.6 Hz, 2 H), 6.02 (dd, J = 1.2,
10.8 Hz, 2 H). 13C NMR (100 MHz, CD2Cl2): d = 164.2,
131.0, 127.8. IR (KBr): nmax = 3041, 1632, 1434, 1364, 1343,
1259, 1075, 1032, 984, 950, 902, 711 cm–1. LC-MS (AP+,
MeOH): 0.04 min, 135.3 [MH+]; HRMS (FI): m/z calcd for
C6H6N4 [M+]: 134.0592; found: 134.0590.
(22) Comprehensive Heterocyclic Chemistry II, Vol. 6;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996, 949.
(23) Panek, J. S.; Zhu, B. Tetrahedron Lett. 1996, 37, 8151.
(24) 3,6-Bis(2-phenylsulfonylethyl)-1,2,4,5-tetrazine (7)
Tetrazine 6 (1.86 g, 5.25 mmol) was dissolved in CH2Cl2
(0.05 M), and the solution was cooled to –10 °C. A solution
of MCPBA (5.38 g, 21.8 mmol) in CH2Cl2 (0.25 M) was
added over a period of 1 h (the temperature was kept below
0 °C), after which TLC analysis indicated completion of the
reaction [Rf(6) = 0.37 (cyclohexane–EtOAc, 7:1), pink spot;
Rf(7) = 0 (cyclohexane–EtOAc, 7:1), pink spot]. The
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