The azaphilic addition of organometallic reagents on tetrazines: Scope and limitations

Article abstract of DOI:10.1016/j.tet.2004.01.013

A series of tetrazines were reacted with organometallic reagents. Depending on the nature of the metal azaphilic addition, reduction of the tetrazine or simple complex formation was the predominant transformation and usually high selectivity was observed.

Full text of DOI:10.1016/j.tet.2004.01.013

Tetrahedron 60 (2004) 1991–1996
The azaphilic addition of organometallic reagents on tetrazines:
scope and limitationsq
a
Janos Farago, Zoltan Novak, Gitta Schlosser, Antal Csampai and Andras Kotschy
a
b
a
a
,
*
´
´
´
´
´
´
a
¨
¨
´
´
´
´
Department of General and Inorganic Chemistry, Eotvos Lorand University, Pazmany Peter s. 1/A, Budapest H-1117, Hungary
bChemical Research Center, Hungarian Academy of Sciences, PO Box 32, H-1525 Budapest, Hungary
Received 23 October 2003; revised 4 December 2003; accepted 8 January 2004
Abstract—A series of tetrazines were reacted with organometallic reagents. Depending on the nature of the metal azaphilic addition,
reduction of the tetrazine or simple complex formation was the predominant transformation and usually high selectivity was observed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
coined ‘azaphilic addition’ is quite unprecedented for other
heterocycles, but had been reported previously for 3,6-
diphenyltetrazine too.24– 27 A common feature of the
published reactions is that they utilize either organolithium
or Grignard reagents, and apparently no rationalization has
been provided so far for this unusual transformation. To
explore the generality of this reaction we decided to react a
series of tetrazines with organometallic reagents. In the light
of the fact that on the same tetrazine soft carbanions can
initiate nucleophilic substitution,20,21 while hard carbanions
give azaphilic addition selectively,23 we also wanted to
explore the territory between this two ‘extremes’. We
planed to achieve this aim by reacting a series of
organometallic reagents containing different metal residues
with a tetrazine that is capable of undergoing nucleophilic
substitution.
The chemistry of tetrazines has gained increased attention in
the last few decades,1 due mostly to their applications in
organic synthesis,2 crop protection3,4 and materials
science.5 Their basic structural feature, the electron-
deficient heterocyclic core, is the key to their most
extensively utilized transformation, the ‘inverse electron-
demand’ Diels–Alder reaction, that provides an attractive
route to pyridazines,6–8 pyrroles,9 and other condensed10,11
and strained heterocyclic ring systems.12 Another charac-
teristic feature of the electron deficient aromatic ring is its
reactivity towards nucleophiles that has been utilized in the
preparation of non-symmetrically substituted tetrazines
through their addition onto the ring13 or substitution of
leaving groups, such as chloro,14,15 methylthio16,17 or
dimethylpyrazolyl15,18,19 with nitrogen, oxygen or sulfur
nucleophiles. The analogous reactions introducing carbon
nucleophiles would also be of synthetic importance, but
there are only a few know examples utilizing potassium
cyanide15 or malonates.20,21 The cross-coupling reactions
on tetrazines, also recently reported have only a limited
scope.22
2. Results and discussion
The first tetrazine selected to test the generality of the
azaphilic route was 3,6-bis(30,50-dimethylpyrazolyl)-tetra-
zine (1). The choice of 1 was based on two facts: the ease
and economy of its preparation28 and its well documented
reactivity towards nitrogen and oxygen nucleophiles.5,14,18,19
The first experiments, including the reaction of butyl-
lithium, phenyllithium and phenylmagnesium chloride
(Table 1, entries 1–3) with 1, led to the formation of
1-butyl-1,4-dihydro-3,6-bis(dimethylpyrazolyl)tetrazine
(6a) or 1-phenyl-1,4-dihydro-3,6-bis(dimethylpyrazolyl)-
tetrazine (6b) in good yield, if the reaction mixtures were
quenched at 278 8C, supporting the generality of the
azaphilic pathway. On prolonged standing of the reaction
mixture on air or letting it warm to room temperature, the
yield of 6a decreased considerably, especially when
organolithium reagents were used. In entry 1, the formation
The use of reactive carbon nucleophiles, such as organo-
lithium or Grignard reagents in an attempt to substitute 3,6-
bis(methylthio)tetrazine led to the addition of the organic
group onto a ring nitrogen atom.23 The transformation,
q Supplementary data associated with this article can be found in the online
version, at doi: 10.1016/j.tet.2004.01.013
Keywords: Tetrazines; Azaphilic addition; Aromatic nucleophilic
substitution; Reduction.
*
Corresponding author. Tel.: þ36-1-209-0555; fax: þ36-1-209-0602;
e-mail address: kotschy@para.chem.elte.hu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.013

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J. Farago et al. / Tetrahedron 60 (2004) 1991–1996
1992
Table 1. Product distribution in the azaphilic addition of tetrazines 1-5 with
organometallic reagents
suggests that the coordinating ability of 1 to the organo-
metallic reagent might also play an important role in the
course of the azaphilic addition.
The reaction of allylindium reagents (entries 8 and 9)
showed a marked dependence on the way the reagent was
formed. Allylindium bromide, prepared from allyl bromide
and indium in DMF (entry 8), gave good conversion and led
only to azaphilic addition (6c). In the same reaction, using
Barbier-type conditions30 (entry 9), we also achieved full
conversion but the crude product was a 1:1 mixture of the
azaphilic adduct 6c and reduced starting material (10) by
NMR. We attributed the observed difference to the different
mechanisms operating under the applied conditions.
No. SM
RM
6-9a (%) 10, 11 (%) 12, 13 (%) 14b (%)
In an attempt to broaden the scope of the azaphilic addition
process other selected tetrazine derivatives (2-5) were also
reacted with organometallic reagents (Table 1, entries
10–21). To our surprise, unlike in the case of 1, organozinc
and Gilmann reagents either failed to react with 2-5 or gave
only poor conversion, which means that they are only of
limited use from preparative point of view. Organolithium
and Grignard reagents on the other hand reacted readily, and
even the least reactive tetrazine (2) gave full conversion at
ambient temperature. Our general observation in these
experiments (entries 10–21) is the favored attack of the
nucleophile at the ring nitrogen atom (azaphilic addition)
although the different tetrazines showed characteristic
side reactions too. 3,6-Di(30-pyridyl)tetrazine (2) for
example also underwent a competing reduction in the
presence of organolithium reagents (entries 10 and 12, cf.
with entry 1), while the analogous organomagnesium
reagents gave only azaphilic addition. Another feature of
2 is the observation that this compound was the least
reactive of the tetrazines examined. Complete conversion of
2 to 7a or 7b required warming of the reaction mixtures to
ambient temperature.
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
2
2
2
2
3
3
3
3
4
4
4
5
BuLi
PhLi
70c
62
85
60
85
90
45
5
PhMgCl
BuCuLiId
BuZnBrd
PhZnBr
40
15
PhZnBrd
35
e
(C3H5)3In2Br3 60
f
9
(C3H5)3In2Br3 50g
50g
32
10
11
12
13
14
15
16
17
18
19
20
21
BuLi
BuMgI
PhLi
PhMgCl
BuLi
BuMgI
PhLi
PhMgCl
BuLi
PhLi
13
96
35
25
58
13h
43h
85h
90h
90
80
56
80
94
dec.
PhMgCl
PhMgCl
a
Numbers refer to isolated yields unless otherwise stated.
Estimated value based on recovered starting material. Reverts to 1 on
acidic workup.
Converts partially to 12 on standing in air.
Prepared by transmetallation form the appropriate lithiumorganic reagent
and anhydrous metal halide.
b
c
d
The addition of the organometallic reagents onto 3-(30,50-
dimethylpyrazol-10-yl)-6-morpholino-tetrazine (3) had two
interesting aspects (entries 14–17). The reaction proceeded
regioselectively, as established by NOE experiments, and
only the formation of adducts bearing the incoming
nucleophile on a nitrogen atom next to the pyrazole moiety
was observed. We attribute the selectivity of the addition to
the coordinating ability of the pyrazole moiety which might
anchor the organometallic reagent in the proximity of the
site of observed attack. The intermediates and products
formed in the reaction underwent a so far unprecedented
transformation in the presence of oxygen. Their solution,
when contacted with air, turned red and the formation of the
appropriate butoxy- (13a) or phenoxy-morpholino-tetrazine
(13b) was observed. The oxidative transformation pro-
ceeded the fastest when the reaction mixture containing 3
and an organolithium reagent was contacted with air and
was the slowest in case of the oxidation of solutions of
purified 8a or 8b. Although we have no sound mechanistic
proposal for this oxidative transformation the above findings
suggest that the opening step of the process is the
electrophilic attack of oxygen on the tetrazine ring.
e
f
Prepared from In and allyl bromide.
Barbier conditions (In, allyl bromide, THF/aq. NH4Cl).
Determined by NMR.
Converts partially to 13 on standing in air.
g
h
of traces of the reduced starting material (10) was also
observed.
Extension of the scope of the reaction by using Gilmann or
organozinc reagents, prepared by the mixing of one
equivalent of copper(I) iodide (entry 4) or zinc bromide
(entry 5) with butyllithium prior to the addition to the
tetrazine, led also to the formation of 6a. The use of
phenylzinc bromide, prepared through oxidative addition,
gave 6b in excellent yield (entry 6), while the same reagent
prepared through transmetallation gave only a moderate
yield of 6b (entry 7). In each reaction, where the reagent was
prepared by transmetallation (entries 4,5 and 7), we
observed the formation of a salt-like byproduct, schemati-
cally represented as 14, which reverted to 1 on acidic
workup. The stability of 14 in the presence of organo-
metallic reagents29 is exacerbated by the addition of
butyllithium to the preformed complex of 1 and CuI at
278 8C leading to marginal conversion to 6a, which
The reactions of 3,6-bis(methylthio)-tetrazine (4) with
organolithium and Grignard reagents (entries 18–20) held

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J. Farago et al. / Tetrahedron 60 (2004) 1991–1996
1993
no surprise, and in analogy with an earlier report,23 the
azaphilic adducts 9a,b were isolated in excellent yield in
each case. Likewise, compounds 1 and 4 also reacted readily
with the organometallic reagents even at 278 8C. On the
other hand, we saw no sign of double addition or follow-up
reactions when using organolithium reagents.23
yielding the more reactive metal hydrides. By changing
the solvent to diethyl ether in the same experiment we
observed only complex formation, also supporting this
hypothesis.34
A similar behavior was observed when butyllithium was
mixed with lead(II) bromide (entry 25) prior to its addition
to 1. At the end of the reaction the azaphilic adduct (6a), the
butoxy substituted tetrazine (12) and starting material (1),
recovered after the decomposition of 14, were isolated in
similar yields.
In an attempt to extend the azaphilic addition to chloro-
tetrazines, 3-chloro-6-morpholino-tetrazine (6)14 was also
reacted withorganolithiumand Grignard reagents. The former
led to the decomposition of the starting material even at
278 8C, probably due to the presence of a lithium–chlorine
exchange reaction, while in case of organomagnesium
reagents, TLC analysis of the reaction mixtures revealed the
formation of a new product, showing an azaphilic adduct-like
behavior, that decomposed during workup.
The last group of organometallic reagents examined (entries
26–29) initiated the reduction of the tetrazine core
selectively. Even careful investigation of the crude reaction
mixtures revealed only the presence of 12 besides some
highly polar decomposed material. It is worth mentioning
that this transformation was selective, not only for
butylmetal halides (entries 26,28, and 29) that are capable
of producing metal hydrides through b-hydride elimin-
ation,33 but also for phenyltin chloride (entry 27). The fact
that these reagents reduced the tetrazine core and not the
solvent, as in entries 22–25, is not well understood but
might probably be attributed to the different complex
forming aptitude of the added metal ions.
Having demonstrated that organolithium and Grignard
reagents initiate, in most cases, azaphilic addition on
tetrazines we turned our attention to other organometallic
reagents. In the next set of experiments the easily available
and reactive dipyrazolyl-tetrazine (1) was reacted with a
series of organometallic reagents prepared by transmetalla-
tion from butyllithium or phenyllithium and the appropriate
metal halide.
Tuning the reactivity of butyllithium with cobalt or
manganese salts (entries 22 and 23) led to a significant
change in reactivity. Besides the formation of substantial
amounts of the complex 14, another product was isolated in
both cases. The spectral data of this newly formed
compound indicated substitution of one of the pyrazolyl
units, but multidimensional NMR and MS experiments
verified that it possesses a butoxy substituent (12) instead of
the expected butyl group. Interestingly, when we carried out
the same reaction using phenyllithium instead of butyl-
lithium (entry 24) three products were formed: the azaphilic
adduct (6b), the butoxy substituted tetrazine (12) and the
complex (14), which suggests that the butoxy moiety in 12
is not coming from the organolithium reagent as in entry 14,
which leaves tetrahydrofuran as the only potential source of
butoxide ions. The capability of THF to undergo reductive
ring opening is known31,32 and the reducing ability of the
butyl-metal-halides used might be further enhanced through
b-hydride elimination under the applied conditions,33
In summary, a series of organometallic reagents were
reacted with different tetrazine derivatives and selective
transformations, such as azaphilic addition, reduction or in
certain cases nucleophilic displacement were observed.
More polar organometallic reagents, especially lithium,
magnesium and zinc derivatives, showed a marked affinity
towards the nitrogen atom of the tetrazine core, a behaviour
fairly unusual in heterocyclic chemistry. The oxidative
rearrangement of the azaphilic adducts to alkoxy/aryloxy
tetrazines was also observed in certain cases.
3. Experimental
3.1. General
Melting points were determined on a hotplate and are
uncorrected. The 1H and 13C NMR spectra were recorded on
a Brucker DRX-250 or DRX-500 spectrometer in CDCl3
1
and CH3SOCH3. For H NMR spectra the residual peak of
Table 2. Product distribution in the reaction of 1 with other organo-metallic
reagents
CHCl3 (7.26 ppm) and CH3SOCH3 (2.50 ppm) were used as
the internal reference, while for 13C NMR spectra the
central peak of CDCl3 (77.0 ppm) and the central peak
CD3SOCD3 (39.43 ppm) were used as the reference. The IR
spectra were obtained on a Bruker IFS-55 FTIR spec-
trometer. Combination gas chromatography and low
resolution mass spectrometry was obtained on a Hewlett–
Packard 5790A Gas Chromatograph (30 m£0.25 mm
column with 0.25 mm RH-5 MSþcoating, He carrier gas)
and VG 12-250 Mass Spectrometer (Ion source: EIþ,
70 eV, 250 8C; interface: 250 8C). Flash silica gel (0.040–
0.063 mm) was used for flash column chromatography.
No.
SM
RM
6a (%)
10 (%)
12a (%)
14b (%)
22
23
24
25
26
27
28
29
1
1
1
1
1
1
1
1
BuCoBrc
BuMnClc
PhMnClc
BuPbClc
BuSnClc
PhSnClc
BuFeClc
60
40
15
30
40
60
40
35
20
25
100d
100d
100d
100d
c
BuCrCl2
a
Numbers refer to isolated yields unless otherwise stated.
Estimated value based on recovered starting material. Reverts to 1 on
acidic workup.
Prepared by transmetallation form the appropriate lithiumorganic reagent
and anhydrous metal halide.
b
c
d
3.2. General procedure for the reaction of tetrazines 1-4
with organometallic reagents
Determined by NMR. .99.9% means that no other identifiable
compound was detected in the crude product.
All reactions were carried out under argon, using dry

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J. Farago et al. / Tetrahedron 60 (2004) 1991–1996
1994
glassware. THF was distilled from potassium/benzo-
phenone. When the organometallic reagent was prepared
by transmetallation a mixture of 1.1 mmol of the appro-
priate salt in abs. THF (3 mL) was treated with 1.1 mmol of
the organolithium reagent and after stirring for 1 h at
240 8C the resulting mixture was added via a canula to the
slurry of 1 mmol of the appropriate tetrazine in dry THF
(3 mL) at 278 8C. The reaction was followed by TLC and
upon completion (which in certain cases required warming
to room temperature) it was quenched with aq. NH4Cl,
extracted with DCM, the combined organic phases were
dried oveg MgSO4 and the solvent was evaporated. The
products were isolated by flash column chromatography
using hexane–ethyl acetate mixtures as eluent.
J¼2.2, 0.8 Hz), 8.78 (dd, 1H, J¼4.9, 1.7 Hz), 8.57 (br s,
1H), 8.50 (d, 1H, J¼5.1 Hz), 8.42 (ddd, 1H, J¼8.0, 2.2,
1.8 Hz), 7.49 (ddd, 1H, J¼8.0, 4.9, 0.9 Hz), 7.23–7.14 (m,
3H), 2.78 (t, 2H, J¼7.6 Hz), 1.62 (qi, 2H, J¼7.7 Hz), 1.35
(sex, 2H, J¼7.6 Hz), 0.91 (t, 3H, J¼7.4 Hz); 13C NMR
(CDCl3, 125 MHz): 151.56, 151.07, 150.06, 149.92, 148.17,
147.96, 136.79, 133.85, 127.90, 126.35, 123.68, 123.63,
52.63, 30.98, 19.99, 14.15; MS (EI, 70 eV) m/z for
C16H18N6 (rel. intensity, ion): 294 (5, Mþ), 224 (22), 161
(39), 145 (50), 132 (42), 118 (90), 104 (37), 78 (47), 51 (44),
43 (100).
3.2.5. 1-Phenyl-3,6-bis(30-pyridyl)-1,4-dihydro-1,2,4,5-
tetrazine (7b). Yellow solid, mp: 180–181 8C (decompo-
sition); 1H NMR (CDCl3, 250 MHz) 9.03 (d, 1H,
J¼1.3 Hz), 8.65 (dd, 1H, J¼4.3, 0.9 Hz), 8.55 (d, 1H,
J¼1.6 Hz), 8.46 (dd, 1H, J¼4.9, 1.4 Hz), 8.07 (dt, 2H,
J¼7.8, 1.9 Hz), 7.39 (dt, 1H, J¼8.2, 2.1 Hz), 7.31 (dd, 1H,
J¼8.0, 4.9 Hz), 7.17–7.04 (m, 5H, J¼16.5 Hz), 6.93 (tt, 1H,
J¼7.1, 1.2 Hz); 13C NMR (CDCl3, 62.5 MHz) 151.67,
150.10, 150.01, 149.94, 147.45, 146.01, 141.14, 136.16,
134.01, 128.64, 128.30, 125.55, 123.64, 123.53, 122.81,
119.28; MS (EI, 70 eV) m/z for C18H14N6 (rel. intensity,
ion): 314 (55, Mþ), 283 (12), 208 (14), 181 (30), 105 (100),
77 (70), 51 (65); IR (KBr): 3426, 3223, 3062, 3033., 2920.8,
1625, 1596, 1491, 1466, 1413, 1348, 1338, 1096, 1021, 988,
812, 764, 713, 697 cm21. HRMS (EI) Calcd for C18H14N6:
m/z 314.1280. Found: m/z 314.1270.
3.2.1. 1-Butyl-3,6-bis(30,50-dimethylpyrazol-10-yl)-1,4-
dihydro-1,2,4,5-tetrazine (6a). Yellow oil, 1H NMR
(CDCl3, 500 MHz): d 7.92 (s, 1H), 5.88 (s, 1H), 5.82 (s,
1H), 3.03 (t, 2H, J¼6.9 Hz), 2.40 (s, 3H), 2.22 (s, 3H), 2.15
(s, 3H), 2.11 (s, 3H), 1.48 (qi, 2H, J¼6.9 Hz), 1.25 (sex, 2H,
J¼6.9 Hz), 0.77 (t, 3H, J¼6.9 Hz); 13C NMR (CDCl3,
125 MHz): d 151.19, 150.43, 146.09, 145.91, 143.30,
142.81, 110.44, 107.41, 50.80, 30.30, 19.98, 14.47, 14.11,
14.02, 13.88, 11.70; MS (EI, 70 eV) m/z for C16H24N8 (rel.
intensity, ion): 328 (100, Mþ), 271 (10), 189 (22), 164 (52),
151 (22), 122 (72), 97 (19), 81 (10); 54 (12); IR (KBr) nmax
:
3357, 2958, 2929, 2870, 2154, 1666, 1639, 1569, 1300,
1216, 1135, 1067, 1029, 970, 937, 900, 789 cm21. HRMS (EI)
Calcd for C16H24N8: m/z 328.2124. Found: m/z 328.2137.
3.2.6. 4-Butyl-3-(30,50-dimethylpyrazol-10-yl)-6-(N-mor-
pholino)-1,4-dihydro-1,2,4,5-tetrazine (8a). Yellow oil,
1H NMR (CDCl3, 250 MHz) 7.60 (s, 1H), 5.95 (s, 1H), 3.72
(t, 4H, J¼4.7 Hz), 3.37 (t, 2H, J¼7.0 Hz), 3.04 (t, 4H,
J¼4.7 Hz), 2.46 (s, 3H), 2.19 (s, 3H), 1.68 (qi, 2H,
J¼14.7 Hz), 1.43 (sex, 2H, J¼18.5 Hz), 0.94 (t, 3H,
J¼7.3 Hz); 13C NMR (CDCl3, 62.5 MHz): 154.22, 150.42,
149.82, 141.94, 109.74, 66.41, 49.70, 48.44, 30.65, 19.59,
13.73; MS (EI, 70 eV) m/z for C15H25N7O (rel. intensity,
ion): 319 (45, Mþ), 262 (65), 122 (83), 57 (50), 42 (100).
3.2.2. 1-Phenyl-3,6-bis(30,50-dimethylpyrazolyl-10-yl)-1,4-
dihydro-1,2,4,5-tetrazine (6b). Yellow solid, mp: 45–
1
46 8C (decomposition); H NMR (CDCl3, 250 MHz) 8.41
(br s, 1H), 7.18 (t, 2H, J¼7.2 Hz), 6.97 (t, 1H, J¼7.2 Hz),
6.92 (d, 2H, J¼7.2 Hz), 6.05 (s, 1H), 5.79 (s, 1H), 2.64 (s,
3H), 2.25 (s, 3H), 2.18 (s, 3H), 2.06 (s, 3H); 13C NMR
(CDCl3, 62.5 MHz) 151.45, 150.93, 149.79, 142.79, 142.47,
141.38, 140.05, 128.57, 122.90, 117.04, 110.72, 107.73,
14.21, 13.58, 13.53, 11.05; MS (EI, 70 eV) m/z for
C18H20N8 (rel. intensity, ion): 348 (65, Mþ), 272 (9,
M-Ph), 198 (63), 122 (100), 77 (41); IR (KBr): 3350, 2926,
1663, 1639, 1599, 1582, 1570, 1496, 1457, 1414, 1399,
1366, 1077, 995, 969, 754, 693 cm21. HRMS (EI) Calcd for
C18H20N8: m/z 348.1811. Found: m/z 348.1819.
3.2.7. 4-Phenyl-3-(30,50-dimethylpyrazol-10-yl)-6-(N-mor-
pholino)-1,4-dihydro-1,2,4,5-tetrazine (8b). Yellow solid,
mp: 170–171 8C (decomposition); 1H NMR (CDCl3,
500 MHz) 7.56 (s, 1H), 7.13 (dd, 2H, J¼8.1, 7.2 Hz), 6.91
(t, 1H, J¼7.2 Hz), 6.88 (d, 2H, J¼8.1 Hz), 5.77 (s, 1H), 3.66
(t, 4H, J¼4.8 Hz), 3.30 (t, 4H, J¼4.8 Hz), 2.20 (s, 3H), 2.00
(s, 3H); 13C NMR (CDCl3, 125 MHz) 156.08, 150.23,
142.41, 140.28, 139.43, 127.48, 121.44, 115.89, 106.66,
65.14, 45.34, 12.65, 10.02; MS (EI, 70 eV) m/z for
C17H21N7O (rel. intensity, ion): 339 (7, Mþ), 154 (95),
121 (38), 105 (35), 94 (86), 77 (24), 43 (100), 39 (53); IR
(KBr): 3307, 2960, 2852, 1595, 1568, 1389, 1369, 1121,
3.2.3. 1-Allyl-3,6-bis(30,50-dimethylpyrazol-10-yl)-1,4-
dihydro-1,2,4,5-tetrazine (6c). Yellow solid, mp: 84–
1
85 8C (decomposition); H NMR (CDCl3, 500 MHz) 8.05
(s, 1H), 5.96 (s, 1H), 5.89 (s, 1H), 5.84 (ddt, 1H, J¼16.9,
10.5, 6.4 Hz), 5.14 (dqa, 1H, J¼16.9, 1.6 Hz), 5.08 (dqa,
1H, J¼10.5, 1.6 Hz), 3.84 (dt, 2H, J¼6.4, 1.6 Hz), 2.49 (s,
3H), 2.31 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H); 13C NMR
(CDCl3, 125 MHz): 150.94, 150.21, 145.90, 145.00, 143.16,
142.72, 133.96, 117.33, 110.11, 107.12, 53.99, 14.06, 13.68,
13.55, 11.49; MS (EI, 70 eV) m/z for C15H20N8 (rel.
intensity, ion) 312 (88, Mþ), 271 (56, M-allyl), 215 (29),
164 (25), 122 (85), 97 (100); IR (KBr): 3209, 3138, 3075,
2961, 2927, 1690, 1571, 1490, 1415, 1362, 1261, 1172,
1078, 1025, 973, 798 cm21. HRMS (EI) Calcd for
C15H20N8: m/z 312.1811. Found: m/z 312.1809.
761, 732, 698, 688 cm21
. HRMS (EI) Calcd for
C17H21N7O: m/z 339.1808. Found: m/z 339.1802.
3.2.8. 1-Butyl-3,6-bis(methylthio)-1,4-dihydro-1,2,4,5-
tetrazine (9a). Pink solid, mp: 39–40 8C (decomposition);
1H NMR (CDCl3, 250 MHz) 6.50 (s, 1H), 3.32 (t, 2H,
J¼7.3 Hz), 2.43 (s, 3H), 2.35 (s, 3H), 1.71 (qi, 2H,
J¼7.2 Hz), 1.38 (sex, 2H, J¼7.2 Hz), 0.93 (t, 3H,
J¼7.3 Hz); 13C NMR (CDCl3, 62.5 MHz) 154.25, 150.43,
51.27, 29.98, 29.86, 19.87, 14.40, 13.38; MS (EI, 70 eV) m/z
for C8H16N4S2 (rel. intensity, ion): 232 (100, Mþ), 189 (50),
3.2.4. 1-Butyl-3,6-bis(30-pyridyl)-1,4-dihydro-1,2,4,5-
1
tetrazine (7a). H NMR (CDCl3, 250 MHz) 9.33 (dd, 1H,

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J. Farago et al. / Tetrahedron 60 (2004) 1991–1996
1995
176 (17), 161 (7), 87 (6), 74 (48), 57 (7), 41 (15); IR (KBr):
4. Supplementary Material
3265, 2961, 2929, 2861, 1603, 1588, 1467, 1440, 1416,
1374, 1268, 1190, 1149, 1129, 776, 608 cm21. HRMS (EI)
Calcd for C8H16N4S2: m/z 232.0816. Found: m/z 232.0814.
1H and 13C NMR spectra of the new compounds reported in
Tables 1 and 2.
3.2.9. 1-Phenyl-3,6-bis(methylthio)-1,4-dihydro-1,2,4,5-
tetrazin (9b). Pale orange solid, mp: 117–118 8C
(decomposition); 1H NMR (CDCl3, 250 MHz) 7.36 (d,
2H, J¼8.1 Hz), 7.27 (dd, 2H, J¼8.1, 7.2 Hz), 7.13 (t, 1H,
J¼7.2 Hz), 7.10 (s, 1H), 2.40 (s, 3H), 2.25 (s, 3H); 13C
NMR (CDCl3, 62.5 MHz) 152.25, 151.95, 142.14, 128.24,
125.97, 123.48, 14.74, 14.20; MS (EI, 70 eV) m/z for
C10H12N4S2 (rel. intensity, ion): 252 (100, Mþ), 150 (12),
135 (11), 91 (7), 74 (50), 65 (6), 51 (14); IR (KBr): 3282,
3258, 3054, 2926, 1613, 1590, 1490, 1416, 1283, 1170,
1151, 1070, 951, 764, 696 cm21. HRMS (EI) Calcd for
C10H12N4S2: m/z 252.0503. Found: m/z 252.0502.
Acknowledgements
´ ´
´
The help of Ms. Zsuzsanna Czegeny-Novak (MS) as well as
financial support from the Hungarian Ministry of Education
(FKFP 0125/2001) and Richter Gedeon Rt. (fellowship to
J. F.) is gratefully acknowledged.
References and notes
1. Sauer, J. 1,2,4,5-tetrazines in comprehensive heterocyclic
chemistry II; Boulton, A. J., Katritzky, A. R., Rees, C. W.,
Scriven, E. F., Eds.; Pergamon: New York, 1996; pp 901–955.
2. Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder method-
ology in organic synthesis; Academic: New York, 1997.
3. Schirmer, U.; Wuerzer, B.; Meyer, N.; Neugebauer; F. A.,
Fischer, H. DE Patent No. 3508214, 1986; Chem. Abstr. 1987,
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3.2.10. 3,6-Bis(30-pyridyl)-1,4-dihydro-1,2,4,5-tetrazine
(11).35 1H NMR (CDCl3, 250 MHz) 9.35 (s, 2H), 8.99
(d, 2H, J¼1.8 Hz), 8.67 (dd, 2H, J¼4.9, 1.6 Hz), 8.18
(dt, 2H, J¼8.5, 1.8 Hz), 7.50 (dd, 2H, J¼7.4, 4.7 Hz);
13C NMR (CDCl3, 62.5 MHz) 113.98, 110.14, 109.22,
96.43, 88.95, 86.58; MS (EI, 70 eV) m/z for C12H10N6
(rel. intensity, ion): 238 (100, Mþ), 105 (62), 78 (34),
51 (23); HRMS (EI) Calcd for C12H10N6: m/z 238.0967.
Found: m/z 238.0965.
4. Zambach, W.; Naef, R.; Trah, S.; Jeanguenat, A.; Eberle, M.;
Steiger, A. WO Patent Appl. 0078739, 2000; Chem. Abstr.
2001, 134, 71613.
3.2.11. 3-Butoxy-6-(30,50-dimethylpyrazol-10-yl)-1,2,4,5-
tetrazine (12). Red solid, mp: 28–29 8C; 1H NMR
(CDCl3, 500 MHz) 6.08 (s, 1H), 4.60 (t, 2H, J¼6.9 Hz),
2.57 (s, 3H), 2.29 (s, 3H), 1.86 (qi, 2H, J¼6.9 Hz), 1.49
(sex, 2H, J¼6.9 Hz), 0.94 (t, 3H, J¼6.9 Hz); 13C NMR
(CDCl3, 125 MHz): 166.66, 159.68, 153.81, 143.31, 11.37,
70.62, 30.98, 19.35, 14.54, 14.15, 14.05; MS (EI, 70 eV) m/z
for C11H16N6O (rel. intensity, ion): 248 (24, Mþ), 194 (5),
163 (6), 122 (100), 96 (7), 57 (18); IR (KBr): 2961, 2873,
1577, 1484, 1431, 1370, 1351, 1084, 953 cm21. HRMS
(EI) Calcd for C11H16N6O: m/z 248.1386. Found: m/z
248.1381
5. Chavez, D. E.; Hiskey, M. A. J. Energ. Mater. 1999, 174,
357–377.
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7929–7933.
3.2.12. 3-Butoxy-6-(N-morpholino)-1,2,4,5-tetrazine
(13a). Red solid, mp: 53–54 8C; 1H NMR (CDCl3,
250 MHz) 4.47 (t, 2H, J¼6.6 Hz), 3.88–3.79 (m, 8H,
J¼11.1 Hz), 1.85 (qi, 2H, J¼14.2 Hz), 1.50 (sex, 2H,
J¼18.7 Hz), 0.96 (t, 3H, J¼7.4 Hz); 13C NMR (CDCl3,
62.5 MHz) 164.32, 161.33, 68.80, 66.34, 44.17, 30.69,
18.96, 13.67; MS (EI, 70 eV) m/z for C10H17N5O2 (rel.
intensity, ion): 239 (93, Mþ), 149 (71), 111 (67), 85 (100),
81 (49), 67 (67), 53 (88), 44 (66), 30 (57); IR (KBr): 2967,
2959, 2936, 2917, 2906, 2865, 1769, 1717, 1530, 1479,
1460, 1330, 1302, 1249, 1120, 1018, 967, 957, 936, 852,
569, 553 cm21. HRMS (EI) Calcd for C10H17N5O2: m/z
239.1382. Found: m/z 239.1371.
´
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´ ´ ˝
14. Novak, Z.; Bostai, B.; Csekei, M.; Lorincz, K.; Kotschy, A.
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3.2.13. 3-Phenoxy-6-(N-morpholino)-1,2,4,5-tetrazine
(13b). Red solid, mp: 95–97 8C; 1H NMR (CDCl3,
250 MHz) 7.91 (d, 2H, J¼7.7 Hz), 7.50–7.35 (m, 3H),
3.87 (t, 4H, J¼5.2 Hz), 3.76 (t, 4H, J¼5.2 Hz); 13C NMR
(CDCl3, 125 MHz); 149.93, 146.95, 138.18, 128.00, 122.30,
120.42, 65.14, 43.99; MS (EI, 70 eV) m/z for C12H13N5O2
(rel. intensity, ion): 259 (5, Mþ), 153 (52), 119 (100), 112
(3), 41 (38).
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are also formed in the process demonstrating the presence of
the same chemistry, we believe that the formation of
significant amounts of 12 in entries 22–25 and the
transformation of 8a into 13a occur by different mechanism.
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