Novel synthesis of 3,6-disubstituted-1,2,4,5-tetrazine derivatives from hydrazones by using [hydroxyl(tosyloxy)iodo]benzene

Article abstract of DOI:10.1016/j.tetlet.2013.06.053

A mild and efficient protocol for the construction of 1,4-dihydro-3,6- disubstituted-1,4-bis(p-toluenesulfonyl)-1,2,4,5-tetrazines from p-toluenesulfonyl hydrazones mediated by [hydroxyl(tosyloxy)iodo]benzene in the presence of pyridine has been developed. This protocol affords the products in good to excellent yields. The corresponding 3,6-disubstituted-1,2,4,5-tetrazines can be easily obtained through one-step N-deprotection of p-toluensulfonyl groups and aromatization by tetrabutyl ammonium fluoride in THF. A mechanism has been proposed.

Full text of DOI:10.1016/j.tetlet.2013.06.053

Tetrahedron Letters 54 (2013) 4645–4648
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel synthesis of 3,6-disubstituted-1,2,4,5-tetrazine derivatives
from hydrazones by using [hydroxyl(tosyloxy)iodo]benzene
⇑
Haixuan Liu, Yunyang Wei
School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient protocol for the construction of 1,4-dihydro-3,6-disubstituted-1,4-bis(p-toluenesul-
fonyl)-1,2,4,5-tetrazines from p-toluenesulfonyl hydrazones mediated by [hydroxyl(tosyloxy)iodo]ben-
zene in the presence of pyridine has been developed. This protocol affords the products in good to
excellent yields. The corresponding 3,6-disubstituted-1,2,4,5-tetrazines can be easily obtained through
one-step N-deprotection of p-toluensulfonyl groups and aromatization by tetrabutyl ammonium fluoride
in THF. A mechanism has been proposed.
Received 18 February 2013
Revised 31 May 2013
Accepted 13 June 2013
Available online 21 June 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Heterocycles
Hydrazones
Hypervalent iodine
Nitrile imide
Tetrazines
1,2,4,5-Tetrazine derivatives are of considerable interest be-
cause of their unique role in constructing diverse aza-containing
heterocycles.1 Moreover, they exhibit versatile applications in
coordination chemistry,2 protein and live cell labeling,3 and as
raw materials or intermediates for the manufacture of organic so-
lar cells,4 high energetic materials,5 and pharmaceuticals including
antitumor,6 insecticidal, and acaricidal drugs.7,8 The most common
way to access these molecules involves treating aromatic nitriles
with hydrazine to give dihydro-1,2,4,5-tetrazines followed by oxi-
dation.6,9 Recently, Devaraj and co-workers utilized divalent nickel
and zinc salts as catalysts in this method and broadened the sub-
stance to unreactive aliphatic nitriles.10
On the other hand, hypervalent iodine reagents have been exten-
sively used in organic synthesis and were proved to be effective to
simplify the construction of heterocyclic frames.11,12 [Hydroxyl
(tosyloxy)iodo]benzene (HTIB), known as Koser’s reagent, is one of
the most investigated hypervalent iodine reagents and has been
established as a powerful reagent in many kinds of transforma-
tions.13 In continuation of our efforts to develop new applications
of hypervalent iodine reagents,14–18 recently, we focus on the
synthesis of heterocycles. Here, we would like to report an
HTIB-mediated mild and efficient procedure for one step
synthesis of 1,4-dihydro-3,6-disubstituted-1,4-bis(p-toluenesulfo-
nyl)-1,2,4,5-tetrazines from easily accessible N-tosylhydrazones.
The key process of this reaction is the generation of nitrile imide
1,3-dipoles (Scheme 1). According to early reports, such intermedi-
ates are difficult to acquire, examples involve either the use of
hydrazonoyl halides to react with triethylamine or extruding nitro-
gen from tetrazole precursors, which have several drawbacks such
as harsh reaction conditions, long reaction time, low yield, and extra
synthetic steps.19,20 Moreover, the N-deprotection and aromatiza-
tion of 1,4-dihydro-3,6-disulstituted-1,4-bis(p-toluenesulfonyl)-
1,2,4,5-tetrazines serve an alternative and promising way for the
synthesis of 3,6-disubstituted-1,2,4,5-tetrazines. We were de-
lighted to find that the known procedure initiated by tetrabutyl
ammonium fluoride (TBAF) is quite competent for this goal. To
our knowledge, there are no reports to exploit hypervalent iodine
reagents on the construction of tetrazines before.
The initial experiments were carried out in CH2Cl2 with
4-chlorobenzaldehyde tosylhydrazone 1a as the model substrate.
HTIB (1.1 equiv) was used as oxidant and 4-dimethylaminopyri-
dine (DMAP, 5 equiv) was used as base. The reaction was per-
formed at room temperature. It was found by TLC plate that the
starting material was consumed completely after 5 min reaction
and two new spots generated. One of the new spots was identified
as the spot of 1,4-dihydro-3,6-bis(4-chlorophenyl)-1,4-bis(p-tolu-
enesulfonyl)-1,2,4,5-tetrazines 2a. The other spot was purple in
Ts
O
N
N
H
N
N
N
R
H
N
SOCl2
R
C
N
Ts
Early work:
This work:
R
N
H
Ts
Cl
Ts
-N2
Et3N
N
N
N
N
H
HTIB
R
R
R
C
H
N
N Ts
R
C N N Ts
pyridine
Ts
⇑
Corresponding author. Tel./fax: +86 (25)84317078.
E-mail address: ywei@mail.njust.edu.cn (Y. Wei).
Scheme 1. Methods to prepare N-p-toluenesulfonyl protected 1,4-dihydro-1,2,4,5-
tetrazines.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.053

4646
H. Liu, Y. Wei / Tetrahedron Letters 54 (2013) 4645–4648
Table 1
Optimization of reaction conditions
Cl
Cl
Ts
NHTs
N
N
N
N
oxidant, base
conditions
N
N
N
N
Cl
N
Ts
Cl
Cl
2a
1a
3a
Entry
Oxidanta
Base
/
DMAP 5 equiv
DMAP 5 equiv
DMAP 5 equiv
Pyridine 6 equiv
Pyridine 6 equiv
Pyridine 3 equiv
Pyridine 6 equiv
Conditions
Yieldb (%)
1
2
3
4
5
6
7
8
HTIB
/
CH2Cl2, rt
CH2Cl2, rt
CH2Cl2, rt
EtOAc, 70 °C
CH2Cl2, rt
CH2Cl2, 0 °C
CH2Cl2, 0 °C
CH2Cl2, 0 °C
Mixture
0
HTIB
HTIB
HTIB
HTIB
HTIB
DIB
45; 40c
0
87
93d
75d
55d
a
1.1 equiv of oxidant was used for the reaction.
The yield represents isolated yield of 2a.
The yield represents isolated yield of 3a.
The reaction time was 15 min.
b
c
d
Table 2 (continued)
Table 2
Synthesis of 1,4-dihydro-3,6-disubstituted-1,4-bis(p-toluenesulfonyl)-1,2,4,5-tetra-
zines
Entry
Hydrazones
Product
2l
Yielda (%)
N
N
Ts
NHTs
12
13
84
65
S
N
R
H
N
N
HTIB 1.1eq. pyridine 6eq.
CH2Cl2, 0 o
NHTs
NHTs
N
2m
R
N
Ts
R
N
O
C
Ts
2
N
14
15
16
2n
2o
2p
39
28
34
1
NHTs
N
Entry
1
Hydrazones
Product
Yielda (%)
93
NHTs
N
N
NHTs
N
NHTs
2a
17
2q
42c
Cl
NHTs
a
N
The yield represents isolated yield and the reaction times were between 15 min
2
3
2b
2c
95
96
and 2 h.
b
c
Isolated as p-dimethylaminobenzaldehyde.
The product identified as 4-methyl-N0-pivaloylbenzenesulfonohydrazide.
NHTs
N
Br
NHTs
NHTs
N
4
5
6
2d
2e
2f
85
90
87
MeO
H3C
color, which was proved to be 3,6-bis(4-chlorophenyl)-1,2,4,5-tetr-
azine 3a after separation and NMR spectra analyses. The ratio of 2a
and 3a isolated was approximately 1:1 and 2a was stable enough
to be separated and dried, but converted into 3a slowly in the sol-
vent. Given the initial success, a survey of reaction parameters was
then conducted with the aim to suppress the formation of 3a
(Table 1).
The control experiments were first examined and it was found
that DMAP alone did not induce this transformation (Table 1, entry
2). While HTIB was used in the absence of base, the reaction gave
complex mixture of byproducts (Table 1, entry 1). So both HTIB and
base were indispensable for this reaction. Changing the solvent to
EtOAc, albeit heated to 70 °C led to no reactions probably due to
the poor solubility of HTIB in EtOAc (Table 1, entry 4). Using
pyridine instead of DMAP successfully suppressed the generation
of 3a, and a great increase in the yield of 2a was observed (Table 1,
entry 5). When the reaction proceeded at 0 °C instead of room tem-
perature, the yield of 2a also increased (Table 1, entry 6). Decreas-
ing the dosage of base to 3 equiv, the reaction became sluggish and
was not completed in 15 min (Table 1, entry 7). When (diacetoxy-
iodo)benzene (DIB) was utilized as oxidant, inferior result was ob-
tained (Table 1, entry 8). Therefore, the following reaction
conditions were selected for further experiments, that is, using
N
NHTs
N
Br
NHTs
NHTs
N
7
2g
80
MeO
OMe
N
8
9
2h
2i
58
15
O2N
NC
N
NHTs
NHTs
N
N
10
11
2j
75b
68
2k
NHTs
N

H. Liu, Y. Wei / Tetrahedron Letters 54 (2013) 4645–4648
4647
It was observed that this protocol was generally feasible with
aryl, heteroaryl, and alkyl substituted N-tosylhydrazones. Benzal-
dehyde and halo, methoxy or methyl functionalized benzaldehyde
derived hydrazones gave the target products in good to excellent
yields (Table 2, entries 1–7). In case of hydrazones bearing highly
electron-withdrawing groups on the aromatic ring, such as the ni-
tro group and cyano group, the yield of isolated products declined
(Table 2, entries 8, 9). When p-dimethylaminobenzaldehyde tos-
ylhydrazone was used as reactant, only dehydrazone product
HO OTs
I
HO Ph
HO Ph
I
I
O
O
O
O
O
O
H
R
S
N
R
Ph
S
N
S
N
R
Ar
N
H
Ar
N
Ar
N
H
H
OTs
OTs
A
B
C
O
O
R
S
N
base
Ar
N
H
Ts
N
N
C R
Ts
N N C R
OTs
was obtained (Table 2, entry 10).
a-Naphthaldehyde derived
D
E
hydrazone and heteroaryl N-tosylhydrazones also underwent
the reaction smoothly and afforded the desired products in mod-
erate to good yields (Table 2, entries 11–13). To our delight, the
alkyl N-tosylhydrazone can take part in the reaction (Table 2, en-
tries 14–16). However, with pivaldehyde derived N-tosylhydraz-
one as substrate, 4-methyl-N’-pivaloylbenzenesulfonohydrazide,
an oxidative product of the N-tosylhydrazone, was formed in
42% yield and no corresponding tetrazine was detected (Table 2,
entry 17).21
Ts
Ts
R
N
N
C
N
R
N N
N N
+
R
R
C
N
Ts
Ts
Scheme 2. Plausible mechanism.
Table 3
Deprotection/aromatization of 1,4-dihydro-3,6-disubstituted-1,4-bis(p-toluenesulfo-
nyl)-1,2,4,5-tetrazines
On the basis of the above results, a plausible mechanism was
proposed (Scheme 2). Initially, N-tosylhydrazones A was oxidized
to nitrenium ion B. The addition of tosyloxy anion to B followed
Ts
N
R
N
N
3
R
TBAF 1.1eq.
THF, reflux
by elimination of iodobenzene and water afforded
a-tosyloxy
N
N
N
substituted N-tosylhydrazone D. Base catalyzed 1,3-elimination
of p-toluenesulfonic acid afforded nitrilesulfonimide E. This
1,3-dipole intermediate readily dimerized to form the desired
products.
N
R
N
Ts
2
R
The ready synthesis of 1,4-dihydro-3,6-disubstituted-1,4-
bis(p-toluenesulfonyl)-1,2,4,5-tetrazines aroused our interest to
examine methods to get synthetically more important 3,6-
disubstituted-1,2,4,5-tetrazines through deprotection of p-tolu-
ensulfonyl groups and presumably aromatization at the same
time.
Entry
R
Product
3a
Yielda (%)
1
2
3
93
96
90
Cl
3b
Among the methods we tested, we found the known procedure
using TBAF was suitable. According to the literature,22 1.1 equiv of
TBAF was used in refluxing THF and the results are summarized in
Table 3.24 Most of the examined 1,4-dihydro-3,6-disubstituted-
1,4-bis(p-toluenesulfonyl)-1,2,4,5-tetrazines gave corresponding
deprotection/aromatization products in high yields by this mild
protocol (Table 3). p-Nitrophenyl substituted substrate can get a
satisfied result by changing the reaction solvent to ethanol (Table 3,
entry 10). However, o-bromophenyl and 2-furyl substituted sub-
strates were inert under the reaction conditions (Table 3, entries
6, 9). We found 2-furyl substituted substrate can be N-deprotected
and aromatized by 40 equiv of conc. H2SO4 to get the desired prod-
uct in 85% yield (Table 3, entry 9).25 But for o-bromophenyl sub-
strate, still no deprotection/aromatization product was observed
using this method.
In summary, we have found a novel way of constructing 1,4-
dihydro-3,6-disubstituted-1,4-bis(p-toluenesulfonyl)-1,2,4,5-tetr-
azines starting from N-tosylhydrozones. This general protocol can
apply to aryl, heteroaryl, and alkyl substituted N-tosylhydrazones.
A [hydroxyl(tosyloxy)iodo]benzene mediated generation of nitrile
imide mechanism was proposed. Meanwhile, 3,6-disubstituted-
1,2,4,5-tetrazines can be afforded in high yields by deprotection/
aromatization of the dihydro products. We believe that this reac-
tion route with metal-free and mild conditions will provide an
alternative method to construct 1,2,4,5-tetrazines especially dihet-
eroaryl and dialkyl substituted 1,2,4,5-tetrazines and make these
heterocycles more accessible.
3c
Br
4
5
6
7
3d
3e
3f
98
97
MeO
H3C
<5
Br
3h
92b
O2N
8
9
3l
99
S
3m
<5; 85c
O
10
11
12
3n
3o
3p
99
92
94
a
The yield represents isolated yield and the reaction times were between 30 min
and 4 h.
Ethanol was used as solvent.
0.5 mmol substrate was dissolved in 5 ml of ethanol at 80 °C, and 1 ml of concd
H2SO4 dropped in.
b
c
HTIB (1.1 equiv) as oxidant and pyridine (6 equiv) as base and car-
rying out the reaction in CH2Cl2 at 0 °C.23
Acknowledgments
With the reaction conditions screened, the scope and generality
of the reaction were then investigated. The results are depicted in
Table 2.
We are grateful to the Nanjing University of Science and Tech-
nology for the financial support.

4648
H. Liu, Y. Wei / Tetrahedron Letters 54 (2013) 4645–4648
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053.
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23. Typical procedure for the synthesis of 1,4-dihydro-3,6-disubstituted-1,4-bis(p-
toluenesulfonyl)-1,2,4,5-tetrazines: To a stirred solution of N-tosylhydrazone
(1.00 mmol) in CH2Cl2 (10 ml) at 0 °C were added pyridine (0.480 ml,
6.00 mmol) and HTIB (0.431 g, 1.10 mmol) sequentially. The stirring was
then continued until TLC monitored the full consumption of hydrazone. Upon
completion, the reaction was quenched with aqueous HCl (1.0 M, 20 ml). The
mixture was stirred for an additional 10 min and extracted with CH2Cl2
(10 ml ꢀ 3). The combined organic layers were concentrated in vacuum. The
crude residue was purified by column chromatography (EtOAc/petroleum
ether, 1:4) to give the pure product.
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A
mixture of 1,4-dihydro-3,6-disubstituted-1,4-bis(p-toluenesulfonyl)-1,2,4,5-
tetrazines (0.500 mmol), TBAF 1.0 M solution in THF (0.550 ml, 0.550 mmol),
and THF (5 ml) was refluxed until TLC monitored the full consumption of the
starting material. Then, the reaction mixture was concentrated in vacuum to
get a purple solid and washed with methanol (10 ml ꢀ 3), or directly filtered
through a pad of silica gel to remove the catalyst and followed by rotary
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Di(furan-2-yl)-1,4-bis(tosyl)-1,4-dihydro-1,2,4,5-tetrazine (0.263g, 0.500 mmol)
was added in 5 ml ethanol and was heated to 80 °C. Then, conc. H2SO4 (1.09 ml,
20.0 mmol) was dropped in slowly. Keep stirring until TLC monitored the full
consumption of the substrate. Then, the reaction mixture was washed with
aqueous NaHCO3 (1.0 M, 10 ml) and extracted with CH2Cl2 (10 ml ꢀ 3). The
combined organic layers were concentrated in vacuum. The crude residue was
purified by column chromatography (EtOAc/petroleum ether, 1:10) to give the
pure product.
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