Chlorination of Arylaldehyde-Derived Arylsulfonylhydrazones with N -Chlorosuccinimide Leading to 1,2,4,5-Tetrazine Derivatives

Article abstract of DOI:10.1055/s-0039-1690712

It has been reported previously that treatment of aryl-ketone-derived arylsulfonylhydrazones with NXS/(n Bu) ₄ NX affords exclusively vinyl halides. In contrast, we have found that treatment of aryl-aldehyde-derived arylsulfonylhydrazones with

Full text of DOI:10.1055/s-0039-1690712

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–F
paper
A
en
Y.-Z. Ji et al.
Paper
Synthesis
ChlorinationofArylaldehyde-DerivedArylsulfonylhydrazoneswith
N-Chlorosuccinimide Leading to 1,2,4,5-Tetrazine Derivatives
Yuan-Zhao Jia
Hui-Jing Li*a,b
Ying Liua,b
SO2Ar2
N
NCS (2 equiv)
KOH (1 equiv)
Ar1
N
NHSO2Ar2
Ar1
N
N
Ar1
N
CH3NO2, 0 °C
Yan-Chao Wu*a,b
0
0
0
0-0
0
0
2-0
1
1
1-7
4
8
4
SO2Ar2
One-pot synthesis
16 examples
Metal-free conditions
Up to 93% yield
a School of Marine Science and Technology, Harbin Institute of
Technology, 2 Wenhuaxi Road, Weihai 264209, P. R. of China
b Weihai Institute of Marine Biomedical Industrial Technology,
Wendeng District, Weihai 264400, P. R. of China
lihuijing@iccas.ac.cn
ycwu@iccas.ac.cn
Received: 21.07.2019
Accepted after revision: 24.09.2019
Published online: 14.10.2019
NCS and KOH under metal-free conditions (Scheme 1). The
discovery of this 1,2,4,5-tetrazine synthetic protocol was
somewhat unexpected. It began with our attempts to syn-
thesize dichlorides from arylaldehyde-derived arylsulfonyl-
hydrazones using Prabhu’s conditions. Regrettably, the
chlorination reaction did not afford the desired dichlorides;
instead, 1,2,4,5-tetrazines were unexpectedly obtained.
Considering the importance of 1,2,4,5-tetrazine derivatives
in chemical, biological, and environmental sciences,1–7 we
decided to study this process further by optimizing the re-
action conditions for the synthesis of 1,2,4,5-tetrazines.
DOI: 10.1055/s-0039-1690712; Art ID: ss-2019-h0398-op
Abstract It has been reported previously that treatment of aryl-
ketone-derived arylsulfonylhydrazones with NXS/(nBu)4NX affords ex-
clusively vinyl halides. In contrast, we have found that treatment of aryl-
aldehyde-derived arylsulfonylhydrazones with N-chlorosuccinimide in
the presence of potassium hydroxide affords 1,2,4,5-tetrazine deriva-
tives in good to excellent yields. The present reactions are carried out
under metal-free and mild reaction conditions.
Key words 1,2,4,5-tetrazines, hydrazones, N-chlorosuccinimide, chlo-
rination, metal-free
Ts
NXS, (nBu)4NX
NCS
KOH, 0 °C
X
R1
NHTs
R
N
Ar
N
N
base, 90 °C
Prabhu's work,13 R = CH2R1
N
this work, R = H
Ar
Ar
Ar
N
1,2,4,5-Tetrazine derivatives are versatile aromatic het-
erocycles1 that have been applied in organic electronics
[e.g., organic photovoltaic (OPV) devices, organic field-ef-
fect transistors (OFETs)],2 energetic materials,3 coordination
chemistry,4 electrofluorochromism,5 and in the synthesis of
biologically active molecules.6 Recently, 1,2,4,5-tetrazines
have also attracted a fair amount of attention in life scienc-
es, with applications in cell imaging, DNA labelling, etc.7 In
general, 1,2,4,5-tetrazines are synthesized predominantly
by the reaction of hydrazine with aromatic nitriles, fol-
lowed by oxidation of the generated 1,2-dihydrotetrazines.8
In addition, further modification of 1,2,4,5-tetrazines has
also emerged as a useful tool.9
On the other hand, arylsulfonylhydrazones are key
building blocks in synthetic chemistry,10,11 especially for the
synthesis of nitrogen-containing heterocycles.12 In 2015,
Prabhu and Ojha13 reported an elegant synthesis of vinyl
halides from arylketone-derived N-tosylhydrazones using
NXS/(nBu)4NX, in which dihalides were the proposed reac-
tion intermediates (Scheme 1). Herein, we report a facile
synthesis of 1,2,4,5-tetrazine derivatives from arylalde-
hyde-derived arylsulfonylhydrazones in the presence of
Ts
X
Cl
not
observed
R1
Ar
X
Ar
Cl
Scheme 1 Synthetic applications of arylsulfonylhydrazones
4-Nitrobenzaldehyde N-tosylhydrazone (1a) was select-
ed as a model substrate for optimizing the reaction condi-
tions (Table 1). Following Prabhu’s procedure [NBS (1.5
equiv), (nBu)4NBr (3 equiv), K2CO3 (3.0 equiv), 1,4-diox-
ane],13 treatment of 4-nitrobenzaldehyde N-tosylhydrazone
(1a) at 25 °C for 3 hours did not afford the corresponding
benzyl dihalide. Instead, 3,6-bis(4-nitrophenyl)-1,4-dito-
syl-1,4-dihydro-1,2,4,5-tetrazine (2a) was obtained, albeit
in only 19% yield (entry 1). The reaction proceeded un-
eventfully in the absence of TBAB (entries 1 and 2). Promot-
ers such as N-chlorosuccinimide (NCS), N-iodosuccinimide
(NIS) and iodine (I2) could be used for this reaction, but NCS
gave the best yield (entries 2–5). Various solvents including
CH3NO2, CH3CN, THF, CH2Cl2 and 1,4-dioxane were also
investigated, among which CH3NO2 was the best (entries 3
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y.-Z. Ji et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditionsa
On using organic bases, such as Et3N and DMAP, no reac-
tion occurred and the starting materials were recovered
(Table 1, entries 20 and 21). The yield of 1,2,4,5-tetrazine 2a
decreased when the loading of KOH was less than 1.0 equiv-
alent (entries 18 and 22–25). The effect of different tem-
peratures was investigated and the reaction at 0 °C was
found to give 1,2,4,5-tetrazine 2a in a higher yield (entries
24 and 26). Furthermore, a large-scale reaction using 4-ni-
trobenzaldehyde N-tosylhydrazone (1a) (1.28 g) also gave
an excellent yield of the corresponding 1,2,4,5-tetrazine 2a
(entry 27).
NO2
Ts
N
NHTs
conditions
N
N
N
O2N
N
1a
2a
Ts
O2N
Entry
Promoter
(equiv)
Solvent
Base (equiv)
Yield (%)b
1c
2
NBS (1.5)
NBS (1.5)
NCS (1.5)
NIS (1.5)
I2 (1.5)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH3CN
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
19
19
63
10
25
40
10
25
65
0
3
Ar2
4
SO2
KOH (1 equiv)
N
Ar1
5
H
NCS (2 equiv)
Ar2
N
N
Ar1
N
S
N
6
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
none
Ar1
N
O2
CH3NO2, 0 °C, 3 h
O2S
Ar2
7
THF
1
2
8
CH2Cl2
R
Ts
Ts
N
9
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
N
NO2
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26d
27d,e
N
NO2
N
N
N
NCS (0.5)
NCS (1.0)
NCS (2.0)
NCS (2.5)
NCS (2.0)
NCS (2.0)
NCS (2.0)
NCS (2.0)
NCS (2.0)
NCS (2.0)
NCS (2.0)
NCS (2.0)
NCS (2.0)
NCS (2.0)
NCS (2.0)
NCS (2.0)
NCS (2.0)
9
Ts
Ts
R
44
72
72
67
69
44
78
50
0
2i: 43%
2a (R = NO2): 88%
2b (R = CF3): 51%
2c (R = F): 72%
2d (R = Cl): 76%
2e (R = Br): 50%
2f (R = H): 67%
Ts
N
N
Cl
Cl
N
N
Na2CO3 (3.0)
Cs2CO3 (3.0)
Li2CO3 (3.0)
KOH (3.0)
K3PO4 (3.0)
Et3N (3.0)
DMAP (3.0)
none
Ts
2g (R = Me): 48%
2h (R = OMe): 50%
2j: 73%
R
Cl
Ts
N
NO2
Cl
N
SO2
N
Cl
N
N
N
0
Ts
N
N
Cl
31
44
78
78
88
85
2k: 62%
SO2
KOH (0.5)
KOH (1.0)
KOH (2.0)
KOH (1.0)
KOH (1.0)
O2N
Cl
Cl
Ts
N
N
R
2n (R = H): 67%
2o (R = OMe): 63%
Cl
Cl
N
N
Ts
a Reaction conditions: 1a (0.2 mmol), promoter (0–0.5 mmol), base (0–0.6
mmol), solvent (1.0 mL), 25 °C, 3 h.
2l: 93%
b Yield of isolated product.
NO2
c (nBu)4NBr (0.6 mmol) was used.
SO2
d Reaction was performed at 0 °C.
N
N
Ts
e Reaction was carried out on a 1.28 g scale of 1a (4.0 mmol).
N
N
N
N
Cl
Cl
Cl
N
N
Cl
SO2
O2N
Ts
and 6–9). The reaction did not work without NCS, and the
reaction with N-tosylhydrazone 1a afforded a higher yield
when using the 2.0 equivalents of NCS (entries 9–14). The
choice of base was also important for this reaction. The re-
action could be achieved with various inorganic bases such
as Na2CO3, Cs2CO3, Li2CO3, KOH and K3PO4 (entries 15–19).
However, KOH was selected for our further studies because
it displayed the best efficiency (entries 13 and 15–19).
2m: 68%
2p: 76%
Scheme 2 Synthesis of 1,2,4,5-tetrazines 2a–p. General conditions: 1 (0.2
mmol), NCS (0.4 mmol), KOH (0.2 mmol), CH3NO2 (1.0 mL), 0 °C, 3 h.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–F

C
Y.-Z. Ji et al.
Paper
Synthesis
Having optimized the reaction conditions, the scope of
the reaction with arylaldehyde-derived arylsulfonylhydra-
zones was subsequently explored and the results are com-
piled in Scheme 2. A wide range of N-tosylhydrazones, with
either hydrogen atoms, electron-withdrawing groups or
electron-donating groups at the ortho, meta or para posi-
tions of their aromatic rings, reacted smoothly in the pres-
ence of NCS (2.0 equiv) and KOH (1.0 equiv) at 0 °C to afford
1,2,4,5-tetrazines 2a–m in moderate to excellent yields
within 3 hours. Arylsulfonylhydrazones derived from me-
thoxy- and methyl-substituted benzenesulfonyl hydrazides
reacted under the optimized conditions to generate 1,2,4,5-
tetrazines 2n–p in good yields. The structures of these
1,2,4,5-tetrazines were determined from their NMR spectra
and by X-ray crystallographic analysis of 1,2,4,5-tetrazines
2c and 2e (Figure 1).14
dianions 5. Finally, removal of the two chlorine anions from
intermediate 5 affords the corresponding 1,2,4,5-tetrazines
2.
According to the literature,9d 3,6-disubstituted-1,2,4,5-
tetrazines 6 can be synthesized via deprotection and aro-
matization of 1,4-dihydro-3,6-disubstituted-1,4-bis(aryl-
sulfonyl)-1,2,4,5-tetrazines 2. For example, following Wei’s
procedure [TBAF (1.1 equiv), EtOH, reflux],9d the reaction of
3,6-bis(4-nitrophenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-
tetrazine (2a) afforded 3,6-bis(4-nitrophenyl)-1,2,4,5-tetra-
zine (6a) in 92% yield (Scheme 4).
NO2
NO2
Ts
N
N
N
N
TBAF (1.1 equiv)
EtOH, reflux
N
N
N
N
Ts
O2N
O2N
2a
6a, 92%
Scheme 4 Deprotection/aromatization of 3,6-bis(4-nitrophenyl)-1,4-
ditosyl-1,4-dihydro-1,2,4,5-tetrazine (2a)
In summary, we have developed a facile method for the
synthesis of 1,2,4,5-tetrazines which proceeds via NCS-me-
diated chlorination of arylaldehyde-derived N-tosylhydra-
zones. The reactions take place under metal-free conditions
and tolerate a wide range of hydrazone substrates to afford
the corresponding 1,2,4,5-tetrazines in good to excellent
isolated yields. Furthermore, the reported procedure for the
preparation of 1,2,4,5-tetrazines and the synthesis of vinyl
halides described by Prabhu13 enrich the reaction diversity.
Studies on the further applications of this method are on-
going in our laboratory.
Figure 1 X-ray crystal structures of 1,2,4,5-tetrazines 2c and 2e14
A possible reaction mechanism for the NCS-mediated
chlorination of N-tosylhydrazones 1 is illustrated in Scheme
3. Initially, the NCS-mediated chlorination of arylaldehyde-
derived N-tosylhydrazones 1 could lead to compounds 3.
The three electron-withdrawing functionalities, i.e., the
N=N double bond, the chlorine and the aromatic substitu-
ents, make the hydrogen on the -carbon very acidic.
Therefore, removal of this hydrogen from 3 in the presence
of the base KOH would take place to provide the anions 4,
and thereby obviating the formation of dichlorides via the
reaction of 3 with a chlorine anion. The double intermolec-
ular azacyclization reaction of 4 may subsequently lead to
Reagents and solvents were obtained from commercial sources and
no further purification was required. The products were purified by
column chromatography on Yantai Xinnuo silica gel (200-300 meshs).
Melting points were recorded on a Gongyi X-5 microscopy digital
melting point apparatus and are uncorrected. IR spectra were mea-
sured on an Electrothemal Nicolet 380 spectrophotometer. 1H and 13
C
NMR spectra were recorded on a Bruker Avance III 400 MHz NMR
spectrometer. All signals for protons are recorded in ppm using the
residual NMR solvent signal as an internal reference (CDCl3, 7.26
ppm). All signals for carbon resonances are recorded in ppm using the
residual NMR solvent signal as an internal reference (CDCl3,
77.0ppm). High-resolution mass spectrometry (HRMS) were per-
formed using an Electrothemal LTQ-Orbitrap mass spectrometer.
O
Cl
C
base
H
N
Ar
N
N
Ts
N
N
N
Ts
Cl
4
Cl
N
Ts
O
Ar
H
Ar
H
Ts
N
N
C
Ar
1
3
1,2,4,5-Tetrazines; General Procedure
base
Cl
4
A mixture of arylaldehyde-derived arylsulfonylhydrazone 1 (1 equiv,
0.2 mmol), NCS (2 equiv, 0.4 mmol) and KOH (1 equiv, 0.2 mmol) in
CH3NO2 (1.0 mL) was stirred at 0 °C for 3 h. After completion of the
reaction, H2O (5 mL) and EtOAc (10 mL) were added and the aqueous
phase was extracted with EtOAc (3 × 10 mL). The combined organic
extracts were dried over anhydrous Na2SO4 and concentrated under
vacuum. Purification of the crude residue by flash chromatography on
silica gel gave the corresponding 1,2,4,5-tetrazine 2.
Ts
N
Ts
Cl
Ar
Ar
N
N
N
N
Ar
Cl
N
Ar
N
N
Ts
5
2
Ts
Scheme 3 Proposed mechanism involving the chlorination of N-tosyl-
hydrazones 1 and the formation of 1,2,4,5-tetrazines 2
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–F

D
Y.-Z. Ji et al.
Paper
Synthesis
3,6-Bis(4-nitrophenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetrazine (2a)
13C NMR (100 MHz, CDCl3):  = 153.8, 145.9, 134.1, 131.6, 130.2,
129.8, 128.6, 128.5, 126.4, 21.7.
Yield: 55.8 mg (88%); yellow solid; mp 101–103 °C.
HRMS (ESI): m/z [M + H]+ calcd for C28H23Br2N4O4S2: 700.9522; found:
700.9526.
IR (film): 2925, 2854, 1595, 1525, 2332, 1174, 855, 605 cm–1
1H NMR (400 MHz, CDCl3):  = 8.27 (d, J = 8.7 Hz, 4 H), 7.75 (d, J = 8.3
Hz, 4 H), 7.66 (d, J = 8.7 Hz, 4 H), 7.42 (d, J = 8.2 Hz, 4 H), 2.51 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 152.2, 149.6, 146.5, 135.6, 133.5,
130.0, 129.7, 128.6, 123.5, 21.8.
.
3,6-Diphenyl-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetrazine (2f)
Yield: 36.5 mg (67%); yellow solid; mp 103–105 °C.
IR (film): 2922, 2850, 1595, 1374, 1331, 1174, 597, 559 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C28H23N6O8S2: 635.1013; found:
635.1017.
1H NMR (400 MHz, CDCl3):  = 7.76 (d, J = 8.2 Hz, 4 H), 7.53–7.49 (m, 6
H), 7.41 (d, J = 7.2 Hz, 4 H), 7.36 (d, J = 8.2 Hz, 4 H), 2.48 (s, 6 H).
1,4-Ditosyl-3,6-bis[4-(trifluoromethyl)phenyl]-1,4-dihydro-
1,2,4,5-tetrazine (2b)
13C NMR (100 MHz, CDCl3):  = 154.6, 149.1, 145.5, 134.4, 131.5,
129.7, 128.8, 128.6, 128.2, 21.7.
HRMS (ESI): m/z [M + H]+ calcd for C28H25N4O4S2: 545.1312; found:
Yield: 34.7 mg (51%); white solid; mp 103–105 °C.
IR (film): 2854, 1595, 1409, 1321, 1175, 843, 597 cm–1
.
545.1318.
1H NMR (400 MHz, CDCl3):  = 7.74 (d, J = 8.2 Hz, 4 H), 7.68 (d, J = 8.3
Hz, 4 H), 7.61 (d, J = 8.2 Hz, 4 H), 7.39 (d, J = 8.1 Hz, 4 H), 2.50 (s, 6 H).
3,6-Di-p-tolyl-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetrazine (2g)
Yield: 27.5 mg (48%); yellow solid; mp 166–168 °C.
IR (film): 2923, 2854, 1596, 1370, 1335, 1174, 817, 668, 589 cm–1
1H NMR (400 MHz, CDCl3):  = 7.78 (d, J = 8.3 Hz, 4 H), 7.42 (d, J = 8.0
Hz, 4 H), 7.37 (d, J = 8.1 Hz, 4 H), 7.21 (d, J = 8.0 Hz, 4 H), 2.47 (s, 6 H),
2.41 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 153.1, 146.2, 133.9, 133.4 (q, JC–F
=
.
33.3 Hz, 2 C), 133.2, 129.9, 129.2, 128.6, 125.3 (q, JC–F = 3.5 Hz, 2 C),
123.6 (q, JC–F = 272.7 Hz, 2 C), 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C30H23F6N4O4S2: 681.1059; found:
681.1066.
13C NMR (100 MHz, CDCl3):  = 154.9, 145.4, 142.0, 134.5, 129.6,
3,6-Bis(4-fluorophenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetrazine
(2c)
128.9, 128.7, 128.5, 126.8, 21.6, 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C30H29N4O4S2: 573.1625; found:
Yield: 41.8 mg (72%); yellow solid; mp 99–101 °C.
573.1629.
IR (film): 3071, 2924, 2852, 1602, 1508, 1375, 1175, 841, 667, 586
cm–1
.
3,6-Bis(4-methoxyphenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetra-
zine (2h)
1H NMR (400 MHz, CDCl3):  = 7.76 (d, J = 8.2 Hz, 4 H), 7.52 (dd, J = 8.6
Hz, 5.3 Hz, 4 H), 7.38 (d, J = 8.2 Hz, 4 H), 7.10 (t, J = 8.5 Hz, 4 H), 2.48 (s,
6 H).
13C NMR (100 MHz, CDCl3):  = 164.7 (d, JC–F = 253.1 Hz, 2 C), 153.9,
145.8, 134.2, 131.0 (d, JC–F = 8.9 Hz, 2 C), 129.7, 128.4, 125.7 (d, JC–F
3.2 Hz, 2 C), 115.5 (d, JC–F = 22.2 Hz, 2 C), 21.6.
Yield: 30.2 mg (50%); yellow solid; mp 153–155 °C.
IR (film): 2921, 2850, 1607, 1257, 1173, 667, 555 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.78 (d, J = 8.3 Hz, 4 H), 7.48 (d, J = 8.8
Hz, 4 H), 7.36 (d, J = 8.1 Hz, 4 H), 6.90 (d, J = 8.8 Hz, 4 H), 3.85 (s, 6 H),
2.47 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 162.3, 155.1, 145.4, 134.7, 130.5,
129.6, 128.5, 121.8, 113.7, 55.3, 21.7.
=
HRMS (ESI): m/z [M + H]+ calcd for C28H23F2N4O4S2: 581.1123; found:
581.1127.
HRMS (ESI): m/z [M + H]+ calcd for C30H29N4O6S2: 605.1523; found:
605.1526.
3,6-Bis(4-chlorophenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetrazine
(2d)
Yield: 46.5 mg (76%); yellow solid; mp 95–97 °C.
3,6-Bis(2-nitrophenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetrazine
(2i)
IR (film): 2921, 2850, 2360, 1595, 1375, 1172, 1092, 1013, 833, 661,
560 cm–1
.
Yield: 27.3 mg (43%); yellow solid; mp 103–105 °C.
1H NMR (400 MHz, CDCl3):  = 7.74 (d, J = 8.3 Hz, 4 H), 7.43 (d, J = 8.6
Hz, 4 H), 7.38 (d, J = 8.7 Hz, 8 H), 2.48 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 153.8, 145.9, 138.0, 134.1, 130.1,
129.8, 128.6, 128.5, 128.1, 21.7.
HRMS (ESI): m/z [M + H]+ calcd for C28H23Cl2N4O4S2: 613.0532; found:
IR (film): 2922, 2851, 1789, 1380, 1176, 761, 673, 563 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.89 (d, J = 8.3 Hz, 2 H), 7.79 (t, J = 7.8
Hz, 2 H), 7.66 (d, J = 7.8 Hz, 2 H), 7.54 (d, J = 8.0 Hz, 4 H), 7.42 (t, J = 7.5
Hz, 2 H), 7.18 (d, J = 8.0 Hz, 4 H), 2.35 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 165.6, 149.6, 146.8, 135.8, 129.8,
129.4, 127.6, 125.8, 116.8, 114.6, 21.7.
613.0536.
HRMS (ESI): m/z [M + H]+ calcd for C28H23N6O8S2: 635.1013; found:
635.1019.
3,6-Bis(4-bromophenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetrazine
(2e)
Yield: 35.0 mg (50%); white solid; mp 104–106 °C.
IR (film): 2923, 2852, 1592, 1375, 1173, 1074, 1010, 628, 521 cm–1
3,6-Bis(3-chlorophenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetrazine
(2j)
.
1H NMR (400 MHz, CDCl3):  = 7.74 (d, J = 8.2 Hz, 4 H), 7.54 (d, J = 8.4
Hz, 4 H), 7.36 (t, J = 8.0 Hz, 8 H), 2.48 (s, 6 H).
Yield: 44.7 mg (73%); white solid; mp 98–100 °C.
IR (film): 2922, 2851, 2361, 1377, 1328, 1176, 1089, 797, 666, 597,
560 cm–1
.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–F

E
Y.-Z. Ji et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 7.74 (d, J = 8.2 Hz, 4 H), 7.48 (d, J = 7.8
Hz, 2 H), 7.43–7.35 (m, 10 H), 2.49 (s, 6 H).
1,4-Bis[(4-methoxyphenyl)sulfonyl]-3,6-bis(4-nitrophenyl)-1,4-
dihydro-1,2,4,5-tetrazine (2o)
13C NMR (100 MHz, CDCl3):  = 153.2, 146.0, 134.2, 134.0, 131.6,
Yield: 42.0 mg (63%); yellow solid; mp 152–154 °C.
IR (film): 2919, 2850, 2361, 1167, 855, 600, 560 cm–1
1H NMR (400 MHz, DMSO-d6):  = 8.35 (d, J = 8.8 Hz, 4 H), 7.73 (t,
J = 9.3 Hz, 8 H), 7.25 (d, J = 9.0 Hz, 4 H), 3.91 (s, 6 H).
.
131.2, 129.9, 129.6, 128.6, 128.5, 127.1, 21.7.
HRMS (ESI): m/z [M + H]+ calcd C28H23Cl2N4O4S2: 613.0532; found:
613.0539.
13C NMR (100 MHz, DMSO-d6):  = 164.5, 151.3, 149.1, 135.4, 130.7,
129.8, 126.3, 123.5, 115.1, 56.0.
HRMS (ESI): m/z [M + H]+ calcd for C28H23N6O10S2: 667.0912; found:
667.0916.
3,6-Bis(2,4-dichlorophenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetra-
zine (2k)
Yield: 42.2 mg (62%); white solid; mp 172–174 °C.
IR (film): 3094, 2924, 1596, 1585, 1381, 1175, 1096, 814, 660, 567
cm–1
.
1,4-Bis(mesitylsulfonyl)-3,6-bis(4-nitrophenyl)-1,4-dihydro-
1,2,4,5-tetrazine (2p)
1H NMR (400 MHz, CDCl3):  = 7.51 (d, J = 7.8 Hz, 4 H), 7.41–7.34 (m, 6
H), 7.25 (d, J = 7.7 Hz, 4 H), 2.45 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 147.1, 145.6, 137.4, 134.8, 133.5,
133.3, 129.4, 129.3, 128.6, 126.9, 126.6, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C28H21Cl4N4O4S2: 680.9753; found:
Yield: 52.4 mg (76%); yellow solid; mp 79–81 °C.
IR (film): 2978, 2940, 1600, 1525, 1348, 1333, 1173, 855, 606 cm–1
1H NMR (400 MHz, CDCl3):  = 8.25 (d, J = 8.6 Hz, 4 H), 7.58 (d, J = 8.6
Hz, 4 H), 7.09 (s, 4 H), 2.51 (s, 12 H), 2.42 (s, 6 H).
.
680.9759.
13C NMR (100 MHz, CDCl3):  = 149.9, 149.4, 145.2, 141.5, 135.6,
132.1, 130.6, 129.8, 123.5, 26.8, 23.1, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C32H31N6O8S2: 691.1639; found:
691.1643.
3,6-Bis(3,4-dichlorophenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetra-
zine (2l)
Yield: 63.3 mg (93%); yellow solid; mp 159–161 °C.
IR (film): 2921, 2850, 1382, 1329, 1174, 814, 662, 565 cm–1
1H NMR (400 MHz, CDCl3):  = 7.74 (d, J = 7.8 Hz, 4 H), 7.50 (d, J = 8.3
Hz, 2 H), 7.44–7.35 (m, 8 H), 2.49 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 152.6, 146.2, 136.2, 133.8, 132.7,
130.46, 130.40, 130.0, 129.3, 128.5, 127.9, 21.7.
HRMS (ESI): m/z [M + H]+ calcd for C28H21Cl4N4O4S2: 680.9753; found:
.
3,6-Bis(4-nitrophenyl)-1,2,4,5-tetrazine (6a)
Yield: 59.6 mg (92%); purple solid; mp 234–236 °C.
1H NMR (400 MHz, CDCl3):  = 8.90 (d, J = 8.6 Hz, 4 H), 8.50 (d, J = 8.6
Hz, 4 H).
The data for this product correspond with the published data.9d
680.9757.
Funding Information
3,6-Bis(2,3-dichlorophenyl)-1,4-ditosyl-1,4-dihydro-1,2,4,5-tetra-
zine (2m)
This work was supported by the Key Research and Development Pro-
gram of Shandong Province (2019GSF108089), the Natural Science
Foundation of Shandong Province (ZR2019MB009), the National Nat-
ural Science Foundation of China (21672046, 21372054), and with
Yield: 46.3 mg (68%); white solid; mp 202–204 °C.
IR (film): 2924, 2853, 1597, 1381, 1177, 1135, 602, 564 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.59 (d, J = 8.0 Hz, 2 H), 7.50 (d, J = 7.6
Hz, 2 H), 7.36 (d, J = 7.9 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 4 H), 7.16 (d, J = 7.9
Hz, 4 H), 2.41 (s, 6 H).
funding from the Huancui District of Weihai City.
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13C NMR (100 MHz, CDCl3):  = 146.7, 145.6, 133.2, 132.9, 132.5,
132.3, 131.8, 129.5, 129.3, 128.4, 127.2, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C28H21Cl4N4O4S2: 680.9753; found:
680.9756.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690712.
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3,6-Bis(4-nitrophenyl)-1,4-bis(phenylsulfonyl)-1,4-dihydro-
1,2,4,5-tetrazine (2n)
References
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Yield: 40.6 mg (67%); yellow solid; mp 102–104 °C.
IR (film): 2919, 2849, 1523, 1332, 1185, 1175, 855, 608 cm–1
1H NMR (400 MHz, DMSO-d6):  = 8.34 (d, J = 8.3 Hz, 4 H), 7.91 (t,
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HRMS (ESI): m/z [M + H]+ calcd for C26H19N6O8S2: 607.0700; found:
607.0704.
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© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–F