Cu-mediated one-pot three-component synthesis of 3-N-substituted 1,4,2-benzodithiazine 1,1-dioxide derivatives

Article abstract of DOI:10.1016/j.tet.2020.131354

A novel and efficient copper-catalyzed one-pot procedure for the synthesis of 3-N-substituted 1,4,2-benzodithiazine 1,1-dioxide derivatives from 2-halobenzenesulfonamides, amines and CS₂ is described. The reaction proceeds through Ullmann-type S-arylation, intramolecular addition of NH₂ with C[dbnd]S and dehydrosulfide, which provides a new and useful strategy for construction of cyclic aromatic sulfonamides.

Full text of DOI:10.1016/j.tet.2020.131354

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cu-mediated one-pot three-component synthesis of 3-N-substituted
1,4,2-benzodithiazine 1,1-dioxide derivatives
,
b
,
, *
Wei Dong a, Zemei Ge a, Xin Wang a, Ridong Li a **, Runtao Li a
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
b Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University, Beijing, 100191, PR
China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient copper-catalyzed one-pot procedure for the synthesis of 3-N-substituted 1,4,2-
benzodithiazine 1,1-dioxide derivatives from 2-halobenzenesulfonamides, amines and CS2 is described.
The reaction proceeds through Ullmann-type S-arylation, intramolecular addition of NH2 with C]S and
Received 26 February 2020
Received in revised form
15 June 2020
Accepted 22 June 2020
Available online xxx
dehydrosulfide, which provides
a
new and useful strategy for construction of cyclic aromatic
sulfonamides.
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
1,4,2-Benzodithiazine 1,1-dioxide
Cyclic sulfonamide
Ullmann coupling reaction
Dithiocarbamate
One-pot synthesis
1. Introduction
demonstrated a series of 3-alkylamino-1,4,2-benzodithiazine 1,1-
dioxides as potent KATP channel openers (Figs. 1, 7) [12]. In 2015,
ꢀ
Sulfonamides are important classes of organosulfur compounds
in bioorganic and medicinal chemistry, possessing diverse biolog-
ical activities [1], such as antibacterial [2], antiinflammatory [3],
diuretics [4], antitumor [5], antitubercular [6], antiviral [7] etc.
Among them, a large number of acyclic sulfonamides have been
widely used as drugs in clinic, for examples, furosemide, acet-
azolamide, celecoxib, pazopanib and so on [8]. Meanwhile, some
cyclic aromatic sulfonamides as therapeutic or potential thera-
peutic agents were also reported and the representative com-
pounds (1e4) shown in Fig. 1 [9]. In recently years, the research on
cyclic aromatic sulfonamides, 1,4,2-benzodithiazine 1,1-dioxides,
has gained more and more attention, due to their wide range of
biological activities. Brzozowski et al. reported a series of novel 6-
chloro-1,1-dioxo-1,4,2-benzodithiazie derivatives (Figs. 1, 5) with
antitumor activity [10]. As a continuation of research, Brzozowski’s
group also revealed several tricyclic sulfonamides as anti-HIV
agents (Figs. 1, 6) [11]. In 2013, Pirotte and his co-workers
Sławinski et al. published the synthesis of new 1,1-dioxo-1,4,2-
benzodithiazines, which exhibited effective cytotoxic activities
against HeLa, MCF-7 and HCT-116 cell lines (Figs. 1, 8) [13].
Although the biological activities of 1,4,2-benzodithiazine 1,1-
dioxide derivatives have been well documented, there are only
few reports on the construction of this framework. Iwakawa et al.
described the synthesis of 3-dimethylamino-1,4,2-benzodithiazine
1,1-dioxides using [2 þ 2] cycloaddition and Friedel-Crafts reaction
in 1991 (Scheme 1, a) [14]. Then, in 2008, Brzozowski’s group re-
ported a new method that construction of this skeleton through
four steps via cyclization of key intermediate aryl dithiocarbamate
starting from 4-chloropyridine-3-sulfonamide (Scheme 1, b) [15].
In 2013, Pirotte’s group provided an alternative strategy for the
synthesis of 3-alkylamino-1,4,2-benzodithiazine 1,1-dioxides from
2-chlorobenzenesulfonamides and isothiocyanates (Scheme 1, c)
[12]. However these methods suffer from several drawbacks, such
as the use of odorous (benzenethiol), unstable (isothiocyanate) and
highly corrosive (chlorosulfonyl isocyanate) reagents, multistep
reactions, long reaction time, the low yield.
In the past two decades, our research group has been devoted to
the synthesis of dithiocarbamates [16]. Thus, we know that the
synthesis of aryl dithiocarbomate is difficult due to the low activity
* Corresponding author.
** Corresponding author. State Key Laboratory of Natural and Biomimetic Drugs,
School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
E-mail addresses: lrd@bjmu.edu.cn (R. Li), lirt@bjmu.edu.cn (R. Li).
https://doi.org/10.1016/j.tet.2020.131354
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: W. Dong et al., Cu-mediated one-pot three-component synthesis of 3-N-substituted 1,4,2-benzodithiazine 1,1-dioxide
derivatives, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131354

2
W. Dong et al. / Tetrahedron xxx (xxxx) xxx
(Table 1, entry 15) or catalyst (Table 1, entries 16) would dramati-
cally reduce the reaction efficiency, whereas the yield was not
improved with higher amounts of catalyst (Table 1, Entries 17).
Whereas no product was obtained when the reaction was per-
formed without the catalysis of CuCl2$2H2O (Table 1, Entries 18).
Changing the reaction temperature is unfavorable for the reaction
and the suitable reaction temperature is still 110 ꢀC (Table 1, Entries
19e21). Therefore, the optimal reaction conditions are CuCl2$2H2O
(1.0 eq) as catalyst, K2CO3 (3.0 eq) as base, DMF as solvent, heating
reaction at 110 ꢀC, and the molar ratio of 2-
halobenzenesulfonamide 9/amine 10/CS2 is 1: 1.5: 1.8.
With the optimal reaction conditions in hand, we next explored
the scope and limitations of the reaction. Different kinds of amines
were first allowed to react with 9a and CS2 under optimized reac-
tion conditions. In the synthesis of 11a, it was found that the yield
of o-iodobenzenesulfonamide was higher than that of o-bromo-
benzenesulfonamide, but the difference was not significant.
Considering o-bromobenzenesulfonamide is cheap and readily
available, we chose o-bromobenzenesulfonamide as the main
substrate for the other reactions. As shown in Table 2, all the tested
secondary amines gave 3-N-disubstituted 1,4,2-dithiazine 1,1-
dioxide derivatives (11a-11l) in good yields (57e82%). Even
amines with large substituent or higher steric hindrance, such as 4-
phenylpiperidine, 1,2,3,4-tetrahydroisoquinoline and diisopropyl
amine, also gave the corresponding compounds 11d, 11e and 11j in
64%, 60%, 73% yield, respectively. The formation of products 11l, 11s
and 11t shows that the reaction is tolerable to the amines with
hydroxyl or amino group. Furthermore, the reaction is also suitable
for various primary amines (11m-11x). Isopropyl amine and
cyclohexylamine gave the corresponding products (11m, 11n) in
73% and 79% yield, respectively. 3,4,5-Trimethoxyaniline provided
the product 11o in 69% yield. For the arylmethyl amines, including
the substituted benzyl amines and hetero arylmethyl amines also
worked well. However, it is apparent that the property of aromatic
ring has some effect on the reaction. Usually, electron-donating
arylmethyl amine is more favorable for the reaction than
electron-withdrawting arylmethyl amine. Such as, products 11p,
11r, 11u and 11v were obtained in over 80% yield; yet the yield of
products 11w and 11x is only 61% and 53%, respectively. Further-
more, the substituted 1,4,2-benzodithiazine 1,1-dioxides de-
rivatives (11y, 11z) were also successfully prepared under optimal
reaction conditions, which further expand the range of substrates.
Based on the above results and related literatures [17], a possible
pathway for this reaction is proposed in Scheme 2. Initially, the
reaction of an amine with CS2 provides the intermediate dithio-
carbamate salts 12. Then, the Ullman coupling between 12 and 9 in
the presence of CuCl2$2H2O afford the key intermediate 13. Sub-
sequently, in the presence of K2CO3, the 13 undergoes intra-
molecular condensation and then removes hydrogen sulfide to
afford the target product 11. To validate whether the formation of
H2S, we have done an easy H2S trapping experiment [18-19] and no
large amount of H2S was released, which may be that the released
H2S reacted with the Cu2þ to form CuS.
Fig. 1. Representative cyclic aromatic sulfonamides as therapeutic or potential thera-
peutic agents.
Scheme 1. Design approach for 1,4,2-benzodithiazine 1,1-dioxides.
of aryl halides. In 2011, Ma et al. developed a copper-catalyzed
three-component reaction for the synthesis of 2-N-substituted
benzothiazoles from
N nucleophiles, CS2, and 2-haloanilines
(Scheme 1, d) [17]. Inspired by Ma’s work, we conceived of a
copper-catalyzed synthesis of 1,4,2-benzodithiazine 1,1-dioxides by
coupling of 2-halobenzenesulfonamides with dithiocarbamate salts
from amines and CS2 (Scheme 1, e).
2. Results and discussion
To examine our hypothesis, 2-bromobenzenesulfonamide 9a
was selected to react with piperidine 10a and CS2 in the presence of
K2CO3 with CuI as catalyst in DMF at 110 ꢀC for 6 h. To our delight,
the reaction proceeded smoothly to afford the desired product 11a
in 63% yield (Table 1, entry 1). Encouraged by this result, the further
optimization of the reaction conditions was performed. The
different copper catalysts were first examined and the CuCl2$2H2O
is best one which improved the yield from 63% to 82% (Table 1,
Entries 2e6). Then, the bases, including inorganic and organic ba-
ses, were screened with CuCl2$2H2O as catalyst and K2CO3
remained as the best one (Table 1, Entries 7e10). The solvent
screening results revealed that DMF was still the best choice
(Table 1, Entries 11e14). In addition, reducing the amounts of K2CO3
3. Conclusion
In summary, we have developed a novel one-pot methodology
for the synthesis of 3-N-substituted 1,4,2-benzodithiazine 1,1-
dioxide derivatives from 2-bromobenzenesulfonamide, amines
and CS2 via in situ generated dithiocarbamate salts. This approach is
characterized by practically simple, short reaction time, and good
functional group tolerance. We expect that this efficient protocol
could be widely used in the synthesis of aromatic cyclic sulfon-
amides, which will benefit the discovery of more potent biologi-
cally active compounds.
Please cite this article as: W. Dong et al., Cu-mediated one-pot three-component synthesis of 3-N-substituted 1,4,2-benzodithiazine 1,1-dioxide
derivatives, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131354

W. Dong et al. / Tetrahedron xxx (xxxx) xxx
3
Table 1
Optimization of reaction conditionsa.
.
Entry
Catalyst
Base
Solvent
T [ꢀC]
Yield of 10 [%]
1
2
3
4
5
6
7
8
CuI (1.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
Cs2CO3 (3.0 eq)
K3PO4 (3.0 eq)
TEA (3.0 eq)
DIPEA (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (2.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
K2CO3 (3.0 eq)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
80
63
58
40
52
72
82
75
63
51
47
60
71
38
41
62
34
78
0
CuO (1.0 eq)
Cu(OAc).2 H2O (1.0 eq)
CuSO4 (1.0 eq)
CuBr2 (1.0 eq)
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (1.0 eq)>
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (0.5 eq)
CuCl2$2H2O (1.5 eq)
e
9
DMF
DMF
10
11
12
13
14
15
16
17
18
19
20
21
1,4-dioxane
DMSO
THF
CH3CN
DMF
DMF
DMF
DMF
DMF
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (1.0 eq)
CuCl2$2H2O (1.0 eq)
41
80
70
DMF
DMF
120
Reflux
a
Reaction conditions: 9a (1.0 mmol), CS2 (1.8 mmol), piperidine (1.5 mmol), catalyst (0e1.5 mmol), base (2.0e3.0 mmol), solvent (8 mL), 6 h.
4. Experimental section
48.6, 25.9, 25.3, 23.9; ESI-HRMS: Calcd for C12H15N2O2S2 [MþH]þ,
283.0497, Found 283.0504.
4.1. General
4.2.2. 3-(pyrrolidin-1-yl)benzo[e][1,4,2]dithiazine 1,1-dioxide (11b)
Brown solid, Yield 71%; m. p. 178e180 ꢀC; 1H NMR (400 MHz,
1H NMR and 13C NMR spectra were recorded on a Bruker
AVANCE 400 MHz spectrometer using CDCl3 or DMSO‑d6 as solvent.
The 1H NMR chemical shifts (in ppm) were referenced to tetra-
methylsilane. The 13C NMR chemical shifts were given using solvent
(CDCl3 or DMSO‑d6) as the internal standard. High resolution mass
spectra were recorded using LCMS-IT-TOF technique (Shimadzu).
Materials obtained from commercial suppliers were used without
further purification. Column chromatography was carried out on
silica gel (particle size 200e300 mesh ASTM).
CDCl3)
d
8.16 (t, J ¼ 4.4 Hz, 1H), 7.57 (t, J ¼ 3.6 Hz, 2H), 7.46 (d,
J ¼ 4.0 Hz, 1H), 3.93e3.80 (m, 8H); 13C NMR (100 MHz, CDCl3)
d
163.8, 133.2, 131.8, 129.4, 128.3, 128.0, 125.4, 66.1, 47.6. ESI-HRMS:
Calcd for C12H13N2O2S2 [MþH]þ, 269.0340, Found 269.0373.
4.2.3. 3-(azepan-1-yl)benzo[e][1,4,2]dithiazine 1,1-dioxide (11c)
Brown solid, Yield 74%; m. p. 170e172 ꢀC; 1H NMR (400 MHz,
CDCl3)
3.69 (t, J ¼ 7.6 Hz, 2H), 3.55 (t, J ¼ 8.0 Hz, 2H), 1.71e1.57 (m, 4H),
1.45e1.38 (m, 4H). 13C NMR (100 MHz, CDCl3)
163.4, 133.4, 131.5,
d 8.19e8.17 (m, 1H), 7.56e7.53 (m, 2H), 7.47e7.44 (m, 1H),
4.2. Preparation of 3-N-substituted 1,4,2-benzodithiazine 1,1-
d
dioxides derivatives (11a - 11z)
129.0, 127.9, 125.2, 125.1, 51.1, 50.3, 30.2, 29.2, 20.0, 13.8. ESI-HRMS:
Calcd for C13H17N2O2S2 [MþH]þ, 297.0653, Found 297.0663.
General procedure for the preparation of compounds (11a -
11z):
4.2.4. 3-(4-phenylpiperidin-1-yl)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11d)
Amine (1.5 mmol) was dissolved in DMF (8 mL), and potassium
carbonate (4.5 mmol), CS2 (1.8 mmol) were added. The mixture was
reacted at room temperature for 0.5 h. Then, 9a (1.0 mmol),
CuCl2$2H2O (1.0 mmol) was added, the mixture was reacted at
110 ꢀC for 6 h. After completion, the solvent was evaporated and
then 10 mL of water was added. The mixture was extracted with
dichloromethane and the combined organic phase was dried over
anhydrous Na2SO4. After removal of solvents, the residue was pu-
rified by silica gel column chromatography using petroleumether/
ethyl acetate (1:1) to afford the desired product (11a e 11z).
Brown solid, Yield 64%; m. p. 189e192 ꢀC; 1H NMR (400 MHz,
CDCl3)
d 8.16e8.14 (m, 1H), 7.56e7.55 (m, 2H), 7.48 (m, 1H),
7.31e7.30 (m, 5H), 2.84 (s, 4H), 2.49 (s, 1H),1.94e1.91 (d, J ¼ 12.8 Hz,
2H), 1.76e1.74 (d, J ¼ 10.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
162.8, 146.5, 134.4, 132.5, 130.1, 129.7, 129.3, 128.8, 126.5, 125.5,
46.8, 45.8, 43.5, 33.4, 32.5. ESI-HRMS: Calcd for C18H19N2O2S2
[MþH]þ, 359.0810, Found 359.0812.
4.2.5. 3-(3,4-dihydroisoquinolin-2(1H)-yl)benzo[e][1,4,2]dithiazine
1,1-dioxide (11e)
4.2.1. 3-(piperidin-1-yl)benzo[e][1,4,2]dithiazine 1,1-dioxide (11a)
Brown solid, Yield 82%; m. p. 164e166 ꢀC; 1H NMR (400 MHz,
White solid, Yield 60%; m. p. 182e184 ꢀC; 1H NMR (400 MHz,
DMSO‑d6)
d 8.19e8.17 (m, 1H), 7.56e7.53 (m, 2H), 7.47 (m, 1H),
CDCl3)
d
8.13 (t, J ¼ 4.0 Hz, 1H), 7.53 (t, J ¼ 4.4 Hz, 2H), 7.46 (d,
7.37e7.36 (m, 1H), 7.22e7.20 (m, 1H), 7.15e7.11 (m, 2H), 4.71 (s, 2H),
J ¼ 3.2 Hz, 1H), 3.94 (s, 2H), 3.74 (s, 2H), 1.72 (s, 6H). 13C NMR
4.02e3.96 (d, J ¼ 11.6 Hz, 2H), 3.86e3.83 (d, J ¼ 11.2 Hz, 2H). 13
C
(100 MHz, CDCl3)
d
162.7, 133.3,131.5, 129.0,128.9,127.7, 125.1, 48.9,
NMR (100 MHz, DMSO‑d6) d 162.2, 135.6, 134.2, 130.6, 129.8, 128.0,
Please cite this article as: W. Dong et al., Cu-mediated one-pot three-component synthesis of 3-N-substituted 1,4,2-benzodithiazine 1,1-dioxide
derivatives, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131354

4
W. Dong et al. / Tetrahedron xxx (xxxx) xxx
Table 2
NMR (100 MHz, CDCl3)
d 13C 161.1, 133.0, 131.5, 129.2, 129.1, 127.6,
Scope of the formation of 3-N-substituted 1,4,2-benzodithiazine 1,1-dioxidesa..
125.4, 77.4, 77.0, 76.7, 50.4, 48.3, 25.5, 24.5. ESI-HRMS: Calcd for
C
11H13N2O2S2 [MþH]þ, 285.0289, Found 285.0264.
4.2.7. 3-(4-methylpiperazin-1-yl)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11g)
White solid, Yield 68%; m. p. 174e177 ꢀC; 1H NMR (400 MHz,
CDCl3)
d 8.18 (s, 1H), 7.56e7.55 (m, 2H), 7.47 (s, 1H), 3.95e3.91 (m,
2H), 3.77e3.74 (m, 2H), 2.79e2.76 (t, J ¼ 4.8 Hz, 4H), 2.16 (s, 3H). 13
C
NMR (100 MHz, CDCl3) d 161.0,133.2,131.5,129.1,129.0,127.6,125.3,
35.5, 34.5, 30.4, 28.3, 23.3. ESI-HRMS: Calcd for C12H16N3O2S2
[MþH]þ, 298.0606, Found 298.0634.
4.2.8. 3-(dimethylamino)benzo[e][1,4,2]dithiazine 1,1-dioxide (11h)
Brown solid, Yield 62%; m. p. 152e154 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
8.18 (s, 1H), 7.56e7.50 (d, J ¼ 3.2 Hz, 2H), 7.47 (s, 1H),
3.35e3.31 (d, J ¼ 16.0 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d 140.8,
132.7, 131.6, 129.3, 128.9, 127.8, 125.4, 40.3, 38.9. ESI-HRMS: Calcd
for C9H11N2O2S2 [MþH]þ, 243.0184, Found 243.0259.
4.2.9. 3-(diethylamino)benzo[e][1,4,2]dithiazine 1,1-dioxide (11i)
Brown solid, Yield 62%; m. p. 145e147 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
8.17 (s, 1H), 7.54 (d, J ¼ 2.8 Hz, 2H), 7.46 (s, 1H), 3.78 (d,
J ¼ 4.0 Hz, 2H), 3.65 (d, J ¼ 8.0 Hz, 2H), 1.35e1.30 (m, 6H). 13C NMR
(100 MHz, CDCl3) d 163.0,133.4,131.5,129.1,129.0,127.8,125.3, 45.8,
44.8, 13.4, 12.5. ESI-HRMS: Calcd for
271.0497, Found 271.0572.
C
11H15N2O2S2 [MþH]þ,
4.2.10. 3-(diisopropylamino)benzo[e][1,4,2]dithiazine 1,1-dioxide
(11j)
Brown solid, Yield 73%; m. p. 141e142 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
8.16e8.14 (m, 1H), 7.55e7.54 (m, 2H), 7.48 (s, 1H), 3.96 (s,
161.6, 132.7, 131.6,
2H), 0.93 (s, 12H). 13C NMR (100 MHz, CDCl3)
d
129.2, 128.9, 127.8, 125.4, 47.1, 22.6. ESI-HRMS: Calcd for
C
13H19N2O2S2 [MþH]þ, 299.0810, Found 299.0818.
4.2.11. 3-(dibutylamino)benzo[e][1,4,2]dithiazine 1,1-dioxide (11k)
Brown solid, Yield 70%; m. p. 121e123 ꢀC; 1H NMR (400 MHz,
CDCl3)
3.83e3.79 (t, J ¼ 6.8 Hz, 2H), 3.63e3.60 (t, J ¼ 6.8 Hz, 2H), 1.80 (m,
4H), 1.62e1.55 (m, 10H). 13C NMR (100 MHz, CDCl3)
163.8, 133.2,
d 8.17e8.16 (m, 1H), 7.55e7.53 (m, 2H), 7.45e7.43 (s, 1H),
d
131.8, 129.5, 128.3, 128.0, 125.5, 49.6, 33.0, 19.9, 18.1. ESI-HRMS:
Calcd for C15H23N2O2S2 [MþH]þ, 327.1123, Found 327.1115.
4.2.12. 3-(bis(2-hydroxyethyl)amino)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11l)
Brown solid, Yield 57%; m. p. 178e180 ꢀC; 1H NMR (400 MHz,
CDCl3)
d 8.16e8.14 (m, 1H), 7.57e7.55 (m, 2H), 7.48e7.47 (m, 1H),
3.60 (s, 2H), 2.79e2.76 (t, J ¼ 4.8 Hz, 4H), 2.61 (s, 4H). 13C NMR
(100 MHz, CDCl3)
d 163.7, 133.8, 131.3, 129.0, 128.8, 128.4, 125.5,
59.1, 52.7. ESI-HRMS: Calcd for C11H15N2O4S2 [MþH]þ, 303.0395,
Found 303.0388.
4.2.13. 3-(isopropylamino)benzo[e][1,4,2]dithiazine 1,1-dioxide
(11m)
Scheme 2. Possible mechanism for the formation of 3-N-substituted 1,4,2-
benzodithiazine 1,1-dioxides.
Brown solid, Yield 73%; m. p. 125e127 ꢀC; 1H NMR (400 MHz,
CDCl3) d 8.17 (s, 1H), 7.54 (s, 2H), 7.47 (s, 1H), 6.66 (s, 1H), 3.23e3.20
(t, J ¼ 12.4 Hz,1H), 0.89e0.88 (d, J ¼ 6.8 Hz, 6H). 13C NMR (100 MHz,
127.8, 126.4, 126.2, 126.0, 50.1, 45.6, 28.6. ESI-HRMS: Calcd for
C
CDCl3) d 163.9, 133.2, 131.8, 129.5, 128.3, 128.0, 125.5, 49.1, 22.0. ESI-
16H15N2O2S2 [MþH]þ, 331.0497, Found 331.0488.
HRMS: Calcd for C10H13N2O2S2 [MþH]þ, 257.0340, Found 257.0315.
4.2.6. 3-morpholinobenzo[e][1,4,2]dithiazine 1,1-dioxide (11f)
White solid, Yield 77%; m. p. 180e183 ꢀC; 1H NMR (400 MHz,
4.2.14. 3-(cyclohexylamino)benzo[e][1,4,2]dithiazine 1,1-dioxide
(11n)
CDCl3)
d
8.18e8.16 (m, 1H), 7.60e7.54 (m, 2H), 7.53e7.43 (m, 1H),
White solid, Yield 79%; m. p. 134e136 ꢀC; 1H NMR (400 MHz,
3.81 (t, J ¼ 6.8 Hz, 2H), 3.61 (t, J ¼ 6.8 Hz, 2H), 2.13e2.02 (m, 4H). 13
C
CDCl3) d 8.18 (s,1H), 7.56 (s, 2H), 7.47 (s,1H), 6.16 (s,1H), 2.23 (s,1H),
Please cite this article as: W. Dong et al., Cu-mediated one-pot three-component synthesis of 3-N-substituted 1,4,2-benzodithiazine 1,1-dioxide
derivatives, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131354

W. Dong et al. / Tetrahedron xxx (xxxx) xxx
5
1.70 (s, 1H), 1.59 (s, 1H). 13C NMR (100 MHz, CDCl3)
d
163.5, 133.5,
4.2.22. 3-((thiophen-2-ylmethyl)amino)benzo[e][1,4,2]dithiazine
131.4, 129.1, 127.8, 125.3, 52.1, 50.1, 27.5, 27.2, 24.7. ESI-HRMS: Calcd
1,1-dioxide (11v)
for C13H17N2O2S2 [MþH]þ, 297.0653, Found 297.0666.
White solid, Yield 87%; m. p. 145e148 ꢀC; 1H NMR (400 MHz,
CDCl3)
7.36e7.34 (m, 1H), 7.18e7.14 (m, 1H), 7.11e7.07 (m, 1H), 6.18 (s, 1H),
4.88 (s, 2H). 13C NMR (100 MHz, CDCl3)
137.1, 132.9, 132.0, 129.1,
d 8.18e8.16 (m, 1H), 7.55e7.53 (m, 2H), 7.45e7.43 (m, 1H),
4.2.15. 3-((3,4,5-trimethoxyphenyl)amino)benzo[e][1,4,2]dithiazine
1,1-dioxide (11o)
d
White solid, Yield 69%; m. p. 215e217 ꢀC; 1H NMR (400 MHz,
128.5, 128.0, 127.6, 127.3, 126.5, 125.8, 42.4. ESI-HRMS: Calcd for
CDCl3)
1H), 6.72 (s,1H), 6.60 (s,1H), 3.88e3.84 (m, 9H). 13C NMR (100 MHz,
CDCl3) 155.7, 153.6, 153.3, 132.6, 132.1, 129.3, 128.8, 127.8, 125.7,
d
8.19e8.17 (m, 1H), 7.59e7.57 (m, 2H), 7.41 (s, 1H), 6.78 (s,
C
12H11N2O2S3 [MþH]þ, 310.9904, Found 310.9977.
d
4.2.23. 3-((pyridin-4-ylmethyl)amino)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11w)
125.0, 124.3, 106.3, 101.5, 61.2, 56.8, 56.4. ESI-HRMS: Calcd for
C
16H17N2O5S2 [MþH]þ, 381.0501, Found 381.0507.
White solid, Yield 61%; m. p. 167e169 ꢀC; 1H NMR (400 MHz,
DMSO‑d6)
J ¼ 4.4 Hz, 2H), 7.56 (m, 1H), 7.41 (m, 1H), 5.99 (s, 1H), 4.64 (s, 2H).
13C NMR (100 MHz, DMSO‑d6)
163.9, 151.0, 136.9, 133.2, 131.8,
d
8.85e8.84 (d, J ¼ 4.4 Hz, 2H), 8.19 (m, 1H), 7.92e7.91 (d,
4.2.16. 3-(benzylamino)benzo[e][1,4,2]dithiazine 1,1-dioxide (11p)
White solid, Yield 81%; m. p. 204e206 ꢀC; 1H NMR (400 MHz,
d
CDCl3)
d
8.16e8.14 (m, 1H), 7.56 (s, 2H), 7.48 (s, 1H), 7.31e7.30 (m,
162.7,
129.5, 128.3, 128.0, 125.4, 121.9, 53.1. ESI-HRMS: Calcd for
5H), 6.26 (s, 1H), 3.59 (s, 2H). 13C NMR (100 MHz, CDCl3)
d
C
13H12N3O2S2 [MþH]þ, 306.0293, Found 306.0342.
133.3, 131.2, 129.0, 127.6, 126.4, 125.9, 124.2, 122.0, 120.8, 48.7. ESI-
HRMS: Calcd for C14H13N2O2S2 [MþH]þ, 305.0340, Found 305.0376.
4.2.24. 3-((quinolin-3-ylmethyl)amino)benzo[e][1,4,2]dithiazine
1,1-dioxide (11x)
4.2.17. 3-((4-fluorobenzyl)amino)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11q)
White solid, Yield 53%; m. p. 238e240 ꢀC; 1H NMR (400 MHz,
White solid, Yield 73%; m. p. 220e223 ꢀC; 1H NMR (400 MHz,
DMSO‑d6) d 9.40e9.30 (m, 1H), 8.91 (s, 1H), 8.19e8.10 (m, 1H),
CDCl3)
7.22e7.18 (m, 2H), 7.15e7.11 (m, 2H), 6.55 (s, 1H), 4.93 (s, 2H). 13
NMR (100 MHz, CDCl3) 162.5,160.1, 140.3,133.7, 133.5, 131.1, 130.8,
d
8.19e8.16 (m, 1H), 7.55e7.18 (m, 2H), 7.45 (m, 1H),
7.91e7.90 (m, 2H), 7.86e7.84 (m,1H), 7.71 (m,1H), 7.55 (m, 2H), 7.48
C
(m, 1H), 6.26 (s, 1H), 4.88e4.87 (d, J ¼ 4.0 Hz, 2H). 13C NMR
d
(100 MHz, DMSO‑d6) d 162.7, 149.7, 149.4, 148.3, 135.1, 134.5, 132.3,
128.3, 128.2, 126.1, 112.7, 49.6. ESI-HRMS: Calcd for C14H12N2O2S2
130.1, 129.3, 129.2, 129.1, 129.0, 127.9, 124.3, 56.1. ESI-HRMS: Calcd
[MþH]þ, 323.0246, Found 323.0233.
for C17H14N3O2S2 [MþH]þ, 356.0449, Found 356.0413.
4.2.18. 3-((4-methoxybenzyl)amino)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11r)
4.2.25. 7-Bromo-3-(piperidin-1-yl)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11y-1)
White solid, Yield 81%; m. p. 211e213 ꢀC; 1H NMR (400 MHz,
Brown solid, Yield 79%; m. p. 196e198 ꢀC; 1H NMR (400 MHz,
CDCl3)
d 8.20e8.18 (m, 1H), 7.57e7.55 (m, 2H), 7.30 (s, 1H),
CDCl3)
d
8.15 (s, 1H), 7.55 (s, 2H), 3.96 (s, 2H), 3.76 (s, 2H), 1.75 (s,
161.9, 134.5, 133.3, 132.1, 130.3,
7.28e7.27 (m, 2H), 6.90e6.89 (m, 2H), 5.97 (s, 1H), 4.66e4.65 (d,
6H). 13C NMR (100 MHz, CDCl3)
d
J ¼ 4.4 Hz, 2H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 159.9,
128.0, 123.8, 48.6, 25.3, 24.0. ESI-HRMS: Calcd for C12H14BrN2O2S2
133.2, 131.9, 130.0, 129.2, 127.6, 125.8, 114.5, 55.4, 47.8. ESI-HRMS:
[MþH]þ, 360.9602, Found 360.9556.
Calcd for C15H15N2O3S2 [MþH]þ, 335.0446, Found 335.0478.
4.2.19. 3-((4-hydroxybenzyl)amino)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11s)
4.2.26. 3-(piperidin-1-yl)-6-(trifluoromethyl)benzo[e][1,4,2]
dithiazine 1,1-dioxide (11y-2)
Yellow solid, Yield 83%; m. p. 206e208 ꢀC; 1H NMR (400 MHz,
White solid, Yield 77%; m. p. 176e178 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
9.78 (s, 1H), 8.28 (s, 1H), 8.14e8.12 (m, 1H), 8.01 (s, 1H),
CDCl3)
d
8.43 (s, 1H), 7.80e7.77 (m, 1H), 7.61e7.59 (m, 1H), 3.98 (s,
161.8,
7.77e7.75 (m, 1H), 7.42e7.41 (m, 1H), 6.90e6.88 (d, J ¼ 5.2 Hz, 2H),
2H), 3.76 (s, 2H), 1.76 (s, 6H). 13C NMR (100 MHz, CDCl3)
d
6.77e6.75 (d, J ¼ 5.2 Hz, 2H), 4.29 (s,1H). 13C NMR (100 MHz, CDCl3)
134.1, 133.3, 132.0e131.0 (m, CF3), 128.7, 128.0, 127.9, 124.3, 122.7,
d
162.9, 156.3, 139.7, 135.6, 135.0, 133.5, 132.3, 130.1, 127.6, 127.5,
122.6, 121.6, 49.2, 49.0, 29.7, 29.3, 27.2. ESI-HRMS: Calcd for
126.5, 120.7, 115.5, 49.3. ESI-HRMS: Calcd for
C
14H13N2O3S2
C
13H14F3N2O2S2 [MþH]þ, 351.0371, Found 351.0398.
[MþH]þ, 321.0289, Found 321.0259.
4.2.27. 7-Methyl-3-(piperidin-1-yl)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11z-1)
4.2.20. 3-((4-aminobenzyl)amino)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11t)
White solid, Yield 77%; m. p. 181e182 ꢀC; 1H NMR (400 MHz,
Yellow solid, Yield 83%; m. p. 210e211 ꢀC; 1H NMR (400 MHz,
CDCl3)
4.04 (s, 2H), 3.88 (s, 2H), 2.26 (s, 3H), 1.57 (s, 6H)$13C NMR
(100 MHz, CDCl3) 160.5, 141.6, 140.6, 133.6, 133.2, 129.7, 129.0,
d 7.71e7.69 (m, 1H), 7.30e7.28 (m, 1H), 6.83e6.81 (m, 1H),
CDCl3)
2H), 7.37e7.35 (m, 4H), 6.99e6.69 (m, 2H), 5.37 (s, 2H). 13C NMR
(100 MHz, CDCl3) 161.3, 144.1, 136.2, 135.2, 132.3, 130.9, 130.8,
d
9.90 (s, 1H), 7.88e7.87 (m, 2H), 7.84e7.82 (m, J ¼ 8.0 Hz,
d
d
46.6, 26.5, 24.9, 24.5, 23.9. ESI-HRMS: Calcd for C13H17N2O2S2
130.2, 129.9, 129.8, 115.9, 37.1. ESI-HRMS: Calcd for C14H14N3O2S2
[MþH]þ, 297.0653, Found 297.0669.
[MþH]þ, 320.0449, Found 320.0456.
4.2.21. 3-((furan-2-ylmethyl)amino)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11u)
4.2.28. 7-Methoxy-3-(piperidin-1-yl)benzo[e][1,4,2]dithiazine 1,1-
dioxide (11z-2)
White solid, Yield 83%; m. p. 217e219 ꢀC; 1H NMR (400 MHz,
White solid, Yield 77%; m. p. 191e193 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
8.19e8.16 (m, 1H), 7.57e7.55 (m, 2H), 7.41 (s, 1H), 7.40 (s,
CDCl3)
4.07 (s, 2H), 4.01 (s, 2H), 3.86 (s, 3H), 1.64 (s, 6H)$13C NMR
(100 MHz, CDCl3) 162.8, 160.0, 138.6, 131.5, 128.7, 127.9, 124.9,
d 7.78e7.76 (m, 1H), 7.54e7.53 (m, 1H), 7.45e7.44 (m, 1H),
1H), 7.39 (s, 1H), 7.28e7.23 (m, 1H), 6.26 (s, 1H), 4.89e4.87 (d,
J ¼ 5.2 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
137.1,132.9,131.9,129.2,
d
127.9, 127.7, 127.2, 126.6, 125.7, 42.8. ESI-HRMS: Calcd for
58.5, 49.1, 48.8, 26.4, 25.9, 24.0. ESI-HRMS: Calcd for C13H17N2O3S2
C
12H11N2O3S2 [MþH]þ, 295.0133, Found 295.0157.
[MþH]þ, 313.0602, Found 313.0618.
Please cite this article as: W. Dong et al., Cu-mediated one-pot three-component synthesis of 3-N-substituted 1,4,2-benzodithiazine 1,1-dioxide
derivatives, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131354

6
W. Dong et al. / Tetrahedron xxx (xxxx) xxx
(2014) 374.
Declaration of competing interest
[6] F. Carta, A. Maresca, A.S. Covarrubias, S.L. Mowbray, T.A. Jones, C.T. Supuran,
Bioorg. Med. Chem. Lett 19 (2009) 6649.
[7] R. Gawin, E.D. Clercq, L. Naesens, M. Koszytkowska-Stawinska, Bioorg. Med.
Chem. 16 (2008) 8379.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[8] F. Carta, A. Scozzafava, T.C. Supuran, Expert Opin. Ther. Pat. 22 (2012) 747.
[9] G. Manfroni, D. Manvar, M.L. Barreca, et al., J. Med. Chem. 57 (2014) 3247.
[10] Z. Brzozowski, F. Saczewski, M. Gdaniec, Bioorg. Med. Chem. 11 (2003) 3673.
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[12] B. Pirotte, P. Tullio, X. Florence, E. Goffin, F. Somers, S. Boverie, P. Lebrun,
J. Med. Chem. 56 (2013) 3247.
Acknowledgments
The authors thank the National Natural Science Foundation of
_
[13] J. Sławinski, B. Zołnowska, Z. Brzozowski, A. Kawiak, Belk M, Ba˛czek T, Mol-
China (No.21372019 & 81502905) for financial support.
ecules 20 (2015) 5754.
[14] T. Iwakawa, H. Tamura, A. Murabayashi, Y. Hayase, Chem. Pharm. Bull. 8
(1991) 1939.
[15] Z. Brzozowski, F. Saczewskia, J. Sawiski, J. Heterocycl. Chem. 45 (2008) 1407.
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(b) R.T. Li, M.S. Cai, Synth. Commun. 29 (1999) 65;
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131354.
(c) Z.M. Ge, R.T. Li, T.M. Cheng, Synth. Commun. 29 (1999) 3191;
(d) R.T. Li, Z.M. Ge, T.M. Cheng, M.S. Cai, Chem. J. Chin. Univ. 20 (1999) 1897;
(e) B.G. Guo, Z.M. Ge, T.M. Cheng, R.T. Li, Synth. Commun. 31 (2001) 3021;
(f) J.L. Cui, Z.M. Ge, T.M. Cheng, R.T. Li, Synth. Commun. 33 (2003) 1969;
(g) Y.Q. Wang, Z.M. Ge, X.L. Hou, T.M. Cheng, R.T. Li, Synthesis 5 (2004) 675;
(h) S. Xia, X. Wang, Z.M. Ge, T.M. Cheng, R.T. Li, Trahedron 65 (2009)
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Please cite this article as: W. Dong et al., Cu-mediated one-pot three-component synthesis of 3-N-substituted 1,4,2-benzodithiazine 1,1-dioxide
derivatives, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131354