Electrochemical synthesis for benzisothiazol-3(2H)-ones by dehydrogenative N[sbnd]S bond formation

Article abstract of DOI:10.1016/j.tetlet.2021.153323

Herein, we report an electrochemical method for the synthesis of benzisothiazol-3(2H)-ones from 2-mercaptobenzamides. The electrochemical reaction proceeds through intramolecular N[sbnd]H/S[sbnd]H coupling cyclization reaction by generating H₂ as the nonhazardous side product. Moreover, the developed procedure is highly advantageous due to its short reaction time, mild conditions and wide substrate scope without the employment of metal catalyst and exogenous-oxidant.2009 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2021.153323

Tetrahedron Letters 80 (2021) 153323
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Electrochemical synthesis for benzisothiazol-3(2H)-ones by
dehydrogenative NAS bond formation
⇑
Qihao Zhong, Zhiqiang Xiong, Shouri Sheng, Junmin Chen
College of Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report an electrochemical method for the synthesis of benzisothiazol-3(2H)-ones from 2-mer-
captobenzamides. The electrochemical reaction proceeds through intramolecular NAH/SAH coupling
cyclization reaction by generating H2 as the nonhazardous side product. Moreover, the developed proce-
dure is highly advantageous due to its short reaction time, mild conditions and wide substrate scope
without the employment of metal catalyst and exogenous-oxidant.2009 Elsevier Ltd. All rights reserved.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 21 June 2021
Revised 28 July 2021
Accepted 9 August 2021
Available online 14 August 2021
Keywords:
Metal-free
Electrochemical
Dehydrogenative SAN bond formation
Benzisothiazol-3(2H)-ones
Introduction
with various oxidants such as H2O2, hypervalent iodine reagent,
(Cl3COO)2O or O2. [11] Although the intramolecular dehydrogena-
Organosulfur compounds containing S-X (X = C N, P, O) bonds are
a class of versatile and important structural motifs, which are exten-
sively found in pharmaceuticals, [1] pesticides, [2] natural products,
[3] and material science. [4] Among these privileged scaffolds, ben-
zisothiazol-3(2H)-ones display special antibacterial, anticancer, and
bactericidal activities and widely used in industrial bactericides, and
so on (Fig. 1). [5] In addition, lurasidone and ziprasidone, are repre-
sentative drugs with benzisothiazole skeletons. [6] Furthermore,
saccharin, an oxidized form of a benzisothiazol-3(2H)-one, is one
of the most common artificial sweeteners. [7] As a result, develop-
ment of efficient synthetic methods for construction of benzisothia-
zol-3(2H)-one motifs is fascinating. Classical approaches for such
compounds mainly relied on the multistep reactions of halogena-
tions, amidation, and cyclization successively, starting from 2,20-
dithiosalicylic acids or their esters. [8] However, it relies on the
use of highly toxic and strong corrosive reagents. From then on, a
number of methodologies for their synthesis have been reported
in the last two decades. [9] Typically, the reaction pathways involv-
ing transition-metal-catalyzed cascade sulfuration of C(sp 2)-X
(X = hal or H) bonds and intramolecular cyclization were reported
by using 2-halobenzamides or N-substituted benzamides as sub-
strates. [10] However, these reactions require the addition of transi-
tion metal catalysis. Recently, direct intramolecular cross-
dehydrogenative coupling (CDC) reactions of N-substituted thiosal-
icylates have been developed for the synthesis of these compounds
tive nitrogen-sulfur (NAS) bond cyclization for the synthesis of ben-
zisothiazol-3(2H)-ones is the most attractive method due issues of
atom economy, an additional oxidant and (or) transition metal are
also needed for this transformation. Based on the importance of
the motifs, the development of an eco-friendly and alternative pro-
tocol for the synthesis of 1,2-benzisothiazol-3(2H)-one derivatives
are challengeable and still highly desirable.
Over the past decade, organic electrosynthesis has been
acknowledged as an environmentally benign and mild synthetic
tool for various organic transformations. [12] In particular, various
simple and elegant electrochemical cross-dehydrogenative cou-
pling reactions (CDC) for achieving X-X (X = O, N, S, P) bond forma-
tions have been extensively developed. [13] Recently, we also
described an electrochemical oxidative reaction protocol for the
synthesis of 5-amino and 3,5-diamino substituted 1,2,4-thiadia-
zole derivatives involving electrooxidative intramolecular SAN
bond formation. [14] Inspired by recent developments in the area
of synthetic electrochemistry [15] and challenged by the problems
in the previous systems. [11] Herein, we intend to develop a versa-
tile and efficient method to access 1,2-benzisothiazol-3(2H)-one
derivatives through electrooxidative intramolecular SAN bond
formation.
Results and discussion
To realize the idea, we initially started with optimization of the
reaction by using 2-mercapto-N-phenyl-benzamide 1a as the
⇑
Corresponding author.
https://doi.org/10.1016/j.tetlet.2021.153323
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Q. Zhong, Z. Xiong, S. Sheng et al.
Tetrahedron Letters 80 (2021) 153323
O
for this electrochemical intramolecular SAN bond formation reac-
tion. Pt (+)/C (ꢀ) and C (+)/C (ꢀ) electrodes both led to slightly
decreased yields (Table 1, entries 14,16), whereas the Pt (+)/Pt
(ꢀ) gave a significantly decreased yield (Table 1, entry 15). Subse-
quently, the amount of the electrolyte was also investigated. Inter-
estingly, a slightly reduced yield was obtained when the amount of
nBu4NBr was decreased to 0.08 M or increased to 0.24 M, respec-
tively (Table 1, entries 17,18). Moreover, we investigated the cur-
rent intensity; Variation of the current intensity from 10 to
30 mA/cm2 was carried out (Table 1, entries 19,20), and no
improvement on the reaction yield was found, which indicated
20 mA/cm2 was the best reaction condition. It is worth mentioning
that reaction time taken to obtain maximum yield was 30 min,
longer reaction time was deleterious and some undesired gelati-
nous complexes were formed (Table 1, entries 21,22). Finally, the
control experiment indicated that a similar yield was obtained
under argon atmosphere, which means that the passage of electric-
ity was essential for this efficient transformation (Table 1, entry
23). Furthermore, No desired product was observed when the reac-
tion was conducted without electricity (Table 1, entry 24).
With the optimized reaction conditions in hand, the scope of
substrates with N-containing different substitution patterns and
various functional groups was investigated to test the generality
and limitations of the reaction. As shown in Table 2. Firstly, we
probed various N-arylamides derivatives containing diverse func-
tional groups at the ortho, meta, and para positions of the phenyl
ring. It was observed that electron-donating substrates such as
CH3 and OCH3, produced very high yields of corresponding prod-
ucts 2b-c. Notably, N-arylamides bearing halides including fluoride
(1d), chloride (1e), bromide (1f, 1l) and iodide (1g) were all com-
patible with the current electrochemically catalytic system, afford-
ing the corresponding products in good to high yields (56–72%).
Meanwhile, the meta-methyl and methoxy substituted N-ary-
O
O
NH
N
S
N
S
ML-089
SCP-1
OH
Cl
N
O
N
O
N
O
N
NH
NH
N
S
O
N
O
O
N
S
S
Saccharin
Ziprasidone
Lurasidone
Fig. 1. Bioactive molecules that contain benzisothiazole skeletons skeletons.
model substrate, and the results are summarized in Table 1. The
reaction occurred when it was carried out in acetonitrile by the
use of graphite as the working electrode and Pt plate as the counter
electrode, with nBu4NBr as an electrolyte, under 20 mA constant
current in an undivided cell at room temperature under air for
0.5 h, affording the corresponding coupling product 2a in 72% iso-
lated yield (Table 1 entry 1). Firstly, various supporting electrolytes
were investigated, with Et4NBr as the supporting electrolyte; the
yield decreases slightly (Table 1, entry 2). But with other support-
ing electrolytes such as Et4NPF6, nBu4NBF4, NH4Br, nBu4NI, and KI,
only dramatically decreased yields of 2a were observed (Table 1
entries 3–8). Subsequently, a series of solvents was examined,
and replacement of CH3CN with C2H5OH or THF only gave a
decreased yield (Table 1, entries 9,10). To our delight, the desired
product 2a could be obtained in 83% yield with DCM (CH2Cl2) as
a solvent (Table 1, entry 11). In addition, when H2O or1,4-dioxane
was used as the solvent, only a trace amount of 2a was observed
(Table 1, entries 12,13). Next, we explored the electrode materials
Table 1
Optimization of the reaction conditionsa.
O
O
electrolysis
N
H
SH
1a
N
S
rt
2a
Entrya
Electrolyte
Electrode
Solvent
Yield(%)b
1
2
3
4
5
6
7
8
nBu4NBr
Et4NBr
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
Pt(+)/C(-)
Pt(+)/Pt(-)
C(+)/C(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
C2H5OH
THF
DCM
H2O
1,4-dioxane
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
72
61
46
51
44
31
56
44
62
37
83
trace
trace
68
36
65
74
78
61
79
77
70
82
trace
nBu4NPF6
nBu4NBF4
NH4Br
KBr
nBu4NI
KI
9
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
nBu4NBr
10
11
12
13
14
15
16
17c
18d
19e
20f
21g
22h
23i
j
24
DCM
aReaction conditions: Graphite rod anode (u 6 mm), platinum plate cathode (10 mm ꢁ 10 mm), 1a (0.3 mmol), electrolyte (0.16 M), solvent (6 ml), the electrolysis was
conducted at a constant current (20 mA) for 0.5 h in an undivided cell under air. b Isolated yield. c nBu4NBr = 0.08 M. d nBu4NBr = 0.24 M. e I = 10 mA. f I = 30 mA. g Time = 1 h. h
i
j
Time = 1.5 h. Under N2. No current.
2

Q. Zhong, Z. Xiong, S. Sheng et al.
Tetrahedron Letters 80 (2021) 153323
Table 2
Scheme 1. Firstly, 2-mercapto-N-phenyl-benzamide 1a could begin
with the anodic oxidation to form the sulfur cation intermediate A.
Then the intermolecular coupling and deprotonation afforded to
the disulfide B. Secondly, the B underwent further anodic oxidan-
tion to affford the cation amidium intermediate C. Finally, the
intermediate C underwent intramolecular cyclization and and
deprotonation to generate the product 2a.
Synthesis of 2-substituted benzisothiazol-3(2H)-ones.
C(+)/Pt(-)
O
O
I = 20 mA
R
N
H
n
N
R
Bu NBr
4
S
DCM, rt, 30 min
SH
2
1
O
O
N
O
O
N
F
N
S
OMe
N
Conclusion
S
S
S
2a, 83%
2d, 71%
2b, 86%
O
2c, 88%
In summary, we have developed an efficient electrochemical
method for the intramolecular NAS bond formation of 2-mercapto-
benzamides for the syntheses of 1,2-benzisothiazol-3(2H)-one
derivatives. The reaction was performed by CCE in an undivided
cell. The present reactions were found to tolerate a wide range of
functional groups and affording the corresponding products in
good to excellent yields. The electrolytic process avoids the utiliza-
tion of external oxidants or transition metal catalyst and therefore
represents an environmentally benign means by which to achieve
the transformation. Further investigation for other heterocyclic
compounds synthesis based on this electrochemical protocol is
underway in our laboratory.
O
O
O
N
S
N
S
Br
N
I
N
S
2e, 72%
Cl
S
2h, 82%
2f, 61%
2g, 56%
O
O
O
O
N
S
Br
N
S
N
S
N
S
OMe
2i, 71%
2l, 74%
2j, 77%
2k, 84%
O
O
O
O
O
N
S
N
N
N
S
N
S
S
S
2m, 68%
2n, 85%
2p, 85%
2o, 88%
2q, 92%
Declaration of Competing Interest
Cl
O
O
O
O
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
N
N
S
N
S
S
N
N
S
2r, 89%
2u, 67%
2t, 78%
2s, 86%
aReaction conditions: Graphite rod anode (u
(10 mm ꢁ 10 mm), 2a (0.3 mmol), electrolyte (0.16 M), solvent (6 ml), the elec-
trolysis was conducted at a constant current (20 mA) for 0.5 h in an undivided cell
under air.
6 mm), platinum plate cathode
Acknowledgment
This work was supported by grants from the National Natural
Science Foundation of China (Grant No. 21762022).
lamides afforded also the desired product 2h-j in very high yields.
Specially, steric hindrance did not affect the cyclization reaction.
For instance, the ortho-methyl and bromo substituted N-ary-
lamides afforded the desired products 2k and 2l in 84% and 74%
yield, respectively. Moreover, the substrate 1m with N-naphthy-
lamine could provide the desired products 2m in 68% yield. Next,
N-alkyl-substituted substrates were also investigated. For example,
alkyl groups such as isopropyl (1n), cyclohexyl (1p), benzyl (1q-s),
and phenethyl (1t) successfully underwent this electrooxidative
dehydrogenative cyclization reaction and afforded the correspond-
ing benzoisothiazolones (2n-t) in high to excellent yields. Interest-
ingly, pyridyl-substituted 2-mercaptobenzamides 1u was well
tolerated under the standard reaction conditions, providing the
corresponding product in 67% yield.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153323.
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