Potassium bromide catalyzed N[sbnd]S bond formation via oxidative dehydrogenation

Article abstract of DOI:10.1016/j.tetlet.2017.03.065

N-Substituted benzo[d]isothiazol-3(2H)-ones are a family of compounds with extremely important application. Recently, we have developed a new green pathway to synthesize these compounds via potassium bromide-catalyzed intramolecular oxidative dehydrogenative cyclization. This reaction has high functional group tolerance and affords excellent yield even in gram scale.

Full text of DOI:10.1016/j.tetlet.2017.03.065

Accepted Manuscript
Potassium bromide catalyzed N-S bond formation via oxidative dehydrogena-
tion
Tian-Qun Yu, Yong-Sheng Hou, Yi Jiang, Wen-Xuan Xu, Tao Shi, Xia Wu,
Jin-Chao Zhang, Dian He, Zhen Wang
PII:
S0040-4039(17)30363-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.065
TETL 48766
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 February 2017
21 March 2017
21 March 2017
Please cite this article as: Yu, T-Q., Hou, Y-S., Jiang, Y., Xu, W-X., Shi, T., Wu, X., Zhang, J-C., He, D., Wang,
Z., Potassium bromide catalyzed N-S bond formation via oxidative dehydrogenation, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.03.065
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Tetrahedron Letters
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Potassium bromide catalyzed N-S bond formation via oxidative dehydrogenation
Tian-Qun Yua,c , Yong-Sheng Houa,c , Yi Jianga,c , Wen-Xuan Xua,c , Tao Shia , Xia Wua , Jin-Chao Zhanga ,
Dian Hea∗ and Zhen Wanga,b∗
a School of Pharmacy, Lanzhou University, West Donggang Road. No. 199, Lanzhou 730000, China.
b State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
c These authors are of equivalent contribution.
ARTICLE INFO
ABSTRACT
Article history:
Received
N-substituted benzo[d]isothiazol-3(2H)-ones are a family of compounds with extremely
important application. Recently, we have developed a new green pathway to synthesize these
compounds via potassium bromide-catalyzed intramolecular oxidative dehydrogenative
cyclization. This reaction has high functional group tolerance and affords excellent yield even in
gram scale.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Potassium bromide
N-S bond formation
Oxidative dehydrogenation
Benzo[d]isothiazol-3(2H)-ones
Intramolecular cyclization
Introduction
Table 1
O
Optimization of reaction conditions.
N-Substituted benzo[d]isothiazol-3(2H)-ones play a very
important role in many fields of everyday life. On one hand, the
compounds are used as bioactive substances like
N
H
O
O
S
S
KBr (5 mol%), O2 (1.0 atm)
N
+
NH
solvent, temp
24 h
pharmaceuticals,1 such as antimicrobial,2
antifungal,3
H
S
N
SH
antithrombotic agents4 and antitumor pills.5 On the other hand, in
the fields of agriculture, they were also used as bactericidal
preservatives,6 herbicide and plant growth regulator and so on.7
However, to our best knowledge, the traditional methods of
synthesizing benzo[d]isothiazol-3(2H)-ones are much too
inconvenient as tedious process,8 expensive reagents9 and
transition metals10 are all required (Scheme 1a).
1a
2a
O
3a
Yield (%)
Temp (oC)
Entry
Solvent
2a
3a
1a
2b
3c
4
DMSO
DMSO
DMSO
DMSO
80
80
80
80
0
5
0
0
0
0
0
21
5
6
7
8
9
DMF
DMA
CH3CN
THF
80
80
80
80
80
80
52
0
0
0
0
0
0
Dioxane
55
23
10
11
12
Toluene
DMF
80
90
0
0
0
0
0
0
0
82
86
DMF
100
110
120
110
DMF
>95
88
13
14
15d
16e
17f
DMF
DMF
73
DMF
DMF
110
110
>95
83
0
0
Unless otherwise noted, the reactions were performed in a sealed tube with
(0.1
1a
mmol), KBr (5.0 mol%), and O2 (1.0 atm) in 1 mL solvent for 24 h. All yields listed
are isolated yield. a Without O2 b Without KBr. c Without O2 or KBr. d 12h. e Under
air condition. f KBr (2.5 mol%).
.
———
∗ Corresponding author. Tel.: +86-182-9831-1530; fax: +86-931-8915686; e-mail: zhenw@lzu.edu.cn
∗ Corresponding author. Tel.: +86-130-0873-8922; fax: +86-931-8915686; e-mail: hed@lzu.edu.cn

2
Tetrahedron
What’s more, toxic matters and heavy metal salts waste
produced during these processes can’t be ignored. Considering
the widely application of these compounds and their values in
pharmaceutical industry,1 developing a novel and green pathway
to construct N-S bond(s) is significant. Herein, we report a
potassium bromide(KBr)-catalyzed oxidative dehydrogenation
reaction for synthesizing this kind of compounds (Scheme 1b).
According to the previous reports, bromide ion (Br-) can be
oxidized to bromine(Br2) in oxygen atmosphere to further
oxidize S-H bond to S-Br bond,11 so KBr is selected as the
catalyst. We initiated the experiment by using o-mercapto-N-
phenylbenzamide 1a as the starting material in the presence of
KBr in DMSO at 80 °C with O2, only 21% yield was achieved in
this trial (Table 1, entry 4). The following control reactions
showed that KBr and oxygen are necessary (Table 1, entries 1-3).
We then screened a series of solvents and found that the
reaction proceeded well in high polar solvents (Table 1, entries
4-10), and DMF (Table 1, entries 5) afforded the highest yield of
2a. Surprisingly, when the solvent was changed to dioxane, 2,2'-
disulfanediylbis(N-phenylbenzamide) 3a was obtained as well
(Table 1, entry 9). The effect of temperature was checked (Table
1, entries 11-14) and 110 °C was found to be the best. When the
reaction time was shortened to 12 h, the yield decreased slightly
(Table 1, entry 15). O2 was also changed to air to further screen
the reaction conditions, and the target compound was found to
have a high yield as well (Table 1, entry 16). When the amount
of KBr was decreased to 2.5 mol%, a slightly decrease occurred
in the yield of the target compound (Table 1, entry 17). We also
evaluated a series of inorganic salts including NaBr, CuBr,
CuBr2, NaI and KI, and all of them exhibited slightly lower
yields than KBr.
With the optimal reaction condition in hand, substrate scope
was investigated. In substrates 1b-1g, the reaction was proved to
be unaffected by electron-donating or -withdrawing groups, and
the functional groups remained unreacted. Sterically hindered
aryl with two bromide substituents in the ortho position 1h also
served as a substrate without any by-product. Excellent yields
were obtained as well for the substrates containing other aryl
substituents including thiazolyl group. Then the alkyl substituents
were checked and we found that they all have an excellent yield,
even when a more crowded tert-butyl group was used. Besides,
cyclopropanyl group didn’t change in this reaction, either.
The reaction can also be performed well in gram scale.
Treatment of 1.02 g of 1a with 5 mol% amount of KBr produced
0.75 g of 2a in 74% yield [eq. (1)].
A sulfoxide 4 was quantitively obtained when 2a was treated
in CH3COOH with H2O2 at room temperature 5 h, and the
structure of the compound was confirmed by X-ray
crystallography (Figure 1).
A primary mechanism research was conducted at last.
According to previous reports11, Br- can be oxidized to Br2, so
Br2 was trialed in the optimal reaction conditions [eq.(4)].
However, only a moderate yield was got, which proved the Br2 is
essential for this reaction. Besides, considering the result of entry
9 from Table 1, disulfide 3a was formed during our reaction as
well. Therefore, we used 3a as a starting material in the optimal
In an attempt to check the synthetic utility of the resulting
products, the reaction of 2a with a terminal alkyne was carried
out under standard conditions,12 and it afforded
a
mercaptoacetylene 6 in 67% isolated yield [eq.(2)], which can be
further transformed into an acetylene 7 via Sonogashira coupling
reaction [eq. (3)]. 12

conditions, the desired product was also acquired in a 95% yield
[eq. (5)], indicating the validation of the mechanism.
Conclusions
In summary, we have successfully realized the KBr-catalyzed
synthesis of benzo[d]isothiazol-3(2H)-ones via intramolecular
oxidative-dehydrogenative cyclization. In this reaction, a small
amount of green catalyst (5 mol% KBr) was used under air
condition at 110 °C to construct a new N-S bond, making this
pathway efficient and environmentally friendly. The simple and
easy handling method also makes our reaction an attractive
pathway for the synthesis of heterocyclic compounds with N-S
bond(s). Further research is still going on in our laboratory.
Acknowledgments
We thank Prof. Ying-Qian Liu for helpful discussions.
Financial support was provided by the Fundamental Research
Funds for the Central Universities(223000/862413), and
the Cuiying Student Innovation Fund of Lanzhou University.
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4
Tetrahedron
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Potassium bromide catalyzed N-S bond
formation via oxidative dehydrogenation
Tian-Qun Yu, Yong-Sheng Hou, Yi Jiang, Wen-Xuan Xu, Tao Shi, Xia Wu, Jin-Chao Zhang, Dian He, Zhen
Wang

6
Tetrahedron
1. We realized potassium bromide, a green
and highly efficient catalyst, to catalyze the
formation of the desired N-S bond.
2. The reaction proceeded in an excellent yield.
3. High functional group tolerance is exhibited
in this reaction as well.
4. The products are obtained in excellent yields
even in gram scale,
5. The products exhibit promising applications
in industry.