Benzisothiazol-3-ones through a Metal-Free Intramolecular N–S Bond Formation

Article abstract of DOI:10.1002/ejoc.201801090

The highly efficient synthesis of benzoisothiazol-3-ones from thiobenzamides has been described with good functional group compatibility and excellent yields. This work represents the first example of selectfluor-promoted N–S bond formation processes. This method provides a facile approach to access various important bioactive benzoisothiazol-3-ones.

Full text of DOI:10.1002/ejoc.201801090

A Journal of
Accepted Article
Title: Metal-free intramolecular N-S bond formation to access
benzisothiazol-3-ones
Authors: KE YANG, Hao Zhang, BEN NIU, tiandi tang, and Haibo Ge
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10.1002/ejoc.201801090
European Journal of Organic Chemistry
COMMUNICATION
Metal-free intramolecular N-S bond formation to access
benzisothiazol-3-ones
Ke Yang,*[a,b] Hao Zhang,[a] Ben Niu,[b] Tiandi Tang,[a] and Haibo Ge*[b]
Abstract: The highly efficient synthesis of benzoisothiazol-3-ones
from thiobenzamides has been described with good functional group
compatibility and excellent yields. This work represents the first
example of selectfluor-promoted N−S bond formation processes.
This method provides a facile approach to access various important
bioactive benzoisothiazol-3-ones.
structure of R2N−F or R3N+−F have gained much attention due
to their applications in fluorination reactions.4 However, the use
of these reagents for other transformations is relatively
5
underexplored.4f, Inspired by the reaction of α-fluorination of
thioethers,6 we conceived that the F+ reagents could be used as
catalysts or mediators to react with thiobenzamides 1, forming
the corresponding cyclic fluorosulfonium salts, and then produce
the desired products 2 (Scheme 1). This might offer a novel and
mild method to access benzoisothiazol-3-ones. Herein, we
disclose our results on the synthesis of benzoisothiazol-3-ones
via a sequential N−S bond formation and C−S bond cleavage
process. It should be mentioned that studies on exploiting F+
reagents for such transformations have not been reported so far.
Introduction
Benzoisothiazol-3-ones are ubiquitous structural units in
medical and agricultural compounds with a broad range of
biological activities including antivirus, anti-bacterial, anti-
psychotic, antithrombotic, and analgesic activities (Figure
1).1 Substantial efforts have been devoted to develop
efficient methodologies to construct such skeletons.2,3
Among them, the metal-free synthetic approach has gained
considerable interest due to the green and sustainable
properties. However, current metal-free processes often
require the use of toxic and/or corrosive thionyl chloride,3a-d
chlorine gas,3e-f trimethyl chlorosilane,3g or strong acids.3h-k
Furthermore, their applications are also severely limited due
to the narrow substrate scope.3 Therefore, the development
of facile and efficient methods to construct benzoisothiazol-
3-ones would be of prime synthetic value.
Scheme 1. The strategy to directly access benzoisothiazol-3-ones with
F+ reagents.
Results and Discussion
To probe chemical selectivity of this reaction, we have chosen
the alkynyl substituted starting material, 2-(methylthio)-N-(prop-
2-yn-1-yl)benzamide 1a as the substrate which could be easily
prepared through the condensation reaction of commercially
available 2-(methylthio)benzoic acid and prop-2-yn-1-amine. We
commenced our investigation on intramolecular cyclization of 1a
in the presence of selectfluor. It was found that the desired
product 2-(prop-2-yn-1-yl)benzo[d]isothiazol-3(2H)-one 2a could
be detected in 54% yield by employing 1.0 equivalent of
selectfluor in MeCN at 40 °C (Table 1, entry 3). To our delight,
the yield was improved to 92% by simply increasing the reaction
temperature to 80 °C (Table 1, entry 9). It was also noticed that
other electrophilic fluorinating reagents such as N-
Figure 1. The selected biologically active compounds containing
benzoisothiazol-3-one skeletons.
Recently, electrophilic fluorinating reagents with the general
[a]
[b]
Dr. Ke Yang, Hao Zhang and Prof. Dr.Tiandi Tang
Jiangsu Key Laboratory of Advanced Catalytic Materials &
Technology, School of Petrochemical Engineering
Changzhou University
1 Gehu Road, Changzhou, Jiangsu 213164, China
Email: keyang@cczu.edu.cn
Homepage: http://che.cczu.edu.cn/lfs/list.htm
Dr. Ke Yang, Ben Niu and Prof. Dr.Haibo Ge
Department of Chemistry and Chemical Biology
Indiana University Purdue University Indianapolis
Indianapolis, Indiana 46202, USA
fluorobenzenesulfonimide
(NFSI)
and
1-fluoro-2,4,6-
trimethylpyridinium triflate (NFPT) could promote the process,
albeit with lower yields (Table 1, entries 10-11). Next, various
substituents including H, Et, Bn and Ph on the sulfur atom were
examined, and either lower yield or no desired product was
observed, indicating that methyl group is the optimal substituent
(Scheme 2).
Email: geh@iupui.edu
Homepage: https://science.iupui.edu/people/ppgenchemge-haibo
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801090
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Optimization of Reaction Conditions[a]
.
F+ reagent
(mol%)
Temperature
(oC)
Yield
(%)[b]
Entry
Solvent
Selectfluor
(20)
1
2
MeCN
MeCN
MeCN
MeCN
Aetone
MeOH
DMF
40
40
40
40
40
40
40
60
80
80
80
10
23
Scheme 3. Scope of aryl-substituted methylthiobenzamide. Conditions: 1 (0.2
mmol), selectfluor (0.2 mmol), MeCN (2.0 mL), 80 °C, 12 h, isolated yield.
Selectfluor
(50)
Selectfluor
(100)
3
54
Selectfluor
(150)
4
42
Selectfluor
(100)
5
20
Selectfluor
(100)
6
trace
50
Selectfluor
(100)
7
Selectfluor
(100)
8
MeCN
MeCN
MeCN
MeCN
75
Selectfluor
(100)
9
92(90)[c]
31
10
11
NFSI (100)
NFPT (100)
36
[a] Conditions: 1a (0.2 mmol), electrophilic fluorinating reagent, 2.0 mL of
solvent, 12 h. [b] Yields are based on 1a, determined by crude 1H NMR using
dibromomethane as the internal standard. [c] Isolated yield.
Scheme 4. Scope of N-substituted methylthiobenzamide. Conditions: 1 (0.2
mmol), selectfluor (0.2 mmol), MeCN (2.0 mL), 80 °C, 12 h, isolated yield. [a]
100 °C.
Next, we explored the substrate scope of N-substituted 2-
methylthiobenzamides under the standard conditions (Scheme
4). Various linear alkyl-substituted substrates provided the
corresponding products (2k-p) in excellent yields. As expected,
both cyclic alkyl-substituted substrates 1q and 1r generated the
corresponding products in good yields. Moreover, different
branched alkyl-substituted substrates also provided the
corresponding products (2s-w) in good yields. Additionally, 2-
methylthiobenzamide 1s was first tested, and to our delight, the
desired product benzo[d]isothiazol-3(2H)-one 2s could be
smoothly obtained in a moderate yield. It is noteworthy that the
bulky t-butyl group afforded the desired product 2w in 75%
Scheme 2. The investigation of substituents on the sulfur atom.
With the optimized conditions in hand, the substrate scope
study of N-substituted 2-methylthiobenzamides was carried out
(Scheme 3). Various aryl-substituted 2-(methylthio)-N-(prop-2-
yn-1-yl)benzamides including an electron-withdrawing groups (F,
Cl, Br or CF3) and electron-donating group (Me or MeO), were
examined, and the desired products (2a-j) were isolated in good
to excellent yields. It is noteworthy to mention that the well-
tolerated halogens enable the further manipulations of the initial
products.
isolated
yield.
Finally,
N-aryl-substituted
2-
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10.1002/ejoc.201801090
European Journal of Organic Chemistry
COMMUNICATION
methylthiobenzamides were also investigated in this system. As
expected, substrates with either an electron-withdrawing or
electron-donating group at the para-, meta- or ortho-position of
the aromatic ring were compatible under the modified reaction
conditions (2y-z and 2af-ak).
Moreover, reaction of 1k with selectfluor in anhydrous MeCN
gave the desired product 2k in high yield, indicating a different
reaction pathway (Scheme 5f and 5g).
On the basis of the above results and previous reports,3, 6-7
a
plausible reaction mechanism has been proposed (Scheme 6). It
is believed that the transient fluorosulfonium salt A is formed in
the presence of selectfluor. Then, the cyclic sulfonium salt E can
be generated through the direct cyclization of this salt (path a).
On the other hand, the cyclic sulfonium salt E can also be
produced through dehydration of intermediate C obtained from
nucleophilic substitution of intermediate A (path b). In the
presence of salt B, nucleophilic displacement of the methyl
group on the sulfonium salt E ultimately gives the desired
product 2k and salt F. It should be mentioned that a radical
cyclization process cannot be excluded. The starting material 1k
might be oxidized to the corresponding amidyl radical which is
further transformed into the desired product 2k through the an
addition to the sulfur atom and subsequent demethylation.8-9
To shed light on the reaction mechanism, a series of control
experiments were performed. The 1H NMR experiment indicated
that the selectfluor was almost completely converted to the salts
B
and F under the standard conditions (Scheme 5a).
Additionally, reaction of 1k with selectfluor produced sulfoxide D
with 90% NMR yield at room temperature in 5 h (Scheme 3b). It
was then found that no desired product 2k could be obtained if
the salt B was absent, indicating that the salt B plays an
important role in this intramolecular cyclization reaction (Scheme
5c and 5d). Furthermore, the desired product 2k could be
obtained in 72% NMR yield while the reaction mixture was kept
at room temperature for 5 h, and then heated to 80 °C for
another 12 h (Scheme 5e). These results suggest that the
sulfoxide intermediate may be involved in this process.
Scheme 5. The control experiments.
Scheme 7. The gram-scale synthesis of drug precursor 2o and the synthesis
of caspase-3 inhibitor 3a
Scheme 6. The plausible reaction mechanism.
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10.1002/ejoc.201801090
European Journal of Organic Chemistry
COMMUNICATION
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Finally, to demonstrate the synthetic utility of this method, a
gram scale reaction was carried out (Scheme 7). When methyl
2-(2-(methylthio)benzamido)acetate 1o was treated with 1.0
equivalent of selectfluor in MeCN (10 mL) at 100 °C , drug
precursor 2o2c was obtained in 83% yield. Furthermore, the
caspase-3 inhibitor 3a1g could also be readily prepared by using
2-(prop-2-yn-1-yl)benzo[d]isothiazol-3(2H)-one 2a and BnN3 as
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Conclusions
In summary, we have developed an efficient selectfluor-
promoted synthesis of benzoisothiazol-3-one derivatives through
a sequential N−S bond formation and C−S bond cleavage
process. This transformation is the first example of selectfluor-
mediated N−S bond formation processes. Moreover, this
reaction tolerates various functional groups with excellent yields.
In combination, this novel method provides an important
complementary approach to access various bioactive
benzoisothiazol-3-one derivatives.
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Experimental Section
A 10 mL Schlenk tube was charged with 2-methylthiobenzamide (1, 0.2
mmol), selectfluor (0.2 mmol, 70.9 mg) and MeCN (2.0 mL). The tube
was sealed and the reaction was then stirred vigorously at 80 ˚C for 12h.
After cooling to room temperature, the reaction mixture was then
concentrated in vacuo. The residue was purified by flash chromatography
on silica gel to yield the desired product 2.
Acknowledgements
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We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (21776022 and
21702019) and Advanced Catalysis and Green Manufacturing
Collaborative Innovation Center, Changzhou University for
financial support. We also gratefully acknowledge Indiana
University Purdue University Indianapolis for financial support.
Keywords: Cleavage reactions • Cyclization • Metal-free •
Selectfluor • Sulfur heterocycles
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Synthetic methodology
Ke Yang,* Hao Zhang, Ben Niu, Tiandi
Tang and Haibo Ge*
Page No. – Page No.
Metal-free intramolecular N-S bond
formation to access benzisothiazol-3-
ones
An efficient selectfluor-promoted synthesis of benzoisothiazol-3-ones through a
sequential N−S bond formation and C−S bond cleavage process was developed.
This article is protected by copyright. All rights reserved.