Trichloroisocyanuric acid (TCCA) and N-chlorosuccinimide (NCS) as efficient reagents for the direct oxidative conversion of thiols and disulfides to sulfonyl chlorides

Article abstract of DOI:10.1080/10426507.2011.621910

Trichloroisocyanuric acid (TCCA) and N-chlorosuccinimide (NCS) were found to be mild and efficient reagents for the direct oxidative conversion of sulfur compounds to the corresponding arenesulfonyl chlorides in good-to-excellent yields through the oxidative chlorination. The overall process is simple and practical, and it provides convenient access to a variety of aryl or heteroarylsulfonyl chlorides. The mild reaction conditions and the broad substrate scope render this method attractive and complementary to existing syntheses of aryl or heteroarylsulfonyl chlorides. Copyright

Full text of DOI:10.1080/10426507.2011.621910

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Phosphorus, Sulfur, and Silicon and the
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Trichloroisocyanuric Acid (TCCA) and
N-Chlorosuccinimide (NCS) as Efficient
Reagents for the Direct Oxidative
Conversion of Thiols and Disulfides to
Sulfonyl Chlorides
Hojat Veisi a , Alireza Sedrpoushan b , Saba Hemmati c & Davood
Kordestani d e
a Chemistry Department, Payame Noor University, Tehran, Iran
b Institute of Industrial Chemistry, Iranian Research Organization for
Science and Technology, Tehran, Iran
c Young Researchers Club, Islamic Azad University, Kermanshah
Branch, Kermanshah, Iran
d Department of Chemistry, Razi University, Kermanshah, Iran
e Nanoscience and Nanotechnology Research Center (NNRC), Razi
University, Kermanshah, Iran
Version of record first published: 05 Apr 2012.
To cite this article: Hojat Veisi , Alireza Sedrpoushan , Saba Hemmati & Davood Kordestani (2012):
Trichloroisocyanuric Acid (TCCA) and N-Chlorosuccinimide (NCS) as Efficient Reagents for the Direct
Oxidative Conversion of Thiols and Disulfides to Sulfonyl Chlorides, Phosphorus, Sulfur, and Silicon and
the Related Elements, 187:6, 769-775
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Phosphorus, Sulfur, and Silicon, 187:769–775, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.621910
TRICHLOROISOCYANURIC ACID (TCCA) AND
N-CHLOROSUCCINIMIDE (NCS) AS EFFICIENT
REAGENTS FOR THE DIRECT OXIDATIVE CONVERSION
OF THIOLS AND DISULFIDES TO SULFONYL CHLORIDES
Hojat Veisi,1 Alireza Sedrpoushan,2 Saba Hemmati,3
and Davood Kordestani4
1Chemistry Department, Payame Noor University, Tehran, Iran
2Institute of Industrial Chemistry, Iranian Research Organization for Science
and Technology, Tehran, Iran
3Young Researchers Club, Islamic Azad University, Kermanshah Branch,
Kermanshah, Iran
4Department of Chemistry, Razi University, Kermanshah, Iran, and Nanoscience
and Nanotechnology Research Center (NNRC), Razi University, Kermanshah, Iran
GRAPHICAL ABSTRACT
TCCA (0.4 equiv.)
R
SH
or
RS SR
O
S
or
NCS (1.1 equiv.)
R
Cl
BnMe3NCl (3 equiv.)
H2O (2.5 equiv.)
CH3CN (5 mL)
O
Cl
O
O
N
O
N Cl
N
N
Cl
Cl
O
O
NCS
TCCA
Abstract Trichloroisocyanuric acid (TCCA) and N-chlorosuccinimide (NCS) were found to
be mild and efficient reagents for the direct oxidative conversion of sulfur compounds to
the corresponding arenesulfonyl chlorides in good-to-excellent yields through the oxidative
chlorination. The overall process is simple and practical, and it provides convenient access to
a variety of aryl or heteroarylsulfonyl chlorides. The mild reaction conditions and the broad
substrate scope render this method attractive and complementary to existing syntheses of aryl
or heteroarylsulfonyl chlorides.
Keywords Oxidative chlorination; sulfonyl chloride; thiol; disulfide; N-chloro reagents
Received 10 August 2011; accepted 3 September 2011.
We are thankful to Payame Noor University (PNU) for the partial support of this work.
Address correspondence to Hojat Veisi, Chemistry Department, Payame Noor University 19395-4697
Tehran, Iran. E-mail: hojatveisi@yahoo.com
769

770
H. VEISI ET AL.
INTRODUCTION
Aryl and heteroarylsulfonyl chlorides are an important class of compounds primarily
used in the preparation of sulfonamides. Sulfonamide motifs are prevalent in a variety
of biologically active compounds with a broad range of biological and pharmaceutical
activities, including inhibition of carbonic anhydrase,1 novel and selective cholecystokinin-
2 receptor antagonists,2 β3-receptor agonists,3 and HCV polymerase inhibitors.4
The development of simple, versatile, and environmentally friendly processes or
methodologies for widely used organic compounds from readily available reagents is one
of the major challenges for chemists in organic synthesis. Organic sulfur compounds are
widespread in numerous natural products and widely used as various artificial chemicals.
Sulfonyl chlorides, in particular, are precursors with extensive uses in organic synthesis.5
The most typical method for the preparation of sulfonyl chlorides is the oxidative chlorina-
tion of sulfur compounds, thiols, sulfides, thioacetates, and thiocarbamates with aqueous
chlorine,6 although other oxidizing agents such as KNO3/SO2Cl2,7 cyanuric chloride,8
HCl/Cl2,9 HCl/NCS,10 H2O2/ZrCl4,11 H2O2/SOCl2,12 Oxone/SOCl2,13 Br2-Cl3PO,14 and
TMSCl/KNO315 have also been used for this purpose. However, in spite of their potential
utility, many of these methods involve various drawbacks such as the use of expensive
or less easily available reagents, vigorous reaction conditions, long reaction time, tedious
manipulations in the isolation of the pure products, and side reactions.
RESULTS AND DISCUSSION
Owing to the drawbacks of oxidative chlorination with different oxidizing agents
(mentioned previously), the discovery of milder and practical routes for the synthesis of
sulfonyl chlorides is highly desirable. As part of our continuing studies on the use of N-halo
reagents in organic synthesis,16 herein we introduce for the first time trichloroisocyanuric
acid (TCCA)/BnMe3NCl/H2O or N-chlorosuccinimide (NCS)/BnMe3NCl/H2O as valu-
able reagent systems for the direct oxidative chlorination of thiols and disulfides to the
corresponding sulfonyl chlorides (Scheme 1).
TCCA (0.4 equiv.)
R
SH
or
RS SR
O
S
or
NCS (1.1 equiv.)
R
Cl
BnMe3NCl (3 equiv.)
H2O (2.5 equiv.)
CH3CN (5 mL)
O
Cl
O
O
N
O
N Cl
N
N
Cl
Cl
O
O
NCS
TCCA
Scheme 1
Initially, we surmised that it might be possible to generate controlled amounts of
chlorine in nonprotic organic solvents by mixing a tetra-alkylammonium chloride salt with

OXIDATIVE CHLORINATION OF THIOLS AND DISULFIDES USING TCCA AND NCS 771
TCCA. We were pleased to find that treatment of tetra-alkylammonium chloride (4 equiv.)
and H2O (2.5 equiv.) with TCCA (0.4 equiv.) in CH3CN (20 min, r.t.) provided a light
yellow solution that was suitable as a chlorinating oxidation system for the synthesis of
benzylsulfonyl chlorides from benzyl thiol (1 equiv.) under mild conditions (Scheme 2).
O
t-Bu4NCl(4 equiv.)
H2O (2.5 equiv.)
SH
Cl
S
TCCA (0.4 equiv.)
CH3CN, 20 min.
98%
O
Scheme 2
Under the abovementioned optimized reaction conditions, the reactions of various
thiols were investigated in this study. As shown in Table 1, aromatic thiols carrying
either electron-donating or electron-withdrawing substituents afforded excellent yields
1
of products with high purity (monitored by H NMR). Heterocyclic thiols, such as 2-
mercaptopyrimidine and 2-mercaptobenzimidazole, were also investigated. Under the same
conditions, the desired products were obtained in excellent yields (Table 1, entries 8 and
9). Furthermore, aliphatic compounds, such as cyclohexanethiol, also afforded the sulfonyl
chloride in excellent yield (Table 1, entry 10).
An investigation into the mechanistic aspects of oxidative chlorination of thiols
showed the corresponding disulfide to be the main intermediate in this transformation.
When the reaction of 4-methoxybenzyl thiol was carried out with 1:0.15 molar ratios of
thiol to TCCA in the presence of tetra-alkylammonium chloride (1.5 equiv.) and H2O (1.5
equiv.) for 5 min, the desired disulfide was obtained as the major product.
In order to further verify the mediation of the disulfides in the oxidative chlorination
of thiols, reactions were repeated with a range of symmetrical disulfides (Scheme 1).
After optimizing the reaction in order to identify conditions that consistently produced
excellent yields of sulfonyl chlorides, we found that the best reaction conditions required
the presence of TCCA (0.4 mmol), TBAB (2 mmol), H2O (1.5 mmol), and disulfide (1
mmol) in acetonitrile at room temperature. The generality and the scope of the reaction
were investigated and the results of the study are summarized in Table 1 (entries 11–16).
As shown, all reactions resulted in the formation of the corresponding sulfonyl chlorides
in excellent yields with high purity. This shows that successive oxidation of the sulfur
atom, followed by S–S bond cleavage and subsequent chlorination, occurs during the direct
conversion of thiols into the corresponding sulfonyl chlorides.
Also, we found that NCS was a suitable reagent for the conversion of thiols and disul-
fides into the corresponding sulfonyl chlorides in excellent yields under same conditions.
The results were presented in Table 1 (entries 1–16).
The possible mechanism for this transformation is shown in Scheme 3.12 It is accept-
able to assume that the thiol is chlorinated in the presence of hypochlorous acid. Therefore,
the mechanism proceeds through hydroxylation of the thiol under formation of a sulfenic
acid (I), which gives the corresponding symmetric disulfide (II). Then, the successive ox-
idation of both sulfur atoms of the disulfide molecule by hypochlorous acid produces the
intermediate (III), which undergoes rapid isomerization to form thiosulfonate (IV), which
can easily furnish the sulfonyl chloride (V).

772
H. VEISI ET AL.
Table 1 Oxidative chlorination of thiols and disulfides with TCCA and NCS
Entry
1
Thiol
Sulfonyl chloridea
TCCA yield (%)
99
NCS yield (%)
98
SH
SO2Cl
2
3
98
98
96
95
SH
SO2Cl
SO2Cl
SH
Me
Me
4
5
6
99
96
96
98
90
96
SH
SO2Cl
SO2Cl
SO2Cl
SO2Cl
MeO
MeO
F
SH
F
SH
SH
O2N
O2N
7
8
9
98
95
96
95
95
96
N
N
SH
SO2Cl
N
N
N
N
SH
SO2Cl
N
H
N
H
10
11
98
99
95
99
SH
SO2Cl
SO2Cl
S
2
2
2
12
13
98
95
97
92
SO2Cl
SO2Cl
S
S
Me
Me
14
15
98
96
95
95
SO2Cl
SO2Cl
S
S
2
2
O2N
O2N
16
98
98
SO2Cl
S
2
aProducts were characterized by their physical properties and spectroscopic methods.

OXIDATIVE CHLORINATION OF THIOLS AND DISULFIDES USING TCCA AND NCS 773
Cl
O
N
O
H2O
RSH
-H2O
RS Cl
H2O
HOCl
N
N
-HCl
Cl
Cl
O
I
RS OH
TCCA
HCl
Cl
S
-Cl
RSH
-H2O
-HCl
HOCl
-OH
RS OH2
RS SR
R
SR
II
H2O
Cl
O
O
S
O
S
O
R
S
SR
-HCl
HOCl
R
S
SR
R
SR
R
S
R
O
O
H
O
III
IV
-RSH HCl
O
S
H
N
O
R
Cl
+
HN
NH
O
O
V
Scheme 3
To compare this method with a few previously published methods for the direct
oxidative chlorination of thiols and disulfides to the corresponding sulfonyl chlorides, we
carried out a few experimental runs, which are presented in Table 2. These results clearly
demonstrate that our novel procedure is a good system for the preparation of sulfonyl
chlorides.
Table 2 Reaction times and yields for previously published methods
Substrate
Product
C6H5SO2Cl
Conditions
Time
Yield (%)
C6H5SH
C6H5SH
TCCA/TBAC/H2O/r.t.
20 min
60 min
98
9217
C6H5SO2Cl
2,4-Dichloro-5,5-dimethyl-hydantoin
CH3CN-HOAc-H2O 5–20 ◦C
TMS-Cl/MNO3/CH2Cl2/50 ◦C
Cyanuric chloride/Et3N/reflux
TCCA/TBAC/H2O/r.t.
2,4-Dichloro-5,5-dimethyl-hydantoin
CH3CN-HOAc-H2O 5–20 ◦C
TMS-Cl/MNO3/CH2Cl2/50 oC
Cyanuric chloride/Et3N/reflux
C6H5SH
C6H5SH
C6H5SO2Cl
C6H5SO2Cl
60 min
20 h
20 min
60 min
858
9015
98
4-Me-C6H4SH 4-Me-C6H4SO2Cl
4-Me-C6H4SH 4-Me-C6H4SO2Cl
8817
4-Me-C6H4SH 4-Me-C6H4SO2Cl
4-Me-C6H4SH 4-Me-C6H4SO2Cl
2-Naphthothiol 2-Naphthosulfonyl chloride TCCA/TBAC/H2O/r.t.
2-Naphthothiol 2-Naphthosulfonyl chloride 2,4-Dichloro-5,5-dimethyl-hydantoin
CH3CN-HOAc-H2O 5–20 ◦C
2 h
20 h
20 min
60 min
858
9015
98
8817
2-Naphthothiol 2-Naphthosulfonyl chloride Cyanuric chloride/Et3N/reflux
20 h
8815

774
H. VEISI ET AL.
CONCLUSIONS
In conclusion, we have developed a simple and effective oxidative chlorination pro-
cedure for the synthesis of aryl and heteroaryl sulfonyl chlorides with TCCA or NCS as a
safe and inexpensive equivalent to chlorine gas. Many aromatic thiols and disulfides can be
converted to the corresponding arylsulfonyl chlorides in good-to-excellent yields, making
it superior to the methods described previously.
EXPERIMENTAL
All commercially available chemicals were obtained from Merck and Fluka and used
without further purifications unless otherwise stated. 1H NMR spectra were recorded on a
Jeol 90 MHz FT NMR spectrometer using TMS as internal standard and chemical shift were
measured in δ (ppm). IR spectra were recorded on a Perkin Elmer GX FT-IR spectrometer.
All yields refer to isolated products.
General Procedure for the Conversion of Thiols and Disulfides
to Sulfonyl Chlorides
To a stirred mixture of the thiol (1.0 mmol), Bu4NCl (4.0 mmol), and water
(2.5 mmol) or the di◦sulfide (1.0 mmol) Bu4NCl (2.0 mmol), and water (1.5 mmol) in
CH3CN (5 mL) at 0 C, TCCA (0.4 mmol) or NCS (1.1 mmol) was added as a solid in
portions over 1–2 min. After the addition, the mixture was stirred at room temperature
for 20 min until completion of the reaction. The mixture was filtered and the filtrate was
evaporated under vacuum. Then, CH2Cl2 (10 mL) was added, and the insoluble reagent
was removed by filtration. The filtrate was evaporated under vacuum to afford the product.
All of the products are known compounds and characterized easily by comparison with
authentic samples (1H NMR, 13C NMR, m.p.).
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