TBAI-HBr system mediated generation of various thioethers with benzenesulfonyl chlorides in PEG400

Article abstract of DOI:10.1039/c6ra02302a

An efficient procedure for the formation of C-S bonds via C-H functionalization was developed for the synthesis of aryl sulfides in good to excellent yields using TBAI-HBr system promoted direct sulfenylation of various compounds, such as phenols, pyrazolones, indoles and related heteroarenes. Low cost and widely available arylsulfonyl chlorides were used as the sulfur source to provide various sulfur-containing compounds. The characteristic of the present protocol is convenient, green, highly efficient with a wide-application and short reaction time.

Full text of DOI:10.1039/c6ra02302a

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TBAI–HBr system mediated generation of various
thioethers with benzenesulfonyl chlorides in
Cite this: RSC Adv., 2016, 6, 54377
PEG400
†
*
*
Dingyi Wang, Shengmei Guo, Rongxing Zhang, Sen Lin and Zhaohua Yan
An efficient procedure for the formation of C–S bonds via C–H functionalization was developed for the
synthesis of aryl sulfides in good to excellent yields using TBAI–HBr system promoted direct
sulfenylation of various compounds, such as phenols, pyrazolones, indoles and related heteroarenes.
Low cost and widely available arylsulfonyl chlorides were used as the sulfur source to provide various
sulfur-containing compounds. The characteristic of the present protocol is convenient, green, highly
efficient with a wide-application and short reaction time.
Received 26th January 2016
Accepted 1st June 2016
DOI: 10.1039/c6ra02302a
www.rsc.org/advances
zenesulfonyl chlorides are their precursor. Apparently, several
issues of these strategies should be addressed: (1) use benze-
Introduction
nesulfonyl chlorides to replace some sulfur sources that they
are green but unavailable, such as sodium benzenesulnates,
benzenesulfonyl hydrazides and so on; (2) nd an efficient
and green reaction system to synthesize sulfur-containing
compounds by directly using benzenesulfonyl chlorides as
a sulfur source in the absence of a transition metal catalyst; (3)
look for a reaction system is suitable for several compound to
synthesize sulfocompounds using benzenesulfonyl chlorides
(Scheme 1).
In order to solve these problems, PPh3-mediated sulfenyla-
tion of indolizines and related heteroarenes by directly using
aryl-sulfonyl chlorides as a sulfur source has been reported by
You.14 The protocol proves to be an efficient and convenient way
to synthesize di(hetero)aryl suldes using benzenesulfonyl
chlorides directly. But in the view of green chemistry, it also
encounters disadvantages, such as a mass of PPh3 as reducing
agent was used. The reaction was nished in toluene under the
conditions of high temperature and longer reaction time.
Previous relevant literature indicates that benzenesulfonyl
chlorides can be readily reduced to reactive aryl sulde
species,15 which reacts with electron donor compounds to
Aryl suldes as important building blocks for creating mole-
cules oen appear in total synthesis, in functional materials
science, and in medicinal chemistry.1 In the last few decades,
many scientists have reported transition metal (e.g., Pd,2 Cu,3
Ni,4 In,5 Fe,6 Co (ref. 7) etc.) catalyzed cross-coupling reactions of
aryl halides, boronic acids and triates with S-containing
nucleophiles. For the preparation of aryl thioethers, the above
mentioned methods are the main techniques of traditional
synthesis. Aryl thiols and disuldes are oen used as the choice
of sulfur sources. Nevertheless, many of these sulfur sources are
oen limited because of their expensiveness, instability and
high-toxicity. Therefore, a new, direct, exible and green sulfe-
nylation of (hetero)arenes to synthesize aryl suldes under
metal-free conditions is always a hot issue for chemists.
In the past few years, many efficient methods to synthesize
sulphur compounds have been reported by groups of Yi,8 Tian,9
Hiebel,10 Bolm11 and others.12 Recently, we reported the I2-
mediated thiolation of phenol/phenylamine derivatives and
sodium arylsulnates in water.13 Obviously, the synthesis of
sulfur-containing compounds have made great progress. From
the perspective of green chemistry, scientists have found the
other new sulfur sources (e.g., sodium benzenesulnates, ben-
zenesulfonyl hydrazides, diphenyl disuldes etc.) to replace
thiophenols. Although these sulfur sources are environmentally
friendly, we are hard to get their derivatives from the market
directly. For example, the derivatives of sodium benzenesul-
nate and benzenesulfonyl hydrazide need to be synthesized.
It is noteworthy that inexpensive and easily available ben-
College of Chemistry, Nanchang University, Nanchang, Jiangxi 330031, China. E-mail:
senlin@ncu.edu.cn; yanzh@ncu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra02302a
Scheme 1 Methods for the construction of thioethers.
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produce various thioethers. To explore a convenient, green and PEG400 proved to be the best choice in the transformation (entries
high efficient reaction system which has a wider substrate scope 4, 12–15). The reaction was less efficient when other acid were
by directly using arylsulfonyl chlorides as a sulfur source thus used (Table 1, entries 4–11). The reactions were investigated
interested us.
using different amounts of TBAI/HBr. The results are shown in
Table 1 (entries 16–20). Under the standard conditions, different
amounts of TBAI ranging from 1.5 to 2.5 equivalents were applied
in the reactions. The obtained yields increased as the TBAI
amounts increased up to 2 equivalents to reach the maximum
(Table 1, entry 5). Decreasing or increasing the amount of HBr
both slightly decreased the reaction yields (Table 1, entries 18–
20). Finally, when the reaction was carried out at 50 ꢀC with
prolonged reaction time, the yield of 3aa was signicantly lower
(Table 1, entry 21). On the basis of the results shown in Table 1,
the TBAI–HBr system at 100 ꢀC in PEG400 for 5 h emerged as the
optimized reaction conditions for follow-up studies.
With optimized conditions now in hand, a series of phenols
and benzenesulfonyl chlorides were applied in the reaction to
investigate the scope and generality of this protocol (Table 2). A
range of benzenesulfonyl chlorides which have electron-
donating and electron-withdrawing groups reacted with 2 to
get the target products 3aa–3dc and 3af–3df in moderate to
excellent yields. It's worth mentioning that we have not found
C–halogen bond cleavage during the reaction. Besides, apart
from phenols, methoxy-benzenes (3d and 3e) were able to react
with benzenesulfonyl chlorides to provide the corresponding
products 3ad–3de in a few hours in 85–92% yields as well. In
general, benzenesulfonyl chlorides with electron-donating
groups on the yield of target products were higher than those
with electron-withdrawing groups.
Results and discussion
To prove the feasibility of our proposed assumption, we started
the investigation by selecting the reaction of tosyl chloride 1a
with 2,7-naphthalenediol 2a as the model reaction (Table 1).
From the perspective of green chemistry, poly(ethylene glycol) is
an ideal solvent for chemical transformation because of its non-
toxic, odorless, neutral, nonvolatile, and non-irritating and is
used in a variety of pharmaceuticals and medications. Tosyl
chloride was treated with 2,7-naphthalenediol (2a, 1.2 equiv.),
tetrabutyl-ammonium iodide (TBAI, 2.0 equiv.) and HCOOH (2.0
equiv.) in 2 mL of PEG400 at 100 ꢀC for 5 h in the opening system
(Table 1, entry 7). Not surprisingly, the reaction provided a 52%
yield of the desired product 3aa. First, several iodide-containing
were initially investigated, and among them TBAI showed the
best efficiency to give the corresponding product 3aa in 86%
(Table 1, entries 1–4). Then, we screened different solvents,
Table 1 Optimization of the reaction conditiona
Table 2 Substrate scopea
Iodide
(equiv.)
Acid
(equiv.)
Yieldb
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
NaI (2.0)
NH4I (2.0)
HI (2.0)
HBr (2.0)
HBr (2.0)
—
HBr (2.0)
HF (2.0)
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
Dioxane
Toluene
EtOH
23
40
27
86
25
45
52
47
32
27
57
82
75
55
42
69
85
71
84
76
51
80
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (1.5)
TBAI (2.5)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
HCl (2.0)
HCOOH (2.0)
AcOH (2.0)
TFA (2.0)
PvOH (2.0)
TsOH (2.0)
HBr (2.0)
HBr (2.0)
HBr (2.0)
HBr (2.0)
HBr (2.0)
HBr (2.0)
HBr (1.5)
HBr (2.5)
HBr (4.0)
HBr (2.0)
HBr (2.0)
9
10
11
12
13
14
15
16
17
18
19
20
21c
22d
H2O
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
a
Conditions: 1a (0.30 mmol), 2a (0.36 mmol), solvent (2 mL), iodide (2.0
b
a
equiv.), acid (2.0 equiv.), 5 h, 100 ꢀC, under air. Yield of isolated
Conditions: 1 (0.30 mmol), 2 (0.36 mmol), TBAI (0.60 mmol), HBr (0.60
product. c 50 ꢀC. Under N2.
mmol, 40% aqueous), PEG400 (2 mL), 100 ꢀC, 5 h.
d
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On the basis of satised results obtained under TBAI–HBr chlorides under TBAI–HBr system. It was found that the
system, we further apply this system to show the functional reactions proceeded well, and the results are showed in Table
group tolerance. For this purpose, we carried out the reactions 4. The result showed that pyrazolones reacted well with ben-
of various benzenesulfonyl chlorides with different benzohe- zenesulfonyl chlorides bearing electron-donating substitu-
terocycles under the aforementioned conditions (Table 3). It ents and electron-withdrawing groups at the para-position
was exhilarating to nd that different benzenesulfonyl chlorides giving good and regioselective thioethers 7aa–7fa in good to
having electron-withdrawing and electron-donating halo excellent yields under an air atmosphere. At the same time,
groups at the 4-position were able to react with indoles (4a) to we are pleased to nd that the reaction was completed
afford the desired products (5aa–5fa) in good yields under the in minutes. Moreover, benzenesulfonyl chlorides do not
optimized conditions. Fortunately, indolizines and related react with phenyl from pyrazolones under the same reaction
heteroarenes were also suitable for this kind of transformation conditions.
in the presence of HBr. It's worth mentioning that we found
In order to gain further insight into the plausible reaction
benzenesulfonyl chlorides could react with benzoheterocycles pathway of TBAI–HBr system mediated generation of various
under mild conditions. The reaction temperature could go thioethers, some control experiments were conducted under
down to 50 ꢀC. Under the optimized conditions, a series of para- various reaction conditions, as showed in Scheme 2. In the
substituted benzenesulfonyl chlorides smoothly reacted with 4b presence of 1.0 equivalents of iodine, tosyl chloride 1a reac-
and 4c to give desired products in moderate yields (Table 3). ted with 2,7-naphthalenediol 2a led to the desired product
According to the results analysis, much lower yields were ob- 3aa in 23% yield (Scheme 2a). In the absence of TBAI, treat-
tained when indolizines (4c) and related heteroarenes (4b) ment of tosyl chloride (1a) with 2,7-naphthalenediol (2a) and
instead of indoles (4a) were employed in this kind of HBr (2.0 equiv.) under standard reaction conditions in
transformation.
a closed tube to yield the target product (3aa, 46%), and
To further examine whether our reaction conditions are bromine was detected aer the end of reaction. On the other
also suitable for ketone compounds, we sought to expand the hand, the reaction was carried out in the presence of HI led to
scope of sulphenylation of pyrazolones with benzenesulfonyl 3aa in 27% (Scheme 2c).
On the basis of the experimental results described above and
together with previous relevant mechanistic studies,14,16 a plau-
Table 3 Reaction of benzenesulfonyl chlorides with indoles, indoli-
sible reaction mechanism for aryl suldes formation from
phenols/benzoheterocycles and benzenesulfonyl chlorides is
proposed below (Scheme 3). HI is formed by the reaction of
TBAI with acid, then HI and HBr started to reduce benzene-
sulfonyl chlorides, electrophilic ArSCl (8) was generated, which
continued to react with phenols, indole, indolizine and related
heteroarene to give intermediates A, B, C and D and then the
loss of protons from intermediates A, B, C and D to ClÀ regio-
selectively afforded target products. In another minor pathway
(Scheme 3), ArSCl (8) also be formed via reduction of benzene-
sulfonyl chlorides (1) with iodine.
zines and related heteroarenesa
Table 4 Cross-coupling of pyrazolones and benzenesulfonyl
chloridesa
a
a
Conditions: 1 (0.30 mmol), 4 (0.36 mmol), TBAI (0.60 mmol), HBr (0.60
Conditions: 1 (0.30 mmol), 6a (0.36 mmol), TBAI (0.60 mmol), HBr
mmol, 40% aqueous), PEG400 (2 mL), 50 ꢀC, 2–4 h.
(0.60 mmol, 40% aqueous), PEG400 (2 mL), 100 ꢀC, 45 min.
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Chemical Reagent Co., Adamas, Aladdin and TCI used as
received.
General procedure: (3)
HBr (40% aqueous, 88 mL, 0.6 mmol) was added to a solution of
2 (0.36 mmol), aryl sulfonyl chlorides 1 (0.30 mmol) and TBAI
(221 mg, 0.60 mmol) in PEG400 (2 mL), and the reaction mixture
ꢀ
was stirred at 100 C for 5 h. Aer completion of the reaction,
the reaction mixture was diluted with ethyl acetate, and
quenched with saturated sodium thiosulfate solution (10 mL)
and extracted twice with ethyl acetate (2 Â 15 mL). The organic
layer was washed with water and dried over anhyd. sodium
sulfate. The solvent was evaporated in vacuo, and the residue
was subjected to column chromatography using ethyl acetate in
petroleum ether as the eluent to afford the pure target
compound 3.
Scheme 2 Control experiments.
General procedure: (5)
HBr (40% aqueous, 88 mL, 0.6 mmol) was added to a solution of
4 (0.36 mmol), aryl sulfonyl chlorides 1 (0.30 mmol) and TBAI
(221 mg, 0.60 mmol) in PEG400 (2 mL), and the reaction mixture
was stirred at 50 ꢀC for 2 h. Aer completion of the reaction, the
reaction mixture was diluted with ethyl acetate, and quenched
with saturated sodium thiosulfate solution (10 mL) and
extracted twice with ethyl acetate (2 Â 15 mL). The organic layer
was washed with water and dried over anhyd. sodium sulfate.
The solvent was evaporated in vacuo, and the residue was sub-
jected to column chromatography using ethyl acetate in petro-
leum ether as the eluent to afford the pure target product.
General procedure: (7)
HBr (40% aqueous, 88 mL, 0.6 mmol) was added to a solution of
6a (0.36 mmol), aryl sulfonyl chlorides 1 (0.30 mmol) and TBAI
(221 mg, 0.60 mmol) in PEG400 (2 mL), and the reaction mixture
ꢀ
was stirred at 100 C for 45 min. Aer completion of the reac-
Scheme 3 Proposed mechanisms for aryl sulfides formation from
tion, the reaction mixture was diluted with ethyl acetate, and
quenched with saturated sodium thiosulfate solution (10 mL)
and extracted twice with ethyl acetate (2 Â 15 mL). The organic
layer was washed with water and dried over anhyd. sodium
sulfate. The solvent was evaporated in vacuo, and the residue
was subjected to column chromatography using ethyl acetate in
petroleum ether as the eluent to afford the pure target product.
phenols/benzoheterocycles and benzenesulfonyl chlorides.
Conclusions
In summary, a classical TBAI–HBr system induced thioether-
generating method is reported. By using this system, phenols,
ketones, indoles and related heteroarenes thioether derivatives
were easily made via using extensive source arylsulfonyl chlorides
as sulfur sources, generating highly regioselective ArS-substituted
products in moderate to good yields in shorter time. The method
has enriched current thioether-producing methods, providing an
alternative method to generate thioethers and instead of iodine-
induced methods. An investigation on other types of reaction
using TBAI–acid system is currently underway.
Acknowledgements
We are grateful for the nancial support from the National
Natural Science Foundation of China (21302084).
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