Generation of thioethers via direct C-H functionalization with sodium benzenesulfinate as a sulfur source

Article abstract of DOI:10.1039/c5ob02073e

A novel ammonium iodide-induced sulfenylation method of flavones, indole and arylimidazo[1,2-a]pyridines using stable and odorless sodium benzenesulfinates as sulfur sources was developed, generating regioselective derivatives in good yields. This method has enriched current thioether-producing methods and provided a good example of using ammonium iodide as a reaction inducer instead of iodine to make thioethers under environmentally friendly and odorless conditions.

Full text of DOI:10.1039/c5ob02073e

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DOI: 10.1039/C5OB02073E
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Generation of Thioethers via Direct C-H Functionalization with
Sodium Benzenesulfinate as Sulfur Source
Yingcai Ding,a Wei Wu,a Wannian Zhao,a Yiwen Li,b Ping Xie,c Youqin Huang,a Yu Liu,a Aihua Zhoua*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel ammonium iodide-induced sulfenylation method of development of new methods to generate thioethers is still highly
flavones, indole and arylimidazo[1,2-a]pyridines using stable and desired.
odorless sodium benzenesulfinates as sulfur sources was
developed, generating regioselective derivatives in good yields.
The method enriched current thioether-producing methods and
provided a good example of using ammonium iodide as a reaction
inducer instead of iodine to make thioethers under
environmentally friendly and odorless condition.
Sulfenylation is an important transformation to generate thioether
molecules in organic chemistry.1 Compounds containing thioether
moiety widely exist in nature and some drug molecules,2 therefore,
any new method to generate these molecules via direct C-H
functionalization is strongly desired. Until now, several methods of
generating thioether molecules have been developed. One typically
traditional method to make thioether is to react alkyl halide with a
metal thiolate.3 Later, transition metal-catalyzed reactions between
halides and different sulfur agents became common methods to
generate thioether molecules.4
Recently, thioether compounds were effectively produced via
transition metal-catalyzed C(sp2)-H functionalization.5 Not only this
Scheme 1. Generation of thioethers via using sodium
kind of method does not need any prefunctionalized reactants, but
also increases the selection scope for starting materials.
benzenesulfinate as a sulfur source.
Very recently, several metal-free thioether-generating methods
were also reported (Scheme 1).6 Among them, the method using
stable and odorless sodium benzenesulfinate as a sulfur source was
also reported. In Scheme 1, three previous representative reactions
to make thioethers were demonstrated.7 It was found that iodine
was commonly used as reaction inducers in these three reactions
and PPh3 was used as a reducing agent in two reactions. All
reactions used stable and odorless sodium benzenesulfinate as a
sulfur source. Despite these impressive achievements, the
In this paper, a new and regioselective thioether-generating
method with odorless sodium benzenesulfinates as sulfur source
and ammonium iodide as an inducer was reported, generating
thioethers in good yields under environmentally friendly condition.
To the best of our knowledgement, this kind of report has not been
reported before.
Flavone, indole and arylimidazo[1,2-a]pyridine are important
class of natural products with a varieties of biological activities,
many medicinal chemists have put their efforts on generating their
derivatives in order to explore biological activities,8 especially new
derivatives which were not studied before. In this paper, our goal is
to make these valuable derivatives. Here, flavone 1a were selected
and used as one of representative molecules. Different reaction
inducers, temperatures and solvents were screened in order to find
a suitable reaction condition.
a Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang, 212013, People’s
Republic of China, Email: ahz@ujs.edn.cn.
b School of Chemical Engineering, Jiangsu University, Zhenjiang, Jiangsu 212013
c Jiangsu University Library, Jiangsu University, Zhenjiang, Jiangsu 212013,
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI: 10.1039/ x
0xx00000x/
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Table 1. Optimization of the reaction conditionsa
Journal Name
Table 2. Regioselective sulfenylation of flavones via using sodium
benzenesulfinate as a sulfur sourcea
Entry
Inducer
(equiv.)
KI
Oxidant
Temp.
(oC)
80
80
80
Solvent
Yield
b (%)
0
O
O
O
O
O
O
S
S
S
1
2
3
4
5
6
7
8
TBHP
THBP
TBHP
TBHP
TBHP
--
--
--
--
--
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
Dioxane
Toluene
DCE
Br
I2
10
trace
12
78
84
20
70
35
5
3a, 84%
3b, 83%
3c, 81%
TBAI
NH4I
NH4I
NH4I
NH4Ic
NH4I
NH4I
NH4I
NH4I
NH4I
O
80
O
O
S
135
135
135
135
135
135
135
135
S
S
O
O
Cl
O
Cl
3d, 80%
3e, 80%
3f, 78%
9
O
O
O
10
11
12
Cl
S
Cl
S
Cl
Br
S
--
--
8
25
EtOH
O
O
O
a
3g, 77%
Reaction conditions: flavone (0.5 mmol, 1.0 equiv), sodium
3h, 60%
3i, 75%
benzenesulfinates (2.0 equiv.), KI and I2 (1.0 equiv.), NH4I (4.0
equiv.), aqueous TBHP (70 wt % in water, 2.0 equiv.), solvent (0.5
mL). b Isolated yields are based on flavone, the reaction was run for
20 hours. c NH4I (1.0 equiv.).
O
O
O
S
Br
S
Br
S
O
O
O
Br
3j, 76%
3k, 75%
3l, 76%
First, KI was used as an inducer with oxidant TBHP for the above
reaction, the reactions didn’t give the expected product 3a at 80 oC
(entry 1). Using I2 as an inducer with TBHP generated only 10% yield
of product 3a (entry 2). When TBAI was used as an inducer, the
reaction only produced a trace amount of 3a (entry 3). Using the
combination of NH4I/THBP in DMF gave a 12% yield of 3a (entry 4).
When temperature was raised to 135 oC, the combination of
NH4I/TBHP in DMF gave a 78% yield (entry 5). Surprisingly, using
NH4I only in DMF without TBHP afforded a good yield of 84% (entry
6). Decreasing the amount of NH4I to one equivalent led to a low
yield of product 3a (entry 7). When CH3CN was used as solvent
instead of DMF, the yield was raised to 70% (entry 8). When
dioxane was used as a solvent, the reaction gave 35 % yield (entry
9). Using toluene or DCE as solvents gave 3a in a yield of 5% or 8%,
respectively (entries 10, 11). When EtOH was used as a solvent, only
a 25% yield of 3a (entry 12) was produced. After screening, the
suitable reaction conditions selected for the couplings of ethers
O
O
NC
S
O2N
Cl
S
O
O
3m, 65%
3n, 63%
a
Reaction conditions: flavone (0.5 mmol, 1.0 equiv), sodium
sulfinates (2.0 equiv.), NH4I (4.0 equiv), DMF (0.5 mL). b Isolated
yields are based on reactant 1a, all reactions were run for 20 hours
at 135 oC.
flavones with methyl function on α and β-position were produced
and employed for the reactions in Scheme 2. When the α-
positioned reaction site was blocked by methyl, no expected
product 3o was isolated, verifying that the regioselectivity of this
sulfenylation was very good, and the reaction only happened on the
α-position. When the methyl group is on the β-position of flavone, a
decreased yield of thioether 3p was observed, possibly due to the
steric effects from neighbouring methyl function.
o
with coumarins are: NH4I, (4.0 equiv), temperature: 135 C, flavone
(0.5mmol, 1.0 equiv.), DMF is used as a solvent (0.5 mL).
After the optimal reaction condition was obtained, different
flavones were reacted with sodium sulfinates. Nine flavones with
different electron-deficient or electron-donating functions and five
sodium sulfinates were employed as reaction partners. All reactions
proceeded well and gave good yields of regioselective flavone
thioethers 3a-3n. By comparing the reaction yields, it was found
that electron-rich flavone reactions gave a little higher yields than
electron-deficient flavone ones (Table 2). Based on H and 13C-NMR
1
Scheme 2. Control reactions.
and HRMS spectra of all products, it was found that all -SAr
functions were added to the α-position of flavone ketone functions,
only trace amount of β-position products were observed.
To further test if our reaction condition is also suitable for the
sulfenylation of other molecules reported in Scheme 1, indole and
To explore how the substituents on α and β-position of flavones
influence the regioselective sulfenylation, two methyl-substituted
2 | J. Name., 2012, 00, 1-3
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imidazo[1,2-a]pyridine were prepared and reacted with sodium
sulfinate under the same reaction condition. It was found that both
Table 3. Regioselective sulfenylation of indole and arylimidazo-[1,2-
a]pyridines via using sodium benzenesulfinate as a sulfur source a
Cl
S
S
S
N
N
N
H
H
H
4a, 80%
4c, 73%
4b, 79%
Scheme 3. Proposed mechanisms for the thioether-generating
reactions.
Br
S
arylimidazo[1,2-a]pyridine to give intermediate E, F and G, then the
loss of proton from intermediate E, F and G to NH3 molecule
regioselectively afforded final products 3, 4 and 5.
S
S
N
N
N
H
N
N
In summary, a novel ammonium iodide-induced thioether-
generating method was reported. By using this method, flavones,
indole and arylimidazo[1,2-a]pyridine thioether derivatives were
easily made via using stable and odorless sodium benzenesulfinates
as sulfur source, generating highly regioselective ArS-substituted
products in good yields. The method has enriched current
thioether-producing methods, providing an alternative method to
generate thioethers instead of iodine-induced method.
Investigation on the biological activities of these products is
currently underway.
5b, 73%
4d, 70%
5a, 75%
Cl
S
S
S
N
N
N
OMe
N
N
N
HO
5e, 78%
5d, 69%
5c, 65%
Br
S
Cl
S
S
N
Br
Br
Author Contributions
N
N
Y.D. and W.W. contributed equally.
N
N
N
HO
5f, 63%
5g, 60%
5h,67%
Acknowledgements
This investigation was generously supported by funds provided by
a
Reaction conditions: indole or arylimidazo[1,2-a]pyridines (0.5
mmol, 1.0 equiv), sodium sulfinates (2.0 equiv.), NH4I (4.0 equiv),
DMF (0.5 mL). Isolated yields are based on reactant indole or
b
Jiangsu University (1281290006).
arylimidazo[1,2-a]pyridines, all reactions were run for 20 hours at
135 oC
Notes and references
reactions proceeded well, the results were demonstrated in Table 3.
The result showed that indole reacted well with different sodium
sulfinates, giving good and regioselective indole thioethers 4a-d,
while the reactions of imidazo[1,2-a]pyridines with sodium
sulfinates also generated good and regioselective ArS-substituted
arylimidazo[1,2-a] pyridine derivatives 5a-h in good yields. These
results proved that our thioether-generating method has a wide
application scope.
Based on the previous literature reports9 and the results obtained
in this work, a plausible reaction mechanism was proposed below
(Scheme 3). Heat split NH4I into HI and NH3, then HI started to
reduce sodium benzenesulfinate, after intermediate A, B, C, D and
the loss of H2O, NaI and I2 molecules, electrophilic ArS-I was
generated, then it continued to react with flavone, indole and
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Generation of Thioethers via Direct C-H Functionalization with Sodium
Benzenesulfinate as Sulfur Source
Yingcai Ding,a Wei Wu,a Wannian Zhao,a Yiwen Li,b Ping Xie,c Youqin Huang,a Yu Liu,a Aihua
Zhoua
*
aPharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang, Jiangsu 212013, People’s
Republic of China
Email: ahz@ujs.edn.cn
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