Synthesis of Thioethers and Thioesters with Alkyl Arylsulfinates as the Sulfenylation Agent under Metal-Free Conditions

Article abstract of DOI:10.1002/asia.201601376

A study on the coupling of cycloalkanes with alkyl arylsulfinates has been performed. Using iodine as the catalyst, through C (Formula presented.) ?H bond activation and sulfinates reduction, a wide range of thioethers were produced in moderate to high yields. Additionally, various thiocarboxylic esters can also be produced by simply performing the reaction under CO pressure. Notably, this is the first report in which alkyl arylsulfinates were used as sulfenylation agents in a cross-coupling transformation.

Full text of DOI:10.1002/asia.201601376

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Synthesis of Thioethers and Thioesters with Alkyl Arylsulfinates
as the Sulfenylation Agent under Metal-free Conditions
Authors: Xiao-Feng Wu, Yahui Li, Fengxiang Zhu, and Zechao Wang
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Synthesis of Thioethers and Thioesters with Alkyl Arylsulfinates
as the Sulfenylation Agent under Metal-free Conditions
Yahui Li,[a] Fengxiang Zhu,[a] Zechao Wang,[a] and Xiao-Feng Wu*[a]
Abstract: An interesting study on the coupling of cycloalkanes with
alkyl arylsulfinates has been performed. With iodine as the catalyst,
through C(sp3)-H bond activation and sulfinates reduction, a wide
range of thioethers were produced in moderate to high yields.
Additionally, various thiocarboxylic esters can be produced as well
by just perform the reaction under CO pressure. Notably, this is the
first report on using alkyl arylsulfinates as the sulfenylation agent in
cross-coupling transformation.
Sulfur-containing compounds are of great importance as
building blocks for natural products, pharmaceuticals and
functional materials (Figure 1).[1] Consequently, the development
of new synthetic methodology for organosulfur compounds
synthesis is an important field in organic chemistry.[2] Indeed,
numerous novel procedures have been established during the
past decades. In general, the developed procedures can be
Figure 1. Selected examples of organosulfur-containing drugs.
divided into two classes; either based on sulfur sources (A + ‘S’
+ B = A’S’B)[3] or with sulfenylation agents (A’S’X + B = A’S’B).
Concerning the sulfenylation agents, disulfides,[4] sulfenyl
Our investigation started with methyl benzenesulfinate and
halides,[5]
N-thioarylphthalimides,[6]
thiols,[7]
arylsulfonyl
cyclohexane as the model substrates under at 140 °C with
iodide as the catalyst (Table 1). By optimizing the possible
reaction parameters, the combination of I2 (10 mol%), diethyl
phosphonate (2 equiv.) and DTBP (1.5 equiv.) were found to be
the best catalyst system here. Under this conditions, 82% of
cyclohexyl(phenyl)sulfane can be successfully isolated (Table 1,
entry 1). The results of control experiments in the absence of
iodine, diethyl phosphonate or DTBP indicated that these
species play indispensable roles in the reaction (Table 1, entries
2-7). Other oxidant such as TBHP, H2O2, cumyl hydroperoxide,
benzoyl peroxide, tert-butyl peroxybenzoate provided less
reaction efficiency (Table 1, entries 8-12). Remove of MeCN or
decrease reaction temperature all gave decreased yields (Table
1, entries 13-15). Additionally, in order to exclude the metal
impurities in the reagents act as the real catalyst, inductively
coupled plasma atomic emission spectroscopy (ICP–AES)
analysis of the reaction reagents were performed. The results
shown the concentrations of the possible transition metals, such
as Cu, Pd, Rh, Ru, and Ni were below the detection limitation
(see the Supporting Information for details). These results
confirmed the catalyst role of iodine in this procedure, and
excluded the effects of the possible transition metal
contaminations in reagents applied.
cyanides,[8] quinone mono-O,S-acetals,[9] sulfonyl hydrazides,[10]
arylsulfonyl chlorides,[11] sodium sulfinates[12] and sulfinic acid[13]
have been reported and applied in various transformations. Alkyl
arylsulfinates is an interesting class of organic compounds which
is ready available, odour-less, stable and miscible with organic
solvents.[14] However, the usage of alkyl arylsulfinates as
sulfenylation agent has been rarely explored.
On the other hand, carbonylative transformations have
already become
a powerful toolbox in modern organic
synthesis.[15] Through carbonylation reactions, CO as one of the
cheapest C1 source can be easily installed into the parent
molecules. By this manner, the carbon chain can be easily
prolonged while the produced carbonyl-containing compounds
are important chemicals as well. In all the developed
carbonylation reaction, regarding the coupling partners applied,
nitrogen, oxygen and carbon nucleophiles are more frequently
applied. The using of ‘S’ as nucleophile in carbonylation
reactions are less explored which might due to the non-pleasant
smell of thiols and also its poison to the metal catalysts.[16]
Taking all these backgrounds into consideration and also as our
continual interests on carbonylation chemistry, we performed
this study on using alkyl arylsulfinates as the sulfenylation agent.
With cycloalkanes as the reaction partners, the corresponding
carbonylated and non-carbonylated products were formed in
moderate to good yields. This study hold the following features:
1) with iodine as the catalyst in carbonylative coupling; 2) metal-
free activation of C(sp3)-H bond of simple cycloalkanes; 3) the first
example on using methyl arylsulfinates as the sulfenylation
agent.
Table
1.
Iodine-catalyzed
cyclohexane
activation:
Optimization reaction conditions.[a]
Entry
Variation from standard conditions (3a) Yield
1
2
3
4
Standard Condition
5 mol% of I2
82%
70%
80%
18%
[a]
Y. Li, F. Zhu, Z. Wang, Prof. Dr. X.-F. Wu
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-
Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: Xiao-Feng.Wu@catalysis.de
Supporting information for this article is given via a link at the end of
the document.
20 mol% of I2
Without I2
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be produced as well; these products are ready for further
functionalization via cross-coupling reactions (Table 3, entries 8-
5
Without DTBP
0%
6
Diethyl phosphonate (1 eq.)
Without diethyl phosphonate
TBHP instead of DTBP
48%
32%
20%
trace
trace
trace
12).
Good
yields
of
and
cyclohexyl(4-
cyclohexyl(4-
7
(trifluoromethoxy)phenyl)sulfane
(trifluoromethyl)phenyl)sulfane were isolated without any further
optimizations (Table 3, entries 13 and 14). 76% yield of
cyclohexyl(4-(methylthio)phenyl)sulfane can be produced under
identical reaction conditions (Table 3, entry 15). Ester functional
group can also be tolerated and gave the corresponding product
in 72% yield (Table 3, entry 16). However, decreased yield was
obtained with nitro substituted substrate (Table 3, entry 17).
8
9
H2O2 instead of DTBP
10
11
Benzoyl peroxide instead of DTBP
Cumyl hydroperoxide instead of DTBP
tert-Butyl peroxybenzoate instead of
DTBP
12
10%
13
14
15
Without CH3CN
120 oC
100 oC
56%
48%
trace
Table 3. Iodine-catalyzed thioethers synthesis from
arylsulfinates.[a]
[a] Methyl benzenesulfinate (0.5 mmol), I2 (10 mol%), diethyl
phosphonate (2 equiv.), DTBP (0.75 mmol; 1.5 equiv.),
cyclohexane/CH3CN (1.5 mL/0.2 mL), 140 oC, 24 h, isolated
yields.
Entry
1
Arylsulfinates
Products
Yield
75%
With the optimized reaction conditions in hand, we examined
the scope of the reaction. Cycloalkanes were tested at the first
stage (Table 2) and moderate to good yields can be achieved in
general. Not only cyclopentane, but larger sized rings are all
suitable substrates here. However, cyclic ethers (1,4-dioxane,
THF) and cyclic amines (piperidine, 1-methylpiperidine,
pyrrolidine) failed under our conditions.
2
3
4
72%
86%
74%
Table 2. Iodine-catalyzed thioethers synthesis from alkanes.
5
71%
Entry
1
Alkanes
Products
Yield
82%
6
7
61%
87%
89%
66%
88%
2
3
4
56%
61%
75%
8
5
6
51%
73%
9
[a] Methyl benzenesulfinate (0.5 mmol), I2 (10 mol%), diethyl
phosphonate (1 mmol), DTBP (0.75 mmol), alkane/CH3CN (1.5
mL/0.2 mL), 140 oC, 24 h, isolated yields.
10
11
12
93%
75%
Regarding the applicable alkyl benzenesulfinates, except
methyl benzenesulfinate, ethyl benzenesulfinate and propyl
benzenesulfinate are applied and give the corresponding
products in good yields successfully (Table 3, entries 1-2). Then
various methyl arylsulfinates were tested under the optimized
reaction conditions. Fluoro substituted methyl arylsulfinates gave
the desired thioethers in good yields (Table 3, entries 3-7). Good
to excellent yields of bromo and chloro substituted products can
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7
53%
13
14
15
65%
79%
76%
[a] Arylsulfinates (0.5 mmol), I2 (10 mol%), diethyl phosphonate
(1 mmol), DTBP (1.5 mmol), CO (20 bar), cyclohexane/CH3CN
(1.5 mL/0.2 mL), 120 oC, 24 h, isolated yields.
16
17
72%
32%
[a] Arylsulfinates (0.5 mmol), I2 (10 mol%), diethyl phosphonate
(1 mmol), DTBP (0.75 mmol), cyclohexane (1.5 mL), MeCN (0.2
mL), 140 oC, 24 h, isolated yields.
As our interests in carbonylation chemistry, we performed the
same reaction under CO pressure. To our delight, the desired
thioester can be successfully produced (Table 4). By increasing
the loading of DTBP and decreasing the reaction temperature,
59% of the desired product can be formed (Table 4, entry 1). For
the success of this transformation, 20 bar of CO pressure is
necessary. Lower pressure gave lower yield of thioester and
thioether can also be detected. Moderate yields of thioesters can
be obtained in general in substrates testing.
Scheme 1. Control experiments.
In order to get insight into the reaction mechanism, some
control experiments were carried out and shown in Scheme 1.
When no DTBP was added into the reaction, no desired
thioether or thioester can be obtained but 58 % yield of phenyl
disulfide was isolated (Scheme 1, eq. 1). Also cyclohexane can
react with phenyl disulfide (Scheme 1, eq. 2 and eq. 3). When 4
equivalents of TEMPO were added to the standard reaction
mixture, no desired product can be obtained (Scheme 1, eq. 4).
And a product from the reaction between cyclohexane and
TEMPO can be found in GC-MS analysis. These results indicate
that the reaction proceeds through radical intermediates and
phenyl disulfide can be the resting state of the sulfinates
reduction process.
Table 4. Iodine-catalyzed thioesters synthesis.[a]
Entry
1
Arylsulfinates
Products
Yield
59%
Based on these results, a possible reaction mechanism is
proposed (Scheme 2). The reaction started with a thermal
homolytic cleavage of a peroxide to generate the tert-butoxy
radical, which reacts with cyclohexane A. After CO insertion into
the radical B, intermediate C can be formed. Meanwhile, methyl
benzenesulfinate D is reduced by diethyl phosphonate and I2 to
generate the phenyl thiol radical E, which is considered as the
resting state of phenyl disulfide. Finally, C reacts with E to afford
the final product G.
2
3
4
57%
54%
44%
5
6
40%
50%
Scheme 2. Proposed reaction mechanism.
In conclusion, an interesting study on the coupling of
cycloalkanes with alkyl arylsulfinates has been performed. With
iodine as the catalyst, through C(sp3)-H bond activation and
sulfinates reduction, a wide range of thioethers were produced in
moderate to high yields. Additionally, various thiocarboxylic
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10.1002/asia.201601376
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esters can be produced as well by just perform the reaction
under CO pressure. Notably, this is the first report on using alkyl
arylsulfinates as the sulfenylation agent in cross-coupling
transformation.
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General procedure A: A 25-mL pressure tube was charged with 0.5 mmol
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Acknowledgements
The authors thank the Chinese Scholarship Council for financial
Support. The analytic supports of Dr. W. Baumann, Dr. C. Fisher,
S. Buchholz, and S. Schareina are gratefully acknowledged. We
also appreciate the generous supports from Professor Matthias
Beller in LIKAT.
Keywords: arylsulfinates • sulfenylation agent • green chemistry
• domino reaction • carbonylation
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[2]
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COMMUNICATION
Yahui Li, Fengxiang Zhu, Zechao Wang,
and Xiao-Feng Wu*
Page No. – Page No.
Synthesis of Thioethers and
Thioesters with Alkyl Arylsulfinates
as the Sulfenylation Agent under
Metal-free Conditions
An interesting study on the coupling of cycloalkanes with alkyl arylsulfinates has
been performed. With iodine as the catalyst, through C(sp3)-H bond activation and
sulfinates reduction, a wide range of thioethers were produced in moderate to high
yields. Additionally, various thiocarboxylic esters can be produced as well by just
perform the reaction under CO pressure. Notably, this is the first report on using
alkyl arylsulfinates as the sulfenylation agent in cross-coupling transformation.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.