Oxidative Thioesterification of Alkenes Mediated by 1,3-Dibromo-5,5-dimethylhydantoin and DMSO for the Synthesis of α-Ketothioesters

Article abstract of DOI:10.1002/ejoc.201900585

A simple and mild approach for the synthesis of α-ketothioesters via 1,3-Dibromo-5,5-dimethylhydantoin (DBH)/DMSO mediated oxidative thioesterification of alkenes has been developed. Various of α-ketothioesters products were produced in moderate to good y

Full text of DOI:10.1002/ejoc.201900585

A Journal of
Accepted Article
Title: 1,3-Dibromo-5,5-dimethylhydantoin (DBH)/DMSO mediated
oxidative thioesterification of alkenes for the synthesis of α-
ketothioesters
Authors: Jiawei Hua, Jiaqi Xu, Jia Xu, Bochao Zhou, Dong Zhang,
Zhao Yang, Zheng Fang, and Kai Guo
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900585
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900585
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10.1002/ejoc.201900585
European Journal of Organic Chemistry
FULL PAPER
1,3-Dibromo-5,5-dimethylhydantoin
(DBH)/DMSO
mediated
oxidative thioesterification of alkenes for the synthesis of α-
ketothioesters
Jiawei Hua, [a] Jiaqi Xu, [a] Jia Xu, [a] Bochao Zhou, [a] Dong Zhang, [a] Zhao Yang, [b] Zheng Fang, * [a] Kai
Guo*[a][c]
Abstract: A simple and mild approach for the synthesis of α-
ketothioesters via 1,3-Dibromo-5,5-dimethylhydantoin (DBH)/DMSO
mediated oxidative thioesterification of alkenes has been developed.
Various of α-ketothioesters products were produced in moderate to
good yields under metal-free conditions. And this method features
readily available starting materials and broad substrate scope.
Moreover, a plausible mechanism was proposed based on the
methyl bromide captured experiment.
mediated oxidative bromination system (Scheme 1a).5 Ahmed’s
group developed an amino catalytic oxidative thioesterification of
2-oxoaldehydes with aliphatic thiols for the synthesis of
α-ketothioesters (Scheme 1b).6 In 2018, Yu and co-workers
discovered a TBAI/K2S2O8 promoted oxidative thioesterification
strategy for synthesizing α-ketothioesters under metal-free
conditions (Scheme 1c).7 However, there are also some
drawbacks including the uneasy available starting materials and
failing to afford alkyl ketone thioester, which have great limitations
for practical applications. Therefore, it is highly necessary to
develop simple and mild methods for the preparation of
α-ketothioesters.
Introduction
α-ketothioesters, one of the unique C-S bond structures units,
play an important role in constructing various natural products.1
And α-ketothioesters have been applied for the synthesis of the
promising cephalosporin, anticonvulsant, analgesic and antitumor
versatile drug precursors,2 which possess a great advantage in
With the X2/HX-DMSO system, various conventional oxidative
transformations by means of oxidative halogenations followed by
DMSO oxidation have been reported.8 Classic process about the
usage and release of X2 (Cl2, Br2 and I2) would result in lots of
environmental pollution. Consequently, looking for a green and
efficient reagent alternative will make these methods more
environmental-friendly. DBH not only performs as a bleaching and
sterilizing agent in handling industrial and domestic water
pollution,9 but also is widely used for various transformations in
chemical synthesis, which is competent for the bromination of
alkenes, alkynes and aromatic C–H bonds.10 Furthermore, as the
simple, commercially available and cheap starting materials,
alkenes provide the C-C double bonds to build valuable and
useful molecules, that possess extensive application in chemical
synthesis.11 For all we know, oxidative thioesterification of
alkenes for the synthesis of α-ketothioesters has never been
reported yet. DBH-DMSO combination might be an interesting
attempt to generate α-ketothioesters from alkenes. Herein, we
develop a mild DBH/DMSO mediated oxidative thioesterification
of alkenes to α-ketothioesters (Scheme 1d).
transforming
to
useful
pharmaceutical
intermediates.
Consequently, these compounds have gradually attracted
chemistry researchers around the world.3
Traditionally, α-ketothioesters were obtained by means of the
hydrolysis of trimethyl α-oxo trithioorthoesters, the aerobic
oxidation of α-hydroxythioesters, and the hydrolysis of β-keto α,
α-dichloro sulfides.2a,4 These classic procedures mentioned
above still suffer from some apparent drawbacks, such as the use
of the flammable reagent (tert-Butyllithium) and the demand of
expensive metal. The reactions involving metal reagents usually
are heterogeneous and have large amount of residue, which may
restrict their application in industry. Recently, several synthetic
methodologies for the oxidative thioesterification reactions under
metal-free conditions have been successfully presented. In 2014,
Das’s group reported a novel method for preparing γ-substituted
β, γ-unsaturated a-ketomethylthioesters via a PPh3·HBr-DMSO
[a]
J. Hua, J. Xu, J. Xu, B. Zhou, D. Zhang, Z. Yang, Prof. Z. Fang, and
Prof. K. Guo
Department: College of Biotechnology and Pharmaceutical
Engineering
Institution: Nanjing Tech University
Address 1: 30 Puzhu Rd S., Nanjing 211816, China
E-mail: guok@njtech.edu.cn; fzcpu@163.com
Z. Yang
Department; College of Engineering
Institution: China Pharmaceutical University
Address 2: 24 Tongjiaxiang, Nanjing, 210003, China
K. Guo
[b]
[c]
Department; State Key Laboratory of Materials-Oriented Chemical
Engineering
Institution: Nanjing Tech University
Address 3: 30 Puzhu Rd S., Nanjing 211816, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900585
European Journal of Organic Chemistry
FULL PAPER
Scheme 1. DBH/DMSO mediated oxidative thioesterification of alkenes for the
synthesis of α-ketothioesters.
Under the optimized reaction conditions, a variety of alkenes 1
were chosen to expand the scope of the oxidative
thioesterification. As shown in Table 2, styrene derivatives
bearing both electron-donating groups (Me, MeO, t-Bu, AcO, Ph),
and halogenated groups (F, Cl, Br), proceeded smoothly to afford
the corresponding products in moderate to good yields (Table 2,
2b-2o). Generally, the positions of substitution patterns (para-,
meta-, and ortho-) have no great influence on the reaction activity
(Table 2, 2b-2d, 2i-2o). However, the strong electron-withdrawing
groups (NO2) substituted styrene failed to generate the desired
product, which might be caused by the decreased electron density
(Table 2, 2p). Fused rings and heterocycle alkenes including 2-
Vinylnaphthalene and 2-Vinylpyridine tolerated well to provide the
corresponding α-ketothioesters in 75% and 60% yields under the
optimal reaction conditions (Table 2, 2q and 2r). Gratifyingly,
simple aliphatic alkenes were successfully suitable for the
approach to transform to 2s and 2t in 51% and 49% yields,
respectively.
Results and Discussion
Initially, the oxidative thioesterification of styrene 1a to form α-
ketothioesters 2a was chosen as the model reaction. And the
results of the reaction optimization were summarized in Table 1.
First, styrene 1a was treated with DBH (2equiv.) and Na2CO3
(1equiv.) at room temperature in anhydrous DMSO for 10h, the
desired product 2a merely obtained in 48% yield (Table1, entry 1).
Several bases were screened to improve the yield of 2a (Table1,
entries 2-7). The results indicated that NaHCO3 was the favorable
choice, compared to a series of bases such as Na2CO3, Cs2CO3,
Et3N, DBU, Pyridine and Piperidine. With the further investigation
of the reaction conditions, we were pleased to discover that DBH
(1.5equiv.) exhibited the better effect with 63% yield of α-
ketothioesters 2a (Table1, entry 10). Raising the reaction
temperature to 40℃ successfully improved the yield of product 2a
to 70% (Table1, entry 12). Finally, either increasing or decreasing
the amount of NaHCO3 failed to afford higher yields of 2a (Table1,
entries 14 and 15). To verify the practical application of this
strategy, a scale-up reaction was conducted by using 10mmol 1a
and 30mL DMSO under the optimized reaction conditions (Table1,
entry 16). We were pleased that the product 2a was obtained in
62% yield, suggesting that the oxidative thioesterification method
is suitable for large scale preparation.
Table 2. Substrate scope of alkenes for the synthesis of 2a [a,b]
Table 1. Optimization of reaction conditions [a]
Entry
1
DBH (eq)
base
Na2CO3
Cs2CO3
NaHCO3
Et3N
T (℃)
rt
Yield [b] (%)
48
2
2
2
rt
40
3
2
rt
58
4
2
rt
25
5
2
DBU
rt
19
6
2
Pyridine
Piperidine
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
rt
17
7
2
rt
20
[a] Reaction conditions:
1 (1mmol, 1equiv.), DBH (1.5equiv.), NaHCO3
8
0.5
1
rt
trace
20
(1equiv.), ( was added into a sealed tube in the end, otherwise fail to
1
react), solved in 4mL anhydrous DMSO and stirred for 10h at 40
Isolated yields.
℃. [b]
9
rt
10
11
12
13
14
15
16
1.5
2.5
1.5
1,5
1.5
1.5
1.5
rt
63
Next, several control experiments were performed to gain an
insight into the mechanism of this strategy (Scheme 2). The
different gas atmosphere (N2, air, O2) was tested smoothly under
the standard reaction conditions, and all gave the product 2a in
excellent yield (Scheme 2a). And the results demonstrated that
O2 was the unnecessary part of the oxidative thioesterification
reaction. The addition of 5 equiv. of H2O into the standard
conditions failed to afford the desired product (Scheme 2b). When
styrene 1a reacted with 2mmol DMSO in 4mL DMF, the product
2a was obtained in 28% yield. Meanwhile, the reaction was
carried out in 4mL DMF without DMSO, no product was generated
(Scheme 2c). Combined with the above results, the oxygen atom
of the newly formed carbonyl could come from DMSO. It was
rt
35
40
60
40
40
40
70
53
20[c]
65[d]
62[e]
[a] Reaction conditions: 1a (1mmol, 1equiv.) DBH, base (1equiv.), (1a was
added into a sealed tube in the end, otherwise fail to react), solved in 4mL
anhydrous DMSO and stirred for 10 h. [b] Isolated yields. [c] 0.5equiv. of
NaHCO3, [d] 1.5 equiv. of NaHCO3. [e] 10mmol of 1a.
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10.1002/ejoc.201900585
European Journal of Organic Chemistry
FULL PAPER
noteworthy that 2-bromoacetophenone 3 and 2-(methylthio)-1-
phenylethan-1-one 5 were the key intermediates of this method,
which was proven by the control experiments (Scheme 2d, 2f).
Besides, adding 1mL dimethyl sulphide into the reaction ensured
the possibility of generating 2a. However, styrene was replaced
by phenyl glyoxal 4 to react under the optimized reaction
conditions with 1mL dimethyl sulfide, no desired product 2a
detected (Scheme 2e). Additionally, methyl bromide was
successfully captured by adding 1mmol 1-butyl-piperidine into the
reaction conditions, and the product 7 was isolated in 60% yield
(Scheme 2g).
Scheme 3. Proposed mechanism
Based on the above results and previous literatures,12 a possible
mechanism is depicted as shown in Scheme 3. First, styrene 1a
reacts with DBH to generate the bromonium ion A, which
undergoes regioselective ring opening and eliminates Me2S to
afford 2-bromoacetophenone 3 in the presence of DMSO. The
intermediate 5 is generated through nucleophilic substitution of 2-
bromoacetophenone 3 and dimethyl sulfide with the release of
methyl bromide. Further bromination of
5 would provide
intermediate 6, followed by Kornblum oxidation to produce the α-
ketothioesters product 2a, which continues to provide the enough
amount of dimethyl sulfide.
Conclusions
In summary, we have developed
a simple and novel
(DBH)/DMSO mediated oxidative thioesterification method for the
synthesis of α-ketothioesters from alkenes under metal-free
conditions. Various of readily available alkenes were consistent
with the standard conditions to afford the corresponding α-
ketothioesters in moderate to good yields. A scale-up reaction to
α-ketothioesters was successfully conducted. Moreover, a series
of control experiments were carried out to investigate the reaction
mechanism and a possible reaction mechanism was proposed.
Further research on the reaction mechanism and the synthetic
applications of this strategy are keeping going in our laboratory.
Scheme 2. Control experiments
Experimental Section
General methods: To a 35 mL sealed tube (with a Teflon cap)
equipped with a magnetic stir bar were sequentially added DBH
(1.5mmol, 1.5equiv.), NaHCO3 (1mmol, 1equiv.), alkenes (1mmol,
1equiv.), (alkenes were added into a sealed tube in the end,
otherwise fail to react) and 4mL anhydrous DMSO. The tube was
capped and submerged into a preheated 40℃ oil bath. The
reaction was stirred for 10 h and cooled down to room
temperature. Then the reaction mixture was washed with
saturated NaCl solution and extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate and
solvent was removed under vacuum. And the crude product was
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10.1002/ejoc.201900585
European Journal of Organic Chemistry
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General procedure for the methyl bromide captured
experiment: To a 35 mL sealed tube (with a Teflon cap) equipped
with a magnetic stir bar were sequentially added DBH (1.5mmol,
1.5equiv.), 1-butyl-piperidine (1mmol, 1equiv.), NaHCO3 (1mmol,
1equiv.), alkenes (1mmol, 1equiv.), (alkenes were added into a
sealed tube in the end, otherwise fail to react) and 4mL anhydrous
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Acknowledgments
The research has been supported by the National Key Research
and Development Program of China (2016YFB0301501); the
National Natural Science Foundation of China (Grant No.
21776130 & 21878145); The Jiangsu Synergetic Innovation
Center for Advanced Bio-Manufacture (NO. X1821 & X1802);
Top-notch Academic Programs Project of Jangsu Higher
Education Institutions (TAPP); Postgraduate Research & Practice
Innovation Program of Jiangsu Province.
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Keywords: oxidative thioesterification • alkenes • α-
ketothioesters • metal-free
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Entry for the Table of Contents
FULL PAPER
A simple and mild approach for the
synthesis of α-ketothioesters via 1,3-
Dibromo-5,5-dimethylhydantoin
synthetic methods *
Jiawei Hua, Jiaqi Xu, Jia Xu, Bochao
Zhou, Dong Zhang, Zhao Yang, Zheng
Fang*, Kai Guo*
(DBH)/DMSO
mediated
oxidative
thioesterification of alkenes has been
developed.
Page No.1 – Page No.4
1,3-Dibromo-5,5-dimethylhydantoin
(DBH)/DMSO mediated oxidative
thioesterification of alkenes for the
synthesis of α-ketothioesters
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