Cs2CO3-promoted cross-dehydrogenative coupling of thiophenols with active methylene compounds

Article abstract of DOI:10.1039/c7ra06904a

A convenient and efficient α-sulfenylation of carbonyl compounds has been achieved via the halogen-free Cs₂CO₃-promoted cross-dehydrogenative coupling (CDC) of thiophenols with active methylene compounds using air as the oxidant unde

Full text of DOI:10.1039/c7ra06904a

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Cs2CO3-promoted cross-dehydrogenative
coupling of thiophenols with active methylene
Cite this: RSC Adv., 2017, 7, 39758
compounds†
ab
Xiaofeng Wang,a Chunxiao Wen,a Yulin Huang,a Xinxing Yana
*
Qian Chen,
and Jiekun Zenga
A convenient and efficient a-sulfenylation of carbonyl compounds has been achieved via the halogen-free
Cs2CO3-promoted cross-dehydrogenative coupling (CDC) of thiophenols with active methylene
compounds using air as the oxidant under mild conditions. This transformation provides
a straightforward route to the construction of carbon–sulfur bonds with wide functional group
compatibility, which produces a-sulfenylated carbonyl compounds in up to 95% yield.
Received 20th June 2017
Accepted 8th August 2017
DOI: 10.1039/c7ra06904a
rsc.li/rsc-advances
The development of new methods to construct carbon–sulfur succinimide (Fig. 1c).9 However, these methods are limited
bonds has been of particular interest due to the wide applica- because the corresponding starting materials are high-cost and/
tions of organosulfur compounds in biological chemistry and or temperature- or moisture-sensitive. Thus, the development of
organic synthesis.1,2 Among them, a-sulfenylated carbonyl a convenient and efficient protocol for the synthesis of a-sul-
compounds are important intermediates for the synthesis of fenylated carbonyl compounds remains a challenge.
heterocycles,3 b-keto sulfones,4 a,b-unsaturated carbonyl
The cross-dehydrogenative coupling (CDC) reactions are
compounds,5 and others.6 Therefore, a-sulfenylation of powerful methods in organic synthesis that can avoid the use of
carbonyl compounds is highly desirable, and a variety of useful pre-functionalized substrates.10 The CDC reactions involving
synthetic methods have been well documented. The traditional thiols have attracted much attention because this strategy
preparation of this class of compounds mainly relies on the use represents more straightforward, efficient, and atom-economic
of pre-functionalized substrates including: (1) nucleophilic to construct carbon–sulfur and sulfur–heteroatom bonds.11 The
substitution of a-halogenated carbonyl compounds with thiols7 oxidative CDC has also been applied to a-sulfenylation of
(Fig. 1a) or disuldes8 (Fig. 1b); and (2) the reactions of carbonyl carbonyl compounds (Fig. 1d).12 The coupling of thiols with
compounds with thio sources such as sulphenyl halides, active methylene compounds in the presence of CBr4 has been
disuldes, sulfonothioates, sulfenamides, and N-(phenylthio) reported by Liang and co-workers.12a Yadav and co-workers have
reported a-sulfenylation of monoketones in the presence of
NCS.12b Recently, Hu, Lei and co-workers developed iodine-
catalyzed oxidative coupling of 1,3-diketones with thiophenols
using DTPB as the oxidant.12c Prabhu and co-workers developed
a couple of a-sulfenylations of monoketones or 1,3-diketones
using K2S2O8 or DMSO (in the presence of I2) as the oxidant.12d–f
However, the current oxidative coupling protocols requires the
use of halogenated reagents and/or strong oxidants. In this
regard, seeking greener oxidants for this CDC reaction is still
a signicant issue. Molecular oxygen as the greener and more
sustainable oxidant has been widely used in organic synthesis.13
Fig. 1 Strategies for a-sulfenylation of carbonyl compounds.
Moreover, inorganic bases have been well utilized for carbon–
sulfur and sulfur–heteroatom bond forming reactions.14 With
these backgrounds, we envisioned that a-sulfenylated carbonyl
aSchool of Chemical Engineering and Light Industry, Guangdong University of
compounds might be formed through the CDC reaction of
Technology, Guangzhou 510006, China. E-mail: qianchen@gdut.edu.cn; Fax: +86 20
thiols with carbonyl compounds using O2 as the oxidant in the
3932 2235; Tel: +86 20 3932 2231
presence of an inorganic base. Herein, we report an efficient
halogen-free Cs2CO3-promoted a-sulfenylation of active
methylene compounds under air.
bKey Laboratory of Functional Molecular Engineering of Guangdong Province, South
China University of Technology, Guangzhou 510640, China
† Electronic supplementary information (ESI) available: General information and
copies of 1H and 13C NMR spectra. See DOI: 10.1039/c7ra06904a
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The reaction conditions were tested by using a model reac- acetylacetone 1a (Table 2). Pleasingly, the results showed that
tion of acetylacetone 1a with 4-bromo-thiophenol 2a in solvents thiophenol substrates bearing different groups such as
under air atmosphere at room temperature, and the results electron-withdrawing halogen groups (Br, Cl and F) and
were shown in Table 1. Initially, no reaction occurred when the electron-donating groups (alkyl, OMe, OH and NH2) at the para,
reaction of 1a with 2a in CH3CN in the absence of bases under meta or ortho or at both positions of aromatic rings, as well as
air was carried out (entry 1). To our delight, when Cs2CO3 the bulky 2-naphthalenethiol, were all well tolerated. The cor-
(1 equiv.) was added, the reaction proceeded smoothly to afford responding 3aa–3as were isolated in moderate to excellent
the desired product 3-(4-bromophenylthio)pentane-2,4-dione yields, indicating that the electronic and steric effects were not
3aa in 82% yield (entry 2). When the reaction of 1a with 2a evident in this reaction. The scale-up reaction was also
was carried out under N2, only trace amounts of 3aa were attempted. When we increased the scale of the reaction from
detected (entry 3). This result demonstrates that the reaction 0.4 to 4 mmol, the yield of 3ad only slightly decreased (from
involved an aerobic oxidative cross-coupling. We then turned to 86% to 79%). We then turned our attention to aliphatic thiols.
screen other bases (entries 4–9), and found that Cs2CO3 was the Unfortunately, a-sulfenylation of 1a with benzylthiol or cyclo-
optimal base. The increase or decrease of Cs2CO3 amount did hexylthiol failed to give the desired 3at or 3au.
not improve the yield (entries 10–14). Notably, the use of cata-
Next, the coupling of 4-bromo-thiophenol 2a with a variety of
lytic amounts of Cs2CO3 also led to the formation of 3aa in active methylene compounds 1 under the optimized conditions
moderate yields (entries 13 and 14). Switching the solvent from was examined, and the results are illustrated in Table 3.
CH3CN to THF, dioxane, DMSO, EtOH, or H2O decreased the 1,3-Diketones bearing methyl, ethyl, isopropyl and phenyl groups
yield of 3aa (entries 15–19), while the use of DMF afforded the were all applicable to the CDC reaction, leading to the formation
desired product in 98% yield (entry 20). It is noteworthy that of 3ba–3da in 68–85% yields. When ethyl acetoacetate was
disulde 4a, which was generated via an aerobic oxidative employed, the reaction also proceeded smoothly to afford 3ea in
homocoupling of thiol 2a,14a was observed in all cases under air. 82% yield. In addition, dialkyl malonates were also well tolerated,
We then set out to explore the generality of the CDC reaction and the desired products 3fa and 3ga were obtained in good
of thiols with active methylene compounds. We rst applied the yields. We then turned to a-sulfenylation of monosubstituted
optimized conditions to the coupling of various thiols 2 with malonates, and the reaction of 2a with a-alkylmalonates led to the
corresponding 3ha and 3ia in 84% and 89% yield, respectively.
Table 1 Optimization of reaction conditionsa,b
Table 2 Scope of thiolsa,b
Entry
Base (equiv.)
Solvent
Yield of 3aa (%)
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
0
2
Cs2CO3 (1)
Cs2CO3 (1)
K2CO3 (1)
Na2CO3 (1)
NaOAc (1)
K3PO4 (1)
82
Trace
65
0
3c
4
5
6
7
8
0
45
16
<10
74
82
75
61
48
73
50
57
25
0
CsF (1)
Et3N (1)
9
10
11
12
13
14
15
16
17
18
19
20
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (1.5)
Cs2CO3 (0.5)
Cs2CO3 (0.2)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Dioxane
DMSO
EtOH
H2O
DMF
98
a
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), base, solvent
Reaction conditions: 1a (0.4 mmol), 2 (0.8 mmol), and Cs2CO3
b
(1 mL), room temperature, open air, 6 h. Yield based on 1a was (0.4 mmol) in DMF (2 mL) stirring at room temperature under air for
determined by 1H NMR analysis of crude products using an internal 6–12 h. Isolated yield based on 1a. The reaction was performed in
b
c
c
standard. The reaction was carried out under N2.
a 4 mmol scale.
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Table 3 Scope of active methylene compoundsa,b
the yield of 3aa reduced from 93% to 0% and 17%, respectively
(eqn (1)), suggesting that this transformation might proceed via
a radical pathway. In consideration of the generation of disul-
des in all cases, the reaction of thiol 2a with Cs2CO3 under air
was carried out, leading to the formation of disulde 4a in
quantitative yield (eqn (2)). The above results suggest that Cs2CO3
could increase the oxidation rate of thiols with dioxygen and
disulde was produced via a thiyl radical homocoupling.14a,15 In
addition, the reaction of 1a with disulde 4a under the standard
conditions gave 3aa in good yields regardless of the presence of
air (eqn (3) and (4)), which demonstrates that disulde might be
an intermediate in the CDC reaction. Moreover, the reaction of 1a
with 4a in the absence of Cs2CO3 failed to give 3aa (eqn (5)),
which indicates Cs2CO3 is indispensable in this reaction.
According to the literatures and our observations, a plausible
reaction mechanism is outlined in Scheme 2. Initially, thiyl
radical is generated from the autoxidation of thiol 2 in the
presence of Cs2CO3 and dioxygen, and thiyl radical undergoes
homocoupling to produce disulde 4.11j,14a,15,16 Meanwhile,
active methylene compound 1 reacts with Cs2CO3 to form
intermediate 5. Finally, the nucleophilic attack of the in situ-
generated enolate 5 on disulde 4 affords a-sulfenylated
carbonyl compound 3.
a
Reaction conditions: 1 (0.4 mmol), 2a (0.8 mmol), and Cs2CO3
(0.4 mmol) in DMF (2 mL) stirring at room temperature under air for
6–12 h. b Isolated yield based on 1.
Conclusions
In conclusion, we have developed the Cs2CO3-promoted cross-
dehydrogenative coupling (CDC) of thiophenols with active
methylene compounds, which provides a highly convenient and
efficient protocol for the synthesis of a-sulfenylated carbonyl
compounds with wide functional group compatibility under
mild conditions. To the best of our knowledge, this nding is
the rst example of aerobic CDC reaction of thiols with carbonyl
compounds. We envision that the reaction mode outlined here
will have potential applications in organic synthesis.
Conflicts of interest
There are no conicts to declare.
Scheme 1 Mechanistic studies.
Acknowledgements
This work was supported by the Science and Technology Plan-
ning Project of Guangdong Province (No. 2015A020211026 and
2017A010103044), 100 Young Talents Programme of Guangdong
University of Technology (220413506), and the Open Fund of the
Key Laboratory of Functional Molecular Engineering of Guang-
dong Province (2016kf07, South China University of Technology).
Notes and references
Scheme 2 Proposed mechanism.
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