Copper-Catalyzed Oxysulfenylation of Enolates with Sodium Sulfinates: A Strategy to Construct Sulfenylated Cyclic Ethers

Article abstract of DOI:10.1021/acs.orglett.6b00272

A new copper-catalyzed oxysulfenylation reaction of enolates with sodium sulfinates has been disclosed. A series of sulfenylated heterocycles including four- and seven-membered cyclic ether were obtained in mild to good yields. This reaction is proposed to go through a radical process, and the sulfur radical (RS^?) may be a reactive species.

Full text of DOI:10.1021/acs.orglett.6b00272

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Oxysulfenylation of Enolates with Sodium
Sulfinates: A Strategy To Construct Sulfenylated Cyclic Ethers
Yinglan Gao,† Yang Gao,† Xiaodong Tang, Jianwen Peng, Miao Hu, Wanqing Wu,* and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A new copper-catalyzed oxysulfenylation reac-
tion of enolates with sodium sulfinates has been disclosed. A
series of sulfenylated heterocycles including four- and seven-
membered cyclic ether were obtained in mild to good yields.
This reaction is proposed to go through a radical process, and the sulfur radical (RS•) may be a reactive species.
he formation of the C−S bond has emerged as a
significant field of research in organic chemistry1 because
and going through a new chemical process for the synthesis of
sulfenylated cyclic ethers under mild conditions with broad
functional group tolerance remain highly desirable.
T
organosulfur compounds are widely present in natural products
and are applied in total synthesis, medical chemistry, and
functional materials science.2 Among them, sulfenylated cyclic
ethers are useful chemical entities and important skeletons for
various useful molecules that exhibit biological activities such as
antiviral, antifungal, etc.3 Therefore, C−S bond synthesis has
received intensive attention and encouraged the development
of new synthetic strategies. Traditionally, sulfenylated cyclic
ethers were synthesized via the episulphonium ion intermedi-
ates, which were formed through the thiofunctionalization of
alkenes with electrophilic sulfur(II) sources, and the cyclic
products arose from the internal nucleophilic displacement
(Scheme 1a).4 Sulfenyl halides,4a,b sulfenamides,4c−e and
Sodium sulfinates as ideal sulfuration reagents have been
widely used to construct the C−S bond since they are readily
accessible and stable. Generally, sodium sulfinates are used as
sulfone sources in radical-coupling reactions. For example,
sulfones have been introduced into heteroaromatics, oxime
acetates, alkenes, or/and alkynes via the radical process.6
However, attempts to construct the sulfur ether bond using
sodium sulfinates as the sulfur sources under reduction
conditions are relatively rare.7 Recently, Yi and co-workers
reported the I2-promoted iodothiolation of alkynes with sodium
sulfinates using PPh3 as a reducing reagent, and sulfur radical
(RS•) was proposed to be a reactive species in the reaction.8 As
for the radical addition reaction, it has also emerged as a
powerful method to achieve the 1,2-difunctionalization of
alkenes,9 and it can be applied to the construction of several
heterocyclic systems as well.10 In this regard, we conceived that
the oxysulfenylation of alkenes via the sulfur radical (RS•)
addition process might be an ideal strategy for the synthesis of
sulfenylated heterocycles, which would serve as versatile
building blocks in organic synthesis. As part of our continuing
interest in the development of efficient and practical methods
for the construction of C−S bonds,6f,g,11 herein we present our
recent progress on a new strategy for the construction of
sulfenylated cyclic ethers via copper-catalyzed oxysulflation of
enolates with sodium sulfinates.
Scheme 1. Synthetic Methods for Sulfenylated Heterocycles
Our initial investigation of this transformation commenced
with pent-4-en-1-ol (2a) and sodium 4-methylbenzenesulfinate
(1a) as model substrates under conditions that used 1a (0.25
mmol), 2a (0.25 mmol), and CuBr2 (10 mol %) in DMSO (2
mL) at 120 °C (Table 1). Interestingly, the sulfenylation
product 2-((p-tolylthio)methyl)tetrahydrofuran (3aa) instead
of the sulfonylation product was detected in 45% GC yield after
24 h (entry 1). This result prompted us to screen different
external reducing reagents. However, the addition of PPh3,
sulfenate esters4f,g were reported as thiolating reagents to take
part in this oxysulfenylation reaction, and dimethyl-
(methylthio)sulfonium fluoroborate (DMTSF)4h was used to
introduce the MeS group. In addition, Mellor and Trost et al.5
achieved this chemical process by employing the disulfides as
thiolating reagents in the presence of Mn3+ or Pb4+ salts,
respectively. Nevertheless, most of these methods suffer from
several limitations: (i) the thiolating reagents are not amenable
to preparation and handling; (ii) the reaction conditions usually
require strong acid and low temperature. In view of green
chemistry, new strategies starting from easily available reagents
Received: January 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00272
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Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Sodium Sulfinate
b
entry
catalyst
ligand
additive
PPh3
solvent
yield (%)
1
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuCl2
CuBr
DMSO
DMSO
DMSO
DMSO
DMF
toluene
DCE
45
2
43
3
Na2S
Zn
nd
30
4
5
88 (83)
nd
nd
58
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9
32
10
11
12
13
14
15
CuI
47
CuCl
20
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
K2CO3
32
EtN3
48
a
Reaction conditions: all reactions were performed with 1 (0.25
mmol), 2a (0.25 mmol), and CuBr2 (10 mol %) in DMF (2.0 mL) at
120 °C under air for 24 h. Isolated yields were given.
CH3SO3H
TsOH·H2O
80
58
c
16
c
1,10-phen
2,2-Bipy
65
17
76
sulfinates, alkyl sodium sulfinates were also suitable substrates
which delivered 3pa in 76% yield.
To further demonstrate the synthetic potential of this
method, various enols were employed in this copper-catalyzed
cyclization reaction (Scheme 3). Pleasingly, besides tetrahy-
18
nd
a
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), Cu salts (10
mol %), and additive (1.0 equiv) in the indicated solvent (2 mL) at
120 °C under air for 24 h. Determined by GC analysis. Dodecane is
used as internal standard. Data in parentheses is isolated yield. nd =
b
c
not detected. 10 mol % of ligand was added.
a
Scheme 3. Substrate Scope of Enols
Na2S, or Zn did not improve the yield of 3aa (entries 2−4).
The examination of solvent effects revealed that the solvent
played an important role in this reaction (entries 5−7).
Notably, when the reaction was carried out in DMF, which has
been reported as a reducing solvent,12 the yield of 3aa increased
to 88% (entry 5). Among the copper salts examined, both
Cu(I) and Cu(II) catalysts could facilitate this transformation,
and CuBr2 was shown to be optimal (entries 8−11). Neither
base nor acid additives could further improve the yield (entries
12−15). In addition, ligands such as 2,2′-bipyridine and 1,10-
phenanthroline were tested; however, no obvious influence on
the reaction could be observed (entries 16 and 17). Finally,
control experiments demonstrated that copper catalyst was
necessary for this transformation (entry 18).
With the optimal reaction conditions in hand, we then
examined the scope of this transformation. As shown in Scheme
2, various sodium sulfinates were found to be suitable substrates
for this transformation. First, a series of para-substituted
sodium benzenesulfinates including some with electron-
donating groups (Me, OMe) and some with electron-
withdrawing groups (F, Cl, Br, CF3) were well tolerated and
converted to the corresponding tetrahydrofuran products 3aa−
ga in good yields. Notably, halo substituents, such as −Cl and
−Br, were well tolerated, providing the possibility for further
functionalization (3da and 3ea). Next, no significant effect was
found for the substituents at the para-, ortho-, and meta-
positions of the phenyl ring (3ha, 3ka, and 3aa). Polysub-
stituted sodium benzenesulfinates were also found to be good
reaction partners. Products 3la and 3ma were isolated in 90%
and 89% yields, respectively. When sodium 2-naphthalenesulfi-
nate and 2-thiophenesulfinate were employed as the substrates,
the desired products 3na and 3oa were obtained in 86% and
62% yields. To our delight, in addition to aromatic sodium
a
Reaction conditions: unless otherwise noted, all reactions were
performed with 1 (0.25 mmol), 2 (0.25 mmol), and CuBr2 (10 mol %)
in DMF (2.0 mL) at 120 °C under air for 24 h. Isolated yields are
given.
drofuran and tetrahydropyran products, four-membered ring
product 3ab, which is known to be a strained ring system, could
be constructed by this method, albeit in medium yield. The
formation of the seven-membered ring ether 3ad is particularly
noteworthy in view of the synthesis of oxepane terpenes.4e 5-
Norbornen-2-methanol was also a suitable reaction partner for
this reaction, and the corresponding product 3ae was obtained
in 79% yield. To our delight, 4-pentenoic acid could react
smoothly with 1a to give 3ah in 78% yield. Nonterminal
enolate was then tested, and the mixed products of 3ag and
B
DOI: 10.1021/acs.orglett.6b00272
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Letter
3ag′ were obtained. Moreover, 2-allylphenol could undergo this
oxysulflation reaction to give the corresponding 2,3-dihydro-
benzofuran products in 76−88% yields. It is worth mentioning
that MeS- and EtS-substituted products could also be obtained.
Furthermore, sulfone derivative 4 was generated in excellent
yields via the oxidation with m-CPBA, which might be a robust
method for the synthesis of sulfone cyclic ether, a versatile and
essential building block in organic chemistry.13
to the sulfur radical (RS•) ether via direct radical cracking or
the sulfenyl halide intermediate.8,15,16 Subsequently, the sulfur
radical (RS•) was added to the double bond of enolate to form
the α-RS-alkyl radical B. Finally, a single-electron oxidation of
the radical intermediate followed by internal nucleophilic
trapping of the resulting carbocation C would lead to the
desired oxysulflation product.10 Alternatively, a copper-
mediated C−O bond formation though an α-RS-alkylcopper
species is also possible.
In conclusion, we have developed an efficient and practical
copper-catalyzed oxysulfenylation reaction of enolates with
sodium sulfinates for the synthesis of sulfenylated cyclic ethers.
This novel transformation used easily available and stable
sodium sulfinates as ideal thiolating reagents to construct
various sulfenylated heterocycles, including four- and seven-
membered cyclic ethers. The reaction conditions are mild, and
no external reducing agents are needed; sodium sulfinates are
proposed to be reduced by Cu(I), which can be regenerated by
the reduction of DMF. Ongoing studies in our laboratory are
dedicated to the detailed reaction mechanism and further
synthetic applications of this transformation.
To gain insight into the mechanism of the chemical reaction,
several control experiments were conducted. First, the reducing
reagent for this reaction is a critical issue. Under the standard
reaction conditions, disulfide 5 was obtained in good yield in
the absence of the enolate substrate (eq 1). However, without
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00272.
General experimental procedure and characterization
data of the products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
copper salts, disulfide 5 could not be detected even upon
heating to 150 °C in DMF. Further experiments indicated that
5 could be transformed into 3aa in 80% yield under the
optimized conditions (eq 2). These observations indicated that
disulfide 5 might be an intermediate for this reaction; sodium
sulfinates were reduced by Cu(I), and the resulting Cu(II) was
reduced to Cu(I) by DMF.12 Next, when the radical scavenger
TEMPO was employed in the reaction system, the oxysulflation
process was totally shut down and TEMPO-trapped compound
6 was isolated in 60% yield (eq 3) and further identified by 1H
and 13C NMR. In addition, sodium sulfinate 1a could react with
TEMPO smoothly to provide 6 under the standard reaction
conditions (eq 4), thus indicating that sulfur radical (RS•)
should be involved as a reactive species in the reaction process.
On the basis of the experimental results and previous
reports,14 a plausible mechanism for this transformation is
proposed in Scheme 4. The reaction was initially triggered by
Cu-catalyzed dimerization of sodium sulfinates for the
formation of disulfide intermediate 5, which then converted
*E-mail: cewuwq@scut.edu.cn.
*E-mail: jianghf@scut.edu.cn.
Author Contributions
†Y.G. and Y.G. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21472051 and 21420102003) and the
Fundamental Research Funds for the Central Universities
(2015ZY001).
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D
DOI: 10.1021/acs.orglett.6b00272
Org. Lett. XXXX, XXX, XXX−XXX