NaI-Mediated Acetamidosulphenylation of Alkenes with Nitriles as the Nucleophiles: A Direct Access to Acetamidosulfides

Article abstract of DOI:10.1021/acs.orglett.5b02752

An example of a transition-metal-free, direct, and efficient acetamidosulphenylation reaction of alkenes using nitriles as the nucleophiles via a radical process is presented. This reaction shows a broad substrate scope and high regioselectivity and provides straightforward access to acetamidosulfide derivatives in moderate to high yields.

Full text of DOI:10.1021/acs.orglett.5b02752

Letter
pubs.acs.org/OrgLett
NaI-Mediated Acetamidosulphenylation of Alkenes with Nitriles as
the Nucleophiles: A Direct Access to Acetamidosulfides
Yang Zheng,‡,§ Yue He,‡,§ Guangwei Rong,‡ Xiaolu Zhang,‡ Yuecheng Weng,‡ Kuiyong Dong,‡
Xinfang Xu,*,‡ and Jincheng Mao*,†,‡
†State Key Laboratory of Oil and Gas Reservoir Geology and Exploitation, Southwest Petroleum University, Chengdu, 610500, P. R.
China
‡Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou, 215123, China
S
* Supporting Information
ABSTRACT: An example of a transition-metal-free, direct, and efficient
acetamidosulphenylation reaction of alkenes using nitriles as the
nucleophiles via a radical process is presented. This reaction shows a
broad substrate scope and high regioselectivity and provides
straightforward access to acetamidosulfide derivatives in moderate to
high yields.
thiiranium intermediate formation and ring-opening addition
with various nucleophiles to give the 1,2-difunctionalized
products (Scheme 1, eq 1).5−7 In contrast to the other
cetamidosulfide derivatives are useful chemical entities,
1
Awhich can be converted to many useful compounds.
These unique motifs are also present in many natural
products,2 and most of them show various bioactivities and
are extensively applied in pharmacology.3 Compound A, which
was isolated by Fahey’s group from M. smegmatis,2a performed
an important role in the detoxification of alkylating agents and
antibiotics;2b,c compound B showed the inhibition of
phospholipase A2 activity in vitro;3a,b and compound C,
which was isolated from heterologous PKS-NRPS experiments,
worked as a useful intermediate for the synthesis of the fungal
polyketide synthase (PKS) products (Figure 1).1
Scheme 1. Sulphenylation of Alkenes with β-Site
Functionalization
1,2-Difunctionalization of alkenes has been proven to be a
useful strategy in organic synthetic chemistry.4 Among these
reported transformations, the sulphenylation of alkenes for the
synthesis of β-functionalized sulfides have drawn much
attention.5−8 In this context, the reaction goes through the
heteroatom nucleophiles, including O,5 S,6 and others,7
examples of using N-based nucleophiles is rare,8 and a
breakthrough in this field was reported by Denmark with
azide as a nucleophile and produced the 1,2-difunctionalized
products with high selectivity.8a Although there are a few other
examples using acetonitrile instead of azide as the nucleophi-
le,8b−d all these reactions are mediated by a stoichiometric
amount of transition metal or strong acid within a handful of
substrates (Scheme 1, eq 2). In this context, we wish to report
Received: September 29, 2015
Figure 1. Selected examples of acetamidosulfides.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02752
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Organic Letters
Letter
our recent results on direct catalytic acetamidosulphenylation of
alkenes with nitriles as nucleophiles under transition-metal-free
conditions (Scheme 1, eq 3). Further study shows that the
reaction goes through a radical pathway,9 which is different
from the previous mechanism via a cationic intermediate.
Initially, the acetamidosulphenylation reaction of styrene
(1a) with phenyl disulfide (2a) and acetonitrile (3a) was
catalyzed by TBAI with ammonium persulfate as the oxidant.
To our delight, the desired product 4a was obtained in 48%
yield (Table 1, entry 1). It should be noted that the amount of
Scheme 2. Acetamidosulphenylation of Alkenes with
Acetonitrile and Phenyl Disulfide
Table 1. Optimization of Reaction Conditions for
a
Acetamidosulphenylation
ones (4d and 4e), which might be due to the steric hindrance.
An aliphatic alkene also proceeded smoothly with phenyl
disulfide and acetonitrile to give the expected products in
acceptable yield (4i).
b
entry
cat.
oxidant
temp (°C)
yield (%)
To further explore the potential of this methodology, a
variety of disulfides and nitriles were investigated under the
optimized conditions (Scheme 3). Generally, the substrates of
1
TBAI
−
TBAI
TBAC
TBAB
TMAI
NaI
(NH4)2S2O8
(NH4)2S2O8
−
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
PhI(OAc)2
TBHP
80
80
80
80
80
80
80
80
80
80
90
100
100
48
2
NR
NR
trace
trace
46
3
4
5
Scheme 3. Acetamidosulphenylation of Styrene with Various
Nitriles and Different Disulfides or Thiophenols
6
7
61
8
I2
55
9
NaI
NR
NR
76
10
11
12
NaI
NaI
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
NaI
88
c
d
13
NaI
92 (89)
a
Reaction conditions: Styrene (1a, 0.6 mmol), diphenyl disulfide (2a,
0.15 mmol), acetonitrile (3a, 2.0 mL), catalyst (0.06 mmol), and
b
oxidant (0.6 mmol) at indicated temperature for 12 h. Isolated yield
c
based on 0.3 mmol scale. H2O (0.6 mmol, 11 μL) was added.
d
Thiophenol (0.3 mmol) instead of phenyl disulfide was used. TBAI =
Tetrabutyl ammonium iodide, TBAC = Tetrabutyl ammonium
chloride, TBAB = Tetrabutyl ammonium bromide, TMAI =
tetramethylammonium iodide.
phenyl disulfide (2a, 0.15 mmol) was used as the limiting
reagent and the yield of 4a was based on a 0.3 mmol scale. The
reaction did not occur in the absence of either catalyst or
oxidant (entries 2 and 3). Subsequently, the other catalysts
were investigated (entries 4−8), and sodium iodide was proven
to be the best (entry 7). In order to enhance the conversion of
this reaction, several oxidants were tested, and only inferior
results were observed (entries 9 and 10; see Table S1 for
details). Further optimization of the reaction temperature
enhanced the yield of 4a to 88% at 100 °C (entries 11 and 12).
The best result was obtained in the presence of 2.0 equiv of
H2O with 4a in 92% isolated yield (entry 13).8b,c In addition,
when thiophenol instead of phenyl disulfide was used, a
comparable yield was obtained (entry 13, result in paren-
theses).
With the optimized results in hand, we have applied this new
protocol to various alkenes and the results are illustrated in
Scheme 2. All of the tested alkenes performed well and gave the
desired products 4 in moderate to excellent yields. When
styrenes with para-substitutions were used, the corresponding
acetamidosulfides were obtained in excellent yields (4b, 4c, and
4f−4h), while styrenes with substituents on the ortho- or meta-
positions were less reactive compared to the para-substituted
a
b
Disulfide (2, 0.15 mmol) was used as the substrate. Aryl thiol (2, 0.3
mmol) was used as the substrate.
disulfide with electron-donating substituent reacted well to
afford 5a−5b in excellent yields, while the one with a strong
electron-withdrawing group showed lower activity and gave 5c
in 55% yield. To our delight, aliphatic disulfides were tolerated
under these conditions (5d, 5e). In addition, diselenide was
also suitable in this methodology to give the corresponding 5f
in 61% yield. Aryl thiols also performed very well compared to
the corresponding disulfides and gave the difunctionalized
products in 84−95% yields (4a, 5g−5i). The substrates of 3
containing an aromatic ring or a vinyl or dicyano group were all
well-tolerated in our system, giving moderate to good yields
(6a−6c). When 3-hydroxypropionitrile was employed, the
corresponding acetamidosulfide was not observed, and β-alkoxy
sulfide 6d was generated in 65% yield, which indicated the
preference of hydroxyl group over the cyano group.
In order to gain insight into the reaction mechanism, several
control experiments were performed as shown in Scheme 4.
B
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Letter
sulfenylation of alkenes.12a The benzylic radical intermediate
E could be oxidized to a benzylic carbon cation F, followed by a
Ritter-type reaction to give difunctionalized products.17 When
thiophenol was employed as the material, it likely went through
two pathways. First, the thiophenol could be oxidized by
ammonium persulfate to generate disulfide;18 alternatively, the
radical A captured a hydrogen atom from thiophenol to
generate thiophenyl radical D and then followed the above-
mentioned process.19 In the case of 3e, the hydroxyl group may
have been attacked by A to form another radical H. Final
radical coupling of E and H gave 6e.12a Additional control
reactions with TEMPO as an additive further confirmed this
radical process (see Table S2 for details).
Scheme 4. Control Experiments
In summary, we have developed an efficient, facile, and direct
acetamidosulphenylation reaction of alkenes using nitriles as
the nucleophiles catalyzed by sodium iodine with ammonium
persulfate as an oxidant. The reaction conditions are mild and
suitable for a wide range of substrates, including aryl or alkyl
nitriles, disulfides, arylthiols, and even diselenide, and all give
the corresponding products in moderate to excellent yields.
This transition-metal-free difunctionalization protocol provides
a practical one-pot access to a variety of acetamidosulfide
derivatives. In addition, a plausible mechanism involving a
radical pathway is proposed for this three-component reaction.
Instead of using sodium iodide as the catalyst, 0.06 mmol of
PhSI10 was introduced to catalyze the reaction and 4a was
obtained in 86% yield, which suggested that intermediate C
(Scheme 5) might be involved in the transformation (Scheme
Scheme 5. Proposed Reaction Mechanism
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.5b02752.
Detailed experimental procedures and characterization
data of the products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xinfangxu@suda.edu.cn.
*E-mail: jcmao@swpu.edu.cn.
Author Contributions
§Y.Z. and Y.H. contributed equally.
Notes
4, eq 4). According to the reported literature,11 the sulfur
radical could be generated from thiophenol and then the
homocoupling could occur to give disulfide 2a. Although this
step took place quickly, the existing sulfur radical in the system
might react with styrene to generate 4a, and the corresponding
control reaction gave 4a in 10% yield (Scheme 4, eq 5), which
indicated that the sulfur radical D (Scheme 5) might be
involved in this transformation. The generation of vinyl sulfide
products 4j and 4j′ further confirmed the existence of the
radical intermediate D in this transformation (Scheme 4, eq
6).12
Based on the above-mentioned investigation, a plausible
reaction mechanism is proposed in Scheme 5. Initially, the
homolytic cleavage of ammonium persulfate gave ammonium
sulfate radical anions A under thermal conditions.13 Sub-
sequently, iodide ions were oxidized by A to generate iodine
and the anion species B;14 a simultaneous process promoted by
ammonium persulfate to generate iodine and the anion species
B is also possible.15 Then the generated iodine reacted with 2a
to yield PhSI C,10 which would undergo homolytic cleavage to
yield the thiophenyl radical D.16 This thiophenyl radical
attacked the double bond of alkenes to furnish radical E; a
similar radical process has been proposed in the oxy-
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research is supported by Open Fund (PLN1409) of State
Key Laboratory of Oil and Gas Reservoir Geology and
Exploitation (Southwest Petroleum University). We are grateful
to the grants from the Scientific Research Foundation for the
Returned Overseas Chinese Scholars, State Education Ministry
and the Key Laboratory of Organic Synthesis of Jiangsu
Province. X.X. was supported by NSFC of Jiangsu province
(SBK2015040101).
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