NH4I-mediated three-component coupling reaction: Metal-free synthesis of β-alkoxy methyl sulfides from DMSO, alcohols, and styrenes

Article abstract of DOI:10.1021/acs.orglett.5b00170

A novel synthesis recipe for β-alkoxy methyl sulfides was developed via NH₄I-mediated three-component oxysulfenylation reaction of styrenes with DMSO and alcohols. This method features simple operation and readily available starting materials, and it provides an alternative sulfenylating agent generated from DMSO for oxysulfenylation reactions.

Full text of DOI:10.1021/acs.orglett.5b00170

Letter
pubs.acs.org/OrgLett
NH4I‑Mediated Three-Component Coupling Reaction: Metal-Free
Synthesis of β‑Alkoxy Methyl Sulfides from DMSO, Alcohols, and
Styrenes
Xiaofang Gao, Xiaojun Pan, Jian Gao, Huanfeng Jiang, Gaoqing Yuan,* and Yingwei Li*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
S
* Supporting Information
ABSTRACT: A novel synthesis recipe for β-alkoxy methyl
sulfides was developed via NH4I-mediated three-component
oxysulfenylation reaction of styrenes with DMSO and alcohols.
This method features simple operation and readily available
starting materials, and it provides an alternative sulfenylating agent generated from DMSO for oxysulfenylation reactions.
he simultaneous introduction of two different functional
groups to the carbon−carbon double bonds of alkenes is a
envisioned that DMSO could serve as a sulfenylating agent in
the oxysulfenylation reactions of alkenes. Herein, we report the
realization of this idea via ammonium iodide mediated three-
component oxysulfenylation reaction of styrenes with DMSO
and alcohols (Scheme 1 (b)).
T
fundamentally important process in organic synthesis.1 Among
the numerous difunctionalization reactions reported, the
oxysulfenylation of alkenes for synthetically useful 1,2-hydroxy
sulfides2 has attracted much attention, due to their interesting
synthetic utilities and biological activities.3 However, the
sulfenylating agents applied in the previous investigations
mainly focused on aromatic sulfur, such as sulfenyl halides,2a−d
disulfides,2e−i sulfenamides,2j−l sulfenate esters,2m,n and sulfonyl
hydrazides2o (Scheme 1 (a)). In contrast, the introduction of
Initially, we employed the oxysulfenylation of styrene 1a,
ethanol 4c, and DMSO as a model reaction to screen the
reaction conditions. To our delight, the three-component
coupling reaction resulted in formation of the desired product
3ac in 47% yield in the presence of NH4I (Table 1, entry 1).
Further investigation revealed that the yield improved
dramatically when increasing the amount of DMSO (Table 1,
entries 2−5). The reaction efficiency did not change obviously
even the amount of EtOH was decreased to 2.0 equiv (Table 1,
entry 6). It is noteworthy that NH4I concentration and reaction
temperature had a significant effect on the yield of 3ac (Table
1, entries 7−10 and 13−16). Shortening the reaction time to 13
h led to only 33% yield, while prolonged reaction time did not
promote the reaction (Table 1, entries 11−12). Hence, the
optimal reaction conditions were determined to be NH4I (3.0
equiv), EtOH (0.5 mL), DMSO (2.5 mL), with 1a (1.0 mmol)
at 125 °C for 26 h, which provided 3ac in 89% yield (Table 1,
entry 5).
Scheme 1. Three-Component Oxysulfenylation Reaction of
Alkenes
With the optimal conditions in hand, a series of styrenes (1)
were investigated to evaluate the generality of this reaction
(Scheme 2). In general, both electron-withdrawing and
-donating styrenes could be successfully converted to the
corresponding β-alkoxy methyl sulfides in good to excellent
yields. Adding the substituted group at different positions on
the phenyl ring of styrenes (Scheme 2, 3b−d) had no obvious
influence on the yields (77−82%). Sterically hindered 2,4,6-
trimethylstyrene and 4-tert-butylstyrene worked well under the
standard conditions, leading to the desired products 3e and 3f
in 75% and 78% yields, respectively. Moreover, the heteroaryl
substrate also participated in the reaction under the optimized
conditions (Scheme 2, 3g). Halides remained untouched in the
alkyl sulfides into alkenes for β-alkoxy sulfides has been rarely
explored. The only disclosure was reported by Capozzi4 and co-
workers and Tiecco5 and co-workers who employed (methyl-
thio)-sulfonium salt and sodium methanethiolate as alkyl sulfide
agents for the three-component oxysulfenylation of alkenes.
However, these systems suffered from low selectivities,
expensive reagents, and harsh reaction conditions. Thus, the
discovery of new sources of alkyl sulfenylating agents generated
in situ from simple and readily available regents for the
oxysulfenylation of alkenes is highly desirable.
Dimethyl sulfoxide (DMSO), as a cheap and commercially
available solvent, has been widely used in organic synthesis.
Actually, besides being an effective polar reaction medium,
DMSO has also been used as a multipurpose precursor for the
−O, −SMe, −CH2SMe, −Me, −CN, and −CHO units, etc.6
Based on our previous work on the utilization of DMSO,7 we
Received: January 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00170
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a,b
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope for Reaction of Styrenes
b
halide
(equiv)
temp (°C)/time
yield
(%)
entry
solvent (v/v)
(h)
1
2
3
4
5
NH4I (4)
NH4I (3)
NH4I (3)
NH4I (3)
NH4I (3)
DMSO/EtOH (2:1)
DMSO/EtOH (1:1)
DMSO/EtOH (2:1)
DMSO/EtOH (3:1)
130/24
125/26
125/26
125/26
125/26
47
53
64
72
89
DMSO/ EtOH
(5:1)
c
6
NH4I (3)
NH4I (1)
NH4I (2)
NH4I (4)
NH4I (5)
NH4I (3)
NH4I (3)
NH4I (3)
NH4I (3)
NH4I (3)
NH4I (3)
KI (3)
DMSO/EtOH
125/26
125/26
125/26
125/26
125/26
125/13
125/32
100/26
110/26
120/26
135/26
125/26
125/26
125/26
125/26
125/26
75
37
69
85
49
33
68
35
47
71
38
0
7
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
8
9
10
11
12
13
14
15
16
17
18
19
20
n-Bu4NI (3) DMSO/EtOH (5:1)
0
NH4Br (3)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
DMSO/EtOH (5:1)
0
NH4Cl (3)
0
d
21
HI
I2
39, 33
38, 23
e
22
125/26
a
b
Reaction conditions: 1a (1.0 mmol), 4c (0.5 mL). Isolated yield.
c
d
e
EtOH (2.0 equiv), DMSO (2.5 mL). HI (0.1 and 0.05 mL). I2 (0.5
and 0.1 equiv).
reaction system, which provided the possibility for further
functionalization (Scheme 2, 3h−j). In addition, substrates
bearing electron-withdrawing groups such as carboxyl, cyano,
and nitro proceeded smoothly to afford the target products in
moderate to good yields (62−79%). Furthermore, the
optimized reaction conditions turned out to be equally
successful for internal alkenes cis- or trans-β-methylstyrene 1n
and 1o, affording the desired products in moderate yields with a
diastereoselective ratio of 1:1.2 and 1:5, respectively (Scheme 2,
3n, 3o). However, cis-β-bromostyrene 1p, cyclohexene 1q, and
even allylbenzene failed to give the corresponding products.
To further explore the potential of our methodology, a
variety of alcohols were investigated (Scheme 3). Generally,
aliphatic primary alcohols reacted well with styrene 1a and
DMSO to afford 3ab−af in good yields (78−89%). To our
delight, bulky alcohol 4g was also transformed into the desired
product (Scheme 3, 3ag) in 66% yield. When secondary
alcohols were subjected to the reaction conditions, such as 2-
propanol and cyclopentanol, oxysulfenylated products 3ah and
3ai were obtained in 81% and 76% yields, respectively.
However, the reaction was not applicable to tertiary alcohols
such as tert-butyl alcohol. Pentane-1,5-diol, an alkyl glycol, also
worked for this reaction, and the corresponding product 3aj
was obtained in 73% yield. Moreover, aromatic alcohol 4k also
proved to be suitable for the three-component oxysulfenylation
reaction with the formation of 3ak in moderate yield (59%).
Heterocyclic alcohol such as 2-(thiophen-2-yl) ethanol gave the
desire product in 48% yield. When alcohol was replaced with
water, the reaction gave the product 3aa with a moderate yield
of 55%.
a
Reaction conditions: 1 (1.0 mmol), NH4I (3.0 equiv) and 4c (0.5
b
c
mL) in DMSO (2.5 mL) at 125 °C for 26 h. Isolated yield. cis-β-
Methylstyrene (0.5 mmol), 32 h. trans-β-Methylstyrene (0.5 mmol),
32 h. 1,1-Diphenylethene (1.0 mmol) was used as substrate. α-
Methylstyrene (1.0 mmol) was used as substrate.
d
e
f
To gain insight into the reaction mechanism, several control
experiments were conducted. No desired product was detected
when NH4I was replaced with KI or n-Bu4NI, which indicated
that iodide anion was not the real species for NH4I participating
in this conversion (Table 1, entries 17 and 18). Nevertheless,
similar ammonium salts including NH4Br and NH4Cl failed to
promote the formation of the desired 3ac, ruling out the
function of NH4+ in this reaction (Table 1, entries 19 and 20).
It was important to find that when HI and I2 were used as
mediator instead of NH4I, the target product 3ac could be
produced (Table 1, entries 21 and 22). When 0.1 mL of HI or
0.5 equiv of I2 was used, styrene 1a was totally converted but
with a poor selectivity of the desired product 3ac (38−39%).
Decreasing the amount of HI or I2 did not improve the yield of
3ac (23−33%), and almost half of the styrene was unreacted in
both cases. These results suggested that HI and I2 could be the
real forms of NH4I that participated in this reaction. Moreover,
the concentration of HI was well controlled in the case of NH4I
since its decomposition was a reversible process, which avoided
the oxidation of styrene into benzaldehyde and benzoic acid
when iodine was used directly as mediator. Thus, the good
selectivity of 3ac was ensured when NH4I was employed as
mediator in this reaction. In addition, we found that the three-
B
DOI: 10.1021/acs.orglett.5b00170
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 3. Substrate Scope for Reaction of Alcohols
Scheme 5. Proposed Reaction Mechanism
for the synthesis of β-alkoxy methyl sulfides under metal-free
conditions. The reaction proceeds smoothly with excellent
regioselectivity, broad substrate scope, and high functional
group tolerance. Furthermore, this process is simple in
operation and makes use of inexpensive and readily available
starting materials. Investigation of the detailed mechanism and
application of methylthiyl radical based on the NH4I-DMSO
system for other transformations are underway in our
laboratory.
a
Reaction conditions: 1a (1.0 mmol), NH4I (3.0 equiv), and ROH or
b
H2O (2.0 equiv) in DMSO (2.5 mL) at 125 °C for 26 h. Isolated
yield.
ASSOCIATED CONTENT
* Supporting Information
General experimental procedure and characterization data of
the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
component coupling reaction was completely inhibited by the
addition of radical scavengers such as 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) or butylated hydroxytoluene (BHT)
(Scheme 4, eqs 1 and 2). The results suggested that the present
■
S
Scheme 4. Preliminary Mechanism Studies
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gqyuan@scut.edu.cn.
*E-mail: liyw@scut.edu.cn.
Notes
The authors declare no competing financial interest.
reaction presumably proceeded through a radical pathway. In
addition, when 1,1-diphenylethene 1r was used, methyl 2,2-
diphenylethenyl sulfide 3r was obtained in 78% yield (Scheme
2, 3r). Moreover, α-methylstyrene 1s afforded a mixture of 3s
and 3s′ under the optimized conditions (Scheme 2, 3s, 3s′).
The generation of vinyl sulfides 3r, 3s, and 3s′ indicated that
methylthiyl radical (MeS•) was probably involved in this
procedure.
According to the above results and previous relevant studies,
a plausible reaction mechanism is proposed in Scheme 5. First,
the radical initiator I2 and precursor MeSH are generated
through a series of reactions, as shown in eqs 3−5.8−10 Then,
iodine radical can be formed by thermal decomposition of the
in situ generated I2 (eq 6),11 which could react with MeSH to
give a methylthiyl radical (MeS•)12 and concurrently abstract
hydrogen atom from alcohols to afford alkoxy radicals (RO•).13
Subsequently, the methylthiyl radical adds to the CC double
bond of styrene, leading to a radical intermediate I.14 Finally,
the rapid combination of RO· and the intermediate I produces
the desired product. Because of the involvement of NH3 and I2
in this reaction system, the possibility of formation and
involvement of nitrogen triiodide might exist, even though we
did not detect it in our experiments.15
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21172079, 21322606, and
21436005).
REFERENCES
■
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C
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DOI: 10.1021/acs.orglett.5b00170
Org. Lett. XXXX, XXX, XXX−XXX