Odorless, One-Pot Regio- and Stereoselective Iodothiolation of Alkynes with Sodium Arenesulfinates under Metal-Free Conditions in Water

Article abstract of DOI:10.1021/acs.orglett.5b01488

A newly developed regio- and stereoselective radical addition of alkyne under metal-free conidtions has been disclosed. This chemistry, in which odorless sodium arenesulfinates in place of thiols are used as the sulfur reagent, provides an efficient, one-pot approach for the generation of β-iodoalkenyl sulfides, which can be easily further functionalized to derive various alkenes and alkynyl sulfides rendering this methodology attractive to both synthetic and medicinal chemistry. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b01488

Letter
pubs.acs.org/OrgLett
Odorless, One-Pot Regio- and Stereoselective Iodothiolation of
Alkynes with Sodium Arenesulfinates under Metal-Free Conditions in
Water
Ya-mei Lin,‡ Guo-ping Lu,*,‡ Chun Cai, and Wen-bin Yi*
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China
S
* Supporting Information
ABSTRACT: A newly developed regio- and stereoselective radical addition of
alkyne under metal-free conidtions has been disclosed. This chemistry, in
which odorless sodium arenesulfinates in place of thiols are used as the sulfur
reagent, provides an efficient, one-pot approach for the generation of β-
iodoalkenyl sulfides, which can be easily further functionalized to derive
various alkenes and alkynyl sulfides rendering this methodology attractive to
both synthetic and medicinal chemistry.
inyl sulfides have found a widespread utilization as
protocols for the formation of C−S bonds8 and designing
organic reactions in water,9 we envisage to explore an odorless
and metal-free route for regio- and stereoselective formation of
β-iodoalkenyl sulfides in water.
On the one hand, several attempts have been made for the
construction of C−S bonds using sodium arenesulfinates,10 aryl
sulfochlorides,11 and aryl sulfonyl hydrazide12 as the sulfur
sources under reduction conditions. On the other hand, sodium
arenesulfinates can react with aryl acetylenes to afford different
sulfones under diverse conditions (Figure 1, path A). Generally,
V
convenient intermediates in organic chemistry1 and
materials chemistry,2 meanwhile many natural products and
compounds exhibiting remarkable biological properties contain
the vinyl sulfide moiety.3 Thus, numerous synthetic methods
have been reported for the preparation of these compounds.4
Owing to the well-known nucleophilic substitution and cross-
coupling importance and utility of halides (especially iodides),
it is significant and interesting on incorporation of halides and
the vinyl sulfides into organic compounds by one-pot means.
Although β-haloalkenyl sulfides are useful intermediates to
prepare various alkenes by the transformation of halogeno
moieties and the C−S bond cleavage,5 the advances of their
synthetic methods have not been well-performed to date.
Typically, β-haloalkenyl sulfides are synthesized by the
addition of sulfenyl halides to alkynes.6 For example,
Nishihara’s group has reported that the chlorothiolation of
terminal alkynes could afford syn adducts catalyzed by
palladium6a and result in anti adducts via a radical process
induced by iron.6b Nevertheless, several issues of these
strategies should be addressed: (1) most of the sulfenyl halides
(especially sulfenyl iodides) are really unstable compounds; (2)
the formation of sulfenyl halides requires toxic and hard to
handle chlorine (or bromine) or smell thiols; (3) the synthesis
of β-iodoalkenyl chalcogenides has not been well-studied.
In order to eliminate these problems, a copper-catalyzed
synthesis of β-haloalkenyl chalcogenides by the addition of
disulfides to internal alkynes have been reported by Taniguchi.7
The approach proves to be an efficient route to generate β-
haloalkenyl sulfides using disulfides in place of sulfenyl halides,
but in the view of green chemistry, it also encounters
disadvantages, such as prepreparation of disulfides from thiols,
the use of transition metal catalysts and toxic organic solvents,
and limited substrate scope of terminal alkynes and
iodothiolation adducts. With our interests in exploring odorless
Figure 1. Transformations of sodium arenesulfinates with aryl
acetylenes under diverse conditions.
vinyl sulfones are obtained from a reactive vinyl radical by atom
transfer radical addition (ATRA).13 The reactive vinyl radical
can be trapped by dioxygen due to its diradical structure to
yield β-keto sulfones.14 β-haloalkenyl sulfones are generated
through similar processes in the presence of halide species.15
Based on these results, we reason that sodium arenesulfinates
can be easily reduced to reactive aryl sulfide species, which
Received: May 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
might add to aryl acetylene with iodine to derive β-iodoalkenyl
sulfides (path B).
Table 2. Iodothiolation of Terminal Alkynes
To verify the feasibility of our proposed assumption, we
started the investigation by selecting the reaction of phenyl-
acetylene 1a with sodium p-toluenesulfinate 2a as the model
reaction (Table 1). Not surprisingly, the reaction provided a
b
c
entry
R
R′
E-3
yield (%)
82
E/Z
a
1
Ph
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-MeO
4-Cl
E-3a
E-3b
E-3c
E-3d
E-3e
E-3f
E-3g
E-3h
E-3i
93/7
Table 1. Optimization of Reaction Conditions
d
2
4-CH3C6H4
4-ClC6H4
4-CF3C6H4
4-n-C3H7C6H4
4-BrC6H4
3-pyridyl
2-thienyl
cyclopropyl
cyclohexyl
n-C8H17
Ph
85
89/11
91/9
3
81
79
54
92
90
86
36
4
92/8
5
94/6
6
97/3
b,
c
c
entry
reducer
solvent
toluene
yield (%)
E/Z
7
99/1
1
OPH(OC2H5)2
PPh3
trace
20
/
8
99/1
2
toluene
toluene
toluene
toluene
1,4-dioxane
EtOH
anisole
t-BuOH
ether
85/15
/
9
99/1
e
3
HCOOH
N2H4·H2O
Zn
trace
0
10
11
12
13
14
15
16
17
18
19
E-3j
13
99/1
4
/
E-3k
E-3l
44
99/1
d
5
0
/
93
87/13
87/13
80/20
85/15
89/11
88/12
90/10
78/22
d
6
PPh3
18
86/14
89/11
92/8
88/12
/
Ph
4-Br
E-3m
E-3n
E-3o
E-3p
E-3q
E-3r
E-3s
89
d
7
PPh3
40
Ph
4-O2N
2-CH3
4-MeO
4-MeO
4-MeO
4-MeO
38
d
8
PPh3
59
Ph
78
9
PPh3
24
Ph
74
84
10
11
12
13
14
15
16
17
18
PPh3
trace
64
4-FC6H4
4-ClC6H4
4-MeOC6H4
f
PPh3
MeOH
glyme
86/14
83/17
/
83, 79
PPh3
49
69
PPh3
MeCN
DMF
trace
65
a
Reaction conditions: terminal alkynes 1 0.250 mmol, sodium
arenesulfinates 2 0.375 mmol, iodine 0.375 mmol, PPh3 0.750
PPh3
87/13
/
b
c
PPh3
THF
trace
87
mmol, H2O 1 mL, 120 °C, 10 h. Isolated yields of E-3. E/Z ratio
d
determined by GC-MS or 1H NMR on crude products. Obtained as a
PPh3
H2O
93/7
/
d
e
PPh3
H2O
10
mixture of E and Z stereoisomers. The yield of E-3j was determined
f
e
by GC-MS. The reaction scale was 10 mmol.
PPh3
H2O
0
/
a
Reaction conditions: phenylacetylene 0.250 mmol, sodium p-
toluenesulfinate 0.375 mmol, I2 0.375 mmol, reductant 3 equiv,
b
c
electron-withdrawing groups such as nitro group (entry 14).
In order to show the possibility for large-scale operation, we
also scaled up the reaction to 10 mmol, and the reaction
proceeded well with 79% yield of the desired product E-3r
(entry 18). Sodium alkylsulfinates failed to produce the desired
adducts in the reaction.
To our delight, the protocol was also efficient for the
addition of internal alkynes to form the β-iodoalkenyl sulfides
(Scheme 1). In all the cases, E-isomers were the major products
with good yields. To further demonstrate the potential of this
methodology, E-4i was smoothly generated by the addition of
sodium p-toluenesulfinate and iodine to diphenylacetylene. The
product (E-4i) could be further modified to synthesize (Z)-
tamoxifen 5a7a that is an estrogen antagonist and effective for
metastatic breast cancer.17 The stereochemistry of E-3a and E-
4a was determined by comparison of the spectroscopic data for
the sulfone E-6a and E-5b,13b,15 which were prepared by
oxidation of E-3a and E-4a, respectively. The precise
configurations were unambiguously confirmed by single-crystal
X-ray analysis of E-6a and E-5b (Schemes 1 and 2).
Furthermore, the versatile synthetic utility of the iodothio-
lation adducts was studied, and the results are summarized in
Scheme 2. The iodine can be subsequently used in Suzuki and
Sonogashira couplings in water at room temperature to afford
6b, E-6c.18 The cyanation of E-3r could also take place
catalyzed by copper.19 Interestingly, E-3c was provided through
the reaction of E-3r and p-thiocresol under basic conditions by
which more β-iodoalkenyl chalcogenides can be prepared. It
should be noted that 6e was generated via hydroxylation and
dehydration processes,20 which may be a robust method for the
solvent 1 mL, 120 °C, 10 h. The yield of E-3a. The yield of E-3a and
d
e
E/Z ratio determined by GC-MS on crude products. At 80 °C. At
room temperature.
24% yield of the desired product 3a (a mixture of E and Z
isomers) using PPh3 as the reductant (entry 2). After screening
different solvents, water proved to be the best option in the
transformation (entry 16) due to its high polarity and good
solubility of 2a in water. Lower temperature resulted in poor
yield of the product (entries 17, 18). To further improve the
results, several surfactants (SDS, CTAB, TX100, Birj35) were
employed in the system, but limited success was found,
suggesting that the aqueous micelle system may inhibit the ion
exchange between substrates and additives and thereby
decrease the reaction rate.16 Various transition metal catalysts
(Pd(OAc)2, PdCl2, CuI, Cu(OAc)2) also failed to enhance the
yield and selectivity.
With the optimized conditions in hand, a series of terminal
alkynes and sodium arenesulfinates were applied in the reaction
to establish the scope and generality of this protocol (Table 2).
A range of arylethynes which have electron-donating and
electron-withdrawing groups reacted with 2a to give the
corresponding adducts E-3a-3f in moderate to excellent yields
(entries 1−6). Heteroaryl acetylenes were also applied in the
reaction successfully with satisfactory results (entries 7, 8).
Likewise, aliphatic terminal alkynes could also provide the
desired products under the identical conditions (entries 9−11).
In most cases, sodium arenesulfinates afforded the desired
products with good yields and selectivity. The reaction was
sluggish using sodium arenesulfinates containing strong
B
DOI: 10.1021/acs.orglett.5b01488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. One-Pot Reactions of Internal Alkynes, Sodium
Arenesulfinates, and Iodine
Scheme 3. Mechanistic Studies and Control Experiments
a,b
a
Reaction conditions: internal alkynes 1 0.250 mmol, sodium
arenesulfinates 2 0.375 mmol, iodine 0.375 mmol, PPh3 0.750
b
c
mmol, H2O 1 mL, 120 °C, 10 h. Isolated yields. 10% yield of Z-
4d was formed. The reaction time was 24 h.
d
Scheme 2. Transformations of β-Iodoalkenyl Sulfides (E-3)
with 1a to afford 3a (eq 5). The addition of p-thiocresol 10 to
1a provided 11 as the product instead of 3a (eq 6). It can be
concluded that neither 9 nor 10 is the intermediate of the
reaction.
A proposed mechanism for the synthesis of β-iodoalkenyl
sulfides was illustrated on the basis of these preliminary results
(Figure 2). At first, a reduction of sodium arylsulfinate 1
synthesis of alkynyl sulfides as versatile and essential building
blocks in organic and polymer chemistry.21
Figure 2. A proposed mechanism for the iodothiolation of alkyne.
To further probe the mechanism, control experiments with
possible intermediates were designed and investigated (Scheme
3). The reaction was inhibited in the presence of TEMPO (3
equiv), and a 18% yield of 7 was separated and further
mediated by a combination of I2−PPh3 leads to arenesulfenyl
iodide 12,10d,22 which may undergo homolytic cleavage to yield
a sulfenyl radical 13.23 Meanwhile, diiodovinyl 14 is afforded via
an electrophilic addition with perfect stereoselectivity. Hence,
there are two plausible paths during the reaction. Path I: 13
adds to the terminal carbon of 2 to form the alkenyl radical A.
Finally, the radical substitution of A with 12 affords the product
E-3 and regenerates 13 to complete the radical chain.6b Path II:
intermediate B is derived through the addition of 13 to 14.
1
identified by MS, H, and 13C NMR suggesting the trans-
formation may include a radical process (eq 1). During the
reaction, a key intermediate, diiodostyrene 8, was observed (eq
2). This species can be directly transformed into final product
E-3a in 96% yield under the standard conditions (eq 4), and
iodine was necessary for the transformation. Furthermore,
disulfide 9 is generated from the 2a (eq 3), which fail to react
C
DOI: 10.1021/acs.orglett.5b01488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, crystallographic data of E-6a, copies of 1H
NMR, 13C NMR spectra of all products, and copies of 2D
1H−13C HMBC of E-3p, E-4d. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b01488.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: glu@njust.edu.cn.
*E-mail: yiwb@njust.edu.cn.
Author Contributions
‡These authors contributed equally to this paper.
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The authors declare no competing financial interest.
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Hadad, C. M.; Badjic, J. D. J. Am. Chem. Soc. 2014, 136, 17337.
ACKNOWLEDGMENTS
■
(c) Taniguchi, N. Synlett 2011, 1308.
We are grateful to Chinese National Natural Science
Foundation (21402093, 21476116), Jiangsu Province Natural
Science Foundation (BK20140776, BK20141394), and the
Center for Advanced and Technology for financial support.
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DOI: 10.1021/acs.orglett.5b01488
Org. Lett. XXXX, XXX, XXX−XXX