Highly selective anti-Markovnikov addition of thiols to vinyl ethers under solvent- and catalyst-free conditions

Article abstract of DOI:10.1016/j.tetlet.2007.10.072

A simple and efficient protocol for the anti-Markovnikov addition of thiols to vinyl ethers under solvent- and catalyst-free conditions has been established. A series of thiol ethers containing oxygen atom were obtained with good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.10.072

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8815–8818
Highly selective anti-Markovnikov addition of thiols to vinyl
ethers under solvent- and catalyst-free conditions
Feng-Wen Lou, Jian-Ming Xu, Bo-Kai Liu, Qi Wu, Qian Pan and Xian-Fu Lin*
Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China
Received 8 August 2007; revised 11 October 2007; accepted 16 October 2007
Available online 22 October 2007
Abstract—A simple and efficient protocol for the anti-Markovnikov addition of thiols to vinyl ethers under solvent- and catalyst-
free conditions has been established. A series of thiol ethers containing oxygen atom were obtained with good to excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Thiol ether moiety has been found in a quite number of
natural products and some pharmaceutically active sub-
stances.1 Some sulfide constitutes an interesting family
of natural compounds in the field of flavour and
fragrance chemistry. Over the past few decades, a great
number of alternative procedures have been developed
to synthesize these potentially bioactive sulfur-contain-
ing compounds.2 A radical initiator such as peroxide,
AIBN, UV irradiation, or an oxidising agent was used
to promote the formation of sulfur centered radicals
and anti-Markovnikov-type adducts.3 However, the
by-product such as disulfides was generated. Other pro-
cedures generally employ transition metal catalysts4
including Pd(OAc)2,5 RhCl(PPh3)3,6 K2PtCl4,6 and
NiCl2.7 Considering the substantial high cost and
high toxicity associated with these metal complex cata-
lysts, chemists are investigating alternative procedure.
Solvent- and catalyst-free reactions have attracted
increasing interest due to the highly facile, efficient,
and environmentally benign process.8 High selectivity
of anti-Markovnikov products from thiols, thiobenzoic
acids and olefins was realized in benzene without any
catalyst.9 Later, Ranu and Mandal developed a simple
protocol for the anti-Markovnikov addition of thiol to
alkenes in water.10
Although the anti-Markovnikov addition of thiols to
carbon–carbon double bonds is well known, the forma-
tion of thiol ether containing other heteroatoms has
been rarely reported.11 In this Letter, we wish to report
a convenient and practical synthesis of the anti-Mark-
ovnikov product by addition of thiols to vinyl ethers
in solvent-free conditions without the use of a catalyst.
A series of thiol ethers containing oxygen atom were
obtained with good to excellent yields under mild condi-
tions (Scheme 1).
An initial experiment on the anti-Markovnikov addition
of benzyl thiol to vinyl butyl ether was carried out in
different conditions, shown in Table 1. We examined
R1
S
O
anti-Markovnikov addition
R1
SH
R2
R3
+
Solvent-free 30-60 o
C
,
O
R2
R3
sulfhydryl reagents
vinyl ethers
1
2
3
3a-3d [1a+2a,2b,2c,2d]
R1=
=
R3=
C2H5
R2
H
3e-3h [1b+2a,2b,2c,2d]
2a
C6H5CH2
C6H5
CH3CO
CH3(CH2)2CH2 1d
CH3(CH2)10CH2 1e
1a
1b
1c
H
C4H9-n 2b
CH2CH2 2c
3i-3l
[1c+2a,2b,2c,2d]
CH2
CH2
3m-3n [1d+ 2b, 2d]
3o-3p [1e+ 2b, 2d]
CH2
2d
Scheme 1.
*
Corresponding author. E-mail: llc123@zju.edu.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.072

8816
F.-W. Lou et al. / Tetrahedron Letters 48 (2007) 8815–8818
Table 1. Anti-Markovnikov addition between benzyl thiol and vinyl
the anti-Markovnikov addition reaction in several
organic media or ionic liquids. The reaction was very
sluggish in common organic solvents. Poor yields were
obtained after 15 h (Table 1, entries 1–5). Two neutral
ionic liquids, [bmim]BF4 and [bmim]PF6, could catalyze
the reaction with moderate yields after 8 h (Table 1,
entries 7 and 8). The reaction catalyzed by basic ionic
liquid gave only 8% anti-Markovnikov adduct (Table
1, entry 6). To our surprise, under the solvent-free
conditions, the reaction proceeded smoothly and could
obtain good yields in 5 h (Table 1, entry 9). Then we
examined the influence of reaction temperature on this
reaction. When the reaction was performed at 15 °C,
only 67% yield was obtained after 5 h (Table 1, entry
10). The reaction yield increased as the increase of
reaction temperature (Table 1, entries 9–11). When the
temperature was higher than 40 °C, the reaction yield
decreased slightly (Table 1, entries 12–14).
ether under different solventsa
Entry
Solvent
Equiv
(2a)
Temp
(°C)
Time
(h)
Yield
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
n-Hexane
Toluene
Chloroform
Ethanol
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
25
25
25
25
25
25
25
25
25
15
30
40
50
60
15
15
15
15
15
8
8
8
5
5
13b,d
17b,d
31b,d
35b,d
56b,d
8b,c
Tetrahydrofuran
[bmim]OH
[bmim]BF4
[bmim]PF6
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
67b,c
82b,c
88b,c
67d
5
5
5
5
90d
95d
92d
91d
a All reactions were run on a 1.0 mmol scale of benzyl thiol with
1.2 equiv of vinyl butyl ether.
b In 1 mL of organic media or ionic liquid.
c Isolated yields.
With optimal conditions in hand, we then examined the
scope of the substrates of this reaction. The protocol
was proved to be effective for a variety of structurally
d Conversion was calculated from the GC results.
Table 2. Anti-Markovnikov addition of thiols to vinyl ethersa
Entry
Nu-H
Substrate
Temp (°C)/time (h)
M/anti-M
Yieldb (%)
SH
SH
SH
1
30/5
0.7/99.3
3a 93
O
2
3
40/5
40/7
0/100
3b 91
3c 85
3
O
3.2/96.8
O
SH
4
5
6
7
40/5
30/5
50/5
50/7
0/100
3d 95
3e 86
3f 83
3g 72
O
SH
1.6/98.4
0.8/99.2
2.7/97.3
O
SH
SH
3
O
O
SH
8
50/5
4.3/95.7
3h 91
O
O
O
9
30/3
30/3
1.8./98.2
5.9/94.1
3i 96
3j 93
O
SH
10
3
O
SH
SH
O
11
30/3
1.0/99.0
3k 91
O

F.-W. Lou et al. / Tetrahedron Letters 48 (2007) 8815–8818
8817
Table 2 (continued)
Entry
Nu-H
Substrate
Temp (°C)/time (h)
M/anti-M
Yieldb (%)
O
12
13
14
15
16
30/3
1.0/99.0
3l 95
O
SH
50/5
50/5
60/5
60/5
1.2/98.8
3m 82
3n 86
3o 76
3p 78
SH
3
O
c
—
SH
SH
O
4.7/95.3
9
9
3
O
c
—
SH
O
a Reactions were carried out on 1.0 mmol scale of thiol with 1.2 equiv of vinyl ethers in solvent-free.
b Yields refer to those of pure isolated anti-Markovnikov product characterized by IR, 1H and 13C NMR spectroscopic data.
c Not determined.
R1
diverse thiols and vinyl ethers. The anti-Markovnikov
addition of benzyl thiol to vinyl ethyl ether, vinyl butyl
ether proceeded smoothly and provided good yields
(Table 2, entries 1 and 2). Compared with vinyl ethyl
ether, the reaction rate of vinyl butyl ether was slightly
slower. Accordingly, higher reaction temperature was
required to obtain good yield. Apart from the chain-like
vinyl ether, cyclic vinyl ether such as dihydropyran and
dihydrofuran also underwent anti-Markovnikov addi-
tion with benzyl thiol leading to the corresponding
adducts with good yields (Table 2, entries 3 and 4). As
seen from the result, dihydropyran showed lower
reactivity than dihydrofuran. Aromatic thiols such as
thiophenol could also be employed as substrates for
the anti-Markovnikov addition reaction. The expected
products were formed in good yields (Table 2, entries
5–8). In the case of the anti-Markovnikov addition
between thioacetic S-acid and acyclic vinyl ethers or
cyclic vinyl ethers, excellent yields were achieved (Table
2, entries 9–12). In addition, some aliphatic thiols with
long carbon chain were tested as the substrate. The reac-
tions of butyl thiol, dodecyl mercaptan with the vinyl
butyl ether, dihydrofuran were furnished in good yields
(Table 2, entries 13–16).
-
H
δ
R1S
H
+
δ
S
O
O
R2
R3
R3
R2
1
R1
R
-
δ
S
H
S
O
O
R3
R2
R3
+
δ
R2
Scheme 2.
thiol could activate the C–C double bond. The beta car-
bon might become partially positive charged and could
be attracted by sulfur. Then the bond between sulfur
and hydrogen would be broken. The alpha carbon could
abstract the proton from oxygen subsequently and give
the anti-Markovnikov addition products.
In summary, we have developed an efficient protocol for
the anti-Markovnikov addition of thiols to vinyl ethers
under solvent- and catalyst-free conditions. This new
methodology constituted the ease of reaction, short
reaction time, high regioselectivity, high yields and green
synthesis of thiol ester containing oxygen atom.
In general, the reaction was highly selective and high-
yielding. The Markovnikov addition by-products were
less than 6%. The work-up procedure was very simple
and suitable for large scale production (see Supplemen-
tary data). All the novel compounds were characterized
by IR, NMR and HR-MS. For the known compounds,
the data are in good agreement with those have been
previously reported.
Acknowledgments
This investigation has enjoyed financial support from
the Natural Science Foundation of China (No.
20572099), the Zhejiang Provincial Science and Technol-
ogy Council (No. 2006C11197) and Ph.D. Programs
Foundation of Ministry of Education of China
(20060335031).
Based on the experimental results, we proposed a mech-
anism for the anti-Markovnikov addition reaction under
solvent-free conditions as shown in Scheme 2. The inter-
action between oxygen in vinyl ether and hydrogen in

8818
F.-W. Lou et al. / Tetrahedron Letters 48 (2007) 8815–8818
5. Kuniyasu, H.; Ogawa, A.; Sato, K. I.; Ryu, I.; Kambe, N.;
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