A simple and green procedure for the conjugate addition of thiols to conjugated alkenes employing polyethylene glycol (PEG) as an efficient recyclable medium

Article abstract of DOI:10.1016/j.tetlet.2005.09.082

Polyethylene glycol (PEG) is found to be an inexpensive, nontoxic, environmentally friendly reaction medium for the conjugate addition of thiols to conjugated alkenes to afford the corresponding adducts in excellent yields under mild and neutral condition

Full text of DOI:10.1016/j.tetlet.2005.09.082

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7951–7953
A simple and green procedure for the conjugate addition of
thiols to conjugated alkenes employing polyethylene glycol
(PEG) as an efficient recyclable medium
Ahmed Kamal,* D. Rajasekhar Reddy and Rajendar
Division of Organic Chemistry, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
Received 27 July 2005; revised 5 September 2005; accepted 14 September 2005
Available online 30 September 2005
Abstract—Polyethylene glycol (PEG) is found to be an inexpensive, nontoxic, environmentally friendly reaction medium for the
conjugate addition of thiols to conjugated alkenes to afford the corresponding adducts in excellent yields under mild and neutral
conditions. Products of undesirable side reactions resulting from polymerization are not observed. The use of PEG avoids the
use of either acid or base catalysts for this conversion and moreover PEG can be recovered and reused.
Ó 2005 Elsevier Ltd. All rights reserved.
Green chemistry is becoming a central issue in both aca-
demic and industrial research in the 21st century,1 and
the development of environmentally benign and clean
synthetic procedures has become the goal of present
day organic synthesis. Organic reactions without the
use of harmful organic solvents are now of great interest
in organic synthesis.2 Attempts have been made to
develop solvent-free chemistry, which to some extent
have been successful in a few transformations.3 More re-
cently, attention has been drawn to the development of
environmentally benign solvents such as ionic liquids,4
water,5 and polyethylene glycol.6 It is customary to mea-
sure the efficiency of a catalyst by the number of cycles
for which it can be reused. Similarly, the value of a new
solvent medium primarily depends on its environmental
impact, the ease with which it can be recycled, low vapor
pressure, nonflammability and high polarity for solubili-
zation. However, in performing the majority of organic
transformations, solvents play an important role in mix-
ing the ingredients to make the system homogeneous
and allow molecular interactions to be more efficient.
The Michael reaction since its discovery in 1889 is one of
the most important reactions in organic chemistry.7 The
conjugate addition of thiols to electron-deficient olefins
to form a carbon–sulfur bond constitutes a key reaction
in biosynthesis as well as in organic synthesis.8 Organo-
sulfur compounds are also useful in the synthesis of
biologically active compounds such as the calcium
antagonist diltiazem.9 Consequently, a large number of
reagents have been reported in the literature for the
addition of mercaptans to conjugated alkenes.10 In
order to avoid side-reactions, several inorganic salts
have been introduced in the presence of strong acid or
base.11 A number of procedures, either based on activa-
tion of thiol by a base or activation of the acceptor ole-
fins with Lewis acids have been used.12 More recently,
tetrabutylammonium halide has been used as phase-
transfer catalyst.13 There is also a recent report of carry-
ing out these reactions in ionic liquids and a mixture of
ionic liquids and water (2:1).14 Ionic liquids have been
shown to have serious drawbacks, especially imidazo-
lium systems with PF6 and BF4 anions are as toxic as
benzene to certain aquatic ecosystems, and also liberate
hazardous HF during recycling. Apart from this, the
high cost15 and disposability of these solvents also limit
their utility. The use of strong acids (polymerization of
vinyl ketones) and bases in the medium, toxic catalysts,
harsh conditions, far from satisfactory yields and selec-
tivities due to the occurrence of side-reactions restrict
practical applications in industry.
Keywords: Conjugate addition; Thiols; Conjugated alkenes; Polyethyl-
ene glycol.
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40
27193189; e-mail addresses: ahmedkamal@iict.res.in; ahmedkamal@
iictnet.org
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.082

7952
A. Kamal et al. / Tetrahedron Letters 46 (2005) 7951–7953
Table 1. Conjugate addition of thiols to conjugated alkenes using PEG
PEG and its monomethyl ethers are inexpensive, ther-
mally stable, recoverable, and nontoxic media for
phase-transfer catalysts.16 PEG, a biologically accept-
able polymer used extensively in drug delivery and in
bioconjugates as tool for diagnostics, has hitherto not
been widely used as a solvent medium but has been used
as a support for various transformations.6,17 Herein, we
report PEG 400 as a recyclable reaction medium for
conjugate addition of various thiols to conjugated
alkenes at room temperature without the use of any acid
or base catalyst (Schemes 1 and 2). Such reactions do
not generate any toxic waste products.
Entry
Conjugated
alkene
Product
Time
(min)
Yielda,b
(%)
O
R
O
O
O
O
1
2
3
4
R = C6H5S
30
25
30
40
92
92
90
88
R = p-ClC6H4S
R = o-MeC6H4S
Our efforts began with thiophenol and 2-cyclohexen-
1-one in the presence of PEG 400 (Table 1, entry 1)
at room temperature for 30 min, the corresponding
adduct was obtained in 92% yield. Other thiols were
reacted with a variety of conjugated alkenes in
polyethylene glycol (Table 1). The reaction proceeds
efficiently at room temperature without the need for
any further acid or base catalyst and goes to comple-
tion in a short time (20–45 min).18 This methodology
is compatible with various a,b-unsaturated ketones,
nitriles, and esters and different substituted aromatic
thiols or cyclohexanethiol under mild reaction condi-
tions. No by-product formation was observed. More-
over, these reactions are clean with excellent yields
compared to conventional methods, have shorter reac-
tion times, higher selectivities and a recyclable reaction
medium.
R = C6H11
S
O
R
O
O
O
5
6
7
R = C6H5S
40
35
45
90
88
86
The catalytic activity of polyethylene glycol for these
conjugate additions was established by the fact that
there was no reaction in the absence of PEG. We suggest
that the mechanism of addition of thiols to conjugated
alkenes employing polyethylene glycol as the reaction
medium involves the formation of a hydrogen bond be-
tween the thiol and the polyethylene glycol hydroxyl
group, which makes the S–H bond weaker, enhancing
the nucleophilicity of sulfur for addition to electron-defi-
cient alkenes.
R = p-ClC6H4S
R = p-OMeC6H4S
R1
R1
R
8
9
10
11
12
R1 = COMe
R1 = COMe
R1 = COMe
R1 = COMe
R1 = COMe
R = C6H5S
20
20
20
20
30
94c
92
88
90
84
R = p-ClC6H4S
R = o-MeC6H4S
R = p-C6H4S
R = C6H11
S
13
14
15
16
17
R1 = CN
R1 = CN
R1 = CN
R1 = CN
R1 = CN
R = C6H5S
20
25
25
30
40
92
90
88
92
86
O
O
R = p-ClC6H4S
R = o-MeC6H4S
R = p-OMeC6H4S
PEG/rt
RSH
+
( )
( )
n
R = C6H11
S
n
SR
18
19
20
R1 = CO2Me
R1 = CO2Me
R1 = CO2Me
R = C6H5S
R = p-ClC6H4S
R = o-MeC6H4S
25
30
30
90
90
86
R = aryl, cyclohexyl
n = 1, 2
Scheme 1.
a All the products were characterized by mass, 1H NMR, and IR
spectroscopy and by comparison with literature data.
b Isolated yields.
c PEG was recovered and reused for five consecutive runs in this
reaction without any change in the yield or purity.
X
PEG/rt
X
RSH
+
RS
Acknowledgements
R = aryl, cyclohexyl
X = COMe, CN, CO2Me
The authors D.R.S.R. and Rajendar are grateful to
CSIR, New Delhi, for the award of research fellowships.
Scheme 2.

A. Kamal et al. / Tetrahedron Letters 46 (2005) 7951–7953
7953
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18. General procedure: A mixture of thiol (1 mmol), alkene
(1.2 mmol) and PEG 400 (2 g) was placed in a 10 mL
round-bottomed flask. The mixture was left stirring at
room temperature until the reaction was complete (Table
1). The reaction mixture was extracted with dry ether, the
extract dried and concentrated under reduced pressure and
the resulting crude product was purified by silica column
chromatography using EtOAc and hexane (1:9) as an
eluent to obtain the adduct in excellent yield. The
recovered PEG can be reused for a number of cycles
without significant loss of activity. Spectral data for
3-phenylthiocyclohexan-1-one (1) (Table 1, entry 1): 1H
NMR 200 MHz (CDCl3): d 1.75 (m, 2H), 2.10 (m, 2H),
2.35 (m, 2H), 2.40 (d, J = 10.9, 1H), 2.70 (dd, J = 10.9,
4.41, 1H), 3.45 (m, 1H), 7.25 (m, 3H), 7.45 (m, 2H); IR:
1712, 749, 693 cmÀ1. Spectral data for 3-phenylthiocyclo-
pentan-1-one (5) (Table 1, entry 5): 1H NMR 200 MHz
(CDCl3): d 1.95–2.05 (m, 1H), 2.34–2.65 (m, 5H), 3.90 (q,
J = 6.3 Hz, 1H), 7.29–7.35 (m, 3H), 7.40–7.43 (m, 2H); IR:
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1743, 742 cmÀ1
.