An atom-economic and odorless thia-Michael addition in a deep eutectic solvent

Article abstract of DOI:10.1016/j.tetlet.2014.01.104

The first 100% atom-efficient and odorless protocol for carbon-sulfur bond formation in a deep eutectic solvent (DES) as both the reaction medium and catalyst is reported. The biodegradable and inexpensive DES provides an efficient and convenient ionic reaction medium for the thia-Michael addition with in situ generation of S-alkylisothiouronium salts in place of thiols without the urea by-product segment. This protocol offers several advantages including short reaction times, high yields, clean reactions, and inexpensive and commercially available starting materials.

Full text of DOI:10.1016/j.tetlet.2014.01.104

Tetrahedron Letters 55 (2014) 1722–1725
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An atom-economic and odorless thia-Michael addition in a deep
eutectic solvent
⇑
Najmedin Azizi , Zahra Yadollahy, Amin Rahimzadeh-Oskooee
Chemistry & Chemical Engineering Research Center of Iran, PO Box 14335-186, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The first 100% atom-efficient and odorless protocol for carbon–sulfur bond formation in a deep eutectic
solvent (DES) as both the reaction medium and catalyst is reported. The biodegradable and inexpensive
DES provides an efficient and convenient ionic reaction medium for the thia-Michael addition with in situ
generation of S-alkylisothiouronium salts in place of thiols without the urea by-product segment. This
protocol offers several advantages including short reaction times, high yields, clean reactions, and inex-
pensive and commercially available starting materials.
Received 6 November 2013
Revised 29 December 2013
Accepted 22 January 2014
Available online 1 February 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Atom economy
Deep eutectic solvent
Green chemistry
Odorless thiol
Thia-Michael addition
Organic reactions in sustainable reaction media such as ionic
liquids, without the use of harmful organic solvents, have attracted
a great deal of attention. These solvents are easily available and
safe, especially in relation to environmental concerns. Deep eutec-
tic solvents (DESs) have many advantageous properties compared
to common organic solvents. They have physicochemical proper-
ties of room-temperature ionic liquids (RTILs) such as negligible
vapor pressure, high thermal and chemical stabilities, non-flam-
mability, and high solvation capacity. However, DESs have many
advantages over ILs such as simple preparation, low price, chemi-
cal inertness to water, high atom economy, and avoid purification
problems and waste disposal encountered with common ILs.
Furthermore, they can be made from biodegradable components,
with 100% atom economy.1
Green carbon–sulfur bond formation under safe and eco-
friendly conditions, to give intermediates that can be converted
into commercially important biological and pharmaceutical prod-
ucts has attracted significant attention.2 Thiol-containing organic
compounds such as cysteine, glutathione, and cysteamine play
important roles in living organisms, and are involved in a number
of biological processes due to the properties of the thiol function.
They have found various applications as enzyme inhibitors and
biologically active calcium antagonists, and abnormal levels of
these species are closely related to certain diseases.3
a variety of electrophilic reagents such as conjugated alkenes,
epoxides, and alkyl halides.4 Although some of these reported pro-
cedures are effective on small scale, the use of highly toxic, volatile,
and foul-smelling thiols could lead to serious environmental and
safety problems in large scale reactions. Therefore, several
attempts have been made to develop odorless protocols in order
to prevent environmental pollution and decrease the stress of
researchers working with them.5
In this context, several recent publications are notable as they
have reported odorless thiol equivalents such as the use of S-alkyl-
isothiouronium salts, to give thiols. However, this odorless thiol
equivalent has poor atom economy, which is an important concept
of green chemistry. The reaction produces equivalent amounts of
urea, which need to be separated from the product and disposed
of as waste.6 As a consequence, there is scope to search for a more
user-friendly and atom-economic reaction. This observation and
our interest in the development of new methodologies using green
solvents, prompted us to investigate carbon–sulfur bond formation
through the in situ generation of S-alkylisothiouronium salts in
place of thiols, without the formation of a urea by-product
(Scheme 1).
Based on our interest in deep eutectic solvents,7 we describe
herein an odorless, atom-economic route for the preparation of
b-keto sulfides via the one-pot reaction of thiourea, alkyl halides,
and electron-deficient olefins in a choline chloride based deep
eutectic solvent, under safe and eco-friendly conditions.
Consequently, a large number of reagents and catalysts have
been reported in the literature for the reactions of mercaptans with
In the initial attempt, and to optimize the reaction conditions,
the one-pot reaction of benzyl chloride and thiourea with methyl
acrylate was examined in a choline chloride–urea based DES under
⇑
Corresponding author. Tel.: +98 21 445 80775; fax: +98 21 44580762.
E-mail address: azizi@ccerci.ac.ir (N. Azizi).
http://dx.doi.org/10.1016/j.tetlet.2014.01.104
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

N. Azizi et al. / Tetrahedron Letters 55 (2014) 1722–1725
1723
catalyst
X
R
SH +
X
R
S
solvent
Foul-smelling thiol
S
O
Previous work:
This work:
X
solvent
base
R
X +
H2N
NH2
+ H2N
NH2
+
X
R
S
Odorless but not atom-economic
S
DES (urea-ChCl)
base
X
R
X +
H2N
NH2
+
X
R
S
Odorless and atom-economic
Scheme 1. General carbon–sulfur bond forming reactions in the literature reported in this work.
basic conditions (K2CO3, Na2CO3, NaHCO3, triethylamine, NaOH,
DBU) (Table 1). It turned out that this three-component reaction
could be carried out in the presence of NaOH and K2CO3 as bases
in the DES at room temperature. It was also found that this reaction
was significantly affected by the reaction temperature. While this
process needed as long as four hours to be complete at room tem-
perature, in the presence of 0.4 mL of 8 M NaOH, full conversion of
the starting material occurred in only one hour at 60 °C (Table 1,
entry 13).
Using the optimized reaction conditions, we investigated the
scope of this odorless and atom-economic thia-Michael addition
with various combinations of substrates, and the results are sum-
marized in Table 2. In general, different alkyl halides 1 as well as
Michael acceptors 3 could be applied successfully in this proce-
dure, providing a diverse set of thia-Michael products under mild
Table 1
Optimization of the reaction conditions in model reaction
S
O
H2N
Cl
NH2
DES (0.5 mL)
additive
S
OMe
+
Ph
Ph
COOMe
Entry
Additive (x mmol)
Time (h)
Temp (°C)
Yielda,b (%)
1
2
3
4
5
6
7
8
—
4
4
4
4
4
4
4
4
4
1
1
1
1
1
1
rt
0
NaHCO3 (1 mmol))
K2CO3 (1 mmol)
Et3N (1 mmol)
DBU (1 mmol)
Na2CO3 (1 mmol)
NaOH (1 mmol)
NaOH (1.5 mmol)
NaOH (2 mmol)
NaOH (2 mmol)
NaOH (0.1 mL)
NaOH (0.2 mL)
NaOH (0.4 mL)
NaOH (0.4 mL)
NaOH (0.4 mL)
60
60
60
rt
60
rt
29
56
30
0
55
0
rt
rt
0
0
reaction conditions. A variety of a,b-unsaturated compounds such
9
as, methyl acrylate, acrylonitrile, methyl vinyl ketone, and cyclo-
hex-2-enone underwent the 1,4-addition smoothly with a wide
range of alkyl halides, in short reaction times, to afford the corre-
sponding products (4a–4n) in high yields. Alkyl chlorides, bro-
mides, and iodides, as well as primary, secondary allylic and
benzylic halides participated in this reaction to give the corre-
sponding products in good to excellent yields. In addition, the reac-
tion was tolerant of a range of functional groups including
methoxy, halides, and C@C in the electron-deficient olefins and
alkyl halides.
10
11
12
13
14
15
60
60
60
60
80
100
30
69
73
95
95
95
a
Isolated yields.
b
Reaction conditions; benzyl chloride (1 mmol), thiourea (1 mmol), methyl
acrylate (1 mmol), DES (0.5 mL), NaOH (8 M); DBU = 1,8-diazabicyclo[5.4.0]undec-
7-ene.
Table 2
One-pot thia-Michael addition using alkyl halides, thiourea, and electron-deficient alkenes in a DES
S
urea/ChCl (0.5 mL)
NaOH, 60 o
S
+
EWG
R
EWG
RX
+
H2N
NH2
C
1
4
2
3
Entry
1
Alkyl halide
Electron-deficient alkene
Product
Time (min)
80
Isolated yielda (%)
93
O
O
Cl
O
Ph
S
O
4a
CN
Cl
Cl
CN
Ph
Ph
S
S
2
3
80
91
75
4b
O
O
100
4c
Cl
Cl
Cl
Cl
CN
O
CN
Cl
Cl
S
S
4
5
80
80
92
4d
O
O
95
O
4e
(continued on next page)

1724
N. Azizi et al. / Tetrahedron Letters 55 (2014) 1722–1725
Table 2 (continued)
S
urea/ChCl (0.5 mL)
NaOH, 60 o
S
+
EWG
R
EWG
RX
+
H2N
NH2
C
1
4
2
3
Entry
6
Alkyl halide
Electron-deficient alkene
Product
Time (min)
90
Isolated yielda (%)
O
O
Br
O
S
O
80
Br
4f
CN
Br
CN
S
7
8
CH3I
80
80
75b
81b
4g
O
O
O
O
O
O
CH3I
S
O
4h
Cl
O
9
10
11
100
80
83
79
72
S
O
4i
4j
Br
O
O
S
S
O
O
O
O
Br
Br
140
O
O
4k
O
O
S
O
12
13
14
140
80
75
MeO
4l
MeO
O
O
Cl
Cl
82b
75b
S
4m
O
O
Cl
S
80
4n
Cl
a
Isolated yields.
Reaction runs at room temperature.
b
The combination of an atom-economic, odorless reaction and
S
NH2
the ease of preparation of the DES as the reaction medium and cat-
alyst are expected to contribute to the development of a novel pro-
tocol for the simple and fast preparation of organosulfur
derivatives. Furthermore, on gram scale (10 mmol), the desired
product was isolated by distillation of the reaction mixture under
reduced pressure after water addition or by removal of the product
from the DES/water layer using a pipette without any organic
solvent.8,9
+
H2N
NH2
X
R
X
R
N
S
NH2
2
1
O
OH
H
H
H
H
N
N
H
H2N
H2N
Cl
N
O
H
H
X
N
R
S
HO
H
O
On the basis of the above observations and a literature survey, a
plausible mechanism for this green, thia-Michael addition is illus-
trated in Scheme 2. Reaction of the benzyl halide 1 with thiourea 2
affords the isothiouronium salt 2, which upon basic hydrolysis in
the presence of NaOH generates the thiolate 3 and urea that acts
as one of the components of the DES. This intermediate is further
reacted in situ with a Michael acceptor to generate the carbon–sulfur
bond (Scheme 2).
R
S
3
X
Scheme 2. Proposed mechanism for thia-Michael addition in DES.
In summary, the green reaction described here offers a rapid,
atom economic, and odorless alternative to other methods for car-
bon–sulfur bond formation using a biodegradable and inexpensive
DES. The reactions proceed under mild conditions and give the
products in good yields with complete atom economy. Advantages
of this procedure include the use of a DES, short reaction times, and
a simple separation and purification. Further investigations on
S-alkylisothiouronium salts in deep eutectic solvents are now
underway in our laboratory.
Acknowledgment
Financial support for this work by the Chemistry and Chemical
Engineering Research Center of Iran is gratefully appreciated.
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(0.4 mL of an 8 M aqueous solution), and the
a,b-unsaturated compound were
added and the reaction was heated for 1–2 h. The mixture was extracted with
EtOAc (5 mL), dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography over silica gel using
EtOAc/petroleum ether as the eluent to afford the corresponding pure product.