Squaric acid as an impressive organocatalyst for Michael addition in water

Article abstract of DOI:10.1016/j.crci.2011.07.003

A simple, green, and environmentally benign protocol for squaric acid (5 mg) catalyst conjugate addition of aromatic amines and thiols to unsaturated carbonyl compounds in water in good to excellent yields is developed. The advantages of low sensitivity toward moisture and oxygen, high tolerance of different functional groups, green reaction media and efficient recyclability make this organocatalyst suitable for both laboratory and industrial scale synthesis of β-substituted carbonyls under very mild conditions.

Full text of DOI:10.1016/j.crci.2011.07.003

C. R. Chimie 14 (2011) 973–977
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Preliminary communication/Communication
Squaric acid as an impressive organocatalyst for Michael addition
in water
*
Najmadin Azizi , Elham Saki, Mahtab Edrisi
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:
A simple, green, and environmentally benign protocol for squaric acid (5 mg) catalyst
conjugate addition of aromatic amines and thiols to unsaturated carbonyl compounds in
water in good to excellent yields is developed. The advantages of low sensitivity toward
moisture and oxygen, high tolerance of different functional groups, green reaction media
and efficient recyclability make this organocatalyst suitable for both laboratory and
Received 3 April 2011
Accepted after revision 5 July 2011
Available online 15 September 2011
Keywords:
industrial scale synthesis of
b-substituted carbonyls under very mild conditions.
Amine
´
ß 2011 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Thiol
Organocatalyst
Squaric acid
Michael addition
Green chemistry
1. Introduction
Given the widespread availability of sulfur and nitrogen
containing nucleophiles and
a,b-unsaturated alkenes,
In recent years, it has been established that small
organic molecules, in addition to metal complexes and
biocatalysts, can be highly selective and efficient catalysts.
As a consequence, organocatalysis is gaining importance in
asymmetric synthesis, complementing bio- and metal-
catalysis [1,2].
On the other hand, the development of water as a green
medium for organic synthesis has become an important
research area. Other than the economical and environ-
mental benefits of using water, it may exhibit unique
reactivity and selectivity in comparison with conventional
organic solvents. Therefore, development of simple reac-
tivity and selectivity that cannot be attained in conven-
tional organic solvents is one of the challenging goals of
aqueous media [3–6].
there is substantial interest in developing efficient Michael
addition from these simple starting materials. Thus,
several efforts have been made to develop newer and
simpler methodologies for thia-and aza-Michael addition
that lead to the development of various base and acid
catalysts and novel reaction media such as water and ionic
liquids [13–53].
2. Results and dissociation
As a part of our research, aimed at developing green
chemistry by using water as reaction medium or by
performing organic transformations under solvent-free
conditions [54–58], herein, we describe the use of simple
small organic catalysts capable of promoting Michael
addition of aromatic, aliphatic thiols and aromatic amines
in water.
As a model reaction, benzylideneacetone was reacted
with thiophenol with different loading of starting materi-
als. It was found that by simple mixing of benzylidenea-
cetone (1 mmol), and thiophenol (1 mmol), in the presence
of squaric acid (5 mg) in water (2 mL) the desired products
was obtained in 97% yield (Scheme 1).
Nitrogen and sulfur-containing motifs are ubiquitous in
natural products [7,8] biologically active molecules [9],
and important synthetic intermediates for various phar-
maceuticals and natural products [10–12].
* Corresponding author.
E-mail address: azizi@ccerci.ac.ir (N. Azizi).
1631-0748/$ – see front matter ß 2011 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2011.07.003

974
N. Azizi et al. / C. R. Chimie 14 (2011) 973–977
O
O
OH
OH
underwent Michael addition with several Michael accep-
tors such as -unsaturated ketones, esters and nitriles
affording the corresponding products in quantitative yield.
cyclohexenone, methyl vinyl ketone, chalcone, methyl
SH
a,b
O
Ph
O
+
5 mg
Ph
CH3
PhS
CH3
acrylate, acrylonitrile,
b-nitrostyrene and benzylidenea-
water, rt, 4 h
97%
cetone underwent 1,4-addition with a wide range of thiols,
such as aliphatic, substituted aromatic thiols bearing an
electron-withdrawing and electron-donating groups in the
presence of very small amount of squaric acid in water at
room temperature to give the corresponding products in
high yields. The results are summarized in Table 1.
To further explore the scope of this simple protocol, a
number of electron-deficient olefins and aromatic amines
Scheme 1. The optimized reaction conditions for Michael addition in
water.
With the optimized reaction conditions in hand, the
scope of the reaction was explored with different
substances. Fortunately, these results proved to be quite
general and a wide range of structurally different thiols
Table 1
Reaction of thiols with Michael acceptors in water.
O
O
OH
OH
5 mg
R
X
X
+
R
1SH
R
R1S
water,rt, 1- 4 h
1
2
3
60-97%
SH
X= CN, COOMe, COR, NO2
SH
SH
SH
SH
SH
OH
Me
Br
2f
2e
2b
2a
2c
2d
Entry
Thiol
Michael acceptor
Yield [%]
Time [min]
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
90
92
85
60
78
90
240
240
240
240
240
240
O
Ph
Ph
Ph
7
2a
2b
2c
2e
2f
97
90
90
65
82
240
240
240
240
240
O
8
9
CH3
10
11
12
13
14
15
2a
2b
2d
2f
97
95
90
92
60
80
O
100
80
16
17
18
2a
2b
2c
92
84
80
120
120
120
O
19
20
21
2a
2b
2c
92
97
80
150
150
150
CN
22
23
24
2a
2b
2c
95
95
92
150
150
150
OMe
O
25
26
27
2a
2b
2c
90
85
82
80
80
80
Ph
NO2

N. Azizi et al. / C. R. Chimie 14 (2011) 973–977
975
Table 2
Reaction of aromatic amines and Michael acceptor in water.
O
O
OH
OH
NHAr
EWG
SQ
(5 mg)
EWG
+
R
ArNH2
R
Water, rt, 8 h
SQ
Entry
1
Michael acceptor
Aromatic amine
Yields (%)a
a R=H
90
OMe
NH2
O
R(X)
2
3
4
5
6
b R=n-butyl
c R=isopropyl
d R=OMe
e R=Cl
86
88
94
70
72
f R=Br
7
g R=H
92
NH2
CN
R(X)
8
h R=n-butyl
i R=isopropyl
j R=OMe
k X=Cl
84
82
80
64
68
9
10
11
12
l X=Br
13
l R=H
92
NH2
O
R(X)
R(X)
14
15
16
m=isopropyl
n R=OMe
o X=Cl
82
80
64
17
p R=H
88
NH2
O
O
Ph
CH3
18
19
20
q X=Cl
r R=H
62
64b
70b
s X=OMe
a
NMR yields b In the cases of X=Cl and Br, reaction run at 60 8C.
were also examined under the optimized conditions
(Table 2). Several aromatic amines underwent smooth
The role of the squaric acid as catalyst is still not clear
[59–61].1 Brønsted acidity is the main factors that influence
the reactivity and selectivity of the process. We tentatively
proposethemechanismofthepresent reactiontoproceedin
a manner similar to that described the analogous Brønsted
acid-catalyzed oxa-Michael addition by Johnson’s group, is
outlined inScheme2[62]. The carbonyloxygenof1aaccepts
one protonfrom the squaricacidto givethe protonated form
and undergoes thia-Michael addition with thiophenol to
give the desired products.
addition with
a,b-unsaturated ketones, nitriles and
esters in water. In all cases, the reactions proceeded
smoothly and gave the corresponding products in good to
excellent yield. As evident from the results, anilines
bearing either electron-donating or electron-withdraw-
ing groups give the Michael addition products in good
yields.
As shown in Table 2, the yields of the products are
affected by the nature of the primary amine. In the case of
aromatic amines with an electron-donating group, such as
4-isopropyl aniline, 4-methoxyaniline, the corresponding
products were obtained in good to high yields. Aromatic
amines with an electron-withdrawing group, such as 4-
nitroaniline, are not good substrates for this reaction and
give the corresponding products in very low yields.
1
Although squaric acid has been known as a commercially available
strong acid, squaric acid itself has attracted little attention from the
synthetic community mainly due to its extremely poor solubility in
organic solvents [59,60]. Recently, some groups have developed a new
chiral Brønsted acid from the squaric acid scaffold and successfully used
in asymmetric organic synthesis [61].

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N. Azizi et al. / C. R. Chimie 14 (2011) 973–977
Table 3
O
OH
Thia-Michael addition of thiophenol with methyl acrylate with different
PhSH (2a)
H
catalyst system.
Me
Me
O
O
O
Entry Catalyst
Mol (%) Solvent
Yields (%) Ref.
1
1
2
–
–
Water
SFC
95
92
99
88
94
78
93
85
88
88
92
93
[16]
[17]
[18]
[26]
[37]
[38]
[39]
[44]
[45]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
–
Montmorillonite
CAN
10
50
1
3
SFC
OH
O
4
Zn(ClO4)
–
SFC
5
–
PEG
CH3CN
SFC
Me
Me
SPh
H
6
Bi(OTf)3
SSA
1
SPh
O
7
25
1
H
3
8
HClO4-SiO2
Cu(BF4)2
FeCl3
SFC
9
1
SFC
Scheme 2. Plausible reaction mechanism in the presence of squaric acid.
10
11
12
13
14
15
16
17
2
SFC
ZrCl4
1
SFC
IL
b
100
100
2
IL
-CD
Water/acetone 98
Silica nanoparticle
B(OH)3
SFC
88
89
92
95
3. Conclusion
10
15
0.1
Water
SFC
n-(Bu)4Br
SQ
In summary, an operationally simple and green aza-
and thia-Michael addition of aromatic and aliphatic thiols
and amines to electron-deficient olefins under solvent free
conditions with good to excellent yields has been
developed. This new protocol has the advantages of
environmental friendliness, higher yields, shorter reaction
times, and convenient operation, which only require
stirring the reaction mixture at ambient temperature
without the use of any additional energy source like
heating or sonication. Moreover, the purification process is
simple which is just a quick washing of the reaction
mixture with water, which allows the isolation of the
desired products in good to excellent yields.
Water
Acknowledgment
Financial support of this work by Chemistry and
Chemical Research Center of Iran is gratefully appreciated.
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