Ecofriendly and efficient procedure for hetero-Michael addition reactions with an acidic ionic liquid as catalyst and reaction medium

Article abstract of DOI:10.1007/s00706-011-0570-y

1-Methylimidazolium trifluoroacetate ([Hmim]-TFA) is reported as a cost-effective catalyst for a simple and environmentally benign hetero-Michael reaction. [Hmim]TFA works both as reaction medium and catalyst. The reaction is applicable to various aromatic sulfur and nitrogen nucleophiles. This method has advantages such as high yields, short reaction time, and simple workup. The catalyst could be recycled several times without any loss of activity.

Full text of DOI:10.1007/s00706-011-0570-y

Monatsh Chem (2012) 143:109–112
DOI 10.1007/s00706-011-0570-y
ORIGINAL PAPER
Ecofriendly and efficient procedure for hetero-Michael addition
reactions with an acidic ionic liquid as catalyst and reaction
medium
•
Minoo Dabiri Peyman Salehi
•
•
Mahboobeh Bahramnejad Mostafa Baghbanzadeh
Received: 12 June 2010 / Accepted: 12 July 2011 / Published online: 16 August 2011
Ó Springer-Verlag 2011
Abstract 1-Methylimidazolium trifluoroacetate ([Hmim]-
TFA) is reported as a cost-effective catalyst for a simple
and environmentally benign hetero-Michael reaction.
[Hmim]TFA works both as reaction medium and catalyst.
The reaction is applicable to various aromatic sulfur and
nitrogen nucleophiles. This method has advantages such as
high yields, short reaction time, and simple workup. The
catalyst could be recycled several times without any loss of
activity.
Conjugate addition of nitrogen and sulfur nucleophiles
to unsaturated carbonyl or nitrile compounds by hetero
Michael reaction is one of the most convenient methods for
the construction of C–N and C–S bonds in organic syn-
thesis. A variety of b-amino carbonyl compounds are
important intermediates for many potent drugs or antibi-
otics, for example b-lactams and anticancer agents [2, 3].
Also, addition of thiols to a,b-unsaturated compounds is a
key reaction in many organic processes including synthesis
of the biologically active calcium antagonist diltiazem [4,
5]. A number of alternative procedures using a variety of
metal catalysts, for example Yb(OTf)3 [6], LiClO4 [7],
CAN [8], Bi(OTf)3 [9], and SnCl4 [10], have been reported
over the past few years. Unfortunately, many of these
procedures often require an excess of reagents, long reac-
tion times, use of expensive heavy metal salts, and harsh
reaction conditions in CH3CN or CH2Cl2, which are toxic
solvents. Additionally, most reported methods are only
successful with aliphatic amines and fail to work with
aromatic amines [11–18]. Finding a new simple, green, and
more efficient catalyst for the hetero-Michael reaction is,
therefore, highly desirable. Exciting developments include
the use of ionic liquids as catalysts and/or solvents for
hetero-Michael addition [19].
Keywords Hetero-Michael reaction Á Ionic liquid Á
Aromatic sulfur and nitrogen nucleophiles Á
a,b-Unsaturated carbonyl compounds
Introduction
Avoidance of user and eco-unfriendly organic solvents is a
very important subject in chemistry research and investi-
gations. In recent years, increasing attention has been
drawn to the synthesis and applications of ionic liquids
(ILs). This is because of their unique advantages of non-
volatility, ease of reuse, immiscibility with many organic
solvents, and good solvating properties for both inorganic
and organic compounds [1].
Recently, we found alkylimidazolium-based ionic liq-
uids to be versatile and efficient catalysts for organic
transformations [20–25]. We have also reported the
application of 1-methylimidazolium trifluoroacetate,
[Hmim]TFA, as an efficient acidic IL and a powerful
medium for synthesis of heterocyclic compounds, not only
for facilitating catalyst recovery but also for the accelera-
tion of the reaction rate and rectification of selectivity
[26–33]. Thus, in this work we wish to report use of
[Hmim]TFA as a reusable, efficient, and mild catalyst for
the hetero-Michael reaction.
M. Dabiri (&) Á M. Bahramnejad Á M. Baghbanzadeh
Department of Chemistry, Faculty of Science, Shahid Beheshti
University, G. C., Evin, 1983963113 Tehran, Iran
e-mail: m-dabiri@sbu.ac.ir
P. Salehi (&)
Department of Phytochemistry, Medicinal Plants and Drugs
Research Institute, Shahid Beheshti University, G. C., Evin,
1983963113 Tehran, Iran
e-mail: p-salehi@sbu.ac.ir
123

110
M. Dabiri et al.
[Hmim]TFA
80 °C, 4 h
Results and discussion
X
EWG +
R
XH
R
EWG
Reaction of a variety of nucleophiles 1 was carried out with
different Michael acceptors 2. All reactions were con-
ducted at 80 °C within 4 h in the presence of [Hmim]TFA,
and produced high yields of the respective Michael adducts
3a–3q (Table 1).
2
1
3a-3q
X= NH, S
Scheme 1
Isolation of the products was convenient. The ionic
liquid was recovered by washing repeatedly with diethyl
ether and was reused without significant loss of its catalytic
activity. To accentuate the reusability of [Hmim]TFA, we
checked the reaction of methyl acrylate (2a) with aniline
In our study, we also investigated the reusability and
recycling of [Hmim]TFA, and found that the catalyst could
be easily recovered after completion of the reaction and
reused in subsequent reactions (Scheme 1).
Table 1 [Hmim]TFA-
catalyzed hetero-Michael
reactions between a variety of
nucleophiles and a,b-
unsaturated carbonyl
compounds or nitriles
Entry Nucleophile
, -Unsaturated
Product
Yield/% Ref.
compounds
H
O
NH2
OCH3
N
1
90
85
56
[36]
[37]
[38]
OCH3
O
1a
2a
3a
3b
O
H
N
OCH2CH3
2
3
1a
OCH2CH3
O
2b
H
N
CN
CN
1a
2c
3c
NH2
H
N
O
OCH3
4
84
[36]
OCH3
O
H3
C
2a
3d
3e
CH3
1b
H
O
OCH2CH3
N
5
6
1b
1b
78
50
[10]
[36]
OCH2CH3
O
H3
C
2b
H
CN
N
CN
2c
H3C
3f
NH2
H
OCH3
N
O
7
8
82
68
60
70
-
OCH3
O
Cl
Cl
2a
Cl
3g
Cl
1c
O
O
O
N
O
[39]
[11]
[39]
OCH3
N
H
2a
1d
OCH3
3h
O
O
N
O
9
1d
OCH2CH3
2b
OCH2CH3
3i
O
N
CN
10
1d
2c
CN 3j
N
O
N
11
72
[39]
OCH3
H
1e
2a
O
H3CO
3k
123

Ecofriendly and efficient protocol for hetero-Michael addition reactions
111
Table 1 continued
Entry Nucleophile
, -Unsaturated
Product
Yield/% Ref.
compounds
N
O
O
12
13
1e
1e
68
65
[39]
[9]
OCH2CH3
2b
H3CH2CO
3l
N
CN
2c
CN
S
3m
O
OCH3
SH
14
15
16
78
70
63
[39]
[1]
OCH3
O
1f
3n
2a
O
S
OCH2CH3
1f
1f
OCH2CH3
O
3o
2b
S
CN
CN
3p
O
[39]
2c
H
N
O
NH2
17
18
92
86
[41,42]
[41,42]
OCH3
SH
1g
2a
S
3q
O
H
N
O
1g
OCH2CH3
2b
S
3q
agreement with literature values for this type of heterocycle
[39]. It is worth mentioning that aromatic ring-fused 1,4-
thiazepine derivatives are an important group of com-
pounds with biologically interesting properties. These
kinds of compounds are selective potent Bradykinin B1
receptor antagonists and can be used for treatment of
subacute and chronic inflammatory disorders [40].
Table 2 Recycling and reusability of the catalyst [Hmim]TFA
O
H
N
NH2
+
OCH3
[Hmim]TFA
80 °C, 4 h
OCH3
O
Run
Time/h
Yield/%
In summary, we have developed a highly efficient and
environmentally friendly Michael-addition reaction of
amines and thiols with a variety of Michael acceptors. The
significance of our finding is also related to reducing the
use of organic solvents, potentially toxic and hazardous
materials, and its simplicity, high yields of the desired
adducts, and mild experimental conditions. Moreover, the
results are further evidence that it is possible to synthesize
activated natural products.
1
2
3
4
4
4
90
87
85
(1a) as model reaction. The results indicated that the
activity of the catalyst did not decrease substantially after
three runs (Table 2).
Furthermore, use of 2-aminothiophenol with two
nucleophilic sites in these reactions results in the formation
of 2,3-dihydro-1,5-benzothiazepin-4(5H)-one 3q in excel-
lent yields (Entries 17 and 18, Table 1). In these reactions
the sulfhydryl group of the nucleophile attacked the
4-position of the a,b-unsaturated electrophile and the
amino group attacked the 2-position. The resulting seven-
membered N,S-heterocycle 3q was characterized on the
basis of its exact mass spectrometry and its NMR data,
which contained a signal at 172.6 ppm in the 13C NMR
spectra for the amide carbon. The chemical shift was in
Experimental
Melting points were measured on an Electrothermal 9200
apparatus. Mass spectra were recorded on a Finnigan-MAT
8430 mass spectrometer operating at an ionization potential
of 70 eV. IR spectra were recorded on a Shimadzu IR-470
spectrometer. 1H and 13C NMR spectra were recorded on a
Bruker DRX-300 Avance spectrometer at 300.13 and
123

112
M. Dabiri et al.
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Typical procedure for synthesis of hetero-Michael
adducts 3a–3q
A mixture of amine or thiol (2 mmol), a,b-unsaturated
compound (2 mmol), and [Hmim]TFA (0.25 mmol) was
stirred at 80 °C for 4 h. After completion of the reaction
the mixture was extracted from the ionic liquid phase with
diethyl ether (10 cm3 9 3). The organic layer was dried
with anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by recrystalli-
zation from EtOH to provide the adduct in excellent yield.
The ionic liquid left was further washed with diethyl ether,
dried under vacuum at 90 °C to eliminate any water trap-
ped, and reused for subsequent reactions. All compounds
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1
were fully characterized by IR, MS, H NMR, and 13C
NMR spectroscopy. Data were in good agreement with
those reported in the literature [1, 7–9, 34–38].
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(2008) Bioorg Med Chem Lett 18:436
Methyl 3-(3,4-dichlorophenylamino)propanoate (3g)
1
Yellow liquid; H NMR (300.13 MHz, CDCl3): d = 2.61
(2H, t, J = 6.2 Hz), 3.39 (2H, t, J = 6.3 Hz), 3.70 (3H, s,
OCH3), 4.21 (1H, s, NH), 6.74-7.18 (3H, m, H–Ar) ppm;
13C NMR (75.47 MHz, CDCl3): d = 33.3, 39.2, 51.9,
112.7, 114.6, 116.3, 120.8, 132.5, 146.1, 172.6 ppm; IR
(KBr): m = 3.345, 1.727, 1.610, 1.190 cm-1; MS (70 eV):
ꢀ
m/z = 247 (M?), 212, 178, 173, 144, 59.
33. Dabiri M, Salehi P, Baghbanzadeh M, Agheb M, Heydari S
(2008) Catal Commun 9:785
34. Bhanushali MJ, Nandurkar NS, Jagtap SR, Bhanage BM (2008)
Catal Commun 9:1189
Acknowledgments The authors would like to acknowledge financial
support from the Research Council of Shahid Beheshti University.
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