Aza-Michael reactions in water using functionalized ionic liquids as the recyclable catalysts

Article abstract of DOI:10.1007/BF03245908

Some recyclable SO₃H-functionalized ionic liquids have been used as catalysts in water for the aza-Michael reactions of amines with α,β-unsaturated compounds to produce β-amino compounds. High yields of the products, short reaction times, mild reaction conditions, simple experimental procedure, reusable catalysts and no obvious loss of the catalytic activity make this protocol a contribution to organic chemistry.

Full text of DOI:10.1007/BF03245908

J. Iran. Chem. Soc., Vol. 8, No. 3, September 2011, pp. 775-781.
JOURIrNaAnLiaOnF THE
Chemical Society
Aza-Michael Reactions in Water Using Functionalized Ionic Liquids as the Recyclable
Catalysts
X. Liu, M. Lu*, G. Gu and T. Lu
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, China
(Received 4 July 2010, Accepted 10 December 2010)
Some recyclable SO3H-functionalized ionic liquids have been used as catalysts in water for the aza-Michael reactions of
amines with α,β-unsaturated compounds to produce β-amino compounds. High yields of the products, short reaction times, mild
reaction conditions, simple experimental procedure, reusable catalysts and no obvious loss of the catalytic activity make this
protocol a contribution to organic chemistry.
Keywords: Aza-Michael reaction, Amine, β-Amino carbonyl compounds, Ionic liquid, Catalyst
INTRODUCTION
been reported to improve and modify this reaction. A variety
of reagents such as InCl3, supported CeCl3.7H2O-NaI,
Yb(OTf)2, Y(NO3)2.6H2O, clay, silica gel, FeCl3, palladium,
RuCl3/PEG, sulfated zirconia and alkaline Al2O3 have been
reported as promoters for this reaction [15-24]. Catalyst- and
solvent-free methods has also been employed for this reaction
[25]. The microwave technique using stoichiometric amount
of acetic acid at high temperature has been reported [26].
However, the search for new, readily available and green
catalysts is still being actively pursued.
Ionic liquids have attracted extensive interest as excellent
alternatives to organic solvents, due to their favorable
properties. Recently, there were reports of aza-Michael
reactions conducted in ionic liquids [27], Cu(acac)2/ionic
liquid [28], ionic liquid/quaternary ammonium salt in water
[29], and boric acid in water [30]. However, these reactions
were unsuccessful in water alone, with no acid or base
catalysts. Combining the useful characteristics of solid acids
and mineral acids, Brønsted acidic task-specific ionic liquids
(TSILs) are designed to replace the traditional mineral liquid
acid catalysts, such as sulfuric acid and hydrochloric acid in
chemical processes. However, TSILs with imidazole as the
As an important reaction in organic chemistry, especially
for the synthesis of heterocycles containing a β-amino
carbonyl unit, the aza-Michael reaction is very much in focus.
β-Amino carbonyl compounds are useful building blocks for
the molecules with applications in pharmaceuticals and fine
chemicals [1-6]. They are versatile intermediates for the
synthesis of biologically important natural products and
antibiotics. The most common method for the construction of
this functionality is the Mannich reaction [7-9]. However, the
reaction is associated with some disadvantages like drastic
reaction conditions and longer reaction times [10].
Alternatively, the conjugate addition of amines to α,β-
unsaturated compounds (aza-Michael reaction) is an attractive
route for the synthesis of β-amino carbonyl compounds due to
its simplicity and atom economy.
The aza-Michael reactions are usually carried out under
acid and base catalysis [11-14]. Recently, many synthetic
methods for preparing the β-amino carbonyl compounds have
*Corresponding author. E-mail: lumingnj302@126.com

Liu et al.
cation are relatively expensive, which hinders their industrial
EXPERIMENTAL
applications. Furthermore, typical ionic liquids consist of
halogen containing anions (such as [PF6]-, [BF4]-, [CF3SO3]-
and [(CF3SO2)2N]-) which, in many respects, limit their
“greenness” [31-33]. Therefore, the synthesis of less
expensive and halogen-free TSILs is clearly in order. Some
SO3H-functional halogen-free Brønsted acidic ionic liquids
[34-39] have been successfully applied to catalyze the
Mannich reaction and the Biginelli reaction. The versatility of
these ionic liquids prompted us to study their appropriacy for
aza-Michael reaction. To the best of our knowledge in the
open literature, the aza-Michael reactions, to be catalyzed by
the functionalized ionic liquids, have not been reported to
date. Herein, we would like to report that functionalized ionic
liquids (Fig. 1) effectively promote aza-Michael reactions of
various amines to conjugated α,β-unsaturated compounds
under relatively mild conditions (Scheme 1).
Materials and Methods
Melting points were determined on a Thomas Hoover
capillary apparatus and were uncorrected. The IR spectra were
recorded with a Bomem Michelson model 102 FTIR. 1H NMR
spectra were recorded on Bruker DRX (300 MHz) and Bruker
DRX500 (500 MHz) spectrometer. Elemental analyses were
performed on a Yanagimoto MT3CHN recorder. Mass spectra
were obtained with automated FININIGAN Trace Ultra-Trace
DSQ GC/MS spectrometer. All starting chemicals (AR grade)
were purchased from commercial suppliers and used without
further purification.
Synthesis of TSILs
The functionalized ionic liquids [TMPSA][HSO4],
[TEPSA][HSO4], [TBPSA][HSO4], [TMBSA][HSO4] and
Fig. 1. The halogen-free ionic liquids TSILs.
Scheme 1. Aza-Michael addition of amines to conjugated alkenes in the presence of TSILs
776

Aza-Michael Reactions in Water Using Functionalized Ionic Liquids
[TEBSA][HSO4] were prepared adopting the procedures
introduced in Refs. [37-39] .
[TEBSA][HSO4]. The starting materils were triethylamine
and 1,4-propanesulftone. The same process as that used for
[TMPSA][HSO4] was performed, except that the first reaction
was carried out for 2 h at 35-40 °C. 1H NMR (300 MHz, D2O):
δ ppm 3.15 (q, J = 7.2 Hz, 6H, -N-CH2-CH3), 3.07 (t, J = 8.4
Hz, 2H, -N-CH2-C3H6SO3), 2.82 (t, J = 7.2 Hz, 2H, -CH2-
SO3), 1.68 (m, 4H, -C2H4-CH2SO3), 1.11 (m, J = 7.2 Hz, 9H,
-CH3). MS (m/z): 335.35 (M+), 208.36 (100) [39].
[TMPSA][HSO4]. Trimethylamine (0.11 mol) and 1,3-
propanesulftone (0.10 mol) were dissolved in 1,2-
dichloroethane (20 ml) and allowed to stir under nitrogen for 2
h at 55-60 °C. A white precipitate was formed, which was
filtered and washed with petroleum ether. The product was
recrystallized from a mixture of chloroform, petroleum ether
and acetone. White solid products (TMAPS) were obtained in
92% yield. Equal molar of TMAPS and acid solutions (98%)
were mixed and stirred for 8 h at 60-80 °C. Then the combined
solution was dried in a vacuum at 100 °C to remove the water.
The produced TSIL [TMPSA][HSO4] was washed repeatedly
with diethyl ether to remove the unreacted starting materials
and dried in a vacuum again. The [TMPSA][HSO4] was
identified by 1H NMR and the resulting datum were compared
General Experimental Procedures for the Aza-
Michael Reactions
To a round-bottomed flask charged with amine (10 mmol),
α,β-unsaturated compound (12 mmol) in 10 ml of water was
added TSIL (1 mmol) under stirring. The mixture was then
stirred for a certain time at room temperature. The progress of
the reaction was monitored by TLC. After completion of the
reaction, the mixture was extracted with ethyl acetate. The
organic layer was separated and washed with brine. The
aqueous layer (containing the catalyst) was reused directly in
the next run without further purification. The organic phase
was then dried (Na2SO4), filtered, and the solvent was
removed under vacuum. The crude product was purified by
passing through a column of silica gel using ethyl acetate-n-
hexane as the eluent. All products were known compounds,
1
with literature datum. H NMR (300 MHz, D2O): δ ppm 3.22
(t, J = 7.2 Hz, 2H, -N-CH2-), 2.90 (s, 9H, -CH3), 2.73 (t, J =
7.2 Hz, 2H, -CH2-SO3), 1.99 (m, 2H, -CH2-). MS (m/z):
279.05 (M+), 182.14 (100) [39].
[TEPSA][HSO4]. The starting materils were triethylamine
and 1,3-propanesulftone. The same process as that used for
[TMPSA][HSO4] was performed, except that the first reaction
1
was carried out for 12 h at 35-40 °C. H NMR (300 MHz,
1
D2O): δ ppm 3.22-3.05 (m, 8H, (6H+2H), -N-CH2-CH3, -N-
CH2-C2H4-), 2.85 (t, J = 7.2 Hz, 2H, -CH2-SO3), 1.97 (m, 2H,
-CH2-), 1.12 (t, 9H, -CH3). MS (m/z): 321.05 (M+), 322.05,
320.15, 194.05 (100) [39].
which were characterized by H NMR spectra data and their
mps compared with literature reports.
The spectral data for some of the selected representative
compounds are given below:
[TBPSA][HSO4]. The starting materils were tributylamine
and 1,3-propanesulftone. The same process as that used for
[TMPSA][HSO4] was performed, except that the first reaction
4-(Phenylamino)butan-2-one (Table 3, Entry 1). 1H NMR
(300 MHz, CDCl3): δ = 7.104 (t, 2H), 6.645 (t, 1H), 6.528 (d,
2H), 3.390 (t, 2H), 2.706 (t, 2H), 2.142 (S, 3H) ppm. ESIMS:
(M+1) 164 m/z [23].
1
was carried out for 24 h at 35-40 °C. H NMR (500 MHz,
D2O): δ ppm 3.28 (t, 2H, J = 4.0 Hz, -N-CH2-), 2.85 (t, J = 7.0
Hz, 2H, -CH2-SO3), 2.03 (m, 6H, -CH2-CH3), 0.84 (t, 9H, J =
7.5Hz, -CH3). MS (m/z): 405.29 (M+), 406.28, 404,28 (100)
[39].
3-(Phenylamino)propanenitrile (Table 3, Entry 2). 1H
NMR (300 MHz, CDCl3): δ = 2.57 (t, 2H, J = 2.2 Hz), 3.46
(dd, 2H, J = 2.0, 1.9 Hz), 3.99 (s, 1H), 6.58-7.22 (m, 5H).
ESIMS: (M+1) 147 m/z [24].
[TMBSA][HSO4].
trimethylamine and 1,4-propanesulftone. The same process as
that used for [TMPSA][HSO4] was performed, except that the
The
starting
materils
were
Methyl-3-(phenylamino)propanoate (Table 3, Entry 3).
1H NMR (300 MHz, CDCl3): δ = 2.60 (t, J = 6.42 Hz, 2H),
3.43 (2H, t, J = 6.42 Hz), 3.68 (s, 3H), 6.62 (d, Ar2H), 6.73 (t,
Ar1H), 7.16 (t, Ar2H). ESIMS: (M+1) 180 m/z [22].
3-(Benzylamino)propanenitrile (Table 3, Entry 4). 1H
NMR (300 MHz, CDCl3): δ = 2.52 (t, J = 2.2 Hz, 2H), 2.83
(2H, t, J = 2.2 Hz), 3.83 (s, 2H), 7.26-7.34 (m, 5H).
1
first reaction was carried out for 2 h at 65-70 °C. H NMR
(300 MHz, D2O): δ ppm 3.24 (t, J = 8.4 Hz, 2H, -N-CH2-),
2.85 (t, J = 7.5 Hz, 2H, -CH2-SO3), 1.82 (m, 2H, -CH2-), 1.70
(m, 2H, -CH2-). MS (m/z): 293.36 (M+), 196.39 (100) [39].
777

Liu et al.
The Aza-Michael Reaction Catalyzed by Different
TSILsa
Table 1.
ESIMS: (M+1) 161 m/z [24].
Methyl-3-(benzylamino)propanoate (Table 3, Entry 5).
1H NMR (300 MHz, CDCl3): δ = 2.56 (t, J = 6.8 Hz, 2H), 2.90
(2H, t, J = 6.8 Hz), 3.66 (s, 3H), 7.24-7.26 (m, 2H), 7.31-7.32
(m, 3H). ESIMS: (M+1) 194 m/z [24].
Entry
TSILs (mmol)
None
Yield (%)b
1
2
3
4
5
6
7
8
0
1
3-(Pyrrolidin-1-yl)propanenitrile (Table 3, Entry 6). H
[TMPSA][HSO4] (1)
[TEPSA][HSO4] (1)
[TBPSA][HSO4] (1)
[TMBSA][HSO4] (1)
[TEBSA][HSO4] (1)
[TMPSA][HSO4] (0.5)
[TMPSA][HSO4] (2)
91
90
85
89
86
81
91
NMR (300 MHz, CDCl3): δ = 1.75 (m, 4H), 2.48 (m, 6H), 8.0
(t, J = 7.2 Hz, 3H). ESIMS: (M+1) 125 m/z [25].
Methyl-3-(pyrrolidin-1-yl)propanoate (Table 3, Entry 7).
1H NMR (300 MHz, CDCl3): δ = 1.75 (m, 4H), 2.48 (m, 6H),
2.76 (t, J =7.2 Hz, 2H), 3.66 (s, 3H). ESIMS: (M+1) 158 m/z
[25].
4-Morpholin-4-yl-butan-2-one (Table 3, Entry 8). 1H
NMR (300 MHz, CDCl3): δ = 3.64 (t, 4H), 2.633-2.538 (m,
4H), 2.404 (t, 4H), 2.154 (s, 3H). ESIMS: (M+1) 158 m/z
[25].
aReaction conditions: aniline (10 mmol), methyl acrylate
(12 mmol), H2O (10 ml), r.t., 3h. bIsolated yield.
3-Morpholinopropanenitrile (Table 3, Entry 9). 1H NMR
(300 MHz, CDCl3): δ = 2.454-2.500 (t, 6H), 2.644 (t, J = 7.2
Hz, 2H), 3.683 (t, J = 4.4 Hz, 4H). ESIMS: (M+1) 141 m/z
[25].
(entries 2-6). The ionic liquids containing the shorter length of
alkyl chain were relatively cheaper. Accordingly, [TMPSA]
[HSO4] was the best catalyst for this reaction among the five
TSILs. The results of the investigation of the amount of
[TMPSA][HSO4] are listed in Table 1 (entries 1, 2, 7 and 8).
The results showed that no products could be detected in the
absence of a catalyst (entry 1), which implied that the catalyst
was absolutely necessary for the aza-Michael reaction. When
the amount of [TMPSA][HSO4] was increased, a ramp in the
yield of the products was clearly observed. The optimum
amount of [TMPSA][HSO4] was 1 mmol (10 mol% based on
aniline) (entry 5). The higher amount of the catalyst did not
improve the result to any greater extent (entry 7). The
chemical industry is under considerable pressure to replace
many of the volatile organic compounds (VOCs) that are
currently used as solvents in organic synthesis. It is thus
obvious that aza-Michael reaction, as a clean and cheap
solvent, should take place in water, for the environmental and
economic reasons.
Methyl-3-morpholinopropanoate (Table 3, Entry 10). 1H
NMR (300 MHz, CDCl3): δ = 2.417-2.404 (m, 4H), 2.480 (t,
J = 7.2 Hz, 2H), 2.659 (t, J = 7.2 Hz, 2H), 3.658-3.678 (m,
7H). ESIMS: (M+1) 174 m/z [25].
3-(Dipropylamino)propanenitrile (Table 3, Entry 11). 1H
NMR (300 MHz, CDCl3): δ = 0.851-0.903 (m, 6H), 1.384-
1.476 (m, 4H), 2.362-2.416 (m, 6H), 2.767 (t, J = 7.2 Hz, 2H).
ESIMS: 153 m/z [25].
Methyl-3-(dipropylamino)propanoate (Table 3, Entry
1
12). H NMR (300 MHz, CDCl3): δ = 0.841 (t, J = 7.2 Hz,
6H), 1.393-1.449 (m, 4H), 2.341 (t, J = 7.2 Hz, 4H), 2.425 (t,
J = 7.2 Hz, 2H), 2.758 (t, J = 7.2 Hz, 2H), 3.646 (s, 3H).
ESIMS: (M+1) 188 m/z [25].
RESULTS AND DISCUSSION
In the initial experiments, we screened different
functionalized ionic liquids for their ability to catalyze the
reactions. Herein, the reaction between aniline and methyl
acrylate was selected as the model. The results are
summarized in Table 1. All the five Brønsted acidic TSILs
proved to be quite active, leading to 85-91% yield of the
desired product within 3 h in the presence of 10% TSILs
Compared with traditional solvents and catalysts, ionic
liquids are easily reused and are far superior to the
conventional solvents and catalysts. When optimizing the
reaction conditions, the recycling performance of [TMPSA]
[HSO4] in the same model as aza-Michael reaction, was
investigated. With the completion of the reaction, the products
778

Aza-Michael Reactions in Water Using Functionalized Ionic Liquids
were separated from the catalytic system by extraction with
ethyl acetate. The aqueous layer (containing the catalyst) was
reused in the subsequent run without further purification. As
shown in Fig. 2, the catalyst was reused at least five times
without any appreciable decrease in its catalytic activity.
With the optimized conditions on hand, we explored the
scope of this method. To a variety of α,β-unsaturated
compounds such as methyl acrylate, acrylonitrile, methyl vinyl
ketone was added a wide range of amines in the presence of 10
mol% [TMPSA][HSO4] at room temperature to give the
corresponding β-amino compounds in impressive yields. The
results are summarized in Table 2. It can be seen that the
reactions catalyzed by [TMPSA][HSO4] proceeded smoothly
to give the corresponding products. Both the primary and
Fig. 2. Reusability of [TMPSA][HSO4].
Table 2. Aza-Michael Reactions Catalyzed by [TMPSA][HSO4] in Water at Room Temperaturea
Entry
Amine
R2
Time (h)
Yield (%)b
1
2
3
4
5
C6H5NH2
COMe
CN
4
4
4
3
3
91
87
88
92
90
C6H5NH2
C6H5NH2
CO2Me
CN
C6H5CH2NH2
C6H5CH2NH2
CO2Me
6
7
CN
2
2
91
90
CO2Me
8
COMe
CN
2
2
2
92
92
90
9
10
CO2Me
11
12
n-Bu2NH
n-Bu2NH
CN
2
2
88
85
CO2Me
aReaction conditions: amine (10 mmol), α,β-unsaturated compound (12 mmol), [TMPSA][HSO4]
(1 mmol), H2O (10 ml), r.t. bIsolated yield.
779

Liu et al.
secondary aliphatic amines underwent the conversion
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smoothly. In comparison with the classical aza-Michael
method, one additional important feature of the present
protocol is that it tolerated variation in all components
simultaneously.
CONCLUSIONS
In conclusion, we have described an efficient protocol for
the aza-Michael reaction catalyzed by the functionalized ionic
liquid, [TMPSA][HSO4], to produce β-amino compounds.
High yields of the products, short reaction times, mild reaction
conditions, simple experimental procedure, the reusability of
the catalysts without obvious loss of the catalytic activity, all
render this protocol superior to the existing methods..
ACKNOWLEDGEMENTS
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Commun. 9 (2008) 1189.
Financial support from National Basic Research Program
of China is gratefully acknowledged.
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(2008) 413.
[24] A. Xin, W. Xin, J. Liu, Z. Ge, T. Cheng, R. Li,
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