Guanidine-based task-specific ionic liquids as catalysts for aza-Michael addition under solvent-free conditions

Article abstract of DOI:10.1007/s11164-011-0296-9

An efficient and facile protocol for aza-Michael addition of aliphatic and aromatic amines to electron-deficit alkenes using [TMG][Lac] as catalyst under solvent-free conditions was established.

Full text of DOI:10.1007/s11164-011-0296-9

Res Chem Intermed (2011) 37:883–890
DOI 10.1007/s11164-011-0296-9
Guanidine-based task-specific ionic liquids as catalysts
for aza-Michael addition under solvent-free conditions
•
•
•
•
Anguo Ying Ming Zheng Haidan Xu Fangli Qiu
Changhua Ge
Received: 14 January 2011 / Accepted: 7 February 2011 / Published online: 22 February 2011
Ó Springer Science+Business Media B.V. 2011
Abstract An efficient and facile protocol for aza-Michael addition of aliphatic and
aromatic amines to electron-deficit alkenes using [TMG][Lac] as catalyst under
solvent-free conditions was established.
Keywords Aza-Michael addition Á Task-specific ionic liquid Á Aliphatic amines Á
Aromatic amines
Introduction
Because of the high atom economic efficiency and mild reaction conditions, aza-
Michael addition has became one of the most versatile methods for the formation of
the C–N bond in modern organic synthesis [1]. The products b-aminocarbonyl
compounds are often used as peptide analogs or precursors of optically active amino
acids, amino alcohols, and lactams [2–4]. Thus, the establishment of an efficient
methodology for the aza-Michael reaction leading to b-aminocarbonyl compounds
has attracted much attention among chemical researchers. In general, this type of
addition needs basic or acidic catalysts, which would lead to by-products or
undesired harmful residues [5–7]. So, a number of alternative procedures have been
reported over the past decade in the presence of some novel catalysts or promoters,
such as LiClO4 [8], FeCl3Á6H2O [9], SmI2 [10], Cu(OTf)2 [11], b-cyclodextrin [12],
bromodimethylsulfonium bromide [13], boric acid in water [14], ZrOCl2Á8H2O on
montmorillonite K10 [15], imidazolium-based polymer supported CuI [16], KF/
Al2O3 [17], [HP(HNCH2CH2)3N]NO3 [18], DBU [19], and so on. Unfortunately,
A. Ying (&) Á H. Xu Á F. Qiu Á C. Ge
School of Pharmaceutical and Chemical Engineering, Taizhou University, Linhai 317000, China
e-mail: agying@tzc.edu.cn; yinganguo@163.com
M. Zheng
Zhejiang Hisoar Pharmaceutical Co. Ltd, Taizhou 318000, People’s Republic of China
123

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A. Ying et al.
many of these approaches often require a large excess of reagents, substrate-
selective for some catalysts, and often the involvement of some toxic solvents like
1,2-dichloroethane or acetonitrile.
Ionic liquid (ILs) have been widely used as reaction media as well as catalysts in
organic chemistry due to their unique properties, good solvating ability, negligible
vapor pressure, variable polarity and ease of work-up [20–22]. Lin et al. reported
that some N-heterocycles can react smoothly with electro-deficient alkenes in a
basic ionic liquid [bmIm]OH without any catalyst [23]. To our disappointment, a
stoichiometric amount of ionic liquid was required, which greatly limited its
application at a large scale, considering the cost of ionic liquid. Thus, a
methodology for aza-Michael addition using a catalytic amount of ionic liquid is
still much needed. 1,1,3,3-Tetramethylguanidine (TMG)-derived ionic liquids
(Scheme 1), prepared by simple neutralization reaction of TMG and acids [24],
have been found to be efficient as catalysts or promoters in aldol reactions [25, 26],
Knoevenagel condensation [27], hydrogenation of olefins [28], N-formylation of
amines [29]. Encouraged by these successful applications and our continuous efforts
to establish facile and green protocol for aza-Michael addition [30, 31], we
attempted to utilize the TMG-based ionic liquids as catalysts for aza-Michael
reaction.
Results and discussion
To optimize the reaction conditions, Michael addition of dibenzylamine to methyl
acrylate was selected as a model reaction. Six TMG-based ionic liquids, [TMG][Tfa],
[TMG][Ac], [TMG][Lac], [TMG][n-Pr], [TMG][n-Bu], and [TMG][i-Bu] were
screened as catalysts for the model reaction. Among the six ionic liquids, [TMG][Lac]
performed better than other five ionic liquids in terms of product yield and reaction rate
(Table 1, entries 1–6). To exhibit the advantage of solvent-free reaction conditions,
organic solvents like acetonitrile, toluene, DMF were also tested (Table 1, entry 3).
Scheme 1 1,1,3,3-
Tetramethylguanidine (TMG)-
derived ionic liquids
N
H
N
X
2
N
[TMG]X
[TMG][Tfa]
[TMG][Ac]
X=CF3COO
X=CH3COO
[TMG][Lac]
X=CH3CH(OH)COO
X=CH3CH2COO
[TMG][n-Pr]
X=CH3CH2CH2COO
[TMG][n-Bu]
[TMG][i-Bu]
X=(CH3)2CH2COO
123

Guanidine-based task-specific ionic liquids
885
Table 1 Solvent-free conjugate addition of dibenzylamine (1 mmol) to methyl acrylate (1.2 mmol) at
room temperature
O
Bn
Bn
O
[TMG][X]
rt
N
+
O
Bn2NH
O
Entry
Catalyst
Amount (mmol)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
a
[TMG][Tfa]
[TMG][Ac]
[TMG][Lac]
[TMG][n-Pr]
[TMG][n-Bu]
[TMG][i-Bu]
–
0.2
0.2
0.2
0.2
0.2
0.2
–
6
4.5
4
53
86
96, 90b, 85c, 87d
4
85
78
73
17
49
72
96
5
5
10
6
[TMG][Lac]
[TMG][Lac]
[TMG][Lac]
0.01
0.1
0.5
4
4
Isolated yield
b
c
d
Using acetonitrile as solvent
Using toluene as solvent
Using DMF as solvent
Although the three organic solvents afforded the good yields, we chose solvent-free
conditions from the economic and environmental viewpoints. The optimal loading of
catalyst was 0.2 equiv., determined from experiments corresponding to entry 3 and
entries 8–10 of Table 1. Finally, a blank experiment was conducted and only 17%
yield was obtained even after 10 h (entry 7), showing the excellent catalytic activity of
the task-specific ionic liquid [TMG][Lac]. As a result, we selected 0.2 equiv. amount
of [TMG][Lac] as catalyst and solvent-free conditions for our further experiments.
With reasonable reaction conditions to hand, various aliphatic amines were
subjected to reactions with methyl acrylate in the presence of 0.2 equiv. amount of
[TMG][Lac] under solvent-free conditions. Morpholine, N-methyl piperazine,
N-ethyl piperazine, piperidine, and pyrazole were all efficient Michael donors,
and good to excellent yields were obtained within short reaction times (Table 2,
entries 1–5). More complicated cyclic amines, like pyrimidine and indole, were also
used as nucleophiles to afford the corresponding Michael adducts in 87–96% yields
(Table 2, entries 7 and 8). It is worthwhile to note that no N-3 addition reaction
(pyrimidines as donors) and Friedel–Crafts alkylation at the C3 position on the
indole ring was observed, which exhibited excellent regioselectivity when using
ionic liquid [TMG][Lac] as catalyst. However, relatively lower yield was obtained
and some di-substituted product was detected when a primary amine was tested as
Michael donor (entry 6).
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A. Ying et al.
Table 2 Results of aza-Michael addition of various aliphatic amines to electron-deficit alkenes using
[TMG][Lac] as catalyst under solvent-free conditions
Aliphatic
amines
Reaction
time (h)
Entry
Michael acceptor
Product
Yielda
95
O
O
O
O
1
2
Morpholine
2
2
O
N
O
O
N-methyl
O
O
91
N
N
piperazine
O
N-ethyl
O
O
3
4
2
2
88
93
N
N
O
piperazine
O
O
O
Piperidine
Pyrazole
N
O
O
O
O
5
6
3
3
N
95
78
O
O
N
O
O
O
BnNH2
BnNH
O
N
O
N
H
O
O
N
H
7
8
3
90
96
O
O
O
N
H
O
O
O
N
20
O
N
H
O
O
O
9
Morpholine
Morpholine
Morpholine
3
5
5
92
93
88
OEt
O
O
N
OEt
O
O
10
11
OBu-n
N
OBu-n
O
O
OMe
OMe
O
N
O
O
12b
13
Morpholine
Morpholine
Morpholine
24
3
70
92
95
N
Ph
O
OEt
Ph
OEt
O
N
CN
CN
O
O
14
3
O
N
NH2
NH2
Reactions were carried out on 1.0 mmol scale of substrate with 1.2 equiv. of a,b-unsaturated compounds
in the presence of 0.2 equiv. ionic liquid at room temperature
a
Yields of isolated products
b
Reaction conducted at 60 °C
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Guanidine-based task-specific ionic liquids
887
In order to extend the scope of this methodology, various other vinyl esters,
acrylonitrile and acrylamide were tested under the same conditions. The results
are shown in Table 2. Acrylonitrile and acrylamide are effective Michael
acceptors and satisfactory product yield was achieved (entries 13 and 14).
Among the acrylate esters, the increasing chain of acrylates prolonged the
reaction time (entries 1, 9 and 10), similar to the phenomenon observed by Lin
and co-workers [23]. a-Methyl substituted ester and b-benzene substituted ester,
ethyl cinnamate, were also tested as acceptors. Both acceptors showed relatively
lower reactivity (entries 11 and 12). Especially the ethyl cinnamate, because of
its strong steric hindrance, gave a yield of 70% even after 1 day of reaction at
60 °C.
Because of the inertness of arylamines compared with aliphatic amines, most
reported methods are not successful with aromatic amines. Duan [33] and Bhanage
[34], respectively, demonstrated that CAN (ceric ammonium nitrate) and
Y(NO3)3Á6H2O are effective catalysts for aza-Michael addition with aromatic
amines as donors. However, both procedures utilized transition metal catalysts,
which limited their applications from an economic and environmental
acceptability.
Thus, aromatic amines as Michael donors were also conducted under the same
conditions. a,b-Unsaturated ketones like ethyl vinyl ketone, 2-cyclohexen-1-one,
2-cyclopenten-1-one and chalcone were investigated as Michael acceptors to react
with aromatic amines. An electron-donating group at the aromatic ring can facilitate
the Michael reaction (Table 3, entries 1–3) and electron-withdrawing substituent
such as NO2 would dramatically decrease the nucleophilicity of aromatic amine
(Table 3, entry 4). To our delight, 2-cyclohexen-1-one and chalcone were effective
Michael acceptors to react with various arylamines, achieving good to excellent
isolated yields (Table 3, entries 5–8, and 12 and 13). However, 2-cyclopenten-1-one
showed relatively lower reactivity (entries 9–11). Unfortunately, the addition of
aniline to methyl acrylate or acrylonitrile was rather sluggish furnishing only 23 and
9%, respectively, even if the time was prolonged to 1 day (Table 3, entries 14 and
15). It is worth mentioning that aza-Michael reactions using aromatic amines as
donors in the presence of a catalytic amount of [TMG][Lac] performed much better
than that promoted by [bmIm]OH (1-Butyl-3-methylimidazolium Hydroxide)
(Table 3 entries 2, 3, and 8).
Finally, the recyclability of the ionic liquid [TMG][Lac] was studied using the
reaction of dibenzylamine and methyl acrylate as a model. The results are shown
in Table 4. Upon the completion of the reaction, the reaction solution was
extracted with ethyl acetate and purified by flash chromatography. The addition
product was identified by 1H NMR, 13C NMR. The residual ionic liquid was
washed with ethyl ether, dried under vacuum at 60 °C for 2 h and reused for
subsequent reactions. As shown in Table 4, the recovered ionic liquid could be
used six times without obvious loss of catalytic activity of the ionic liquid. The
1
ionic liquid [DBU][Lac] used for eight runs remained intact, judging from its H
NMR spectrum.
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Table 3 [TMG][Lac] catalyzed aza-Michael reactions of various aromatic amines with electron-deficit
alkenes at room temperature
O
O
R2
[TMG][Lac], 0.2 equiv
R2
NH2
+
solvent-free, rt
R1
N
H
R3
R1
R3
Entry
R1
R2
R3
Time (h)
GC yield (%)
Isolated yield (%)
1
2
3
4
5
4-MeO
4-Me
4-Cl
Et
Et
Et
Et
H
H
H
H
0.5
0.5/8b
1/8b
2
100
96
92
92
NR
80
100/98b
98/97b
NR
2-NO2
4-H
4
88
CH2
CH2
CH2
CH2
CH2
CH2
CH2
3
3
3
3
6
4-Cl
5
90
79
78
90
66
70
76
7
2-Me
4-Me
2-Cl
10
87
8
3/24b
12
98/71b
73
9a
10a
11a
2
2-Br
2-Me
12
78
2
2
12
84
12c
13c
14
4-H
Ph
Ph
Ph
Ph
8
92
88
23
85
83
12
4-MeO
4-H
8
24
O
O
15
4-H
24
9
–
CN
Reaction conditions: aromatic amines (1 mmol), electron-deficit alkenes (1.3 mmol), [TMG][Lac]
(20 mol %), solvent-free conditions, rt
a
Reaction conducted at 50 °C
Results obtained from ref. 32, reaction conditions: [bmIm]OH (0.3 equiv.), aromatic amines
b
(1.0 mmol), acceptors (1.5 mmol), rt, solvent-free
c
1.0 mL of [TMG][Lac] required for dissolving chalcone and aromatic amines
Conclusion
In conclusion, we have developed a green and efficient protocol for aza-Michael
addition of aliphatic and aromatic amines to electron-deficient olefins in the
presence of catalytic amounts of task-specific ionic liquid [TMG][Lac] under
123

Guanidine-based task-specific ionic liquids
889
Table 4 Recycling and reusability of the catalyst [TMG][Lac] in the Reaction between dibenzylamine
and methyl acrylate
Cycle
t (h)
Yielda (%)
1
2
3
4
5
6
4
4
4
4
5
5
96
93
94
90
93
92
Reaction conditions: 1 mmol of dibenzylamine, 1 mmol of methyl acrylate, 0.2 mmol of [TMG][Lac]
without solvents at rt
a
Isolated yields
solvent-free conditions. The advantages of a wide range of Michael donors
(aliphatic and aromatic amines), ready work-up, and excellent recyclability of ionic
liquid means this methodology has potential for industrial applications.
Experimental
All chemicals were purchased from Aldrich or Fluka. 1H and 13C NMR were
recorded on a Bruker Avance DPX 400 spectrometer at 400 and 100 MHz in CDCl3
and D2O, respectively. Chemical shifts were reported in parts per million (d),
relative to the internal standard of tetramethylsilane (TMS). All reactions were
monitored by thin layer chromatography (TLC). Flash chromatography was
performed on silica gel (100–200 mesh). All Michael adducts were purified
through column chromatography and were characterized by NMR analysis.
The preparation of TMG-based ionic liquids was the same as the method
depicted in [7].
General procedure for aza-Michael reaction of aliphatic amines
with electron-deficient olefins
Ionic liquid [TMG][Lac] (0.2 mmol) was added to a mixture of the amine (1 mmol)
and Michael acceptor (1 mmol or 1.2 mmol) in 10-mL flask equipped with a
magnetic stirrer. The reaction mixture was stirred at room temperature for the
desired time until the disappearance of starting material monitored by TLC. Upon
completion of the reaction, the mixture was extracted with ethyl acetate several
times. The combined organic phase was concentrated through vacuum evaporation
and the resulting crude product was purified by silica column chromatography to
give the desired product. These products are in good agreement with spectra data in
the literature. The ionic liquid [DBU][Lac] after extraction was dried in vacuo at
60 °C for 5 h. The recovered ionic liquid was then reused in subsequent reactions.
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