Aza-Michael addition of aliphatic or aromatic amines to α,β-unsaturated compounds catalyzed by a DBU-derived ionic liquid under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2009.01.123

A task-specific ionic liquid, 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate has been successfully used as a catalyst for aza-conjugate addition of aliphatic or aromatic amines to various electron deficient alkenes under solvent-free conditions and at room temperature. The catalyst can be reused for six times without noticeable loss of activity.

Full text of DOI:10.1016/j.tetlet.2009.01.123

Tetrahedron Letters 50 (2009) 1653–1657
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aza-Michael addition of aliphatic or aromatic amines to a,b-unsaturated
compounds catalyzed by a DBU-derived ionic liquid under solvent-free
conditions
b,
An-Guo Ying a,b, Luo Liu a,b, Guo-Feng Wu a,b, Gang Chen b, Xin-Zhi Chen a, , Wei-Dong Ye
*
*
a Department of Chemical Engineering, Zhejiang University, Hangzhou 310027, PR China
b Zhejiang Medicine Co.,LTD. Xinchang Pharmaceuticals Factory, Xinchang 312500, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A task-specific ionic liquid, 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate has been successfully used
as a catalyst for aza-conjugate addition of aliphatic or aromatic amines to various electron deficient
alkenes under solvent-free conditions and at room temperature. The catalyst can be reused for six times
without noticeable loss of activity.
Received 20 November 2008
Revised 20 January 2009
Accepted 24 January 2009
Available online 29 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Ionic liquid
Aza-Michael addition
Aza-conjugate addition
Aliphatic amines
Aromatic amines
Carbon–nitrogen bond forming reaction is one of the most
important methodologies in synthetic organic chemistry for prep-
aration of b-aminocarbonyl compounds, which not only constitute
components of biologically active natural products but also serve
as key intermediates for the synthesis of b-aminoalcohols, b-lac-
tams, and b-amino acids.1 Mannich reaction of enolates with imi-
nes provides a classic route for the construction of b-amino
carbonyl compounds.2 However, this type of reaction often re-
quires harsh reaction conditions and long reaction times. In con-
trast to the Mannich reaction, the aza-Michael addition of amines
to electron-deficient alkenes has attracted considerable attention
as an alternative protocol for C–N bond formation due to its atom
economy and operational simplicity. Most aza-Michael reactions
are usually carried out under a strong base or acid, which would
lead to by-products or undesired harmful residues. Thus, milder
Lewis acidic catalysts such as LiClO4,3a Yb(OTf3),3b,c Bi(NO3),3d
KF/Al2O3,4f and [HP(HNCH2CH2)3 N]NO34g. However, many of the
above methods suffered from some drawbacks, such as the
requirement for a large excess of reagents, substrate-selective for
some catalysts, and the involvement of some toxic solvents such
as 1,2-dichloroethane or acetonitrile. Ionic liquids5 as catalysts
or/and medium in reactions have been widely used in organic
transformations due to their advantages such as good solvating
ability, negligible vapor pressure, variable polarity and ease of
work-up. However, the related report about basic ionic liquid as
catalyst as well as reaction medium for organic condensation is rel-
atively rare6 and in most cases, large amount of ionic liquid was re-
quired as reaction solvent. Considering the relatively high cost of
ionic liquid, the development of a novel, efficient, and basic ionic
liquid used in catalytic amount loading for aza-conjugate reaction
is highly desirable.
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was found to be far
superior to other tertiary amines and its nucleophilic nature as
well as its utility in organic synthesis has also been investigated
over the past decades.7 Recently, Kim et al. have successfully intro-
duced DBU as promoter for aza-Michael addition.8 However, this
procedure suffered from hardly recyclability and unpleasant flavor
of DBU, which went against the promising viewpoint of green
chemistry in modern chemical research. Thus, considering both
DBU’s excellent catalytic properties and advantages of ionic liq-
uids, we developed a new basic task-specified ionic liquid, 1,8-
diazabicyclo[5.4.0]-undec-7-en-8-ium acetate ([DBU][Ac]) through
3i
FeCl3Á6H2O,3e CeCl3Á7H2O,3f InCl3,3g SmI2,3h and Cu(OTf)2 were
employed in the Michael protocol. Recently, some novel reagents
that are used as a catalyst or promoter in conjugate addition have
also been reported, including b-cyclodextrin,4a bromodimethy-
lsulfonium bromide,4b boric acid in water,4c ZrOCl2Á8H2O on mont-
morillonite K10,4d imidazolium-based polymer supported CuI,4e
* Corresponding authors. Tel.: +86 571 87951615; fax: +86 571 87951742.
E-mail addresses: xzchen@zju.edu.cn (X.-Z. Chen), yewd@xcpharma.com (W.-D.
Ye).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.123

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A.-G. Ying et al. / Tetrahedron Letters 50 (2009) 1653–1657
line, piperidine and pyarzole in the presence of ionic liquid
H
N
N
[DBU][Ac] reacted faster and afforded higher or comparable yields
compared with those mediated by DBU (entries 1, 4, and 5). It is of
interest to note that when imidazole as a Michael donor was trea-
ted with methyl acrylate, imidazole disappeared in 2 h and no Mi-
chael product was detected. Judging from the disappearance of
OCH3 group in the 1H NMR spectrum of the product, acylation
product was formed instead, which may provide a possible method
for acylation reaction of Michael acceptors (entry 7). However, 2-
isopropylimidazole could react with methyl acrylate and 93% of
Michael adduct was provided in 10 h (entry 6). It is suggested that
steric bulkiness of reagent can assist in the formation of Michael
adduct and is detrimental to acylation process. Benzylamine was
also treated with methyl acrylate and 20% yield of di-substituted
product was formed which was the same with the result catalyzed
by DBU8 (entry 8).
CH3COOH
+
CH3COO
N
N
DBU
[DBU][Ac]
Scheme 1. Synthesis of ionic liquid [DBU][Ac].
the neutralization reaction of DBU and acetic acid (Scheme 1).9 The
DBU salt is the ionic liquid with weakly basicity at room tempera-
ture. The main aim of the work was to examine if the solventless
addition of amines to electron-deficient olefins can proceed
smoothly with [DBU][Ac] as catalyst.
For the comparison with DBU as promoter for aza-Michael addi-
tion reported by Kim et al.,8 50 mol % of the ionic liquid [DBU][Ac]
was employed for the model reaction between dibenzylamine and
methyl acrylate in acetonitrile at ambient temperature. The reac-
tion catalyzed by [DBU][Ac] is slightly faster than that promoted
by its parent base DBU (Table 1, entries 1 and 2), indicating the
rationality of [DBU][Ac] as catalyst for the reaction. Other solvents
such as methanol, toluene, and dichloromethane were also tested
and they were all effective reaction mediums for the model reac-
tion (entries 3–5). However, because of the toxicity of organic sol-
vents and our pursuit for the establishment of the environmentally
benign process for organic transformations, we attempted to con-
duct the reaction of dibenzylamine and methyl acrylate under sol-
vent-free conditions and to our delight, the comparable yield (96%)
was obtained within 4.5 h (entry 6). Thus, we chose solvent-free
conditions for further studies. When the amount of catalyst
[DBU][Ac] was reduced to 0.3 equiv, almost no decrease in the
yield was observed (entry 7). However, the yields decreased obvi-
ously when the amount was further reduced to 0.01 equiv (entries
8 and 9). As a result, we adopted 0.3 equiv of [DBU][Ac] under sol-
vent-free conditions at room temperature for the following
examinations.
With the efficient catalytic system in hand, we investigated the
suitability of a wide range of nitrogen nucleophiles for the
[DBU][Ac]-catalyzed aza-Michael reactions using methyl acrylate
as the substrate. The aliphatic secondary amines such as morpho-
line, piperidine, 1-methylpiperazine, 1-ethylpiperazine and pyra-
zole all underwent conjugate reactions with methyl acrylate
favorably, and excellent yields of Michael adducts were obtained
at ambient temperature under solvent-free conditions within short
reaction times (Table 2, entries 1–4). Like dibenzylamine, morpho-
Having obtained satisfactory results with methyl acrylate, we
then studied the solvent-free reaction of morpholine with other
a,b-unsaturated compounds under the same conditions. Other var-
ious vinyl esters, acrylonitrile, and acrylamide were effective sub-
strates to give the desired products in good to excellent yields
(Table 2, entries 9–11, 13–14). Among the acrylate esters, the
increasing chain of acrylates would lead to decreased reactivity
(entries 9 and 10), as the result reported by Lin et al.6c
a-Methyl-
substituted ester and b-phenyl-substituted ester, ethyl cinnamate
were also tested as acceptors, respectively, and were found that
the former gave the rational yield smoothly and the latter exhib-
ited relatively inert reaction activity due to the strong steric hin-
drance of phenyl group at b-position (entries 11 and 12).
Relatively few reports about aza-Michael reaction involving
aromatic amines were published due to the weak nucleophilicities
of arylamines.3a,4d,11 Thus, the task-specific ionic liquid [DBU][Ac]
was used as a promoter for conjugate addition of aromatic amines
to Michael acceptors under mild conditions. Cyclic ketones such as
2-cyclohexen-1-one and 2-cyclopenten-1-one were found to be
suitable substrates to react smoothly with various aromatic amines
and good to excellent yields were obtained (Table 3, entries 1–4).
However, using [bmim]OH as catalyst, the reaction of p-toluidine
with 2-cyclohexen-1-one gave lower yield than that catalyzed by
[DBU][Ac] , even though the reaction time was prolonged to 24 h
(entry 3). Chalcone was also treated as an acceptor to react with
aromatic amines to afford good yields (entries 5 and 6), while no
reaction occurred in the presence of [bmim]OH.11 In addition, reac-
tion of methyl acrylate with p-methoxyaniline proceeded effi-
ciently with moderate heating (entry 7). All cases shown in Table
3 clearly indicate that the ionic liquid [DBU][Ac] has the excellent
catalytic activity for the aza-Michael addition with aromatic
amines as Michael donors.
Table 1
Solvent-free conjugate addition of dibenzylamine (1 mmol) to methyl acrylate
(1.3 mmol)
In order to demonstrate the industrial applicability of this
methodology, the solvent-free aza-Michael condensation of piper-
idine and methyl acrylate was carried out on a larger scale
(100 mmol). The reaction was completed in 2 h. An excellent yield
of 94% was obtained. On the same scale, the recyclability of the cat-
alytic system was investigated using the same reaction as the mod-
el reaction. Upon the completion of the reaction, the product was
isolated by vacuum distillation, while the residue ionic liquid
was dried to remove water at 60 °C under vacuum for 5 h. The
recovered ionic liquid was reused in subsequent reactions. As
shown in Figure 1, the ionic liquid [DBU][Ac] could be recycled
six times without considerable decrease of activity, and the used
ionic liquid remained intact (1H NMR).
Entry
Solvent
Catalyst amount (mmol)
Time (h)
Yielda (%)
1b
2
3
4
5
6
7
8
9
Acetonitrile
Acetonitrile
Methanol
0.5
0.5
0.5
0.5
0.5
0.5
0.3
0.1
0.01
6
5
5
5
95
94
86
89
90
96
95
72
43
Toluene
Dichloromethane
Solvent-free
Solvent-free
Solvent-free
Solvent-free
5
4.5
4.5
4.5
4.5
O
Bn
O
[DBU][Ac]
Although [DBU][Ac] has weaker basicity than DBU, its catalytic
property for aza-Michael reaction is better than that for DBU. The
reason, we speculated, is that amines exhibited higher nucleophi-
licity in the presence of ionic liquids than in organic solvents.12,6c
The reason for the better performance of [DBU][Ac] in conjugate
N
O
+
Bn2NH
rt
O
Bn
a
Isolated yields.
Ref. 8: using DBU as catalyst.
b

A.-G. Ying et al. / Tetrahedron Letters 50 (2009) 1653–1657
1655
Table 2
Results of aza-Michael addition of various amines to electron-deficit alkenes using [DBU][Ac] as catalyst under solvent-free conditionsa
Entry10
Nitrogen nucleophile
Michael acceptor
Reaction time/Ref. 8 (h)
Product
Yieldb/Ref. 8 (%)
93/90
O
O
O
O
1
1.5/4
O
N
O
N
H
N
O
O
O
2
3
4
5
6
7
1.5
90
N
N
N
O
N
H
N
O
O
O
1.5
87
N
O
N
H
O
O
O
1.5/4
5/14
10
92/88
93/95
93
N
O
N
H
O
O
O
O
N
N
N
O
O
N
H
N
O
O
N
N
N
H
N
N
O
N
O
O
2/14
O
0/95
N
H
O
O
O
8
9
BnNH2
3/3
3
80/75
90
O
BnNH
O
O
O
OEt
O
O
O
N
OEt
N
H
O
O
O
10
11
12
13
5
93
90
65
88
93
OBu-n
OMe
N
OBu-
n
N
H
O
O
O
4
OMe
O
N
N
H
O
O
15
3
N
Ph
OEt
O
N
H
Ph
OEt
O
CN
O
N
CN
N
H
O
O
O
14
3
N
O
NH2
NH2
N
H
a
Reactions were carried out on 1.0 mmol scale of substrate with 1.3 equiv of
Yields of isolated products.
a,b-unsaturated compounds in the presence of 0.3 equiv ionic liquid at room temperature.
b
reaction with aromatic amines than that catalyzed by imidazolium
ionic liquid [bmim]OH is not very clear, which needs further de-
tailed study.
In conclusion, we have developed a mild, simple, and efficient
methodology using a new basic ionic liquid [DBU][Ac] as a catalyst
for the conjugate addition of various aliphatic or aromatic amines

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A.-G. Ying et al. / Tetrahedron Letters 50 (2009) 1653–1657
Table 3
[DBU][Ac] catalyzed aza-Michael reactions of various aromatic amines with
a
,b-unsaturated compounds at room temperaturea
O
O
R2
[DBU][Ac], 0.3 equiv
solvent-free, rt
R2
NH2
+
R1
N
H
R3
R1
R3
Entry
R1
R2
R3
Time (h)
Yieldb (%)
CH2
CH2
CH2
CH2
1
H
5
89
3
3
2
4-Cl
6
90
3
4-Me
2-Cl
5/24d
8
85/71d
73
3
4c
2
5e
6e
7c
a
4-MeO
4-Cl
Ph
Ph
Ph
H
8
88
75
80
Ph
12
6
4-MeO
MeO
Reaction conditions: aromatic amines (1 mmol), Michael acceptors (1.5 mmol), 0.3 mol % [DBU][Ac], neat conditions, rt.
GC yield for comparing with Ref. 11.
Reactions at 60 °C.
Results obtained in Ref. 11.
1.0 Equiv of [DBU][Ac] required for dissolving chalcone and aromatic amines.
b
c
d
e
References and notes
100
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1994, 827; (d) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109; (e) Xu, L.
W.; Li, L.; Xia, C. G. Helv. Chim. Acta 2004, 87, 1522; (f) Bartoli, G.; Bosco, M.;
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(g) Loh, T. P.; Wei, L. L. Synlett 1998, 975; (h) Reboule, I.; Gil, R.; Collin, J.
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X. X. Synlett 2003, 2425.
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60
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47, 2125; (b) Khan, A. T.; Parvin, T.; Gazi, S.; Choudhury, L. H. Tetrahedron Lett.
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Abdollahifar, A.; Khalili, B. Tetrahedron 2006, 62, 672; (e) Alleti, R.; Woon, S.
O.; Perambuduru, M.; Ramena, C. V.; Reddy, V. P. Tetrahedron Lett. 2008, 49,
3466; (f) Kantam, M. L.; Roy, M.; Roy, S.; Sreedhar, B.; De, R. L. Catal. Commun.
2008, 9, 2226; (g) Yang, L.; Xu, L. W.; Xia, C. G. Tetrahedron Lett. 2005, 46, 3279.
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W. S.; Chan, T. H. Acc. Chem. Res. 2006, 39, 897. and references there cited in; (c)
Paczal, A.; Kotschy, A. Monatsh. Chem. 2007, 138, 1115. and references there
cited in; (d) Ying, A. G.; Chen, X. Z.; Ye, W. D.; Zhang, D. F.; Liu, L.; Chen, J. H.
Prog. Chem. 2008, 20, 1642. and references there cited in.
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W. B.; Qian, C.; Lin, X. F. J. Org. Chem. 2006, 71, 3991; (c) Xu, J. M.; Qian, C.; Liu,
B. K.; Wu, Q.; Lin, X. F. Tetrahedron 2007, 63, 986; (d) Xu, J. M.; Wu, Q.; Zhang, Q.
Y.; Lin, X. F. Eur. J. Org. Chem. 2007, 1798; (e) Ranu, B. C.; Adak, L.; Banerjee, S.
Tetrahedron Lett. 2008, 49, 4613; (f) Yue, C. B.; Mao, A. Q.; Wei, Y. Y.; Lü, M. J.
Catal. Commun. 2008, 9, 1571.
Runs
Figure 1. Reuse of ionic liquid for aza-Michael reaction between piperidine
(100 mmol) and methyl acrylate under solvent-free conditions.
to a variety of structurally diverse
a,b-unsaturated compounds.
The reactions were conducted at room temperature under sol-
vent-free conditions and in most cases, good to excellent yields
of the desired 1,4-adducts were obtained. Also, the protocol could
be scaled up to 100 mmol and proceeded smoothly showing the
potential for industrial application. Upon completion of the reac-
tion, the catalyst [DBU][Ac] could be recovered by drying under
vacuum at 60 °C for 5 h and reused for six times without significant
loss of the activity. The applicability of the task-specific ionic liquid
[DBU][Ac] in other fields of organic transformation is underway in
our laboratory.
7. (a) Reed, R.; Réau, R.; Dahan, F.; Bertrand, G. Angew. Chem., Int. Ed. 1993, 32,
399; (b) Ghosh, N. Synlett 2004, 574; (c) Baidya, M.; Mayr, H. Chem. Commun.
2008, 1792; (d) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311; (e)
Ghosh, N. Synlett 2004, 574. and references cited in.
8. Yeom, C. E.; Kim, M. J.; Kim, M. B. Tetrahedron 2007, 63, 904.
9. General procedure for preparation of ionic liquid [DBU][Ac]: To a 50 mL three-
necked flask was added 6 mmol of DBU. Acetic acid (6 mmol) was then added
dropwise at the temperature of 65 °C cooled by ice bath. After dropwise
addition, the ice bath was removed and the reaction mixture was stirred at
room temperature for 24 h. The oil residue was dried in vacuo at 60 °C for 24 h
to afford [DBU][Ac] as a light yellow, viscous liquid. 1H NMR (400 MHz, D2O)
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China for financial support (No. 20776127) and by the
National Key Technology R&D Program (No. 2007BAI34B07).

A.-G. Ying et al. / Tetrahedron Letters 50 (2009) 1653–1657
1657
(ppm): 3.50–3.48 (m, 2H, 9-H), 3.44–3.41 (m, 2H, 11-H), 3.23–3.20 (m, 2H, 2-
H), 2.75–2.72 (m, 2H, 6-H), 1.89–1.83 (m, 2H, 10-H), 1.68–1.51 (m, 6H, 3-H, 4-
H, 5-H), 1.63 (s, 3H, CH3); 13C NMR (100 MHz, D2O) (ppm): 174.4, 165.2, 53.1,
47.9, 37.8, 31.2, 28.6, 26.5, 25.1, 24.0, 19.5. Anal. Calcd for [DBU][Ac]: C, 62.10;
H, 9.55; N, 13.11; O, 15.24. Found: C, 62.23; H, 9.50; N, 13.20; O, 15.07.
extracted with ethyl acetate for 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 of literatures.
The ionic liquid [DBU][Ac] after extraction was dried in vacuo at 60 °C for 5 h.
The recovered ionic liquid was then reused in subsequent reactions.
11. Yang, L.; Xu, L. W.; Zhou, W.; Li, L.; Xia, C. G. Tetrahedron Lett. 2006, 47, 7723.
12. (a) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc. 2002, 124, 10278; (b)
Crowhurst, L.; Lancaster, N. L.; Arlandis, J. M. P.; Welton, T. J. Am. Chem. Soc.
2004, 126, 11549; (c) Meciarova, M.; Toma, S.; Kotrusz, P. Org. Biomol. Chem.
2006, 4, 1420.
10. General procedure for aza-Michael reaction of aliphatic amines with
a,b-
unsaturated compounds: To a mixture of the aliphatic amine (1 mmol) and
Michael acceptor (1.3 mmol) in 10 mL flask equipped with a magnetic stirrer
was added ionic liquid [DBU][Ac] (0.3 equiv). The reaction mixture was stirred
at ambient temperature for several hours until the disappearance of starting
material monitored by TLC. Upon completion of the reaction, the mixture was