A green, ionic liquid and quaternary ammonium salt-catalyzed aza-Michael reaction of α,β-ethylenic compounds with amines in water

Article abstract of DOI:10.1039/b312047c

The first environmentally benign, highly efficient conjugate addition of aliphatic amines to α,β-unsaturated compounds catalysed by simple quaternary ammonium salts and ionic liquids in the green solvent, water, is described.

Full text of DOI:10.1039/b312047c

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L E T T E R
A green, ionic liquid and quaternary ammonium salt-catalyzed
aza-Michael reaction of a,b-ethylenic compounds with amines
in water
Li-Wen Xu, Jing-Wei Li, Shao-Lin Zhou and Chun-Gu Xia*
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical
Physic, Chinese Academy of Sciences, Lanzhou 730000, P R China. E-mail: cgxia@ns.lzb.ac.cn;
Fax: þ86-931-8277088
Received (in London, UK) 29th September 2003, Accepted 27th October 2003
First published as an Advance Article on the web 15th January 2004
The first environmentally benign, highly efficient conjugate addi-
tion of aliphatic amines to a,b-unsaturated compounds catalysed
by simple quaternary ammonium salts and ionic liquids in the
green solvent, water, is described.
reactions in water will contribute to the progress of green
and biomimetic catalysis chemistry. Surprisingly however,
there are few reports on the conjugate addition of amines to
a,b-unsaturated carbonyl compounds in water.
Quaternary ammonium salts and ionic liquids have been
shown to be extraordinarily effective and useful catalysts for
alkylation,15 aldol,16 epoxidation,17 and Michael reactions.18
Room temperature ionic liquids such as bmimBF4 are finding
growing application as alternative reaction media and effective
catalysts for separation and organic transformations. The
desirable advantages of ionic liquids such as the lack of vapour
pressure, wide liquid phase temperature range and thermal sta-
bility have made them exceptional reaction media and environ-
mentally benign solvents. Accordingly, they are emerging as
novel replacements for volatile organic synthesis and transfor-
mations.19 Similarly, a systematic study of the Michael addition
of thiols to a,b-unsaturated ketones in the presence of
quaternary ammonium salts, Cinchona alkaloids and ionic
liquids as a catalyst has been reported.20,21 Although there
have been reported ammonium salt- (1 M TBAF in THF)22
and symmetric pentacyclic guanidine ion-23 promoted aza-
Michael reactions, no reports are available on a quaternary
ammonium salt or ionic liquid-catalysed approach for the
aza-Michael reaction in water.
We tried to explore the catalytic activities of quaternary
ammonium salts in the aza-Michael reaction, so the initial stu-
dies were carried out using benzylamine and ethyl acrylate as a
model system (Scheme 1). To our satisfaction, rapid conver-
sion was observed when the reaction was carried out at room
temperature in water, the total product (a mixture of mono
and di-substituted products, 3b/3a ¼ 1.6/1 to 2.0/1) was
obtained in high yield catalyzed by TBAB (tetrabutyl-
ammonium bromide), TBAI, THAB (tetrahexylammonium
bromide), TEAB (tetraethylammonium bromide), TEAC (tet-
The hydroamination of olefins is a long-standing goal for tran-
sition metal catalysis,1 and the conjugate addition of amines to
carbon–carbon double bonds is an unsolved, synthetically
important problem.2,3 The products of aza-Michael additions,
b-amino carbonyl compounds and derivatives, can be used in
peptide analogues or as precursors to optically active amino
acids, amino alcohols, diamines, and lactams, many of which
serve as powerful antibiotics or other drugs.4 As such, the
development of efficient synthetic methods leading to b-amino
carbonyl compounds and derivatives has attracted much atten-
tion in organic synthesis.5 Among the methods for generating
b-amino carbonyl compounds, the conjugate addition of nitro-
gen nucleophiles to a,b-unsaturated compounds is one of the
most simple and effective methods for preparing b-amino car-
bonyl compounds.6 However, most Lewis acid catalysts are
likely to be poisoned by alkyl- and arylamine regents.7 In the
past few years, a number of alternative procedures have been
developed, and in particular, various transition metal cata-
lysts have been investigated, such as palladium,7 InCl3 ,8
10
CeCl3ꢀ7H2O–NaI,9 Bi(NO)3
and Bi(OTf)3 .11 Although
recent advances have made this route more attractive, the
development of cheaper, simpler, and more efficient metal
catalysts is highly desirable.
In our search for an economical, environmentally friendly
route to b-amino carbonyl compounds, we have recently dis-
covered iron salt catalysts for the addition of carbamates to
enones and the aza-Michael addition of amines or azides to
a,b-unsaturated compounds.12 Herein, we report a new proto-
col that employs catalytic amounts of cheap, readily available
and nontoxic quaternary ammonium salts and ionic liquids as
efficient catalysts in the aza-Michael reaction under mild
reaction conditions. Advantages of the protocol include
high-yielding reactions that can be conducted at ambient
temperature in the environmentally benign solvent, water.
The recent interest in aqueous medium metal-mediated
carbon–carbon and carbon–heteroatom formations led to
the conditions for such reactions.13 The previous findings
prompted us to investigate quaternary ammonium salts and
ionic liquid catalysis in aqueous media in aza-Michael reac-
tions, because reactions in such media have several advan-
tages,14 such as, it is not necessary to dry solvents, and
substrates or hydrated substrates can be directly used without
further drying. Furthermore, the development of organic
raethylammonium
chloride),
benzyltrimethylammonium
chloride, (ꢁ95% yield). We also found that the simple hydro-
philic ionic liquid, bmimBF4 , was effective giving almost quan-
titative yields for the aza-Michael reaction.
A control
Scheme 1
T h i s j o u r n a l i s Q T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 1 8 3 – 1 8 4
183

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well for the development of asymmetric aza-Michael reactions
and industrialization. Current efforts are focused on these
approaches.
experiment was conducted in the absence of catalyst and it was
observed that addition of benzylamine to ethyl acrylate
resulted in the formation of the desired product only in low
yields (20%). Furthermore, traditionally, the aza-Michael reac-
tion can only be performed with special activation, such as
high temperatures,24 high pressures,25 or use of appropriate
catalysts etc.26
Acknowledgements
We then carried out the aza-Michael reaction of aromatic
amines under the same conditions in water, and so aniline
was subjected to this reaction with these quaternary ammo-
nium salts as catalyst and ethyl acrylate as the Michael accep-
tor. This clearly shows that the quaternary ammonium salt is
suitable only to activate aliphatic amines and failed in the case
of aromatic amines for the aza-Michael addition reaction. This
selectivity could be useful in synthetic applications.
Finally, we have utilized a variety of aliphatic amines
successfully with different a,b-unsaturated compounds catalyzed
by the simple hydrophilic ionic liquid, bmimBF4 (Scheme 2).27
Interestingly, all the aliphatic amines gave almost quantitative
yields with a,b-ethylenic compounds (Table 1). The feasibility of
recovery and reuse of the catalyst in the water was also examined
through a series of sequential Michael reactions of benzylamine
with ethyl acrylate as model substrate. In a typical reaction, the
recovered bmimBF4 catalyst was reused five times without loss
of activity, and the product was obtained with similar yields.
In conclusion, we have developed a new methodology for
the conjugate addition of aliphatic amines to a,b-unsaturated
compounds in the green solvent, water. The successful applica-
tion of quaternary ammonium salts and ionic liquids bodes
The authors thank the National Natural Science Foundation
for financial support of the work (29933050).
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Scheme 2
Table 1 Ionic liquid (bmimBF4) catalyzed aza-Michael reaction of
aliphatic amines with a,b-unsaturated compounds in water
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27 General procedure for the aza-Michael addition reactions. A mix-
ture of amine (1.2 mmol), a,b-unsaturated compound (1 mmol)
and quaternary ammonium salt or bmimBF4 (10 mol%) in water
was kept at room temperature under vigorous stirring for 7 h.
After completion of the reaction, the reaction mixture was
extracted with diethyl ether and purified by using column chroma-
tography on silical gel to obtain the pure product. All the known
compounds were fully characterized by GC-MS (Agilent 6890N
GC/5973N MS, HP-5MS) and the usual spectral methods.
Entrya Amine
Unsaturated compound Productb Yield (%)c
1
2
3
4
5
6
7
8
9
M
97
M
95
M/D
M
94/2
96
M/D
M
78/17
97
M/D
M
60/36
98
M
94
10
M
95
a
All the reactions were performed in water and 10 mol% bmimBF4 as
b
catalyst at room temperature for 7 h. M refers to mono-substituted
c
product; D refers to di-substituted product. Isolated yield.
T h i s j o u r n a l i s Q T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
184
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 1 8 3 – 1 8 4