β-Cyclodextrin promoted aza-Michael addition of amines to conjugated alkenes in water

Article abstract of DOI:10.1016/j.tetlet.2006.01.124

Highly efficient and environmentally benign aza-Michael additions of amines to α,β-unsaturated compounds catalyzed by β-cyclodextrin in water to produce the corresponding β-amino compounds in excellent yields under mild conditions are described. β-Cyclodextrin can be recovered and reused in subsequent reactions without loss of activity.

Full text of DOI:10.1016/j.tetlet.2006.01.124

Tetrahedron Letters 47 (2006) 2125–2127
b-Cyclodextrin promoted aza-Michael addition of amines
to conjugated alkenes in waterI
K. Surendra, N. Srilakshmi Krishnaveni, R. Sridhar and K. Rama Rao*
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 December 2005; revised 19 January 2006; accepted 25 January 2006
Available online 10 February 2006
Abstract—Highly efficient and environmentally benign aza-Michael additions of amines to a,b-unsaturated compounds catalyzed by
b-cyclodextrin in water to produce the corresponding b-amino compounds in excellent yields under mild conditions are described.
b-Cyclodextrin can be recovered and reused in subsequent reactions without loss of activity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
SnCl4, TiCl4, InCl3, CeCl3Æ7H2O, Yb(OTf)2, phos-
phine/TMSCl, Cu(OTf)2, Bi(NO)3, Bi(OTf)2, LiClO4,
KF/alumina, etc. have been reported as promoters for
this reaction.7 Heterogeneous solid acids have also been
utilized to promote the reaction.8 Recently, there was
also a report of this reaction conducted in ionic liquids,9
Cu(acac)2/ionic liquid,10 ionic liquid/quaternary ammo-
nium salt in water,11 and boric acid in water.12 These
reactions were unsuccessful in water alone, without
using acid or base catalyst.13,6a,11 Furthermore, acid or
base induced conjugate addition frequently suffers from
polymerization of the starting olefin. However, despite
their remarkable success, the use of heavy metal salts
coupled with hazardous solvents is not desirable from
the ‘green chemistry’ point of view. Ranu14 and Basu15
disclosed solvent-free and catalyst-free conjugate
additions, but even these reactions have the drawback
of elevated temperatures. Most of these procedures are
not successful with arylamines. Thus, the aza-Michael
addition of arylamines needs a more generalized and
environmentally friendly approach.
The aza-Michael reaction is an important reaction in
organic chemistry especially for the synthesis of hetero-
cycles containing a b-amino carbonyl unit.1 b-Amino
carbonyl compounds are versatile synthetic intermedi-
ates for the synthesis of a variety of biologically impor-
tant natural products, antibiotics, b-amino alcohols,
chiral auxiliaries, and other nitrogen-containing com-
pounds.2 These compounds also find wide applications
in fine chemicals and pharmaceuticals.3 This has led to
the development of novel synthetic methodologies for
b-amino carbonyl compounds. The Mannich reaction
is one of the classical methods for the construction of
this functionality,4 however, this reaction can suffer
from drawbacks such as long reaction times, low yields,
and harsh conditions which limit its use in the synthesis
of complex molecules.5
An alternative approach for the synthesis of b-amino
carbonyl compounds is the widely used conjugate addi-
tion of amines to a,b-unsaturated compounds (aza-
Michael reaction) due to its simplicity and atom
economy. The conjugate addition of amines to elec-
tron-deficient alkenes is usually promoted by either
acidic or basic catalysts.6 A variety of reagents such as
With ‘green chemistry’ becoming an important issue in
the 21st century,16 developing the aza-Michael addition
in water with a recyclable catalyst and without the use of
any harmful organic solvents is desirable. Water is a
safe, economical and environmentally benign solvent.17
To achieve this we chose to study supramolecular catal-
ysis involving cyclodextrins. However, there is a report
of aza-Michael addition using water-soluble N-donor
ligands with sodium vinylsulfonates in water.18a Michael
additions of nitroalkanes to methyl vinyl ketone are also
known in the presence of sugars.18b
Keywords: Aza-Michael addition; b-Amino carbonyl compounds;
Amines; Conjugated alkenes; b-Cyclodextrin; Water.
q IICT Communication No. 060108.
Corresponding author. Tel.: +91 40 27193164; fax: +91 40
27160512; e-mail: drkrrao@yahoo.com
*
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.124

2126
K. Surendra et al. / Tetrahedron Letters 47 (2006) 2125–2127
Table 1. Aza-Michael addition of amines to conjugated alkenes in the
presence b-CD in water
Cyclodextrins (CDs) are cyclic oligosaccharides possess-
ing hydrophobic cavities, which bind substrates selec-
tively and catalyze chemical reactions with high
selectivity by involving reversible formation of host–
guest complexes with noncovalent bonding as seen in
enzymes. Complexation depends on the size, shape,
and hydrophobicity of the guest molecule. Thus, by
mimicking biochemical selectivity, which is due to orien-
tation of the substrate by complex formation thus posi-
tioning the substrate for favorable attack, could be
superior to random attack based on the intrinsic reactiv-
ity of the substrate. Our earlier expertise in the field of
biomimetic modeling of organic chemical reactions
involving cyclodextrins19 prompted us to attempt the
aza-Michael addition of various amines to conjugated
alkenes under biomimetic conditions using cyclodextrins
with water as a solvent at room temperature (Scheme 1).
R
R1
R2
R
R1
β-CD/H2O
R2
NH
N
Entry Amine
R2
Time (h) Yielda,b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5NH2
C6H5NH2
C6H5NH2
COMe
CN
CO2Me
COMe
CN
CO2Me
CN
CN
6
8
8
6
6
6
8
8
8
8
8
8
8
90c
88
88
92
90
88
85
86
88
86
85
82
80
p-FC6H4NH2
p-FC6H4NH2
p-F-C6H4NH2
o-ClC6H4NH2
o-MeC6H4NH2
p-MeC6H4NH2
p-MeC6H4NH2
o-MeOC6H4NH2 CO2Me
C6H5CH2NH2
C6H5CH2NH2
CN
CO2Me
CN
CO2Me
The reaction was carried out by the in situ formation of
the b-CD complex of the amine in water followed by the
addition of olefin and stirring for 12 h at room temper-
ature to give the corresponding b-amino carbonyl com-
pounds in impressive yields (Table 1). This is the first
practically feasible aza-Michael addition reaction of
amines with a variety of conjugated alkenes in water.
14
CN
6
85
NH2
15
16
C6H5NHCH3
n-Bu2NH
COMe
CN
8
6
84
82
17
CN
6
86
1
N
H
All the products were characterized by H NMR, IR,
and mass spectrometry. The reaction proceeded effi-
ciently at room temperature without the need of any
acid or base catalyst. This methodology is compatible
with various a,b-unsaturated ketones, esters, and nitriles
and different aliphatic primary and secondary amines,
fluoro-, chloro-, methyl-, and methoxy-, aromatic
amines, and benzyl amines. In the case of conventional
aza-Michael addition, for example, in a report by Xia
et al.11 the yields with primary amines were in the ratio
60:36 corresponding to the product monomer and
dimer, thereby reducing the selectivity, whereas in our
case only the monomer is formed with high selectivity.
In the case of aliphatic amines only 0.1 mmol of
b-CD was used. These reactions do take place with
a-CD, however, b-CD was chosen as the catalyst since
it is inexpensive and easily accessible.
O
18
CN
6
84
N
H
a All the products were characterized by 1H NMR, IR, and mass
spectrometry.
b Isolated yields.
c Catalyst was recovered and reused for three consecutive runs in this
reaction without change in the yield and purity.
view. b-Cyclodextrin, apart from being nontoxic, is also
considered as metabolically safe.20 We have demon-
strated the successful use of b-cyclodextrin in water as
a solvent for the aza-Michael addition of amines to elec-
tron-deficient olefins to produce b-amino compounds in
good yields. The experimental conditions are simple
with ease of recovery and reuse of the catalyst. This
method precludes the use of acid or base catalysts.
The catalytic activity of cyclodextrins for these aza-Mi-
chael additions was established by the fact that no reac-
tion was observed in the absence of cyclodextrin. We
suggest that the mechanism of addition of amines as
b-cyclodextrin complexes to conjugated alkenes is as
follows. Hydrogen bonding of amines with the CD
hydroxyl makes the N–H bond weaker enhancing the
nucleophilicity of nitrogen for addition to electron-
deficient alkenes.
2. General procedure for the aza-Michael addition
b-CD (1 mmol) was dissolved in water (15 ml) by warm-
ing up to 60 °C until a clear solution was formed, then
the amine (1 mmol) dissolved in acetone (1 ml) was
added dropwise and the mixture allowed to cool to
room temperature. The alkene (1.5 mmol) was then
added and the mixture stirred at room temperature until
the reaction was complete (Table 1). The organic mate-
rial was extracted with ethyl acetate. The organic phase
was separated, filtered, and washed with brine. b-CD
was recovered by filtration and reused. 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 (2:8) as the eluent.
These CD-mediated aqueous reactions are very useful
from both economical and environmental points of
R2
R
R
R2
β-CD
H2O/rt
+
NH
N
R1
R1
R = R1 = aryl, benzyl, alkyl
R2 = COMe, CN, CO2Me
Scheme 1.

K. Surendra et al. / Tetrahedron Letters 47 (2006) 2125–2127
2127
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Acknowledgements
We thank the Indo-French Center for the Promotion of
Advanced Research (IFCPAR), for financial support of
this project.
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