Significant rate acceleration of the aza-Michael reaction in water

Article abstract of DOI:10.1016/j.tetlet.2006.10.142

The addition of amines to conjugated alkenes has been carried out in water at room temperature very efficiently without any catalyst. Significant rate acceleration of this reaction is observed in water compared to organic solvents.

Full text of DOI:10.1016/j.tetlet.2006.10.142

Tetrahedron Letters 48 (2007) 141–143
Significant rate acceleration of the aza-Michael reaction in water
*
Brindaban C. Ranu and Subhash Banerjee
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 28 August 2006; revised 16 October 2006; accepted 26 October 2006
Available online 21 November 2006
Abstract—The addition of amines to conjugated alkenes has been carried out in water at room temperature very efficiently without
any catalyst. Significant rate acceleration of this reaction is observed in water compared to organic solvents.
ꢀ
2006 Elsevier Ltd. All rights reserved.
Organic reactions in water have received increased
attention primarily because of their environmental
acceptability, abundance and low cost. However, water
procedure for the aza-Michael addition in water without
any catalyst or organic solvent (Scheme 1).
1
also exhibits unique reactivity and selectivity that cannot
be attained in conventional organic solvents. Thus, the
development of efficient procedures for useful chemical
transformations in water without any catalyst is highly
appreciated.
The experimental procedure is very simple.13 Several pri-
mary and secondary amines underwent smooth addi-
tions with a,b-unsaturated carboxylic esters, ketones,
nitriles and amides in water at room temperature. The
results are summarized in Table 1. Aromatic amines
and tertiary amines did not undergo any reaction using
this procedure. Addition to a,b-unsaturated aldehydes
was also unsuccessful. Primary amines produced only
monoaddition products and no bis-addition product
was isolated in any reaction unlike several existing meth-
2
The aza-Michael addition, that is, addition of an amine
to an electron deficient alkene, is of much synthetic
importance since it provides an easy route to b-amino
3
carbonyl derivatives which are versatile intermediates
5
a,11a
for the synthesis of a variety of biologically important
ods,
which led to mixtures of mono- and bis-addi-
natural products, antibiotics, b-amino alcohols and
other nitrogen-containing molecules. Thus, a number
tion products.
4
of procedures have been developed for aza-Michael
addition leading to b-amino carbonyl compounds. This
reaction is usually carried out in the presence of an acid
or a base. A variety of Lewis acids such as transition
In general, the reactions were very clean and high yield-
ing. All the reactions in water were very fast (20–50 min)
compared to the reactions in organic solvents using
catalysts which were reported to take longer periods
5
6
7
8
5–11
metal and lanthanide halides, triflates or silica gel
(2–8 h).
The products were characterized from their
1
13
have been employed. Heterogeneous solid salts,
spectroscopic (IR, H and C NMR) data. No catalyst
or co-organic solvent was required. It was observed that
the reactions in common organic solvents such as THF
or methylene chloride under identical experimental con-
ditions were very slow and proceeded only partially even
after 10–15 h.
9
Cu(acac) /ionic liquid, quaternary ammonium salt/
2
1
0
11a
ionic liquid/H O, boric acid in H O, b-cyclodextrin
2
2
1
1b
in H O
have also been used for this transformation.
2
In addition, solvent-free and catalyst-free procedures
1
2
at elevated temperature have been demonstrated.
However, despite satisfactory results, many of these
methods used heavy metal salts and hazardous organic
solvents, which is not desirable from a green chemistry
point of view. We report here a very simple and greener
R2
R1
H2O
rt
R2
X
NH
N
X
R1
Keywords: Aza-Michael reaction; b-Amino carbonyl compound;
Amine; Conjugated alkene; Water.
R , R2 = H/alkyl; X = CO R, COR, CONH , CN
1
2 2
*
Corresponding author. Tel.: +91 33 24734971; fax: +91 33
4732805; e-mail: ocbcr@iacs.res.in
2
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.142

142
B. C. Ranu, S. Banerjee / Tetrahedron Letters 48 (2007) 141–143
Table 1. Aza-Michael reaction in water
Table 1 (continued)
a
R2
Entry Amine
Michael
acceptor
Time Yield
(min) (%)
Ref.
11b
R1
H2O
X
R2
NH
N
O
X
R1
1
9
CN
CN
30
35
90
a
Entry Amine
Michael
acceptor
Time
(min)
Yield
(%)
Ref.
N
H
1
2
3
4
5
n-BuNH
2
CO2Me
30
30
30
50
35
90
92
85
85
85
11a
11a
11a
11a
14
2
2
0
1
Ph N
NH
85
00
15
—
n-BuNH
2
CN
NH2
PhCH
2
2
NH
2
2
CN
CO2Me 24 h
PhCH
NH
CONH2
a
Yields refer to those of pure isolated products characterized by
1
13
c-HexNH
2
CO Me
2
spectroscopic data (IR, H, C NMR).
Et
6
7
8
9
CO2Me
30
30
50
35
86
88
85
85
11a
8b
NH
A comparison of a few reactions in organic solvents with
those in water is reported in Table 2. The amount of
water used in the reaction did not have any significant
influence on the overall rate of the reaction and yields
of products. Without water, the neat reactions at room
temperature were very inconsistent. The reactions of
pyrrolidines (Table 1, entries 10–14) were extremely vig-
orous whereas additions of other acyclic primary and
secondary amines were sluggish, particularly conjugated
acid amides (Table 1, entries 4 and 8). It is possible that
water promotes the reaction through hydrogen bond
formation with the carbonyl oxygen atom of the a,b-
unsaturated carbonyl compound increasing the electro-
philic character at the b-carbon, which is attacked by
the nucleophilic amine. On the other hand, hydrogen
bond formation involving the oxygen atom of water
and the H-atom of the amine increases the nucleophilic
character of the N atom of amine. Thus, water activates
the amine as well as the conjugated alkene and thereby
greatly facilitates the addition (Scheme 2).
Et
Et
CN
NH
Et
Et
CONH2
CO2Me
11a
6a
NH
Et
i-Pr
NH
i-Pr
1
1
1
0
1
2
COMe
20
20
30
90
95
85
5e
8b
8b
N
H
CO2Me
CO2Me
N
H
N
H
Table 2. Comparison of several reactions in organic solvents with
those in water
1
1
1
3
4
5
CO2Et
CN
35
25
30
86
90
92
12
N
H
Entry Amine
Michael
acceptor
Solvent
Time Yield
(h)
(%)
8b
N
H
1
2
3
4
n-BuNH2
CO Me
THF
10
40
90
70
92
2
n-BuNH
2
2
2
CO2Me
H
2
O
0.5
10
0.5
n-BuNH
CN
CN
2 2
CH CI
CO2Me
11a
N
H
n-BuNH
2
H O
Et
5
6
7
CONH2 THF
15
15
30
60
85
NH
Et
1
1
6
7
CN
25
30
90
86
11a
12
N
H
Et
CONH2 CH CI
2
NH
2
Et
O
O
Et
CONH2
H
2
O
0.8
NH
N
H
Et
8
9
0
PhCH
PhCH
PhCH
2
2
2
NH
NH
NH
2
2
2
CONH2
CONH2
CONH2
THF
CH CI
15
15
30
50
85
O
2
2
CO2Me
18
30
86
11a
N
H
1
H
2
O
0.8

B. C. Ranu, S. Banerjee / Tetrahedron Letters 48 (2007) 141–143
143
O
H
H
4. (a) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25,
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7
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In conclusion, the present procedure provides an effi-
cient methodology for the synthesis of b-amino carbonyl
compounds via aza-Michael reaction. The notable
advantages offered by this method are simple operation,
mild (room temperature) and environment friendly reac-
tion conditions, much faster (20–50 min) reactions, high
yields of products and cost effectiveness. Most signifi-
cantly, this demonstrates the potential of water as an
efficient promoter and provides much promise for the
use of water in other chemical transformations.
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3. Representative experimental procedure for the aza-
Michael reaction (Table 1, entry 11): methyl acrylate
(
1
130 mg, 1.5 mmol) was added to pyrrolidine (71 g,
mmol) in water (1 mL) and the heterogeneous mixture
Acknowledgements
was stirred (on standing, the progress of the reaction was
very slow and it was only 50% complete even after 20 h) at
room temperature for 20 min until completion as indicated
by TLC. The reaction was found to be slightly exothermic;
however no temperature control was necessary. The
reaction mixture was extracted with ethyl acetate
We are pleased to acknowledge the financial support
from CSIR [Grant No. 01(1936)/04/EMR-1]. S.B. also
thanks CSIR for his fellowship.
(
2 · 10 mL) and the combined extract was dried (Na SO )
2
4
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