Boric acid: A novel and safe catalyst for aza-Michael reactions in water

Article abstract of DOI:10.1016/j.tetlet.2005.09.167

Boric acid efficiently catalyzes the conjugate addition of aliphatic amines to α,β-unsaturated compounds to produce β-amino compounds, with great alacrity and excellent yields, in water under mild conditions. Aromatic amines do not participate effectively in the reaction.

Full text of DOI:10.1016/j.tetlet.2005.09.167

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8329–8331
Boric acid: a novel and safe catalyst for aza-Michael
reactions in water
a
b,
b
Mihir K. Chaudhuri,a,* Sahid Hussain, M. Lakshmi Kantam and B. Neelima
*
aDepartment of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
bIndian Institute of Chemical Technology, Hyderabad 500007, India
Received 29 June 2005; revised 21 September 2005; accepted 28 September 2005
Available online 14 October 2005
Abstract—Boric acid efficiently catalyzes the conjugate addition of aliphatic amines to a,b-unsaturated compounds to produce
b-amino compounds, with great alacrity and excellent yields, in water under mild conditions. Aromatic amines do not participate
effectively in the reaction.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Owing to their wide range of biological activities1 and
pharmacological properties,2 b-amino ketones and
derivatives are much sought after. Such compounds
not only constitute components of biologically active
natural products, they also serve as essential intermedi-
ates in the synthesis of b-amino acids and b-lactam anti-
biotics.3 Consequently, the development of novel
synthetic methods for their synthesis has attracted sus-
tained interest in organic synthesis. The most common
method for the preparation of b-amino ketones is the
Mannich reaction.4 Classical Mannich type reactions
are certainly very powerful but need quite severe reac-
tion conditions and are rather sluggish. Conjugate addi-
tion reactions are, to the contrary, atom economic and
quite easy to carry out. However, these reactions require
either basic conditions5 or acidic catalysts,6 which can
be detrimental to the desired synthesis. Moreover, most
Lewis acid catalysts are likely to be poisoned by alkyl
and arylamine reagents.7 In order to overcome some
of these limitations, a number of alternative procedures
have been reported over the past few years using a vari-
ety of catalysts such as palladium,7 InCl3,8 supported
CeCl3Æ7H2O–NaI,9 Yb(OTf)2,10 Bi(NO3)2,11 Bi(OTf)2,12
been employed for this reaction. Recently, ionic liquids,
either alone20 or in combination with quaternary ammo-
nium salts,14b have been shown to catalyze efficiently
conjugate addition to a,b-unsaturated compounds albeit
with long reaction times.
In continuation of our efforts towards a simplified ver-
sion of catalytic aza-Michael condensation reactions
and encouraged by the information gathered from the
seminal contributions of Spencer and co-workers,21 we
are quite convinced that it is the Brønsted acid, which
is important in bringing about aza-Michael type con-
densations irrespective of whether the reaction was cat-
alytic or not. Considering all these and in view of our
interest in developing reactions that use a catalytic
amount of either a non-toxic or minimally toxic, readily
available and ecologically favourable agent, we opted
for boric acid as the catalyst of choice and water as
the solvent.
The selection of boric acid as catalyst was because of
one of its most fundamental properties, namely it pro-
duces a Brønsted acid from its reaction with water:
BðOHÞ3 þ H2O ! Hþ þ BðOHÞꢀ4 . Thus, boric acid in
water is expected to be ideal for Michael type additions.
The reaction in water is an important advantage of this
protocol. Michael additions in water are relatively
scarce but not unprecedented.8,14 The use of water as a
reaction solvent has received considerable attention22
because reactions in this medium have several advanta-
ges including the fact that the solvent and substrates can
be used directly without drying. Also, it is believed that
18
Cu(OTf)2,13,14a LiClO4,15 clay,16 silica gel,17 FeCl3
and KF/alumina.19 Heterogeneous solid acids have also
Keywords: Aza-Michael; Boric acid; Amines; a,b-Unsaturated com-
pounds; Water.
*
Corresponding authors. Tel./fax: +91 361 2690762; e-mail addresses:
mkc@iitg.ernet.in; mlakshmi@iict.res.in
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.167

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M. K. Chaudhuri et al. / Tetrahedron Letters 46 (2005) 8329–8331
R2
R3
Table 1. Boric acid catalyzed conjugate addition of amines to a,b-
unsaturated compounds in water at room temperature
R1
R
R1
R
Boric Acid
H2O / rt
X
Time (h) Yield (%)a
NH
Entry Amine
a,b-Enone
+
X
N
H
R2
R3
a
3.5
4
90
88
CO2Me
N
Et
Et
Scheme 1.
H
N
b
CO2Me
n
Bu-n
-Bu
reactions in water contribute to green chemistry and
pseudo natural catalysis chemistry.
c
d
e
f
1.5
1.5
2.5
2.5
3
85
CO2Me
CO2Me
CO2Me
COMe
COMe
O
NH
NH
90, 93b
90
We have recently disclosed a Cu catalyst immobilized in
an ionic liquid23 for the facile addition of amines to a,
b-unsaturated compounds. However, we have been look-
ing for a simpler methodology for aza-Michael reac-
tions. To this end, we have now succeeded in the use
of boric acid as an innocuous and highly efficient catal-
yst for the Michael addition of amines to a,b-unsatu-
rated compounds in water to afford the corresponding
b-amino derivatives (Scheme 1). To our knowledge this
is perhaps the most simple protocol for this type of
reaction, which is expected to interest a wide range of
organic chemists.
NH2
80
NH
NH
g
85
O
Ph
Ph
h
i
5.5
5
70
80
NH
COMe
COMe
H
N
A variety of a,b-unsaturated compounds such as methyl
acrylate, acrylonitrile, methyl vinyl ketone, acrylamide
and methyl methacrylate underwent 1,4-addition with
a wide range of aliphatic amines in the presence of
10mol % of boric acid at room temperature to give
the corresponding b-amino compounds in high yields.
The results are summarized in Table 1. In general, sec-
ondary amines gave higher yields than primary amines.
It is pertinent to mention that benzylamines gave only
mono adducts (entries e, l, o, s) whereas with primary
amines bis-adducts (entries u and v) were mostly
formed. A sterically hindered amine also gave the corre-
sponding 1,4-adduct in good yield (entry h).
n
Bu-n
-Bu
j
4
6
87
78
CONH2
CONH2
O
NH
H
N
k
Et
Et
NH2
l
4
5
85
85
CONH2
CONH2
H
N
m
n
Bu-n
-Bu
n
o
p
1.5
2.5
2
95
92
90
NH
CN
CN
CN
In order to investigate the fate of attempted aza-Michael
condensations involving aromatic amines such as ani-
line, p-methoxyaniline or p-nitroaniline with methyl
acrylate as Michael acceptor, the B(OH)3–water proto-
col was studied. Not surprisingly, only p-methoxyaniline
reacted to afford a maximum of 15% of the addition
product (reaction time 12 h). This enables us to state
that the B(OH)3–water protocol is more appropriate
for aliphatic amines. In order to lend support to our
assertions, a separate reaction was conducted between
methyl acrylate and an equimolar mixture of p-methoxy-
aniline and diethylamine. The result is depicted in
Scheme 2 and augments our assertion.
NH2
H
N
n
Bu-n
-Bu
q
r
2
88
90
90
O
NH
NH
CO2Me
CO2Me
CO2Me
2
NH2
s
3.5
Finally, upon completion of the reaction, catalyst recy-
clability was examined through a series of reactions with
piperidine and methyl acrylate using an aqueous phase
containing boric acid (Table 2). The reaction continued
to give good yields, however, only with relatively longer
reaction times. This can be explained by leaching of the
catalyst. It is also important to note that the reaction
can be performed on a relatively larger scale (5 g) giving
good yields (Table 1, entry d) showing its potential for
industrial applications.
t
5
1
1
80
O
NH
CO2Me
u
v
n-BuNH2
(85c)
30
CO2Me
CN
c
n-BuNH2
(89c+) 35
a Isolated yields.
b Yield on a 5 g scale.
c Bis product (with 2 equiv of a,b-unsaturated compound).

M. K. Chaudhuri et al. / Tetrahedron Letters 46 (2005) 8329–8331
8331
O
NH2
NH2
O
Et
Et
OMe
Et
Et
NH
+
+
N
OMe
Boric Acid, rt, Water
OMe
98%
OMe
87%
Scheme 2.
Table 2. Recycling of the catalyst for the reaction of piperidine and
methyl acrylate in water
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Cycle
Yield (%)
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1.5
1
2
3
92
902.5
90
5
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and b-substituted Michael acceptors were tested under
the present conditions. It was found that with Me
groups at either the a- or b-positions, the procedure
gave good yields (Table 1, entries q–t), whereas with a
Ph group at the b-position it failed.
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In conclusion, we have developed a very easy way to
operate, safe and cost-effective method for the 1,4-addi-
tion of aliphatic amines to a,b-unsaturated olefins using
boric acid as the catalyst in water.
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General experimental procedure: Boric acid (0.3 mmol,
0.018 g) was dissolved in water (3 mL) (pH = 5.7) fol-
lowed by the addition of amine (3 mmol) and a,b-unsat-
urated compound (3.3 mmol) and the whole was stirred
at room temperature. The progress of the reaction was
monitored by TLC. After completion of the reaction,
the mixture was extracted with ethyl acetate
(3 · 10mL). The combined organic extracts (dried over
Na2SO4) were concentrated in vacuo and the resulting
product was purified by column chromatography on sil-
ica gel with ethyl acetate and n-hexane (ratio varied with
product) (for amides, ethyl acetate and methanol (9:1))
as eluent to afford the pure b-amino adduct. The aque-
ous layer containing boric acid was reused for the next
run.
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Acknowledgement
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S.H. and V.N. thank the Council of Scientific and
Industrial Research, New Delhi, India, for research
fellowships.
20. Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah,
A. V. Chem. Lett. 2003, 988–989.
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