Synthesis of β-amino esters via aza-Michael addition of amines to alkenes promoted on silica: A useful and recyclable surface

Article abstract of DOI:10.1055/s-2004-834836

A solvent-free protocol for the synthesis of β-amino esters and nitriles has been developed via conjugate addition of amines to electron-deficient alkenes promoted on silica. The silica surface may be recycled. Both aliphatic and aromatic primary or secondary amines worked efficiently to yield the desired adducts in good to excellent yields.

Full text of DOI:10.1055/s-2004-834836

2
630
LETTER
Synthesis of b-Amino Esters via Aza-Michael Addition of Amines to Alkenes
Promoted on Silica: A Useful and Recyclable Surface
S
B
ynthesis of
b
-A
a
s
via
A
za-M
u
ichael
A
dd
d
ition of
A
mi
e
nes to Alke
b
nes Basu,* Pralay Das, Ismail Hossain
Department of Chemistry, North Bengal University, Darjeeling 734 430, India
Fax +91(353)2581546; E-mail: basu_nbu@indiatimes.com
Received 30 April 2004
has been successful with aliphatic and aromatic amines
yielding b-amino esters or nitriles in good to excellent
yields (Scheme 1).
Abstract: A solvent-free protocol for the synthesis of b-amino
esters and nitriles has been developed via conjugate addition of
amines to electron-deficient alkenes promoted on silica. The silica
surface may be recycled. Both aliphatic and aromatic primary or
secondary amines worked efficiently to yield the desired adducts in
good to excellent yields.
Key words: aza-Michael addition, amines, conjugated alkenes, b-
amino esters, silica gel
Scheme 1
b-Amino esters and derivatives are attractive targets for
chemical synthesis of products with a wide range of bio-
1
2
logical activities and pharmacological properties. For For our method to be successful, the silica gel of the type
example, b-amino esters are useful intermediates in3 used for thin layer chromatography was a prerequisite. In
14
certain very attractive syntheses of b-lactam antibiotics.
a typical experiment, a mixture of the amine and a,b-un-
Optically active b-amino esters and derivatives often find saturated ester in a 1:2.5 ratio were mixed with activated
applications as chiral auxiliaries in asymmetric synthesis.4 silica gel (1 g; E. Merck; silica gel HF254 for TLC) and the
One of the most straightforward routes for their synthesis solid mixture was stirred at 40–70 °C for 1–12 hours. The
involves conjugate addition of amines to electron-defi- desired product was then isolated by column chromato-
5
cient alkenes, promoted by acid or base catalysts. Several graphy over silica gel.
Lewis acids, such as AlCl , TiCl or SnCl , etc. have been
3
4
4
An array of aliphatic and aromatic amines and a,b-ethyl-
enic compounds were tested as substrates for aza-Michael
addition reaction and the results are summarized in
Table 1. Aliphatic cyclic secondary amines (entries 1–5)
underwent nucleophilic addition to ethyl acrylate and
acrylonitrile efficiently to yield the desired adducts in ex-
cellent yields. Diisopropylamine and dicyclohexylamine
5
employed to effect this addition. However, their use in
stoichiometric amounts often poses severe environmental
problems in waste streams. Over the last few years, sever-
al groups have reported sub-stoichiometric use of some
6
7
8
Lewis acids such as Yb(OTf) , Bi(OTf) , Bi(NO ) , hy-
3
3
3 3
10
9
drated CeCl –NaI supported on silica gel or clay. De-
3
spite their remarkable success, however, the literature
reveals that these catalysts are very substrate-selective. In
addition, use of these heavy metal salts coupled with
hazardous solvents are not desirable for a ‘green’ reaction.
Recently, environmentally friendly ‘green’ synthesis has
(
entries 6–9), which were previously reported to be unpro-
12
ductive, also reacted to provide the desired products in
good yields. Aliphatic primary amines, for example cy-
clohexylamine on treatment with ethyl acrylate on silica
surface afforded the bis-adduct only (entry 10). With this
success, we turned our attention to aromatic amines that
1
1
become very important and popular. Ranu and cowork-
ers disclosed solvent-free and catalyst-free conjugate ad-
were also unsuccessful according to many reported proce-
1
2
dition of amines to electron-deficient alkenes. However,
like some of the other methods, this procedure failed with
aryl amines and some aliphatic secondary amines. There-
fore, the need for the development of more general and en-
vironmentally benign methods remains. As part of our
continuing effort to develop novel methods of surface-
7,9,10,12
dures.
To our satisfaction, aromatic amines under
our optimized conditions gave the corresponding addition
products in good to excellent yields (entries 11–16).
While the primary aliphatic amine yielded the bis-adduct
smoothly, the aromatic primary amine gave rise to the
mono-adduct only. This reactivity difference may be at-
tributed to the reduced nucleophilicity of the aromatic
amines. The o-amino thiol afforded the bis-adduct indicat-
ing that thiols are also reactive under similar conditions
1
3
mediated solvent-free organic reactions, herein we re-
port an efficient and practical procedure for conjugate ad-
dition of amines to a,b-unsaturated esters and derivatives
promoted on a surface of silica gel. The addition reaction
(
entry 16). The methyl ester of proline also underwent
aza-Michael additions using mild conditions (entry 17)
furnishing the desired adduct in 72% yield. To extend fur-
ther scope of this procedure, we examined the tolerance of
acid-labile protecting group under the reaction conditions.
SYNLETT 2004, No. 14, pp 2630–2632
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834836; Art ID: D11104ST
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2
.1
1
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©
Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of b-Amino Esters via Aza-Michael Addition of Amines to Alkenes
2631
Table 1 Aza-Michael Addition of Amines to Electron-Deficient Alkenes on Silica Surface
Entry
1
Amine
Alkene
Time (h)/Temp (°C)
1/40
Producta
Yield (%)b
93
A
2
B
1/40
87
3
4
5
C
A
B
6/60
1/50
1/50
80
93
96
6
7
8
9
A
B
A
B
6/50
6/50
8/50
8/50
50
65
50
55
1
1
0
1
A
B
6/50
9/60
52
80
1
1
2
3
A
B
9/60
9/60
78
99
14
B
9/70
70
15
16
17
18
A
A
B
A
12/70
12/70
9/60
55
88
72
93
3/50
a
1
All products were characterized by IR, H NMR and 13C NMR spectral data.15,
Isolated yield.
b
Amine containing ketal as protecting group was found to In general, the reactions proceed smoothly and no solvent
tolerate our conditions affording the desired adduct in is necessary except in eventual purifications by column
9
3% yield (entry 18).
chromatography. Both the aliphatic and aromatic amines
(
primary or secondary) undergo addition efficiently,
Synlett 2004, No. 14, 2630–2632 © Thieme Stuttgart · New York

2
632
B. Basu et al.
LETTER
which is one of the important developments. In a few
cases, the reaction has been scaled up to 10 mmol of the
amines and the desired products were isolated without any
significant change of yield. The recovered silica gel was
washed with methanol, dried under vacuum (0.5 mm Hg)
for 10 min at 120–130 °C and then employed for further
reaction. Recycling of the silica was tested for a particular
reaction (entry 6) where the loss of activity of the surface
did not occur appreciably in two further operations.
(6) (a) Jenner, G. Tetrahedron Lett. 1995, 36, 233.
b) Matsubara, S.; Yoshiyoka, M.; Utimoto, K. Chem. Lett.
994, 827.
(
1
(7) Varala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 720;
and references cited therein.
(
(
8) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109.
9) Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.; Sambri,
L.; Torregiani, E. J. Org. Chem. 2001, 66, 9052; and
references cited therein.
(
10) Shaikh, N. S.; Deshpande, V. H.; Bedekar, A. V.
Tetrahedron 2001, 57, 9045.
In conclusion, we have developed a mild and general
method for the synthesis of b-amino esters and derivatives
via conjugate addition of amines to electron-deficient
alkenes promoted on a surface of silica gel. The best re-
sults are realized by using the silica usually used for TLC.
The applicability of this ‘green’ methodology to a diverse
variety of amines including aromatic and hindered amines
is an attractive feature, which can be utilized by synthetic
and industrial chemists.
(
11) (a) Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem.
Commun. 2001, 2159. (b) Tanaka, K.; Toda, F. Chem. Rev.
2000, 100, 1025. (c) Metzger, J. O. Angew. Chem. Int. Ed.
1998, 37, 2975.
(
(
12) Ranu, B. C.; Dey, S. S.; Hajra, A. Arkivoc 2002, 7, 75.
13) (a) Basu, B.; Jha, S.; Mridha, N. K.; Bhuiyan, M. M. H.
Tetrahedron Lett. 2002, 43, 7967. (b) Basu, B.; Das, P.;
Bhuiyan, M. M. H.; Jha, S. Tetrahedron Lett. 2003, 44,
3817. (c) Das, P.; Basu, B. Synth. Commun. 2004, 34, 2184.
(14) General Procedure for the Aza-Michael Addition
Reaction: A mixture of the amine (2 mmol) and alkene (5
mmol) was added to activated [by heating silica gel (10 g) at
Acknowledgment
120–130 °C for 10 min under vacuum (0.5 mm Hg) and then
cooled under N ] silica (1 g; E. Merck; silica gel HF for
2
254
We thankfully acknowledge the CSIR, New Delhi (01-1863-03-
EMR-II) for financial support. PD is a JRF under this CSIR project.
TLC) and stirred at the appropriate temperature for several
hours (see Table 1). TLC monitoring showed in most cases
that the reaction was complete. The solid surface was then
taken in MeOH, filtered off and the filtrate was concentrated
to afford the crude products. Pure products were isolated by
chromatography on a silica gel column eluting with various
ratios of EtOAc to light petroleum. They were identified by
References
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1
(
(
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H, J = 7.1 Hz), 2.38 (t, 2 H, J = 7.1 Hz), 2.75 (t, 2 H, J = 7.1
1
3
Hz), 2.99 (sep, 2 H, J = 6.6 Hz), 4.10 (q, 2 H, J = 7.1 Hz). C
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1
Entry 9: H NMR: d = 1.02–1.31 (m, 10 H), 1.60–1.77 (m,
10 H), 2.34 (t, 2 H, J = 7.1 Hz), 2.47–2.55 (m, 2 H), 2.87 (t,
1
3
2 H, J = 7.1 Hz). C NMR: d = 20.6, 26.0, 32.1, 42.6, 58.3,
(
c) Salzman, T. N.; Ratcliffe, R. W.; Christensen, B. G.;
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1
Boufford, F. A. J. Am. Chem. Soc. 1980, 102, 6161.
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J = 7.1 Hz), 1.59–1.78 (m, 4 H), 2.37–2.43 (m, 1 H), 2.41 (t,
4 H, J = 7.1 Hz), 2.79 (t, 4 H, J = 7.1 Hz), 4.11 (q, 4 H,
J = 7.1 Hz). C NMR: d = 14.2, 26.1, 26.2, 29.1, 34.8, 46.2,
60.2, 172.7.
Entry 13: H NMR: d = 2.60 (t, 2 H, J = 6.5 Hz), 3.46 (t, 2
H, J = 6.5 Hz), 3.75 (s, 3 H), 6.60 (d, 2 H, J = 8.9 Hz), 6.80
(d, 2 H, J = 8.9 Hz). C NMR: d = 18.1, 40.8, 55.7, 114.8,
115.0, 118.2, 140.0, 153.9.
(
(
1
3
1995.
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1
1
3
1
2000, 1257. (d) Davies, S. G.; McCarthy, T. D. Synlett 1995,
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1
3
J = 7.1 Hz). C NMR: d = 14.1, 32.5, 34.7, 50.9, 53.1, 60.3,
64.1, 106.9, 172.5.
Synlett 2004, No. 14, 2630–2632 © Thieme Stuttgart · New York