Chemistry Letters Vol.32, No.11 (2003)
989
Table 1. Conjugate addition of amines to enones in ionic liq-
uids
ionic liquids as green solvents for the 1,4-addition of amines
to electron-deficient olefins to produce ꢀ-amino compounds,
which are key intermediates in the syntheis of ꢀ-amino acids
and ꢀ-lactam antibiotics. This method avoids the use of acid cat-
alysts and environmentally unfavorable volatile organic solvents
by playing the dual role of solvent and the promoter. The enones
show significant increase in reactivity in ionic liquids thereby re-
ducing the reaction times and improving the yields considerably.
The simple experimental and product isolation procedures com-
bined with ease of recovery and reuse of this novel reaction me-
dia is expected to contribute to the development of green strat-
egy for synthesis of ꢀ-amino compounds.
[bmim]PF6
[bmim]BF4
Time/h
Enone
Producta
Amine
Entry
Time/h Yield/%c
Yield/%c
1
3
2
CO2Et
CO2Et
A
8.0
89
87
9.0
9.5
85
83
Ph N NH
Ph N
N
N
EtO2C
B
8.5
2.0
PhCH2
N
NH
PhCH2
N
EtO2C
NC
CN
C
D
E
96
93
78
2.5
3.0
95
91
O
NH
NH
NH
O
O
N
N
CO2Et
MeO2C
2.5
O
CN
10.0
12.0
72
BVS, AKB thank CSIR, New Delhi, for the award of fellow-
ships.
N
NC
NC
CN
NH2
N
H
83c
89c
87c
92c
F
7.5
8.0
8.5
9.5
References and Notes
CO2Me
1
a) G. Bartoli, C. Cimarelli, E. Marcantoni, G. Palmieri, and M.
Petrini, J. Org. Chem., 59, 5328 (1994). b) Y. F. Wang, T. Izawa,
S. Kobayashi, and M. Ohno, J. Am. Chem. Soc., 104, 6465
(1982). c) S. Hashiguchi, A. Kawada, and H. Natsugari, J. Chem.
Soc., Perkin Trans. 1, 1991, 2435.
NH2
N
H
G
MeO2C
O
O
NH2
NH2
N
85
12.0
10.0
78
H
I
H
O
2
3
4
a) Y. Hayashi, J. J. Rode, and E. J. Corey, J. Am. Chem. Soc., 118,
5502 (1996). b) E. L. Eliel and X. C. He, J. Org. Chem., 55, 2114
(1990).
P. Traxler, U. Trinks, E. Buchdunger, H. Mett, T. Meyer, M.
Muller, U. Regenass, J. Rosel, and N. Lydon, J. Med. Chem., 38,
2441 (1995).
a) Yi, J. Zou, H. Lei, X. Liu, and M. Zhang, Org. Prep. Proced. Int.,
23, 673 (1991). b) A. Graul and J. Castaner, Drugs Future, 22, 956
(1997). c) E. J. Corey and G. A. Reichard, Tetrahedron Lett., 30,
5207 (1989).
N
H
Ph
Ph
O
80c
75
12.0
15.0
83c
80
10.0
16.5
Ph
Ph
CO2Me
NH2
Ph
N
H
J
CO2Me
Ph
85
K
L
Ph
Ph
N
8.0
88
9.0
MeO2C
NC
Ph
N
N
CO2Et
CN
H
NH
85
90
12.0
6.0
9.5
5.5
80
87
Ph
M
Me
5
6
M. Arend, B. Westermann, and N. Risch, Angew. Chem., Int. Ed.
Engl., 37, 1044 (1998).
a) N. Srivastava and B. K. Banik, J. Org. Chem., 68, 2109 (2003).
b) L. Fadini and A. Togni, J. Chem. Soc., Chem. Commun., 2003,
30.
N
Ph
Ph
N
Me
H
O
O
CO2Me
92c
90c
12.0
14.0
NH2
N
MeO2C
N
H
1
aAll the products were characterized by H NMR, IR, and
mass spectra. bYield refers to the isolated pure products after
column chromatography. c5–9%of bis-adducts were ob-
served by GCanalysis.
7
8
9
a) T. P. Loh and L. L. Wei, Synlett, 1998, 975. b) G. Bartoli, M.
Bosco, E. Marcantoni, M. Petrini, L. Sambri, and E. Torregiani,
J. Org. Chem., 66, 9052 (2001).
a) S. Matsubara, M. Yashioka, and K. Utimoto, Chem. Lett., 1994,
827. b) T. C. Wabnitz and J. B. Spencer, Tetrahedron Lett., 43,
3891 (2002). c) G. Jenner, Tetrahedron Lett., 36, 233 (1995).
a) J. Cabral, P. Laszlo, and L. Mahe, Tetrahedron Lett., 30, 3969
(1989). b) N. S. Shaikh, V. H. Deshpande, and A. V. Bedekar, Tet-
rahedron, 57, 9045 (2001).
compounds was studied in both hydrophobic [bimim]PF6 and
hydrophilic [bmim]BF4 ionic liquids and the results are present-
ed in the Table 1. Among these ionic liquids, [bmim]PF6 was
found to be superior in terms of conversion. In most cases, the
products could be easily isolated by simple extraction with di-
ethyl ether. The recovered ionic liquid was reused in several
times without loss of activity, even after fourth cycle the product
3C was obtained with the similar yield and purity of those ob-
tained in the first cycle. Ionic liquids used in this study have been
prepared in our laboratory from the readily available and inex-
pensive N-methyl imidazole, 1-chlorobutane and sodium hexa-
fluorophosphate or sodium tetrafluroborate12 and their purity
was determined by comparing of their 1H NMR spectra with
commercial samples. The purity of [bmim]PF6 ionic liquid is
ꢀ97:0% (NMR). The use of ionic liquids as reaction media for
this transformation avoids the use of moisture sensitive reagents
or heavy metal Lewis acids or solid acids as promoters thereby
minimizing the production of toxic waste during work-up. The
scope and generality of this process is illustrated with respect
to various ꢁ,ꢀ-ethylenic compounds and amines and the results
are presented in the Table 1.13
10 a) T. Welton, Chem. Rev., 99, 2071 (1999). b) P. Wasserscheid and
W. Keim, Angew. Chem., Int. Ed. Engl., 39, 3772 (2000). c) C. M.
Gordon, Appl. Catal., A, 222, 101 (2001).
11 R. Sheldon, J. Chem. Soc., Chem. Commun., 2001, 2399.
12 a) S. Park and R. J. Kazlauskas, J. Org. Chem., 66, 8395 (2001). b)
P. A. Z. Suarez, J. E. L. Dullius, S. Einloft, R. F. De Souza, and J.
Dupont, Polyhedron, 15, 1217 (1996). c) B. C. Ranu, S. S. Dey, and
A. Hajra, Tetrahedron, 59, 2417 (2003).
13 Experimental procedure: The mixture of amine (1 mmol) and ꢁ,ꢀ-
ethylenic compound (1.5 mmol) in 1-butyl-3-methylimidazolium
hexafluorophosphate (3 mL) was stirred at room temperature for
the appropriate time (Table 1). After completion of the reaction,
as indicated by TLC, the product was extracted with diethyl ether
(3 Â 10 mL). The combined ether extracts were concentrated in va-
cuo and the resulting product was directly charged on small silica
gel column and eluted with a mixture of ethyl acetate: n-hexane
(2:8) to afford pure ꢀ-amino adduct. The rest of the ionic liquid
was further washed with ether and recycled in subsequent reactions.
The products were characterized by comparison of their NMR, IR,
and mass spectra with authentic samples. The spectral data of all
the products were identical with those of authentic samples.7,9
In summary, we have demonstrated the successful use of
Published on the web (Advance View) September 27, 2003; DOI 10.1246/cl.2003.988