LETTER
Efficient Copper-Catalyzed Chemo Selective Conjugate Addition
2427
(4) (a) The Organic Chemistry of b-Lactams; George, G. I., Ed.;
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Interestingly, all the aliphatic amines gave excellent yield
with a,b-ethylenic compounds (Table 2, entries 1–8).
Many of the reactions are almost quantitative in yield.
Further more, when benzylamine was treated with acry-
lonitrile and ethyl acrylate, highly chemo selectivity oc-
curred in this reaction, only mono-addition product was
obtained (entries 3, 6). To the best of our knowledge, there
have not been reported the monosubstituted aza-Michael
of aliphatic amines without special activation.19,20 And to
our surprise, the reactions of n-propylamine, n-butyl-
amine with a,b-ethylenic compounds in the presence of
copper salts was completed in giving a mixture of mono
and disubstitute products. For example, the addition of
n-butylamine to ethyl acrylate produced 65% mono-sub-
stitute product and 32% di-substitute product. However,
the reaction of ethyl acrylate with unsym-dimethylethyl-
enediamine was only gave monosubstituted product in
high yield. This can be explained by the less solubility of
benzylamine and unsym-dimethylethylenediamine when
compared to propylamine, n-butylamine in water with
copper salts as a catalyst. The high selectivity in aza-
Michael addition of benzylamine could also be usefully in
the synthesis of the b-second amino ethylenic compounds.
To further explore the reaction, we have found that a,b-
unsaturated ketones could also be applied in this aza-
Michael reaction. The b-amino ketones could be obtained
in moderate to excellent yields (entries 10–13). A control
experiment was conducted in the absence of catalyst and
it was observed no desired product in the aza-Michael re-
action of a,b-unsaturated ketones with aliphatic amines.
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Organometallics 2003, 22, 3031.
(16) Kobayashi, S.; Manabe, A. K. Acc. Chem. Res. 2002, 35,
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345, 643. (b) Bartoli, G.; Bosco, M.; Dalpozzo, R.;
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Synlett 2003, 39.
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125, 4062. (b) Doncaster, J. R.; Ryan, H.; Whitehead, R. C.
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8112.
In conclusion, we have first developed a new methodolo-
gy for the conjugate addition of aliphatic amines to a,b-
unsaturated compounds in the green solvent, water. The
present reaction with its mild reaction conditions opens a
novel entry to synthesis of b-amino carbonyl compounds
by simple procedure. Finally, the successful application of
very cheaper catalysts, copper salts, bodes well for the de-
velopment of asymmetric aza-Michael reaction and in-
dustrialization. We believe it would be successful in the
asymmetric aza-Michael reaction in water. Current efforts
are focused on the approaches.
Acknowledgment
This study was supported in part by the Natural Science Founder of
National for financial support of the work (29933050).
(21) Jenner, G. Tetrahedron Lett. 1995, 36, 233.
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References
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(23) General Procedure for the aza-Michael Addition
Reactions. A mixture of amine (1.2 mmol), a,b-unsaturated
compound (1 mmol) and copper salts (5 mol%) in
acetonitrile/H2O (1/1) or H2O was kept at r.t. under vigorous
stirring for 12 h. After completion of the reaction, the
reaction mixture was extracted with EtOAc and purified by
using column chromatography on silical gel to obtain pure
product. All the known compounds were fully characterized
by GC-MS (Agilent 6890N GC/5973N MS, HP-5MS) and
usual spectral methods.
Synlett 2003, No. 15, 2425–2427 © Thieme Stuttgart · New York