1552
R. Varala et al.
LETTER
All sec-alicyclic amines underwent conjugate addition to promoter for Michael additions (3 mol%), with good
afford the corresponding products in excellent yields, and yields and this establish as another motif of interest for the
the reaction times are also very short. Among various lanthanide compound, CAN, as a result of ease of han-
amines tested, the order of reactivity and yields is as fol- dling, low cost. Furthermore, this method is capable of be-
lows: piperidine > N-phenyl, N-Boc > N-benzyl morpho- ing scaled-up.
line > piperazine > N-methyl (see Table 2, entries 1–6 and
8). Piperazine gave the bis-addition product. N-acetyl pip-
erazine did not give the expected addition product even
Acknowledgment
Ravi Varala thanks Council of Scientific Industrial Research (CSIR,
India) for financial support.
after stirring the reaction mixture for 12 hours and starting
material was recovered quantitatively after usual work-
up.
References and Notes
We have further studied the aza-Michael reaction using a
variety of a,b-unsaturated carbonyl compounds or nitriles
such as methyl acrylate, acrylonitrile, methyl vinyl ke-
tone, and cyclohexenone. All Michael acceptors studied,
underwent 1,4-addition with a wide range of aliphatic
amines in the presence of 3 mol% CAN at room tempera-
ture to give the corresponding b-amino compounds in
high yields. The results from this study are shown in
Table 3. It has been observed that cyclic secondary
amines such as pyrrolidine, piperidine, morpholine under-
go smooth addition with a,b-unsaturated carbonyl com-
pounds or nitriles, while reactions of open chain
secondary amines like diisopropyl amine, diallyl amine
are sluggish (Table 3, entry 6 and 7). However, dimethyl
amine is an exception that adds quite readily (Table 3,
entry 1). Diethanolamine also gave no desired product on
reacting with methyl acrylate. Several aromatic amines
such as p-nitroaniline, p-aminophenol, p-toluidine, o-ami-
nophenol were subjected to this reaction with CAN as
catalyst and methyl acrylate as the Michael acceptor, in all
cases, aromatic amines remained unchanged.
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In order to extend the scope of this methodology, different
aromatic amines such as diphenylamine and benzyl phen-
ylamine were tested under the same reaction conditions
with methyl acrylate as Michael acceptor.
As expected, the reaction did not proceed at all even after
12 hours, while aliphatic primary amines such as cyclo-
hexylamine and benzylamine undergo facile additions
with methyl acrylate; ethyl acrylate giving 10–12% of the
bis-addition products was also formed (Table 3, entries 3
and 5). Surprisingly, sterically hindered dibenzylamine
gave the corresponding addition product in 4.5 hours in
modest yield (Table 3, entry 8).
In general, secondary amines gave higher yields than the
primary amines. To demonstrate the scope of practical ap-
plicability of this methodology, the reaction was per-
formed with piperidine and ethyl acrylate on a 20-mmol
scale (Table 1) using CAN. The reaction was complete in
15 minutes affording the corresponding product in 97%
yield, thus confirming the possibility of being scaled up.
(9) (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.;
Kolb, H. C.; Sharpless, K. B. Angew. Chem. Int. Ed. 2005,
44, 3275. (b) Lindstrom, U. M. Chem. Rev. 2002, 102,
2751. (c) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125,
9584.
In conclusion, we have developed a new methodology for
the conjugate addition of aliphatic amines to a,b-unsatur-
ated compounds in the green solvent – water – in short re-
action times using CAN. In our procedure, CAN acts as a
Synlett 2006, No. 10, 1549–1553 © Thieme Stuttgart · New York