Improved Heteroatom Nucleophilic Addition to Electron-Poor
Alkenes Promoted by CeCl
3
‚7H
2
O/NaI System Supported on
Alumina in Solvent-Free Conditions
Giuseppe Bartoli,
‡
Massimo Bartolacci,
†
Arianna Giuliani,
†
Enrico Marcantoni,*
,†
Massimo Massaccesi,
†
and Elisabetta Torregiani
†
Dipartimento di Scienze Chimiche, Universita ` di Camerino, via S. Agostino 1, I-62032 Camerino (MC),
Italy, and Dipartimento di Chimica Organica “A. Mangini”, Universita ` di Bologna, viale Risorgimento 4,
I-40136 Bologna, Italy
enrico.marcantoni@unicam.it
Received September 21, 2004
Conjugate addition of heteroatom nucleophiles to carbon-carbon double bonds conjugated with a
strong electron-withdrawing group is one of the most important new bond-forming strategies in
synthetic organic chemistry. Among the methods for these Michael additions, Lewis acids have
shown the best promoter activity, and in particular, the use of reagents impregnated over inorganic
supports is rapidly increased. With the increase of environmental consciousness in chemical
research, the solvent-free Michael addition has attracted our attention. In continuation of our
ongoing program to develop synthetic protocols utilizing cerium trichloride, we report an extension
of the CeCl
3
‚7H
2
O/NaI combination supported under solvent-free conditions to promote heteroatom
Michael addition. Using neutral alumina (Al
2
O
3
) as solid support permits us to circumvent some of
the problems associated with the procedure where the inorganic support is silica gel. The CeCl
3
‚
7H
2
O/NaI/Al
2
O
3
system works well for hetero-Michael additions utilizing weakly nucleophiles such
as imidazoles and carbamates, and also the reaction proceeds with good yields in the case of Michael
acceptors different from R,-unsaturated carbonyl compounds. An important synthetic application
of this our methodology is the intramolecular aza-Michael reaction in producing 4-piperidinone
derivatives, which are of interest as synthetic intermediates toward important classes of
heterocycles.
Introduction
Conjugate addition (1,4-addition or Michael addition)
of nucleophiles to R,-unsaturated compounds is one of
the most important new bond-forming strategies in
synthetic organic chemistry.
1
The versatility of the
conjugate additions is mainly due to the large variety of
nucleophiles (organometallic reagents, other carbanions,
heteroatom Michael donors) and acceptors (R,-unsatur-
ated carbonyl compounds, -nitriles, -esters, -phosphates,
-sulfones, and nitroalkenes) that can be used.
2
Among
this variety of synthetic transformations, the develop-
ment of new methods for new and efficient conjugate
addition reaction with a wide range of heteroatom
nucleophiles has attracted special attention.
3
In particu-
lar, the conjugate addition of nitrogen nucleophiles to R,-
enones (aza-Michael reaction) is noteworthy as a widely
used method for carbon-nitrogen bond formation. This
organic transformation has been especially employed in
the synthesis of products generally recognized as building
blocks for the preparation of important natural and no
natural target molecules.
4
In the past years Lewis acids have been shown as the
best promoters for these Michael additions, especially
* To whom correspondence should be addressed. Phone: +39 0737
402255. Fax: +39 0737 637345.
†
University of Camerino.
‡
University of Bologna.
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10.1021/jo048329g CCC: $30.25 © 2005 American Chemical Society
J. Org. Chem. 2005, 70, 169-174 169 Published on Web 11/20/2004