Improved heteroatom nucleophilic addition to electron-poor alkenes promoted by CeCl3·7H2O/NaI system supported on alumina in solvent-free conditions

Article abstract of DOI:10.1021/jo048329g

(Chemical Equation Presented). 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 CeCl₃·7H₂O/NaI combination supported under solvent-free conditions to promote heteroatom Michael addition. Using neutral alumina (Al₂O₃) 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· 7H₂O/NaI/Al₂O₃ 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 α,β-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.

Full text of DOI:10.1021/jo048329g

Improved Heteroatom Nucleophilic Addition to Electron-Poor
Alkenes Promoted by CeCl3‚7H2O/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 CeCl3‚7H2O/NaI combination supported under solvent-free conditions to promote heteroatom
Michael addition. Using neutral alumina (Al2O3) as solid support permits us to circumvent some of
the problems associated with the procedure where the inorganic support is silica gel. The CeCl3‚
7H2O/NaI/Al2O3 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,â-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
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,â-
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
Conjugate addition (1,4-addition or Michael addition)
of nucleophiles to R,â-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,â-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
In the past years Lewis acids have been shown as the
best promoters for these Michael additions, especially
(2) (a) Bull, S. D.; Davies, S. G.; Delgado-Ballester, S.; Fenton, G.;
Kelly, P. M.; Smith, A. D. Synlett 2000, 1257-1260. (b) Christoffers,
J. Eur. J. Org. Chem. 1998, 1259-1260. (c) Giuseppone, N.; Van der
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51, 9891-9898.
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Engl. 1995, 34, 527-529. (b) Simpkins, N. S. Tetrahedron 1990, 46,
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* To whom correspondence should be addressed. Phone: +39 0737
402255. Fax: +39 0737 637345.
† University of Camerino.
‡ University of Bologna.
(1) (a) Perlmutter, P. Coniugate Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1992. (b) Lee, V. J. In Compre-
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Press: New York, 1991; Vol. 4, Chapter 1.2, pp 69-137.
10.1021/jo048329g CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/20/2004
J. Org. Chem. 2005, 70, 169-174
169

Bartoli et al.
SCHEME 1
concerning the simplicity, economy, and atom efficiency
aspects.5 With the aim to improve the reaction’s ef-
ficiency, several heterogeneous catalysts have been stud-
ied, and excellent results have been achieved by using
palladium,6 InCl3,7 bismuth(III) salts,8 and copper salts.9
Despite these results, the methods described require the
use of hazardous solvents and expensive catalyst or a
special treatment for its activation and are also not time
efficient. These aspects are in disagreement with clean
chemistry,10 and hence the challenge for a sustainable
environment calls for the use of alternative procedures
avoiding the use of harmful solvents. The solvent-free
approach11 and, in particular, the use of reagents im-
pregnated over inorganic supports12 can offer a step
forward in this direction even if, for exactness, these
procedures do not meet the definition of ‘no-solvent’. The
solvent is only eliminated at the primary reaction stage,
whereas an appreciable amount of solvent is still required
for the adsorption of reactants and elution of the product
at the pre- and post-reaction stages, respectively. Thus,
with this increase of environmental consciousness in
chemical research, the solvent-free Michael addition has
attracted our attention, and in the course of our ongoing
program to develop synthetic protocols using cerium
trichloride,13 we have recently reported that a CeCl3‚
7H2O/NaI combination supported on silica gel is able to
promote the Michael addition of indoles to electron-poor
alkenes.14
versatile building blocks for the preparation of many
nitrogen-containing biologically important compounds.16
Herein we report the extension of our results, and we
have been able to generalize the original route and to
expand its scope, thereby providing ready access to a new
promoter system that allows various nucleophiles to react
with carbon-carbon double bonds conjugated with a
strong electron-withdrawing group (EWG). In particular
we report the advantages obtained in Michael additions
promoted by the CeCl3‚7H2O/NaI combination utilizing
other inorganic supports than silica gel.
Results and Discussion
Since in our preliminary experiments aimed to obtain
â-amino ketones via aza-Michael addition of amines to
(E)-R,â-unsaturated ketones in the presence of CeCl3‚
7H2O/NaI/SiO2 the starting material was completely
recovered, consistent with the well-documented17 insta-
bility of â-amino carbonyl compounds on silica gel,18 we
thought to circumvent this problem by changing the
inorganic material support. It is known, in fact, that
alumina (Al2O3) is a particularly interesting metal oxide
widely used to carry out surface organic chemistry,19 and
we tested the neutral alumina (Fluka, neutral, Brockman
activity, grade 1, 150 mesh) as support of our Lewis acid
promoter.Immobilization of CeCl3‚7H2O/NaI system by
stirring an acetonitrile mixture of CeCl3‚7H2O/NaI with
neutral Al2O3 at room temperature and then removing
the solvent by rotary evaporation at 35 °C affords the
heterogeneous Lewis acid promoter. Promoter activity of
this powder is not weakened by absorption of moisture
from the air, and such a system can be stored for long
periods without any appreciable loss of the activity. Then,
we found that with this new CeCl3‚7H2O/NaI/Al2O3
promoter system the Michael addition of nucleophiles 1
to electron-deficient alkenes 2 was achieved in good yields
(Table 1). In the absence of alumina, the reaction gave
very low yields of adducts and many side products were
formed. Moreover the yields were improved when the
We next attempted to extend our solventless methodol-
ogy to aza-Michael additions, and in pioneering studies15
we have reported, by addition of secondary amines to (Z)-
R,â-enones, the synthesis of â-amino ketones, which are
(4) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117-128.
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2003, 2425-2427.
(10) For general references on green chemistry, see: (a) Anastas,
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tion of 1 equiv of amine, leading to R,â-enone 2b. This result is
consistent with reversibility of the Michael reaction in the presence of
silica gel.
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170 J. Org. Chem., Vol. 70, No. 1, 2005

Heteroatom Nucleophilic Addition to Electron-Poor Alkenes
TABLE 1. Michael Addition Promoted by CeCl3‚7H2O/NaI System Supported on Al2O3 at 35 °C for 24 ha
a Reactions performed in the presence of 1.35 equiv of CeCl3‚7H2O and 1.15 equiv of NaI supported on neutral alumina (1.00 g/mmol
amines 1). The rate and yields of this reaction improved when it was warmed to 35 °C. b All products were identified by their IR, NMR,
and GC-MS. c Yields of products isolated by column chromatography over neutral alumina.
J. Org. Chem, Vol. 70, No. 1, 2005 171

Bartoli et al.
reaction mixture was mechanically stirred at an external
temperature of 35 °C for 24 h. The first clear point coming
out is that the Michael addition of amines as nitrogen
nucleophiles proceeds well, giving the corresponding
â-amino ketones, but the most important feature of the
present method seems to be the possibility of using a
Michael acceptor such as (E)-R,â-unsaturated carbonyl
compounds (Table 1, entry 2). Furthermore, although the
nucleophilic addition of primary and secondary aryl-
amines generally proceeds sluggishly, owing to their
reduced nucleophilicity,20 with our protocol of Michael
addition, their addition is accomplished with good yields
(Table 1, entry 3).
Encouraged by our recent discovery, we examined the
hetero-Michael addition of a class of less nucleophilic
nitrogen compounds. Because carbamates and imidazoles
are weak nucleophiles,21 the development of more ef-
ficient promoter systems for addition reactions with these
nucleophiles is highly desirable.22 For this, our attention
has been focused on similar Michael donors, and we found
that our reaction constitutes a new synthetic procedure
for the preparation of N-substituted oxazolidin-2-ones
and 1-alkylimidazoles23 (Table 1, entries 10 and 11) with
good yields and under mild reaction conditions. It is also
noteworthy that the N-(p-methoxybenzyl) protecting
group of amino acids can be utilized as nitrogen nucleo-
phile, and the corresponding â-amino ketone 3ea has
been obtained without racemization as confirmed by the
optical rotation of the product (Table 1, entry 9).
In continuing our quest to exploit the usefulness of the
CeCl3‚7H2O/NaI/Al2O3 system, we were interested to find
whether thiols could undergo 1,4-addition to suitable
Michael acceptors in the presence of our promoter system.
In a typical experiment thiophenol (1h) was treated with
methyl vinyl ketone (2a) in the presence of the CeCl3‚
7H2O/NaI combination supported on neutral alumina,
and the corresponding â-phenylthio ketone 3ha24 was
isolated in near quantitative yield.25 Certainly, the fact
that the reaction can be accomplished without solvent
allowed us to adopt the best experimental conditions to
reduce the large amounts of organic solvents.26 In gen-
eral, the use of neutral alumina support makes the
workup of the reaction mixture easy and improves the
rate and yield of products, even though the reaction
occurred even in its absence. Presumably, Al2O3 acts as
a carrier to increase the surface area in our heteroge-
neous reaction, and it is very probable that cerium salt
interacts with oxide groups at the surface of the support,
forming new active sites on the alumina local structure.
FIGURE 1. The amount of alumina influences the efficiency
of the reaction.
However, the fact that our methodology is clean and the
adducts have been obtained in high yields without any
side reactions such as polymerization and bis-addition,
normally observed under the influence of strong acids,
excludes the existence in the solid of a distribution of sites
that may contain simultaneously Bro¨nsted and Lewis
sites.14b Furthermore, the CeCl3‚7H2O/NaI/Al2O3 system
has been used for addition of thiophenol (1h) in the
presence of 2,6-di-tert-butyl-4-methylpyridine,27 and as
expected our Lewis acid promoter has afforded adduct
3ha in high yield and with absolutely purity. In fact, a
strongly hindered base, namely, 2,6-di-tert-butyl-4-me-
thylpyridine, has been added to neutralize traces of HX,
which might contaminate the reaction mixture, without
deactivating the CeCl3‚7H2O/NaI/Al2O3 system because
side reaction polymerization of the reagents is promoted
by residual HX. Also, the amounts of CeCl3‚7H2O and
NaI used in the reaction were tested and optimized.
Neither CeCl3 nor NaI alone could accomplish the
Michael reaction even after 1 week, and the optimal
molar ratio of nucleophile, Michael acceptor, CeCl3‚7H2O,
and NaI was found to be 1:1.25:1.35:1.15. Anyway, it was
found that the amount of Al2O3 was decisive for comple-
tion of this type of Michael addition (Figure 1). The
results indicate that 1.00 g over mmol of Michael donor
is the most appropriate ratio, and the use of an excessive
amount of alumina (more than 1.00 g/mmol) caused a
significantly lower yield of Michael adduct 3aa. Analo-
gously, a decrease in the amount of alumina led to the
partial recovery of the starting material even when the
reaction time was prolonged. It is plain, thus, the minor
activity of the CeCl3‚7H2O/NaI/Al2O3 system with regard
to the CeCl3‚7H2O/NaI/SiO2 system as previously re-
ported,14 and this can be due to the chemical properties
of alumina.28 The undercoordinate Al sites are thought
to generate sp2 hybridized aluminum atoms capable of
strong Lewis acidic behavior.29 Hydrolysis reaction of
these sites for the presence of water in the reaction
mixture produces stable hydrates, and undercoordinate
Lewis acid sites can be reformed by dehydration from
(20) (a) Darubrough, S.; Mervic, M.; Condou, S. M.; Burns, C. J.
Synth. Commun. 2001, 31, 3173-3280. (b) Kelly, T. A.; McNeil, D. W.
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(26) The reaction mixture was treated with an organic solvent
(diethyl ether) able to dissolve the organic material while the CeCl3‚
7H2O/NaI/Al2O3 system could be easily removed by filtration.
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172 J. Org. Chem., Vol. 70, No. 1, 2005

Heteroatom Nucleophilic Addition to Electron-Poor Alkenes
adjacent OH groups.30 However, this minor activity of
Al2O3 with respect to SiO2 as solid support was exploited
to improve productivity in many critical aspects of the
generation of new chemical entities, first of all, the
possibility to accomplish the aza-Michael addition of
primary amines to an electron-deficient alkene, without
the problem of double-conjugate addition15 (Table 1,
entries 4, 7 and 8).
SCHEME 2
With regard to Michael acceptors, â-disubstituted
electron-poor alkenes are less reactive than their mono-
and nonsubstituted homologues as a result of increased
steric interaction with the Lewis acid promoter; for
example, with mesityl oxide the Michael adduct was
obtained in very modest yield even after extended reac-
tion time. Our procedure, on the contrary, works well for
R,â-unsaturated sulfones (Table 1, entries 5-8), given
their known ability to undergo efficient conjugate addi-
tion reactions with a wide range of nucleophiles.31 The
use of a Lewis acid to activate alkenyl sulfone as a
Michael acceptor has been reported in the literature,32
and as shown in Table 1, our system promotes this aza-
Michael addition. The resulting â-amino sulfone deriva-
tives are versatile synthons for the synthesis of alka-
loids,33 â-lactams,34 and nitrogen heterocycles.35 We then
tried to extend this aza-Michael reaction finding to see
if with phenyl-R-bromovinyl sulfone 2d our conditions
promoted the cyclization into aziridines.36 These are
attractive targets as a result of their occurrence in
biologically active compounds, synthetic intermediates,
or chiral auxiliaries.37 Nevertheless, by utilizing benzyl-
amine (1c) and cyclohexylamine (1d) as primary amine
nucleophiles, the corresponding R-bromo-â-amino sul-
fones 3cd and 3dd were isolated in good yield, and no
aziridine was detected under these conditions. It should
be noted that in the case of heteroatom nucleophilic
addition to R-nitroalkenes our procedure gives, contrary
to the results of the solvent-free aza-Michael addition
proposed by Pellacani et al.,38 very low yield of adduct,
and many side products are formed.
alkaloids and pharmacological active compounds.39 We
focused our attention on the development of a very
convenient route (Scheme 2) to the selectively substituted
piperidin-4-ones, which are ubiquitous scaffolds in me-
dicinal chemistry.40 The earlier organic transformation
involves the reaction of aldimine 4 with 4-aryl-2-tri-
methylsilyloxy-1,3-butadiene (1.2 equiv to aldimine) in
the presence of a Lewis acid in dichloromethane. Then,
the intramolecular aza-Michael reaction for â-amino
ketones 6a and 6b using our combination system of
CeCl3‚7H2O/NaI/Al2O3 afforded the corresponding N-
substituted 2-arylpiperidin-4-one 7a and 7b, respec-
tively.41
The availability of precursors â-amino ketones 6a,b
having a terminal olefin42 substantiates the scope of our
procedure.
In conclusion, we have shown that improved Michael
addition of heteroatom nucleophiles to carbon-carbon
double bonds conjugated with a strong electron-with-
drawing group has been obtained exchanging the amor-
phous silica gel with neutral alumina as an inorganic
solid support. In our procedure cerium(III) salt acts as
Lewis acid promoter of Michael additions, and this
establish another motif of interest for this lanthanide
compound, as a result of its low toxicity, ease of handling,
low cost, and stability in the presence of moisture.43
Furthermore, the combination of these advantages with
the use of an organic solvent-free approach by using an
inorganic oxide support makes our procedure a more
An important extension of the outlined protocol is the
intramolecular aza-Michael reaction to generate substi-
tuted six-member nitrogen-heterocycles, which are key
intermediates particularly useful in the synthesis of
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J. Org. Chem, Vol. 70, No. 1, 2005 173

Bartoli et al.
4.30 Hz), 6.70 (d, 1H, J ) 15.96 Hz), 7.17-7.26 (m, 3H), 7.30-
7.48 (m, 7H); 13C NMR δ 39.6, 52.7, 56.4, 60.3, 114.8, 126.3,
127.6, 128.3, 128.6, 129.0, 136.4, 153.2, 160.4, 196.6; HR-MS
(ESI) m/z 296 [M + H], 318 [M + Na], 334 [M + K]. Anal.
Calcd for C19H21NO2: C, 77.27; H, 7.17; N, 4.74. Found: C,
77.10; H, 7.12; N, 4.59.
efficient method for the preparation of compounds that
are of profound importance in organic chemistry. Un-
doubtedly the presence of NaI is essential for the Michael
reaction too. In considering the mechanistic role of NaI,
this is intriguing and complex because the exact nature
of the intermediate obtained by the reaction of reagents
with the CeCl3‚7H2O/NaI system on Al2O3 is not yet
known. The characterization then of all components
generated during the treatment of CeCl3‚7H2O, NaI, and
Al2O3 is being carried out in our laboratories. The
development of this new protocol also prompts us to
investigate further applications of our reagent system in
new schemes of synthesis, and the preparation of biologi-
cally important substances is in progress in our labora-
tories.
N-Benzyl-2-(4-methoxyphenyl)-4-pipiridinone (7b). Alu-
minum oxide (Fluka, neutral, Brockman activity, grade 1, 150
mesh, 1.35 g) was added to a mixture of CeCl3‚7H2O (0.68 g,
1.82 mmol) and NaI (0.23 g, 1.55 mmol) in acetonitrile (10 mL),
and the mixture was stirred overnight at room temperature.
The acetonitrile was removed by rotary evaporation, and to
the resulting powder reagent was added Mannich base 6b (0.4
g, 1.35 mmol). Then, the mixture was mechanically stirred for
24 h at an external temperature of 35 °C. The intramolecular
Michael adduct was extracted from the solid mass by filtration
chromatography over a short plug of neutral alumina using
diethyl ether as solvent. The filtrate was washed with aqueous
saturated NaHCO3 solution and with saturated NaCl solution
and finally dried over anhydrous Na2SO4. Evaporation of the
solvent under reduced pressure furnished the crude product,
which was further purified by column chromatography over
neutral alumina to give 0.28 g (70% yield) of the corresponding
4-piperidinone 7b as oil: IR (neat, cm-1) 3028, 1723, 1645; 1H
NMR δ 2.29-2.39 (m, 2H), 2.52-2.78 (m, 3H), 2.92 (s, 3H),
3.03 (d, 1H, J ) 14.12 Hz), 3.19-3.32 (m, 1H), 3.64 (dd, 1H, J
) 11.30 and 5.70 Hz), 3.83 (d, 1H, J ) 14.00 Hz), 7.21-7.27
(m, 3H), 7.45-7.71 (m, 6H); 13C NMR δ 40.6, 46.7, 53.2, 56.0,
59.3, 70.2, 114.7, 126.5, 128.0, 129.3, 136.5, 138.3, 165.0, 207.3;
EI-MS m/z 295 [M+], 294, 237, 207, 131, 91 (100), 104, 77, 65.
Anal. Calcd for C19H21NO2: C, 77.27; H, 7.17; N, 4.74. Found:
C, 77.08; H, 7.12; N, 4.68.
Experimental Section
NMR spectra were recorded in a CDCl3 solution at 300 MHz
(1H) and 75.5 MHz (13C). Mass spectra were determined by
means of the EI technique (70 eV) or by means of a source
API-electronspray. IR absorption spectra were recorded with
thin films on NaCl plates, and only noteworthy absorptions
(cm-1) are listed. All solvents were dried and distilled according
to standard procedures.44
(E)-5-(Benzylamino)-1-(4-methoxyphenyl)-1-penten-3-
one (6b). To a stirred solution of zinc triflate (2.71 g, 4.53
mmol) and water (0.136 mL, 1.53 mmol) in dichloromethane
(25 mL) were added Mannich reagent 445 (0.45 g, 3.77 mmol)
and 4-methoxyphenyl-2-trimethylsilyloxy-1,3-butadiene46 (1.12
g, 4.53 mmol) at room temperature. The reaction mixture was
stirred at room temperature for 5 h, quenched with aqueous
saturated NaHCO3, and extracted with dichloromethane. The
organic layers were dried over MgSO4, the solvent was
evaporated, and the resulting oil residue of 6b (0.87 g, 78%
yield) was sufficiently spectroscopic pure for further use:47 IR
Acknowledgment. The authors are grateful to Dr.
Massimo Ricciutelli performing mass spectral analyses.
This work was carried out under the framework of the
National Project ‘Stereoselezione in Sintesi Organica.
Metodologie ad Applicazioni’ supported by MIUR, Rome,
and by the University of Camerino. M.B. gratefully
acknowledges the Pharmacia Gruppo Pfizer Inc. Ascoli
Piceno Plant for post-graduate fellowship.
1
(neat, cm-1) 3301, 1675, 1620, 1588; H NMR δ 2.26 (s, 3H),
3.01-3.08 (m, 1H), 3.09-3.16 (m, 2H), 3.64 (d, 1H, J ) 13.62
Hz), 3.61 (d, 1H, J ) 13.45 Hz), 4.43 (dd, 2H, J ) 8.96 and
Supporting Information Available: Detailed description
of experimental procedures, NMR spectra, MS spectra, and
other characterization data for new compounds, not reported
previously, designated by their entries in Table 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(44) Parrin, D. D.; Armarego, W. L. Purification of Laboratory
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Bioorg. Med. Chem. Lett. 1997, 7, 1985-1988.
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(47) The Mannich-type bases 6 are not stable at room temperature
for a long period (>8 h) after aqueous NaHCO3 workup.
JO048329G
174 J. Org. Chem., Vol. 70, No. 1, 2005