Conjugate addition of amines to α,β-enones promoted by CeCl3·7H2O-NaI system supported in silica gel

Full text of DOI:10.1021/jo0108764

9052
J . Org. Chem. 2001, 66, 9052-9055
reagents to N-methoxyamides, the approach based on
Con ju ga te Ad d ition of Am in es to
Michael addition of amines to R,â-unsaturated carbonyl
compounds is one of the most simple and effective
methods for preparing â-amino ketones.10
r,â-En on es P r om oted by CeCl3‚7H2O-Na I
System Su p p or ted in Silica Gel
The conjugate addition of nucleophiles to R,â-unsatur-
ated compounds usually requires basic conditions11 or
acid catalysis.12 To avoid typical disadvantages resulting
from the presence of such catalysts, a number of alterna-
tive procedures have been developed in the past few
years,13 and in particular, various Lewis acid-induced
reactions have been studied. However, the fact that
stoichiometric amounts of Lewis acids such as AlCl3,
TiCl4, or SnCl4 are required constitutes a serious draw-
back since these oxophilic promoters have a significant
cost factor and cause environmental problems due to
strongly acidic waste streams. The development of al-
ternatives is therefore highly desirable, and herein, we
report a new protocol that employs only air stable
ingredients and is then distinguished by its practicalness.
Recently, during our studies on application of cerium
compounds in organic synthesis,14 we found that the
CeCl3‚7H2O-NaI system is able to catalyze the Michael
addition of 1,3-dicarbonyl compounds to R,â-unsaturated
ketones and aldehydes.15 Though this reaction without
solvent satisfies the demands of environmentally benign
“green” chemistry, in the case of conjugate addition of
amines to R,â-enones the reaction has been sluggish and
gave very low yields. These limitations prompted us to
investigate further new convenient methodology, in
which we can exploit the utility of CeCl3 as a Lewis acid
due to its ready availability and its price. The use of the
combination of CeCl3‚7H2O and NaI as Lewis acid is very
well documented in the literature;16 however, its utility
has not been explored in Michael additions of amines to
R,â-enones. By our continuing effort to improve the utility
of CeCl3‚7H2O-NaI system,17 we have revealed that,
expanding the generality of our methodology, the Michael
addition reaction of amines to electrondeficient olefins
in refluxing acetonitrile mixture provided â-amino ke-
tones 5 in moderate to good yields (Scheme 1).
Giuseppe Bartoli,*,† Marcella Bosco,†
Enrico Marcantoni,*,‡ Marino Petrini,‡
Letizia Sambri,† and Elisabetta Torregiani‡
Department of Organic Chemistry “A. Mangini”, University
of Bologna, v.le Risorgimento 4, I-40136 Bologna, Italy, and
Department of Chemical Sciences, University of Camerino,
via S. Agostino 1, I-62032 Camerino (MC), Italy
enricom@camserv.unicam.it
Received August 27, 2001
The development of novel synthetic methods leading
to â-amino ketones or their derivatives has attracted
much attention in organic synthesis. These â-amino
ketones are attractive targets for chemical synthesis
because of their prevalence and wide utility. One of their
earliest applications was in the preparation of important
γ-amino alcohols, versatile synthetic intermediates for a
large number of natural products,1 antibiotics,2 and chiral
auxiliaries.3 Further, the â-amino ketone moiety is com-
mon in a large variety of biologically active compounds4
and finds use as an important intermediate for fine
chemicals5 and pharmaceuticals.6 Among the methods for
generating â-amino ketones, the Mannich reaction is a
classical method for the preparation of these derivatives.7
However, due to the drastic reaction conditions and the
long reaction times, the classical Mannich reaction
presents serious disadvantages.7 Therefore, a variety of
methods have been reported for the synthesis of â-amino
ketones, and next to the elegant chemistry from the
Gomtsyan9 group on the addition of vinyl Grignard
* To whom correspondence should be addressed. Phone: +39 0737
402255. Fax: +39 0737 637345.
† University of Bologna.
‡ University of Camerino.
(1) Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini,
M. J . Org. Chem. 1994, 59, 5328-5335 and references therein.
(2) (a) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J . Am. Chem.
Soc. 1982, 104, 6465-6466. (b) Hashiguchi, S.; Kawada, A.; Natsugari,
H. J . Chem. Soc., Perkin Trans. 1 1991, 2435-2444.
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Vandenbassche, C. P.; Wald, S. A. Tetrahedron Lett. 1999, 40, 819-
822. (b) Genov, M.; Dimitrov, V.; Ivanova, V. Tetrahedron: Asymmetry
1997, 8, 3703-3706. (c) Hayashi, Y.; Rode, J . J .; Corey, E. J . J . Am.
Chem. Soc. 1996, 118, 5502-5503. (d) Eliel, E. L.; He, X.-C. J . Org.
Chem. 1990, 55, 2114-2119.
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Mu¨ller, M.; Regenass, U.; Ro¨sel, J .; Lydon, N. J . Med. Chem. 1995,
38, 2441-2448 and references therein. (b) Takahashi, K.; Shimizu, S.;
Ogata, M. Synth. Commun. 1987, 17, 809-815.
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Trost, B. M., Ed.; Pergamon: New York, 1991; Chapter 4.1. (b) Yi, L.;
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Uses; CRC: Boca Raton, FL, 1994; and references therein.
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66, 3613-3616. (b) Gomtsyan, A. Org. Lett. 2000, 2, 11-13.
(10) Perlmutter, P. Conjugated Addition Reactions in Organic
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10.1021/jo0108764 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/22/2001

Notes
J . Org. Chem., Vol. 66, No. 26, 2001 9053
Sch em e 1
possibility includes the ability to enhance the activity of
cerium trichloride as Lewis acid. It is probable that a
halide-exchange reaction between CeCl3 and NaI occurs
during the preparation of CeCl3-NaI silica gel support,
which is responsible for the enhancement of activity of
system. Thus, the characterization of all components
generated during the treatment of the CeCl3‚7H2O, NaI,
and SiO2 in acetonitrile is being carried out in our
laboratories. So far, the results are too complicated and
many kinds seem present.
Since several organic trasformations under solvent-free
conditions have gained in popularity in recent years,18
and papers on the use of rare earth on silica gel have
been reported,19 we further examined our Michael addi-
tion reaction on silica gel surface under no-solvent
conditions. The CeCl3‚7H2O-NaI system dispersed on
chromatography silica gel (Baker Analyzed reagent) has
been prepared by simple mixing of both reagents in
acetonitrile followed by complete removal of the solvent.20
Addition of amines 3 and R,â-unsaturated derivatives 4
to this mixture gave the desired Michael adduct in good
to excellent yields (Table 1). The fact that the reaction
can be carried out without solvent allowed us to adopt a
very simple workup procedure for the recovery of the
CeCl3-NaI-SiO2 system. The reaction mixture was
treated with an organic solvent (Et2O) able to dissolve
the organic material, while the CeCl3-NaI silica gel
support could be easily removed by filtration and it was
found to be a recyclable reactive system. Thus, the
recovered promoter, which was dried at room tempera-
ture for 2 h under reduced pressure, showed non ap-
preciable decrease in activity for the reaction after being
used three times. Unfortunately, every time it is neces-
sary to use acetonitrile for preparing the CeCl3-NaI
silica gel support. The amounts of CeCl3‚7H2O and NaI
used in the reaction have been tested and optimized.
Neither CeCl3 nor NaI alone could effect the conjugate
addition even after 2 days. It has been found that the
amount of CeCl3‚7H2O has been decisive for completion
of addition of amine. When less than 1 equiv of cerium
salt was used, the addition proceeded rather slowly and
after 3 days only 45% of Michael adduct was observed.
The optimal molar ratio of enone, amine, CeCl3‚7H2O,
and NaI is 1:1.25:1.35:1.15. The role of the sodium iodide
remains to be established in the reaction, but one
These reactions have been also accomplished on CeCl3‚
7H2O-NaI system, i.e., without silica gel support, but
the Michael adducts have been obtained in lower yields.
In fact, the treatment of amines 3a and 3b with Michael
acceptor 4a in the presence of CeCl3-NaI system gave,
under the same conditions, the desired adducts 5a a and
5ba only 45% in both cases after a much longer period
of time, 3 and 4 days, respectively. Then, although the
mechanism of this reaction is not clear, silica gel has an
important role, and its presence was found to be essential
for the high efficacy of the reaction. A reasonable
explanation may be that the silica gel is mildly acidic
and must interact favorably with CeCl3 at its surface.
The enones and the amines probably coordinate at a
vacant coordination site of Ce metal that therefore
promotes the reaction.
With regard to amines, secondary ones (Figure 1) are
better reagents than primary amines since 1,4-conjugate
addition products with primary amines undergo further
additions giving rise to side products. The problem of
double-conjugate addition is not observed in the reactions
of secondary amines, evidently, because, protonation of
the initially formed enolate anion is relatively fast
compared with a second conjugate addition reaction,
dodging so a possible dimerization or polimerization of
the R,â-unsaturated ketone catalyzed by the amine.
This Michael addition reaction also works well for R,â-
unsaturated esters and nitriles (Table 1, entries 9-11).
The resulting â-amino derivatives are versatile synthons
that can be converted into â-amino acids, which have
been used in the synthesis of products with a wide range
of biological activity21 and pharmacological properties.22
On the other hand, in the case of R,â-unsaturated
aldehydes such as acrolein, the reaction suffers from
regiochemical restriction caused by competing 1,2- versus
1,4-addition (Scheme 2). As is well know, iminium salts
generally react faster and more regioselectively than the
corresponding carbonyl compounds,23 and thus, in R,â-
unsaturated iminium salt 7 the hard electrophilic char-
acter of the N-linked carbon atom is enhanced, that 1,2-
attack by a second molecule of amine 3a takes place
almost exclusively. In addition, it has been observed that
although the conjugate additions of amines to enones of
(Z)-configuration have been generally clean and efficient
(Table 1, entries 6, 7, and 12), the attempt extend this
(17) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.;
Sambri, L. Torregiani, E. J . Org. Chem. 2001, 66, 4430-4432. (b)
Bartoli, G.; Bellucci, M. C.; Marcantoni, E.; Petrini, M.; Sambri, L.;
Torregiani, E. Org. Lett. 2000, 2, 1791-1793.
(18) For some recent applications of solvent-free reactions, see: (a)
Loh, T.-P.; Huang, J .-M.; Goh, S.-H.; Vittal, J . Org. Lett. 2000, 1255-
1256. (b) Christoffers, J .; Mann, A. Eur. J . Org. Chem. 2000, 1977-
1982. (c) Loupy, A. Top. Curr. Chem. 1999, 206, 155-207. (d) Metzger,
J . O. Angew. Chem., Int. Ed. 1998, 37, 2975-2978. (e) Loh, T.-p.; Wie,
L. L. Tetrahedron 1998, 54, 7615-7624. (f) Soriente, A.; Spinella, A.;
De Rosa, M.; Giordano, M.; Scettri, A. Tetrahedron Lett. 1997, 38, 289-
290. (g) Laszlo, P. In Solid Supports and Catalysts in Organic
Synthesis; Smith, K., Ed.; Horwood: Chichester, 1992; pp 288-301.
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242.
(19) (a) Yadav, J . S.; Subba Reddy, B. V.; Srinivas, R.; Ramalingam,
T. Synlett 2000, 701-703. (b) Kotsuki, H.; Arimura, K. Tetrahedron
Lett. 1997, 38, 7583-7586. (c) Bianco, A.; Brufani, M.; Melchioni, C.;
Romagnoli, P. Tetrahedron Lett. 1997, 38, 651-652. (d) Kotsuki, H.;
Hayashida, K.; Shimanouchi, T.; Nishizawa, H. J . Org. Chem. 1996,
61, 984-990. (e) Laszlo, P.; Montaufier, M.-T.; Randriamahefa, S. L.
Tetrahedron Lett. 1990, 31, 4867-4870. (f) Nishiguchi, T.; Kanio, C.
J . Chem. Soc., Perkin Trans. 1 1989, 707-710.
(20) Studies showed that the yield of the Michael adduct was solvent
dependent. Among a few solvents tested, acetonitrile was shown to be
the best. In less polar solvents resulted in lower yields, CH2Cl2 (42%)
and CHCl3 (56%). A strongly coordinating solvent, i.e., DMF and THF,
showed no reaction at all, probably due to the deactivation of CeCl3 as
Lewis acid.
(21) (a) Frackenpohl, J .; Arvidson, P. I.; Screiber, J . V.; Seebach, D.
ChemBioChem 2001, 2, 445-455. (b) Cardillo, G.; Tomasini, C. Chem.
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1631.
(22) (a) Hayashi, Y.; Katada, J .; Harada, T.; Tachiki, A.; Lijima, K.;
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Sato, Y.; Yasuda, E.; Yano, M.; Uno, I.; Ojima, I. J . Med. Chem. 1998,
41, 2345-2360. (b) Rodriguez, M.; Fulcrand, P.; Laur, J .; Anmelas,
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9054 J . Org. Chem., Vol. 66, No. 26, 2001
Notes
Ta ble 1. Mich a el Ad d ition of Secon d a r y Am in es to r,â-En on es P r om oted by CeCl3‚7H2O-Na I System Su p p or ted in SiO2

Notes
J . Org. Chem., Vol. 66, No. 26, 2001 9055
Ta ble 1 (Con tin u ed )
a
b
All products were identified by their IR, NMR, and GC/MS spectra. The rate and yields of this reaction are improved when it was
warmed to 35 °C. c Yields of products isolated by column chromatography.
ture conditions as well as Bro¨nstedt basic terms are
avoided resulting excellent chemoselectivities. Then the
mildness of the reaction conditions and simplicity of
operation should make the present reaction highly syn-
thetically useful. Thus, further explorations of the scope,
selectivity, and mechanism of Michael addition of amines
F igu r e 1. Amines used as Michael donors.
to R,â-enones by using inexpensive and commercially
available salts such as CeCl3‚7H2O and NaI on solid
Sch em e 2
supports are in progress.
Exp er im en ta l Section
Gen er a l Meth od s. General experimental details are pro-
vided as Supporting Information.
Typ ica l E xp er im en t a l P r oced u r e. Silica gel (Baker
30-60 µm, 0.63 g) was added to a mixture of CeCl3‚7H2O (0.50
g, 1.36 mmol) and NaI (0.17 g, 1.16 mmol) in acetonitrile (5 mL),
and the mixture was stirred overnight at room temperature. The
acetonitrile was removed by rotary evaporation and to the
resulting reagent was added dibenzylamine (3a ; 0.2 g, 1.01
mmol) and methyl vinyl ketone (4a ; 88 mg, 1.26 mmol). Then,
the mixture was mechanically stirred at an external temperature
of 35 °C. After completion of the reaction (4.5 h) and addition of
conjugate addition of amines to enones of (E)-configura-
tion met with failure. In fact, the addition of amine 3a
and ethyl fumarate or (E)-3-nonen-2-one to CeCl3-NaI-
SiO2 system gave only starting material in both cases.
It is highly probable that these Michael adducts have
been difficult to obtain as it is unstable on SiO2 with
respect to retro-conjugate addition,24 and, thus, further
investigations on this unfavorable selectivity for (E)-
configuration are in progress in our laboratory.
diethyl ether (75 mL), the mixture was passed through a short
pad of Celite and the filtrate was washed with 10% aqueous citric
acid to remove the possible excess amine, with aqueous satu-
rated NaHCO3 solution, and with saturated NaCl solution and
finally dried over anhydrous Na2SO4. The extracts were then
concentrated under reduced pressure and the crude purified by
flash chromatography on a silica gel column (eluent: 30% EtOAc
in hexanes) to give 0.24 g (91% yield) of the corresponding
â-amino derivative 5a a as oil.
Ack n ow led gm en t. This research was carried out
within the framework of the National Project “Stereo-
selezione in Sintesi Organica. Metodologie ed Appli-
cazioni” supported by the Ministry of University and
Technological Research (MURST), Rome, and by the
University of Camerino.
In conclusion, we have shown that efficient conjugate
addition of secondary amines to R,â-enones have been
obtained with the use of amorphous silica gel. Its
promoting role, although not well understood, is ex-
plained through the adsorption of the reactants that come
into closer contact to each other on the silica surface. The
efficiency of our CeCl3‚7H2O-NaI system supported on
silica gel is remarkable: no inert conditions are required,
since oxygen and moisture are tolerated. Further, the
methodology does not require drastic and low tempera-
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, 1H NMR spectra, MS spectra, and other characteriza-
tion data for new compounds, not reported previously, desig-
nated by their entries in Table 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
(24) Toda, F.; Takumi, H.; Nagami, M.; Tanaka, K. Heterocycles
1998, 47, 469-479.
J O0108764