Cu(acac)2 immobilized in ionic liquids: A recoverable and reusable catalytic system for aza-Michael reactions

Article abstract of DOI:10.1002/adsc.200404361

Copper(II) acetylacetonate immobilized in ionic liquids efficiently catalyzes the aza-Michael reaction of amines with α,β-unsaturated carbonyl compounds to produce the corresponding β-amino carbonyl compounds with great alacrity in excellent yields. The reactions are far more facile than those reported earlier. The recovered ionic liquid phase containing the copper catalyst can be reused for several cycles with consistent activity.

Full text of DOI:10.1002/adsc.200404361

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Cu(acac)2 Immobilized in Ionic Liquids: A Recoverable and
Reusable Catalytic System for Aza-Michael Reactions
M. Lakshmi Kantam,a,* V. Neeraja,a B. Kavita,a B. Neelima,a
Mihir K. Chaudhuri,b,* Sahid Hussainb
a
Indian Institute of Chemical Technology, Hyderabad, 500007, India
Fax: (þ91)-40-27160921, e-mail: mlakshmi@iict.res.in
b
Indian Institute of Technology, Guwahati, 781039, India
E-mail: mkc@iitg.ernet.in
Received: November 26, 2004; Accepted: March 12, 2005
Abstract: Copper(II) acetylacetonate immobilized in
ionic liquids efficiently catalyzes the aza-Michael re-
action of amines with a,b-unsaturated carbonyl com-
pounds to produce the corresponding b-amino car-
bonyl compounds with great alacrity in excellent
yields. The reactions are far more facile than those
reported earlier. The recovered ionic liquid phase
containing the copper catalyst can be reused for sev-
eral cycles with consistent activity.
come some of the disadvantages, a good number of alter-
native procedures have been reported over the past few
years using Yb(OTf)3,[9] InCl3,[10] CeCl3 ·7 H2O,[11]
Bi(NO)3,[12a] Bi(OTf)3,[12b] Cu(OTf)2,[13] FeCl3 ·7 H2O/
Co(OAc)2,[14] LiClO4
and heterogeneous solid
[15]
acids,[16] but the need for an environmentally benign
and facile protocol still exists. Room temperature ionic
liquids are acknowledged as eco-benevolent alterna-
tives to volatile organic solvents and have also other use-
ful properties like very low vapor pressure, wide liquid
range, high thermal stability and possess highly conduc-
tive solvation ability for a variety of organic substrates
and catalysts including Lewis acids and enzymes.[17,18]
Recently, ionic liquids[19] and quaternary ammonium
salts in water[19b] have been reported to efficiently cata-
lyze the aza-Michael reaction. Considering all these, it
was thought that a combination of a suitable catalyst im-
Keywords: amides; amines; b-amino ketones; aza-Mi-
chael reaction; copper(II) acetylacetonate; esters;
ionic liquids; a,b-unsaturated carbonyl compounds
The aza-Michael reaction is one of the important reac- mobilized in an ionic liquid would enable facile conju-
tions in organic chemistry especially for the synthesis gate additions, as desired. Incidentally, our attention
of C N heterocycles[1,2] containing the b-amino carbon- was drawn to this problem at a juncture when we were
ꢀ
yl functionality. Such a functionality[3] not only consti- engaged[20] in the aziridination of olefins catalyzed by
tutes a component of biologically active natural prod- Cu(acac)2 immobilized in ionic liquids. To the best of
ucts but also serves as an essential intermediate in the our knowledge, aza-Michael reactions involving a com-
synthesis of b-amino ketones, b-amino acids and b-lac- bination ofthe chosencatalyst and an ionic liquid are un-
tam antibiotics, in addition to its use in the fine chemicals precedented. Herein, we report the aza-Michael reac-
and pharmaceutical sectors.[4] Because of the intrinsic tion of amines with a,b-unsaturated carbonyl com-
importance of b-amino carbonyl compounds, they pounds and nitriles to produce the corresponding b-ami-
have attracted sustained attention in organic synthesis, no ketones and nitriles in very high yields under mild re-
and the methods of construction of the functionality action conditions (Scheme 1) using arecyclable catalytic
have undergone a metamorphosis from the classic Man- system, Cu(acac)2 immobilized in ionic liquids.
nich-type reactions to the more widely used conjugated
BmimBF4 and bmimPF6 were synthesized according
addition of nitrogen nucleophiles to a,b-unsaturated to the procedures reported in the literature.[21] First,
carbonyl compounds[5] which is commonly known as
the aza-Michael reaction. The classical Mannich-type
reactions are certainly very powerful but need quite se-
vere reaction conditions and are rather sluggish thereby
limiting their use in practice.[6] The conjugated addition
reactions are, in the contrast, atom economic and quite
easy to operate. However, these reactions require either
basic conditions[7] or acidic catalysts[8] which seem to be
detrimental to the desired synthesis. In order to over- Scheme 1.
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DOI: 10.1002/adsc.200404361
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763

M. Lakshmi Kantam et al.
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Table 1. Aza-Michael reaction between piperidine and me-
tries 4 and 8). In the case of primary amines, 8–15% of
the bis-adducts were also formed (entries 7 and 12).
Sterically hindered amines were found to be less active
and gave the corresponding 1,4-adducts in moderate
yields after 2 h (entries 13 and 14). Both bmimBF4 and
bmimPF6 showed almost similar activities in the aza-Mi-
chael reaction of amines with a,b-unsaturated carbonyl
compounds (entry 1). When benzylamine and cyclohex-
ylamine were reacted with an excess of methyl acrylate,
bis-addition products were observed.
In order to extend the scope of this methodology, a,b-
substituted Michael acceptors like methyl methacrylate,
and methyl trans-cinnamate were tested under the same
reaction conditions (Table 2). It was found that methyl
methacrylate reacted readily with piperidine to give
the corresponding 1,4-adduct in a very high yield (en-
try 15) where as methyl trans-cinnamate reacted rather
sluggishly to give the 1,4-adduct in a relatively low yield
(entry 16). Some other electron-deficient olefins like w-
thyl acrylate under different reaction conditions.[a]
Entry
Catalyst
Solvent
Isolated Yield [%]
1
2
3
4
5
6
7
8
Cu(acac)2
CuCl2
–
Cu(acac)2
Cu(acac)2
CuCl2
Cu(acac)2
–
IL
IL
IL
CH3CN
H2O
98[b]
95[b]
60[b]
30
46
H2O
40
H2OþIL
54[c]
32[c]
H2OþIL
[a]
Reaction conditions: piperidine (1 mmol), methyl acrylate
(1.2 mmol), Cu catalyst (2 mol %) at room temperature
for 10 min.
Using 1 mL of the ionic liquid (IL).
Using 1 mL of H2O and 10 mol % of ionic liquid.
[b]
[c]
we demonstrated the catalytic effect of Cu(acac)2/CuCl2 nitrostyrene and cinnamaldehyde, for instance, failed to
for the conjugate addition of piperidine with methyl react with piperidine, although acrylamide afforded the
acrylate and the results are summarized in Table 1. In or- corresponding 1,4-adduct in good yield (entry 17). Fur-
der to investigate if CuCl2 would catalyze similar aza- thermore, with a view to demonstrate the scope of prac-
Michael reactions, an independent experiment was car- tical applicability of this methodology, the aza-Michael
ried out using CuCl2 in lieu of Cu(acac)2 (Table 1, en- reaction was carried out on a larger scale (20 mmol) us-
try 2). The result was quite interesting showing that ing IL-Cu(acac)2. The reaction was complete in 15 min
CuCl2 is equally effective as an aza-Michael catalyst in affording the 1,4-adduct in 96% yield (Table 2, entry 1)
ionic liquids. Furthermore, in recognition of the fact leading credence to the contention that the method can
that an ionic liquid alone is capable of catalyzing both be scaled up.
Michael[22] as well as aza-Michael[19b] reactions, an ex-
Finally, upon completion of the reaction, the ionic liq-
periment was conducted without any metal catalyst uid phase containing bmimBF4 and Cu(acac)2 was al-
but using only either bmimBF4 or bmimPF6 with other most quantitatively recovered by simple extraction of
conditions being similar to those maintained in the the product with Et2O. The recovered ionic liquid phase
Cu(acac)2-catalyzed reactions (Table 1, entry 3). It was containing the catalyst was reused for several cycles with
observed that the yield of product was far lower but consistent activity (Table 2, entry 1).
was, however, improved to some extent by prolonging
In conclusion, a soft, facile and clean aza-Michael re-
the reaction time. Thus, the importance of the metal cat- action of amines with a,b-unsaturated carbonyl com-
alysts in the presentmethodologyis quite clear. To ascer- pounds and nitriles by Cu(acac)2 immobilized in ionic
tain the superior performance of ionic liquids over other liquids has been developed. The methodology works
solvents, several experiments were conducted using very well using a low catalyst loading with easy catalyst
Cu(acac)2 or CuCl2 as the catalyst separately in acetoni- and solvent recycling. This method is capable of being
trile (Table 1, entry 4), water (entries 5 and 6), and a scaled up, if desired.
mixture of water and ionic liquid with and without amet-
al catalyst (entries 7 and 8). The conjugate addition took
place in each case albeit with low yields.
A variety of a,b-unsaturated carbonyl compounds or
Experimental Section
nitriles such as methyl acrylate, acrylonitrile, methyl vi-
nyl ketone, and cyclohexenone underwent 1,4-addition
with a wide range of aliphatic amines in the presence
of 2 mol % of Cu(acac)2 in 1 mL ionic liquid at room
temperature to give the corresponding b-amino com-
pounds or nitriles in high yields in a very short time.
The results are summarized in Table 2. In general, sec-
ondary amines gave higher yields than the primary
amines. Cyclic a,b-unsaturated ketone such as cyclohex-
enone reacted readily with benzylamine and piperidine
General Procedure for the Aza-Michael Reaction of
Amines with a,b-Unsaturated Carbonyls or Nitriles
A mixture of Cu(acac)2 (0.005 g, 2 mol %), amine (1 mmol) and
a,b-unsaturated compound (1.2 mmol) in ionic liquid (1 mL)
was stirred at room temperature for the appropriate time (Ta-
ble 2). After completion of the reaction, as indicated by TLC,
the product was extracted with diethyl ether (3ꢁ10 mL). The
combined ether extracts were concentrated under vacuum
and the resulting product was purified by column chromatogra-
to give the corresponding 1,4-adducts in high yields (en- phy on silica gel with ethyl acetate and n-hexane (2:8) as eluent
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Table 2. Cu(acac)2-catalyzed aza-Michael reaction of amines with a,b-unsaturated carbonyl compounds and nitriles in
[bmim]BF4
Entry
Amine
a,b-Unsaturated Compound
Time [min]
10
Yield [%][a]
1
98, 98[b], 96[c], 97[d]
2
3
10
10
98
96
4
5
25
15
85
90
6
7
10
15
92
85[e]
8
25
80
9
10
11
15
10
20
90
86
88[e]
12
13
14
15
80[f]
60
120
90
70
15
16
30
60
30
85
62
80
17
[a]
Yield of isolated product.
With Bmim[PF6].
Reaction on 20 mmol scale.
Yield after fifth cycle.
8–15% of the bis-adducts were formed.
With 2 mmol of a,b-unsaturated compound.
[b]
[c]
[d]
[e]
[f]
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M. Lakshmi Kantam et al.
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to afford the pure b-amino adduct. The ionic liquid containing
Cu(acac)2 was dried under vacuum for the next run. The prod-
ucts were characterized by comparison of their NMR, IR and
mass spectra with those of authentic samples.
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