Highly efficient KF/Al2O3-catalyzed versatile hetero-Michael addition of nitrogen, oxygen, and sulfur nucleophiles to α,β-ethylenic compounds

Article abstract of DOI:10.1016/j.tetlet.2005.03.112

The first example of KF/Al₂O₃-catalyzed versatile hetero-Michael addition reaction of nitrogen, oxygen, and sulfur nucleophiles was developed for facile preparation of organic compounds of widely different structures. In contrast with the existing methods using many acidic catalysts, this method is very general, simple, high-yielding, environmentally friendly, and oxygen and moisture tolerant.

Full text of DOI:10.1016/j.tetlet.2005.03.112

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3279–3282
Highly efficient KF/Al2O3-catalyzed versatile
hetero-Michael addition of nitrogen, oxygen, and
sulfur nucleophiles to a,b-ethylenic compounds
Lei Yang, Li-Wen Xu* and Chun-Gu Xia*
State key laboratory of Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Lanzhou 730000, PR China
Received 24 February 2005; revised 14 March 2005; accepted 17 March 2005
Available online 5 April 2005
Abstract—The first example of KF/Al2O3-catalyzed versatile hetero-Michael addition reaction of nitrogen, oxygen, and sulfur nucleo-
philes was developed for facile preparation of organic compounds of widely different structures. In contrast with the existing meth-
ods using many acidic catalysts, this method is very general, simple, high-yielding, environmentally friendly, and oxygen and
moisture tolerant.
Ó 2005 Elsevier Ltd. All rights reserved.
The Michael reaction is one of the most important reac-
tions in organic chemistry. In general, conjugate addi-
tion reaction of nucleophiles to unsaturated carbonyl
compounds requires basic conditions or acidic cata-
lysts.1 This classical procedure often suffers from the
drawback of many side reactions such as polymerization
of starting olefins. Recently, the development of novel
synthetic methods of atomic economical hetero-Michael
addition reactions has attracted much attention due to
the importance of this structure motif in organic synthe-
sis.2 The heteroatom conjugate addition of nucleophiles
to a,b-unsaturated compounds is noteworthy as a
widely used method for carbon–heteroatom bond
formation. Several nucleophiles such as aliphatic and
aromatic amines have been used in this reaction and a
variety of Lewis acidic reagents or catalysts such as
Bi(OTf)3, FeCl3, InCl3, CeCl3Æ7H2O–NaI, Bi(NO3)3,
palladium, and other Lewis acids have been used suc-
cessfully in hetero-Michael additions.3
of carbamates have only been recently the subject of
investigations. Spencer and co-workers4 demonstrated
that PdCl2(MeCN)2, Brønsted acids, polymer-sup-
ported acids, and Cu(OTf)2 could be used in the
aza-Michael reactions of enones with carbamates. Koba-
yashi et al.5 surveyed catalytic activity of various tran-
sition metal salts in the aza-Michael reaction of enones
with benzyl carbamate and demonstrated that noble
transition metal salts, such as platinum salts, iridium
salts, gold salts are effective for this aza-Michael reac-
tion. Very recently, bismuth nitrate6 and TMAF7 were
also found to be effective catalysts in this aza-Michael
reaction of enones with carbamates. We are also inter-
ested in aza-Michael reactions of enones with carb-
amates and other nitrogen-containing reagent, and
have first reported several novel catalyst systems that
could be used in the aza-Michael reaction of chalcone
with carbamates.8 Although recent advances have made
this route more attractive, some of these methods are
limited by long reaction times, expensive catalysts.
Especially, there are few report in the literature for
the intermolecular Michael addition of carbamates to
The conjugate addition of carbamates to a,b-unsatu-
rated carboxylic acid derivatives can directly provide
the N-protected b-amino carbonyl compounds. Com-
pared to other Michael reaction, aza-Michael reaction
O
O
O
O
Keywords: Michael reaction; Oxygen; Nitrogen; Heteroatom; Lewis
base.
10mol% KF/Al2O3
Solvent , r. t. 20h
N
OEt
O
NH
O
OEt
Scheme 1.
*
Corresponding authors. Tel.: +86 931 4968129; fax: +86 931
8277088; e-mail addresses: licpxulw@yahoo.com; cgxia@lzb.ac.cn
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.112

3280
L. Yang et al. / Tetrahedron Letters 46 (2005) 3279–3282
a,b-unsaturated esters, acrylates, or acylonitrile.7
Therefore, the development of a cheaper, simpler,
milder, and more efficient method for this transforma-
tion is highly desirable.
became intrigued by the idea of using catalytic amo-
unts of cheap, readily available, and nontoxic bases.
Although large amount of strong base mediated, mostly
intramolecular aza- and oxa-Michael reactions have
been described, and no universal method for base-cata-
lyzed hetero-Michael reactions has been reported. Here-
in, we reported a novel catalyst, KF/Al2O3,9 which is
quite effective for the aza-Michael reactions of a,b-
unsaturated compounds with oxazolidinone. In the ini-
tial studies of the screening of catalysts, we found the
application of KF/Al2O3 as catalyst in this aza-Michael
reaction of ethyl acrylate with oxazolidinone resulted in
excellent yield (Scheme 1). Rapid conversion was
observed when the reaction was carried out in CH3CN
(97% yield) or DMF (96% yield). Low conversion
(21%) was obtained in CH2Cl2 when 10 mol% KF/
Al2O3 as catalyst. And moderate yield (65%) was
achieved in THF.
In our search toward an economical, environmentally
friendly route to b-amino carbonyl compounds, we
O
O
O
O
10mol% KF/Al2O3
Solvent , r. t.
N
X
O
X
O
NH
R
R
Scheme 2.
Table 1. KF/Al2O3 catalyzed aza-Michael addition of oxazolidinone
to a,b-unsaturated compounds10
With the effective catalyst system in hand, the conjugate
addition of oxazolidinone to other a,b-unsaturated com-
pounds were also investigated (Scheme 2). As shown in
Table 1, the catalytic system is suitable for a variety
of a,b-unsaturated compounds including enones, a,b-
unsaturated esters, a,b-unsaturated amide, and a,b-
unsaturated nitriles. This pathway offers a possible route
to the corresponding aza-Michael adducts in high yields.
These N-protected b-amino derivatives can be easily
converted into corresponding b-amino acids and other
derivatives that are very useful intermediates in the syn-
thesis of various biologically active compounds.11 And it
b
Time (h) Yield (%)
Entrya
a,b-Unsaturated compound
1
2
3
4
5
6
7
CH2@CHCN
20
20
20
20
24
24
24
96
97
96
95
93
94
92
CH2@CH–COOMe
CH2@CH–COOEt
CH2@CH–COOBu
CH2@CH–CONH2
CH2@CH–COC2H5
CH2@C(CH3)–COOMe
a Reaction conditions: a,b-unsaturated compound (1 mmol), oxazo-
lidinone (1.2 mmol), KF/Al2O3 (10 mol %), in CH3CN, rt.
b Isolated yield.
Table 2. KF/Al2O3 catalyzed hetero-Michael addition of ethyl acrylate with other weakly nucleophiles
Entrya
Nucleophile
Solvent
Time (h)
Product
Yieldb (%)
96
O
NH
N
1
CH3CN
18
OEt
OEt
N
N
O
O
NH
N
2
3
CH3CN
DMF
18
24
98
42
N
N
H
N
OEt
O
N
O
O
4
DMF
24
36
NH
N
OEt
O
O
O
O
5
6
C2H5SH
CH3CN
CH3CN
12
18
99
90
C2H5S
C2H5O
OEt
OEt
C2H5OH
O
O
7
8
DMF
DMF
24
24
48
16
S
O
SO2NH2
N
H
OEt
O
NH2COOEt
EtOOCHN
OEt
aAll reactions were carried out using 10 mol%KF/Al2O3 as catalyst, ethyl acrylate (1 mmol), nucleophile (1.2–1.5 mmol) in CH3CN or DMF at rt.
b Isolated yield.

L. Yang et al. / Tetrahedron Letters 46 (2005) 3279–3282
3281
is noteworthy to mention that it is the first example of
the catalytic aza-Michael reaction of oxazolidinone (car-
bamate) with a,b-unsaturated compounds other than
enones.
the experimental simplicity, the advantage of methodol-
ogy is the use of a cheaper, milder, and efficient catalyst
for the hetero-Michael addition reaction.
In contrast to previous transition metal catalysts, KF/
Al2O3 also efficiently mediates oxa-Michael reactions
of alcohol and other hetero-Michael reaction of sulfur
nucleophiles, heterocyclics. As shown in Table 2,
although both imidazole and pyrromonazole are weak
nucleophiles,12 they both are suitable nucleophiles
and good yields were obtained with the preparation
of 1-alkylimidazoles and 1-alkylpyrazoles. Alcohols
are considerably less reactive than carbamate,13 hence
poor yields were obtained with many transition
metal-based catalyst. However, with this KF/Al2O3 cat-
alyst, good yield was obtained interestingly in CH3CN.
Extension of this method with aliphatic thiols also
gives Michael products in good yield. Other nucleo-
philes such as pyrrole, phthalimide, p-toluene sulfon-
amide, was used in the hetero-Michael reaction,
moderate yields were obtained in the presence of
10 mol%KF/Al2O3 in DMF (Scheme 3). However,
NH2-based carbamates such as ethyl carbamate, was
not suitable nucleophile and low yield (16%) was
obtained with ethyl carbamate and ethyl acrylate in
DMF at room temperature. And only little aza-
Michael adducts were obtained when using chalcone,
cyclic enones as Michael acceptors. Compared to
conventional methods, enhanced reaction rates,
improved yields, and versatile utility are the features
observed in KF/Al2O3-catalyzed hetero-Michael
reactions. These examples demonstrate that Lewis base
catalysis can be superior to metal ion and Lewis acid
catalysis when weakly basic nucleophiles and versatile
a,b-unsaturated compounds are used in the hetero-
Michael reaction. In addition, this inorganic Lewis
base is not only advantageous in terms of reactivity,
but also regarding waste disposal and cost.
Acknowledgements
The study was financially supported by the Natural
Science Founder of China (No. 20402017).
References and notes
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9. The KF/neutral alumina was prepared according to the
literature: Schmittling, E. A.; Sawyer, J. S. Tetrahedron
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10. General experimental procedure, method A: To a solution
of a,b-unsaturated compounds (1 mmol) with solvents
(2 ml), nucleophiles (1.2–1.5 mmol) was added, and KF/
neutral alumina (10 mol%, 15 mg) was added in one
portion. After the mixture was stirring for given time, H2O
and CH2Cl2 was added, followed by 5 min stirring. The
catalyst was separated and the filter liquor extracted three
times with CH2Cl2. The organic layer was dried over
MgSO4, concentrated to give the crude product, and then
purified by silica column chromatography to afford pure
product. (eluting solvent: EtOAc–petroleum ether).
Method B: it is different in workup. After the mixture
To check the catalytic efficiency of recycling KF/Al2O3,
acrylonitrile was subjected to the conjugate addition of
oxazolidinone. KF/Al2O3 could be reused in several
times, after four runs, the yield of corresponding com-
pound was decreased to moderate (96%, 76%, 70%,
55%).
In conclusion, we have demonstrated the first use of KF/
Al2O3 as green catalyst for the conjugate addition of
oxazolidinone to a series of a,b-unsaturated com-
pounds. And it is the first example of catalytic aza-
Michael reaction of a,b-ethylenic compounds with
oxazolidinone. The present catalytic system was also
exhibited efficient catalytic activity in the hetero-Mi-
chael reaction of a,b-unsaturated compounds with other
nitrogen, oxygen, and sulfur nucleophiles. Apart from
O
O
10 mol% KF/Al2O3
CH3CN or DMF, r. t.
HX-R
R
OEt
X
OEt
X = NH, O, S
Scheme 3.

3282
L. Yang et al. / Tetrahedron Letters 46 (2005) 3279–3282
was stirring for given time, the catalyst was removed by
12. (a) Bartoli, G.; Bartolacci, M.; Giuliani, A.; Marcantoni,
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simple filtration. The solvent was evaporated to give the
crude and then purified by silica column chromatography
to afford pure product.
11. Although there is no report in the literature about the
conversion of these product in this aza-Michael reaction,
the functional moiety can undergo further conversions
using well-established procedure group chemistry Kocien-
ski, P. J. Protecting Groups; Georg Thieme: Stuttgart, 1994,
p 195.