Enamination of β-dicarbonyl compounds with amines

Article abstract of DOI:10.1002/jccs.200800032

Enamination of a wide variety of primary amines was successfully described with excellent chemoselectivity in the presence of catalytic amounts of β-cyclodextrin in water under mild conditions. Aliphatic amines also reacted efficiently to produce the corresponding enaminones.

Full text of DOI:10.1002/jccs.200800032

Journal of the Chinese Chemical Society, 2008, 55, 217-221
217
Enamination of b-Dicarbonyl Compounds with Amines
M. M. Khodaei,* A. R. Khosropour* and C. Cardel
Department of Chemistry, Faculty of Science, Razi University, Kermanshah 67149, Iran
Razi University Center for Enviromental Studies, Razi University, Kermanshah 67149, Iran
Enamination of a wide variety of primary amines was successfully described with excellent chemo-
selectivity in the presence of catalytic amounts of b-cyclodextrin in water under mild conditions. Aliphatic
amines also reacted efficiently to produce the corresponding enaminones.
Keywords: Enaminones; b-Dicarbonyl compounds; b-Cyclodextrin; Water.
INTRODUCTION
b-Enaminones are of pharmacological relevance1 and
bonding as seen in enzymes.16 The size, shape and lipo-
philicity of the guest molecule have an affect on complexa-
tion. Rao and co-workers17 reported that ring opening of
epoxides and aziridines, conversion of oxiranes into thi-
iranes, allylation of aldehydes, synthesis of thiazoles, oxi-
dation of THP ethers, and sulfides can be catalyzed by b-
CD. Oxidation of alcohols with b-CD was also reported.18
represent useful synthetic building blocks for the synthesis
of aminoacids,2 peptides,3 alkaloids4 and heterocyclic com-
pounds.5 In spite of their importance in organic synthesis as
intermediates and in pharmaceuticals, little attention has
been paid to synthesis of these compounds. The traditional
approach to the preparation of b-enaminones involves the
direct condensation of b-dicarbonyl compounds with amines
at reflux in an aromatic solvent with azeotropic removal
of water.6 Several catalysts like Al2O3,7 clay K-10/US,8
NaAuClO4,9 silica/MW10 and Bi(TFA)3/TBAB11 have been
reported to effect this synthesis. In addition, the reactions
of b-dicarbonyl compounds with amines have been carried
out in water12 and solvent-free conditions.13 However,
some of these methods have limited synthetic scope due to
the use of toxic solvents, long reaction times, unsatisfac-
tory yields or low selectivity. Thus the development of a
simple and high yielding method for the preparation of
b-enaminones under mild conditions is desirable.
RESULTS AND DISCUSSION
In this study, different types of primary amines were
subjected to reaction with b-dicarbonyl compounds to pre-
pare b-enaminones by b-CD in water (Scheme I).
Scheme I
b-Cyclodextrins (b-CD) are important natural host
compounds due to their encapsulating ability of drugs and
bioactive substances.14 In addition, they have lipophilic
cavities, which bind substrates and catalyze chemical reac-
tions selectively. In fact, a substrate hidden inside the b-CD
cavity is less inclined to undergo transformation than a free
one. It has been shown that in many b-CD catalysis exam-
ples,15 formation of inclusion compounds may accelerate
the unexpected reaction. They catalyze reactions by revers-
ible formation of host-guest complexes by noncovalent
The results are summarized in Table 1. The reactions
were completed at room temperature within 5-90 min. The
products were obtained in excellent yields and chemo-se-
lectivity to afford Z-b-enaminones, confirmed by 1H NMR
spectrum of the crude products (d = 7.5-12.8 for NH).
Probably, the reaction proceeds through the activa-
* Corresponding author. E-mail: mmkhoda@razi.ac.ir

218 J. Chin. Chem. Soc., Vol. 55, No. 1, 2008
Khodaei et al.
Table 1. Enamination reaction catalyzed with b-CD in water at room temperature
Entry
119
R1
R2
R3
R4
Time (min) Yield (%)
Product
CH3(CH2)2CH2NHC=CHCO2C2H5
CH3
CH3
H
OC2H5 CH3(CH2)2CH2
OC2H5 H2NCH2CH2
5
5
99
99
O
O
212
CH3
H
-C=CHCOC H
NH
C2H5OCCH=CNH
CH3
2
5
CH3
HOCH2CH2NH-C=CHCO2C2H5
CH3
312
412
CH3
CH3
H
H
OC2H5
OC2H5
HOCH2CH2
C6H5CH2
5
8
95
97
CH2NH-C=CHCO2C2H5
CH3
NH-C=CHCO2C2H5
CH3
520
619
721
CH3
CH3
CH3
H
H
H
OC2H5
OC2H5
OC2H5
C6H5
10
13
20
85
90
70
NH-C=CHCO2C2H5
CH3
CH3
Cl
4-CH3C6H4
4-ClC6H4
NH-C=CHCO2C2H5
CH3
CH3
NH-C=CHCO2C2H5
822
CH3
H
OC2H5
a-naphthyl
15
90
60
20
90
80
90
96
95
96
H3C
NH
O
919
CH3 CH2CH2R
CH3 CH2CH2R
CH3 CH2CH2R
O
O
O
C6H5
O
H3C
NH
CH3
1013
1123
1213
4-CH3C6H4
O
O
H3C
NH
Cl
4-ClC6H4
O
O
H3C
NHCH2
CH3 CH2CH2R
O
O
C6H5CH2
O
O
H3C
NHCH2CH2OH
1323
CH3 CH2CH2R
HOCH2CH2
80
40
95
91
O
O
-CH=CHCOCH
CH3CH2CHNH
3
1419
CH3
H
CH3 CH3CH2CHCH2
CH3
CH3

Enamination of b-Dicarbonyl Compounds with Amines
J. Chin. Chem. Soc., Vol. 55, No. 1, 2008 219
O
O
1512
CH3
H
CH3
H2NCH2CH2
30
90
-C=CHCCH
NH
CH3CCH=C-NH
CH3
3
CH3
HOCH2CH2NH-C=CHCOCH3
CH3
1612
1720
CH3
CH3
H
H
CH3
CH3
HOCH2CH2
C6H5
30
20
90
80
NH-C=CHCOCH3
CH3
Cl
NH-C=CHCOCH3
CH3
18
CH3
CH3
CH3
H
H
H
CH3
4-ClC6H4
20
35
35
78
90
92
-CH=CHCOC H
CH3CH2CHNH
CH3
6
5
1912
2023
Ph CH3CH2CHCH2
CH3
NH-C=CHCOC6H5
H3C
Ph
Ph
Ph
4-CH3C6H4
H2NCH2CH2
C6H5CH2
CH3
O
O
2123
CH3
CH3
H
H
30
15
92
82
-C=CHCC H
NH
C6H5CCH=C-NH
CH3
6
5
CH3
CH2NH-C=CHCOC6H5
CH3
2224
2319
2412
CH3
CH3
H
H
Ph
Ph
C6H5
20
30
75
88
NH-C=CHCOC6H5
CH3
HOCH2CH2NH-C=CHCOC6H5
HOCH2CH2
CH3
a All products were identified by comparison of their physical or spectral data with those reported in the literature.
b Isolated yields.
tion of the carbonyl group of the acetyl part by complexa-
tion with b-CD followed by nucleophilic addition of amines
to the carbonyl group and subsequently the enaminone for-
mation.
equivalent of ethylene diamine, the diamination product
was produced as a sole product and no monoamination
product was observed (Scheme II).
However, the reaction of one equivalent of b-dicar-
bonyl compound with one equivalent of ethylene diamine
was not complete.
Although it was reported that the synthesis of b-en-
aminones is limited to soluble amines in water, we achieved
that in the presence of b-CD; water insoluble amines were
also converted efficiently to the corresponding enaminones
in high yields. However, anilines with strong electron with-
drawing groups such as 4-nitroaniline did not give any
product under the present reaction conditions. Aliphatic
amines also reacted efficiently to produce the correspond-
ing enaminones. This method was successfully applied to
linear (Table 1, entries 1-8), and cyclic b-ketoesters (Table
1, entries 9-13), and b-diketones (Table 1, entries 14-24).
The use of b-CD showed rate enhancements, high yields
and short reaction times. It was found that when one or two
equivalents of b-dicarbonyl compound reacted with one
In conclusion, b-CD is a highly efficient catalyst for
enamination of b-dicarbonyl compounds. Short reaction
times, mild reaction conditions, high chemo-selectivity and
high yield products are noteworthy advantages of this pro-
cedure. Water insoluble amines were also converted effi-
ciently to the corresponding enaminones in high yields.
Moreover, stability and non-toxicity of the catalyst are the
other merits of this method.
EXPERIMENTAL SECTION
Products are known compounds and were character-

220 J. Chin. Chem. Soc., Vol. 55, No. 1, 2008
Khodaei et al.
Scheme II
ized by comparison of their spectral data (1H NMR, IR) or
melting points with those reported in the literature. Moni-
toring of the reactions was accomplished by TLC on pre-
coated silica gel 60 F254 sheets. All yields refer to isolated
products.
ACKNOWLEDGEMENTS
We are grateful to the Research Council of Razi Uni-
versity for partial financial support of this work.
Received March 5, 2007.
General experimental procedure for synthesis of
enaminones
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