Uncatalyzed synthesis of β-enamino ketones in PEGWater

Article abstract of DOI:10.1071/CH08041

β-Enamino ketones have been synthesized in excellent yield by the reaction of aromatic or aliphatic amines with 1,3-dicarbonyl compounds in polyethylene glycol (PEG)-600water. The PEG-600 is recycled and reused. CSIRO 2008.

Full text of DOI:10.1071/CH08041

Short Communication
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 552–555
www.publish.csiro.au/journals/ajc
Uncatalyzed Synthesis of β-Enamino Ketones in PEG–Water
Babasaheb P. Bandgar,A,B Sachin A. Patil,A Balaji L. Korbad,A
Sunita B. Bandgar,A and Baliram S. HoteA
AOrganic Chemistry Research Laboratory, School of Chemical Sciences, Swami Ramanand
Teerth Marathwada University, Nanded-431606, India.
BCorresponding author. Email: bandgar_bp@yahoo.com
β-Enamino ketones have been synthesized in excellent yield by the reaction of aromatic or aliphatic amines with 1,3-
dicarbonyl compounds in polyethylene glycol (PEG)-600–water. The PEG-600 is recycled and reused.
Manuscript received: 1 February 2008.
Final version: 1 June 2008.
An increase in regulatory pressure on the use, manufacture,
and disposal of organic solvents has focussed attention on the
development of non-hazardous alternatives essential for the
sustainable development of chemical enterprise.[1,2] One such
interesting solvent system is polyethylene glycol (PEG) in aque-
ous solution which is comparable to currently favoured solvents
such as ionic liquids, supercritical carbon dioxide, and micellar
systems.[3]
The development of facile synthetic methods leading to β-
enamino compounds and their derivatives without side products
constitutes an active area of investigation in synthetic organic
chemistry. β-Enamino compounds are useful precursors for the
synthesis of a variety of heterocyclic compounds.[4] They are
the synthons for construction of biologically active compounds
such as dopamine auto-receptor agonists,[5] acetylcholinesterase
inhibitors, oxytoxin antagonists,[6] and anticonvulsants.[7]
Recently, the β-enamino ketone moiety has attracted much atten-
tion because of its use as an intermediate for preparation of part
of the side chain of taxol.[8]
K-10 in benzene or as a solid support as catalysts or
as reactants.[10] Efficient room-temperature syntheses of
β-enaminones and β-enamino esters have been reported under
solvent-free conditions using ZrOCl2·H2O.[11] Other synthetic
methodsreportedforβ-enaminoketonesareadditionofanamine
to halo vinyl ketones, hydrogenation of isoxazoles,[12] and Pd-
catalyzed amination to electron-deficient olefins.[13] Recently,
improvements to the synthesis of β-enamino ketones have also
been reported.[14]
As part of our ongoing program on the development of novel
methods in organic synthesis,[15] we report herein an efficient
method for the synthesis of β-enamino ketones. In this pro-
cedure (Scheme 1), 1,3-dicarbonyl compound 1 and amine 2
in PEG-600–water were refluxed and the progress of the reac-
tion monitored by TLC. Following completion of the reaction,
aqueous workup afforded β-enamino ketone 3 in 60–90% yield.
A series of reactions of various amines and 1, 3-dicarbonyl com-
pounds was carried out to evaluate the synthetic utility of the
procedure, with results presented in Table 1.
Several methods have been reported for the prepara-
tion of β-enamino compounds. One of the most versa-
tile approaches is condensation of β-dicarbonyl compounds
with amine by azeotropic removal of water.[9] Research has
focussed on environmentally benign synthetic methods with
a concomitant increase in reported procedures for the syn-
thesis of β-enaminones. These methods include the use of
ammonium or alkyl ammonium acetate, Lewis acids such
as boron trifluoride etherate, alumina, and montmorillonite
The reaction proceeded very smoothly and cleanly at reflux
conditions. This protocol offers several advantages, mainly in
terms of its simple procedure and workup combined with excel-
lent product yields. In addition the procedure requires neither
addition of catalyst nor azeotropic removal of water. We note
that both aliphatic and aromatic amines reacted well with cyclic
1,3-dicarbonyl compounds (entries a–i, Table 1). The protocol
is also applicable for the synthesis of β-enamino esters (entries
j–m, Table 1).
O
O
O
PEG–water
ϩ
R
NH2
R
N
H
Reflux
OH
O
1
2
3
Scheme 1.
© CSIRO 2008
10.1071/CH08041
0004-9425/08/070552

Synthesis of β-Enamino Ketones in PEG–Water
553
Table 1. Synthesis of β-enamino ketones in polyethylene glycol-600 and water
Entry
a
Starting material 1
Starting material 2
Product 3
Time [h]
YieldA,B [%]
O
O
NH2
0.5
90
N
H
O
3a
3b
NH2
O
O
Me
b
c
d
1.0
1.1
1.0
80
85
83
N
H
O
Me
NH2
O
O
OMe
N
H
3c
3d
O
OMe
NH2
O
O
Br
N
H
O
Br
NH2
O
O
O
CI
e
f
1.2
2.0
80
60
N
H
3e
3f
O
CI
O
NH2
N
H
O
NH2
NO2
O
O
NO2
g
4.0
70
85
N
H
3g
O
O
O
h
1.5
1.0
O
N
H
NH2
O
O
3h
O
O
NH2
i
82
N
H
O
3i
(Continued)

554
B. P. Bandgar et al.
Table 1. (Continued)
Starting material 2 Product 3
Entry
Starting material 1
Time [h]
1.0
YieldA,B [%]
NH2
j
83
NH
O
O
O
O
O
OEt
OEt
OEt
OEt
3j
NH2
k
1.1
82
HN
O
3k
HN
HN
l
1.2
1.3
80
85
O
O
O
O
O
O
NH2
OEt
OEt
OEt
OEt
3l
m
NH2
3m
AYields of pure isolated product.
BProducts were characterized by IR, NMR, and mass spectroscopy.
Table 2. Reaction between dimedone and aniline using polyethylene glycol (PEG)–water systems at
different temperatures
O
O
NH2
Solvent
ϩ
Temperature [°C]
N
H
O
Entry
1
Solvent
Temp. [◦C]
Time [h]
Yield [%]
PEG-300 + water
PEG-400 + water
PEG-600 + water
25
50
100
25
50
100
25
2
2
2
2
2
2
2
2
2
20
45
50
10
40
45
30
50
90
2
3
50
100
The reaction was optimized at various temperatures using the
same PEG with good to excellent yields obtained at 100◦C. For
the reaction between dimedone and aniline the effect of different
PEG such as PEG-300, PEG-400, and PEG-600 was tested with
excellent yields obtained for PEG-600 at 100◦C (Table 2).
Furthermore, we note that PEG-600 may be recycled several
times and recovered in almost pure form by distillation of the
aqueous layer under vacuum (Table 3).
Table 3. Reuse of recovered polyethylene glycol (PEG)-600
No. of uses
Yield of product [%]
Recovered PEG-600 [%]
1
2
3
4
90
88
87
85
98
95
93
90

Synthesis of β-Enamino Ketones in PEG–Water
555
Inconclusion, wehavedevelopedanovel, ecofriendlymethod
for the synthesis of β-enamino ketones under neutral conditions.
[6] F. Gatta, M. R. Delguidice, M. Pomponi, M. Marta, Heterocycles 1992,
34, 991.
[7] K. R. Scott, I. O. Edafiogho, E. L. Richardson,V.A. Farrar, J.A. Moore,
E. I. Tietz, C. N. Hinko, H. Chang, A. El-Assadi, J. M. Nicholson,
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Experimental
Typical Procedure
Dimedone (1 mmol) and aniline (1 mmol) in PEG-600 (5 mL)
and water (5 mL) were refluxed, and the progress of the reaction
was monitored by TLC. After completion of the reaction, the
product (β-enamino ketone) was filtered off and dried to the
product in 90% pure form.
[10] (a) F. Texier Boullet, B. Kelin, J. Hamelin, Synthesis 1986, 408.
(b) M. E. F. Baribanbte, H. S. Baribabte, L. Missio, A. Andicoputto,
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Accessory Publication
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Spectroscopic data for compounds 3a–m are available from the
authors or, until July 2013, the Australian Journal of Chemistry.
Acknowledgement
We thank Council of Scientific and Industrial Research (CSIR), New Delhi,
for financial assistance (project no: 01/2023/05/EMR-II) and for fellowships
(S.A.P., B.L.K., and B.S.H.).
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