Zinc oxide as an economical and efficient catalyst for the one-pot preparation of β-acetamido ketones via a four-component condensation reaction

Article abstract of DOI:10.1016/j.tetlet.2007.01.060

A new, efficient, one-pot, four-component condensation of benzaldehyde derivatives, acetophenone derivatives, acetyl chloride and acetonitrile in the presence of zinc oxide as catalyst is described for the synthesis of β-acetamido ketones.

Full text of DOI:10.1016/j.tetlet.2007.01.060

Tetrahedron Letters 48 (2007) 1729–1734
Zinc oxide as an economical and efficient catalyst
for the one-pot preparation of b-acetamido ketones
via a four-component condensation reaction
Malek Taher Maghsoodlou,a,* Asadollah Hassankhani, Hamid Reza Shaterian,
a
a
a
b
Sayyed Mostafa Habibi-Khorasani and Elaheh Mosaddegh
a
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan, PO Box 98135-674, Zahedan, Iran
b
Department of Chemistry, Shahid Bahonar University of Kerman, Kerman 76169, Iran
Received 18 May 2006; revised 27 December 2006; accepted 10 January 2007
Available online 14 January 2007
Abstract—A new, efficient, one-pot, four-component condensation of benzaldehyde derivatives, acetophenone derivatives, acetyl
chloride and acetonitrile in the presence of zinc oxide as catalyst is described for the synthesis of b-acetamido ketones.
Ó 2007 Elsevier Ltd. All rights reserved.
5
1
. Introduction
mycine or neopolyoxines. The best known route for
the synthesis of this class of compounds is the Dakin–
6
a
Multicomponent reactions (MCRs) are important for
the achievement of high levels of diversity, as they allow
more than two building blocks to be combined in prac-
tical, time-saving one-pot operations, giving rise to com-
plex structures by simultaneous formation of two or
West reaction, the condensation of an a-amino acid
with acetic anhydride in the presence of a base provides
the a-acetamido ketones via an azalactone intermedi-
ate. Recently, other synthetic methods have been used
for the formation of b-acetamido ketones through the
multicomponent condensation of aryl aldehydes, enoliz-
able ketones and acetyl chlorides in acetonitrile in the
presence of Lewis or Brønsted acid catalysts such as
Montmorillonite K-10 clay, silica sulfuric
acid, BiCl generated from BiOCl, ZrOCl Æ8H O,
sulfuric acid absorbed on silica
gel, Sc(OTf)3 and silica supported H PW O .
3 12 4
6
b
1
more bonds, according to the domino principle. MCRs
contribute to the requirements of an environmentally
friendly process by reducing the number of synthetic
steps, energy consumption and waste production.
Researchers have transformed this powerful technology
into one of the most efficient and economic tools for
7
,8
9
CoCl ,
2
1
0
11
12
3
2
2
1
3
heteropoly acid,
1
,2
14
15
16
combinatorial and parallel synthesis.
Due to their
inherent simple experimental procedures and their one-
pot character, they are perfectly suited for automated
synthesis. Thus, MCRs have attracted considerable
interest owing to their exceptional synthetic effi-
In recent years, zinc oxide (ZnO) has gained much inter-
1
7
est in the synthesis of nitriles from aldoximes, the
1
8
19
20
Beckmann rearrangement, Friedel–Crafts acylation
and the acylation of alcohols, phenols and amines.
1
–3
ciency.
Herein, we describe a new, simple, mild and effective
procedure for the one-pot synthesis of b-acetamido
ketones via a four-component condensation reaction
between aldehydes, enolizable ketones, acetyl chloride
and acetonitrile in the presence of zinc oxide as catalyst
Acetamido- or amino-ketone derivatives are important
for their biological and pharmaceutical properties,
and in the preparation of antibiotic drugs such as nikko-
4
(
Scheme 1). The MCRs for the preparation of b-acetam-
ido ketones were carried out under reflux at 80 °C.
Keywords: b-Acetamido ketone; Multicomponent synthesis; One-pot
reaction; Zinc oxide; Catalyst.
First, we prepared N-(3-oxo-1,3-diphenylpropyl)acet-
amide from the reaction of benzaldehyde, acetophe-
none, acetyl chloride and acetonitrile (reactant as well
*
Corresponding author. Tel.: +98 541 2446565; fax: +98 541
431067; e-mail: MT_maghsoodlou@yahoo.com
2
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.060

1730
M. T. Maghsoodlou et al. / Tetrahedron Letters 48 (2007) 1729–1734
Y
Y
X
CH COCl
3
X
+ H C
3
CH
CN
3
CHO
ZnO(cat) H C
NH
O
3
O
X=H, Cl, Me, NO2
Y = H, Cl, Me
O
Scheme 1.
as solvent) in the presence of different metal oxides
including CuO, Fe O , CdO, TiO , Th O , neutral
formation of any side products, in high to excellent
yields at reflux (Table 3, entries 1–23).
2
3
2
2
3
Al O and ZnO (Table 1).
2
3
The proposed mechanism for the ZnO catalyzed trans-
formation is shown in Scheme 2. Although it is not clear
how ZnO acts as a catalyst for the reaction, on the basis
of previously reported mechanism for applying of ZnO
for the preparation of acylium ion in Friedel–Crafts
The results in Table 1 show that amongst these catalysts,
ZnO was the catalyst of choice in terms of yield. Fur-
thermore, it is moisture stable, non-toxic and easy to
handle; it is also an inexpensive and commercially avail-
able inorganic solid Lewis acid.
1
9
acylation reaction and also acylation of alcohols, phe-
2
0
nols and amines it is suggested that the aldehyde is first
acylated to an intermediate I which then reacts with the
enol form of acetophenone derivative to produce III
Next, we optimized the amount of zinc oxide in the reac-
tion between benzaldehyde, acetophenone, acetyl chlo-
ride and acetonitrile (Table 2). The optimum amount
of ZnO was found to be 50 mol %.
+
after exchange of H from II. Next, acetonitrile attacks
III with elimination of acetate to give IV. Generated
HCl could be trapped by ZnO which is converted to
2
1
Thus, we prepared a range of b-acetamido ketones
ZnCl2. Hydrolysis of IV accompanied by tautomeriza-
tion gave the desired b-acetamido ketone. Furthermore,
the reaction was also performed in the presence of ZnCl2
as catalyst which also led to the one-pot synthesis of the
b-acetamido ketone.
under the optimized reaction conditions: aldehyde
(
(
1 equiv), enolizable ketone (1 equiv), acetyl chloride
2 equiv) and acetonitrile (reactant as well as solvent,
4
mL) in the presence of ZnO (50 mol %) (Table 3).
As shown in Table 3, aromatic aldehydes or acetophe-
nones with both electron-withdrawing or -donating sub-
stituents produced b-acetamido ketones without the
In summary, we have demonstrated ZnO as a cheap,
commercially available, reusable and non-corrosive cat-
alyst for the synthesis of b-acetamido ketones in excel-
lent yields under mild reaction conditions. The simple
experimental procedure combined with the easy work-
up and excellent yields of products are salient features
of the presented method.
Table 1. Preparation of b-acetamido ketones from benzaldehyde and
acetophenone in the presence of acetyl chloride and acetonitrile
catalyzed using a variety of metal oxides under reflux at 80 °C
a
b
Entry
Metal oxide
Time (h)
Yield (%)
2
. General experimental procedure for the one-pot
preparation of b-acetamido ketones
1
2
3
4
5
6
7
CuO
20
20
18
18
45
45
6
40
65
35
20
—
—
90
Fe
CdO
TiO
Th
2
O
3
A solution of the aryl aldehyde (2 equiv), aryl ketone
2 equiv), acetyl chloride (4 equiv), acetonitrile (4 mL)
2
(
2 3
O
Neutral Al
ZnO
2
O
3
and ZnO (1 equiv) was heated at 80 °C under reflux.
The reaction mixture was stirred for the appropriate
time (Table 3). The progress of the reaction was
followed by TLC. After completion of the reaction,
the mixture was cooled and poured into 50 mL of ice-
water. The solid residue was separated and dissolved
in dichloromethane. The solution was filtered and zinc
oxide was isolated and could be reused. The organic
phase was absorbed on silica gel and purified by column
chromatography petroleum ether (60–80 °C)/ethyl ace-
tate (9/1). All the products were identified by compari-
a
5
0 mol % used for each reaction.
Isolated yield.
b
Table 2. Preparation of b-acetamido ketones from benzaldehyde and
acetophenone in the presence of acetyl chloride and acetonitrile
catalyzed using ZnO under reflux at 80 °C
a
Entry
Metal oxide (mol %)
Time (h)
Yield (%)
1
son of their H NMR and IR data with those of
authentic samples.
sentative b-acetamido ketones are given below.
1
2
3
4
5
6
7
10
20
30
40
50
60
70
48
24
12
9
70
75
87
89
90
90
91
7
–16
The spectral data of some repre-
6
5.5
5.2
b-Acetamido-b-(phenyl)propiophenone (Table 3, entry
). Mp: 102–104 °C; H NMR (CDCl , 300 MHz): d
.03 (s, 3H), 3.45 (dd, J = 6.0 and 16.9 Hz, 1H), 3.77
1
1
2
3
a
Isolated yield.
(dd, J = 5.2 and 16.9 Hz, 1H), 5.58 (dd, J = 5.6 and

M. T. Maghsoodlou et al. / Tetrahedron Letters 48 (2007) 1729–1734
1731
Table 3. Preparation of b-acetamido ketones from aldehydes and enolizable ketones in the presence of acetyl chloride and acetonitrile catalyzed
using 50 mol % zinc oxide
a
Entry
Aldehyde
Ketone
Product
Time (h)
Yield (%)
1
H C
6
90
3
CHO
H C
NH
O
3
O
O
Cl
Cl
2
H
3
C
5.5
93
O
H C
NH
O
CHO
3
O
Cl
Cl
3
H
3
C
5.5
92
H C
NH
O
CHO
3
O
O
O N
2
O N
2
4
H
3
C
5.5
88
H C
NH
O
CHO
3
O
O
NO2
NO2
5
H
H
H
3
3
3
C
C
C
5
90
O
H C
NH
O
CHO
3
O
H C
3
H C
3
6
5.5
89
H C
NH
Cl
O
CHO
3
O
O
Cl
Cl
Cl
7
5
93
H C
NH
O
CHO
3
O
O
Cl
Cl
8
H C
6
89
3
H C
NH
O
CHO
3
O
(continued on next page)
O

1732
M. T. Maghsoodlou et al. / Tetrahedron Letters 48 (2007) 1729–1734
Table 3 (continued)
a
Entry
9
Aldehyde
Ketone
Product
Time (h)
Yield (%)
CH3
CH3
5
92
H C
3
CHO
CHO
CHO
H C
NH
O
3
O
O
Cl
CH3
CH3
Cl
1
1
1
0
1
2
H C
6
87
3
H C
NH
O
CHO
3
O
O
Cl
CH3
Cl
CH3
H C
6
88
3
H C
NH
O
O
3
O
O N
2
CH3
CH3
O N
2
H C
5.5
87
3
H C
NH
O
CHO
3
O
O
NO2
CH3
CH3
CH3
NO2
CH3
1
3
H C
5
86
3
H C
NH
Cl
O
O
3
O
Cl
CH3
Cl
Cl
1
4
H C
5
91
3
H C
NH
O
CHO
3
O
O
H C
3
CH3
H C
3
15
H C
5.5
93
3
H C
NH
O
CHO
3
O
O
Cl
Cl
Cl
16
5
89
H C
3
H C
NH
O
Cl
CHO
3
O
O

M. T. Maghsoodlou et al. / Tetrahedron Letters 48 (2007) 1729–1734
1733
Table 3 (continued)
Entry Aldehyde
a
Ketone
Product
Time (h)
Yield (%)
Cl
Cl
Cl
Cl
17
H C
6
92
3
CHO
O
H C
NH
O
3
O
O N
2
Cl
Cl
O N
2
18
H C
6
88
3
H C
NH
O
CHO
3
O
O
1
2
9
0
H
3
C
2
2
89
87
H C
NH
O
CHO
CHO
3
O
O
CH3
CH3
H C
3
H C
NH
O
3
O
O
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
1
2
3
5
5
6
94
H C
3
H C
NH
O
CHO
3
O
O
O
O
H C
3
Cl
Cl
H C
3
91
H C
3
H C
NH
O
CHO
3
O
Cl
Cl
O N
2
87
H C
3
O N
CHO
H
3
C
NH
O
2
O
a
1
7–16
Isolated yield and all of the products were identified by comparing their H NMR and IR data with those for authentic samples.
1
8
3
3.1 Hz, 1H), 6.90 (d, J = 6.3 Hz, 1H), 7.24–7.60 (m,
5.54 (dd, J = 5.6 and 13.5 Hz, 1H), 7.17–7.24 (m, 4H),
7.34 (s, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.85 (d, J =
8.6 Hz, 2H); IR (KBr, cm ) 3300, 3135, 1687, 1638,
À1
H), 7.91 (d, J = 7.5 Hz, 2H) ppm; IR (KBr, cm
)
À1
423, 1772, 1659, 1500, 1374, 1295, 1188, 1023, 704, 585.
1584, 1532, 1394, 1361, 1086, 989, 817, 782, 698.
b-Acetamido-b-(3-chlorophenyl)-4-chloropropiophen-
1
one (Table 3, entry 16). Mp: 111–113 °C; H NMR
b-Acetamido-b-(2,4-dichlorophenyl)-4-chloropropio-
1
(
CDCl , 300 MHz): d 2.07 (s, 3H), 3.42 (dd, J = 5.9
phenone (Table 3, entry 21). Mp: 163–165 °C, H NMR
3
and 17.3 Hz, 1H), 3.75 (dd, J = 5.4 and 17.5 Hz, 1H),
(CDCl , 300 MHz): d 2.08 (s, 3H), 3.42 (dd, J = 5.4 and
3

1734
M. T. Maghsoodlou et al. / Tetrahedron Letters 48 (2007) 1729–1734
O
OH
O
O
O
CH3
O
CH3
O
, ZnO
H
R'
CH2
H
R
H C
Cl
3
R
H
CH2
R'
H
R
H
Cl-
-
II
I
O
O
O
H
CH CN
R
O
CH3
CH2
3
H C
3
C
N
+ H
3
C
OH
H
R
R'
CH
2
R'
IV
III
O
O
H
H
H
H
O
C
O
R
H
H
H C
3
C
N
R
-H
R
H O
N
H C C
3
N
2
H C
3
CH2
R'
H
Work-up
CH2
CH2
R'
R'
IV
O
O
O
O
H
O
C
H
R
R
Tautomerism
H
3
C
NH
H C
N
3
CH2
R'
CH2
R'
O
O
Scheme 2.
1
7.2 Hz, 1H), 3.77 (dd, J = 6.0 and 17.2 Hz, 1H), 5.79
5. (a) D a¨ hn, U.; Hagenmaier, H.; H o¨ hne, H.; K o¨ nig, W. A.;
Wolf, G.; Z a¨ hner, H. Arch. Microbiol. 1976, 107, 249; (b)
Kobinata, K.; Uramoto, M.; Nishii, M.; Kusakabe, H.;
Nakamura, G.; Isono, K. Agric. Biol. Chem. 1980, 44,
(
dd, J = 5.8 and 13.5 Hz, 1H), 7.22 (dd, J = 2.0 and
8
4
2
.4 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.41–7.47 (m,
H), 7.84 (d, 8.5 Hz, 2H); IR (KBr, cm ) 3285, 3130,
À1
1
709.
985, 1682, 1650, 1586, 1547, 1469, 1399, 1093, 990, 815.
6
7
8
9
. (a) Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 745; (b)
Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91.
. Mukhopadhyay, M.; Bhatia, B.; Iqbal, J. Tetrahedron
Lett. 1997, 38, 1083.
. Bhatia, B.; Reddy, M. M.; Iqbal, J. J. Chem. Soc., Chem.
Commun. 1994, 713.
Acknowledgement
We are thankful to the Sistan and Baluchestan Univer-
sity Research Council for partial support of this work.
. Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003,
6
8, 5735.
1
0. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P.
Tetrahedron Lett. 2005, 46, 2105.
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