Silica supported tungstosilicic acid as an efficient and reusable catalyst for the one-pot synthesis of β-acetamido ketones via a four-component condensation reaction

Article abstract of DOI:10.5012/bkcs.2010.31.12.3653

Silica supported tungstosilicic acid has been used as an effective catalyst for a modified Dakin-West one-pot, four- component condensation of an aryl aldehyde, an aryl ketone, acetyl chloride and acetonitrile for the synthesis of β-acet- amido ketones. This catalytic system can act as an active, inexpensive, recoverable and recyclable catalyst. Some advantages of this system are short reaction times, good to excellent yields, easy work up and the ability to be carried out at the large scale reactions.

Full text of DOI:10.5012/bkcs.2010.31.12.3653

Silica Supported Tungstosilicic Acid
Bull. Korean Chem. Soc. 2010, Vol. 31, No. 12 3653
DOI 10.5012/bkcs.2010.31.12.3653
Silica Supported Tungstosilicic Acid as an Efficient and Reusable Catalyst
for the One-Pot Synthesis of β-Acetamido Ketones
via a Four-Component Condensation Reaction
Masoud Nasr-Esfahani,* Morteza Montazerozohori, and Tahere Gholampour
Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran. *E-mail: manas@mail.yu.ac.ir
Received August 19, 2010, Accepted October 7, 2010
Silica supported tungstosilicic acid has been used as an effective catalyst for a modified Dakin-West one-pot, four-
component condensation of an aryl aldehyde, an aryl ketone, acetyl chloride and acetonitrile for the synthesis of β-acet-
amido ketones. This catalytic system can act as an active, inexpensive, recoverable and recyclable catalyst. Some
advantages of this system are short reaction times, good to excellent yields, easy work up and the ability to be carried
out at the large scale reactions.
Key Words: β-Acetamido ketone, Silica supported tungstosilicic acid, Four-component, Dakin-West reaction
Introduction
ketones,28 or photoisomerisation of phthalimides.29
The Dakin-West reaction is the conventional way for the
synthesis of β-acetamido ketones, involving condensation of
an α-aminoacid with acetic anhydride in the presence of a base
via an intermediate azalactone.30 Iqbal and coworkers reported
the best known route for the synthesis of β-acetamido carbonyl
compounds in the one-pot condensation of an aldehyde, an
enolizable ketone, acetyl chloride, and acetonitrile catalyzed
both CoCl231 and Montmorillonite K-10 clay.32 A few catalysts
have already been applied for the synthesis of β-acetamido ke-
tones using this method, including Sn(II),33 Sc(III) triflates,34
InCl3,34 H2SO4/SiO2,35 Zirconia,36 ZnO,37 phosphotungstic acid,38
sulfamic acid,39a aluminium hydrogen sulfate,39b CeCl3,40 ce-
rium(IV) sulfate,41 and Nafion-H.42 The role of these acidic
catalysts is activation of the carbonyl group of the aldehyde
toward the addition of acetonitrile43,44 or toward the attack of the
enole of aryl ketone.45 These methods are valuable but they suffer
from different drawbacks such as hazardous reagents, high tem-
perature, expensive catalysts, long reaction time, tedious work-
up and low yield. Hence, the development of a simple and new
protocol with more efficiency is still in demand.
Multicomponent reactions (MCRs) have proved to be re-
markably successful in generating highly complex structures
in a single synthetic step operation.46 This process has emerged
as an efficient and powerful tool in modern synthetic chemistry
allowing the facile creation of several new bonds in a one-pot
transformation. The organic chemists have transformed this po-
werful technology into one of the most efficient and economic
tools for parallel and combinatorial synthesis.47 One eminent
MCR that produces an interesting class of compounds is the
Dakin-West reaction, which is a powerful synthetic method
for the preparation of β-acetamido carbonyl compounds.
It is, therefore, interesting to find out the behavior of a new
catalytic system in the synthesis of β-acetamido ketones in a
one-pot multicomponent way.
Heteropoly acids (HPAs) are a unique class of active ma-
terials in both redox and acid catalysis,1-3 which are widely used
as catalysts in various reactions. HPAs with Keggin structure
are the most studied class within polyoxometalates, because
they possess relatively high thermal stability4 and acidity,5 and,
12-tungstophosphoric acid and 12-tungstosilicic acid are the
usual catalysts of choice because of their high acidic strength,
relatively high thermal stability, and lower oxidation potential.
HPAs can be used either directly as a bulk material or in support-
ed form in both homogeneous and heterogeneous systems. They
are highly soluble in polar solvents but insoluble in non-polar
ones. Some advantages of HPAs are non-corrosive, environ-
mentally friendly because of its reusability, economically fea-
sible solid acid catalysts compared to conventional homogene-
ous acids, high flexibility, in modification of the acid strength,
ease of handling, non-toxicity and experimental simplicity.6
From the synthetic point of view, a variety of useful transform-
ations such as oxidation of alcohols,7 Friedel-Crafts8 and Man-
nich reactions,9 cyanosilylation,10 ring-opening of epoxides,11
and dehydration,12 have been developed using HPAs as cataly-
sts. Increasing of the surface area or even better, increasing of
the number of accessible acid sites of the HPAs is important.
This can be achieved by dispersing the HPAs on solid supports
with high surface area.13-15 These supported catalysts have been
widely studied and found useful in many reactions such as the
synthesis of 2,4-dihydropyrimidones,16 metanethole,17 α-amino-
nitriles18 and esterification.19,20
The β-acetamido carbonyl compounds, in that their skeletons
exist in a number of valuable biologically or pharmacologically
active compounds,21,22 has gained considerable attention in or-
ganic synthesis, owing to their importance as versatile inter-
mediates for preparation of β-amino acids,23 or 1,3-amino al-
cohols24 as well as for the synthesis of various antibiotics such
as nikkomycins or neopolyoxines25 and potent molecules in
α-glucosidase inhibitory activity.26
Experimental
β-Acetamido ketones were usually prepared through Michael
addition to α,β-unsaturated ketones,27 acylation of β-amino-
Chemicals were purchased from Merck, Fluka and Aldrich

3654 Bull. Korean Chem. Soc. 2010, Vol. 31, No. 12
Masoud Nasr-Esfahani et al.
chemical companies. All of the products were identified by
comparison of their physical and spectral data with those of au-
thentic samples. IR spectra were recorded on a JASCO-FTIR-
680 spectrophotometer. 1H NMR spectra were obtained with
a Bruker 400 Ultrasheild (400 MHz) spectrometer.
Preparation of the supported catalyst. The silica gel support-
ed H4SiW12O40 was prepared by mixing silica gel (1.4 g, Merck
grade 40, 0.063 - 0.2 mm) with a solution of acid (0.60 g) in
distilled water (20 mL). The resulting mixture was stirred for
30 min. After removal of water in a rotary evaporator, the solid
powder was dried at 80 oC for 4 h followed by 4 h calcinations
at 170 oC.
N-[3-(3-Nitrophenyl)-1-(4-nitrophenyl)-3-oxopropyl]acet-
amide (Table 3, entry 28): mp 157 - 159 oC; Rf = 0.49 (n-hexane:
ethyl acetate = 1:4); IR [(KBr) cm‒1]: 3300, 3090, 1692, 1642,
1607, 1424, 1325, 1125,1105, 670,593; 1H NMR (400 MHz,
CDCl3) δ 1.89 (s, 3H), 3.41 (dd, J = 6.5 and J = 17.5 Hz, 1H),
3.72 (dd, J = 6.5 and J = 18.0 Hz, 1H), 5.55 (m, 1H), 7.50 (d,
J = 8.5 Hz, 1H), 7.59 (dd, J = 9.0 Hz, J = 16.5 Hz, 2H), 8.07
(d, J = 8.4 Hz, 1H), 8.17 (m, 1H), 8.31 (dd, J = 8.5 Hz, J = 17
Hz, 2H), 8.65 (d, J = 9.0 Hz, 1H); 13C NMR (CDCl3), δ 23.15,
42.34, 49.06, 122.93, 128.72, 132.81, 134.85, 135.92, 137.44,
146.86, 148.72, 149.41, 151.78, 169.45, 198.75. Anal. Calcd.
for C17H15N3O6: C, 57.14; H, 4.23; N, 11.76; Found: C, 57.0;
H, 4.1; N, 11.8.
General procedure forthe preparation of β-acetamido ke-
tones. A mixture of the aryl aldehyde (1 mmol), aryl ketone
(1 mmol), acetyl chloride (0.3 mL) and acetonitrile (2 mL) in
the presence of H4SiW12O40-SiO2 (0.1g, equal to 0.04 mmol H+)
was heated at 80 oC, with stirring for 20 - 60 min. The progress
of the reaction was monitored by TLC. After completion of the
reaction, the mixture was filtered and the filtrate was poured
into 50 mL ice-water. The solid product was filtered, washed
with ice-water and recrystallized from ethyl acetate/n-heptane
to give the pure products in 75 - 92% yields based on the starting
aldehyde (Table 3). Spectroscopic data of new compounds:
N-[3-(4-Nitrophenyl)-1-(2,6-dichlorophenyl)-3-oxopropyl]
acetamide (Table 3, entry 25): mp 78 - 81 oC; Rf = 0.43 (n-hex-
ane:ethyl acetate = 1:4); IR [(KBr) cm‒1]: 3406, 3105, 1689,
1674, 1605, 1520, 1428, 1400, 1324,1150, 1008, 856, 740, 670,
618; 1H NMR (400 MHz, CDCl3) δ 2.00 (s, 3H), 3.70 (dd, J = 8.0
and J = 16.8 Hz, 1H), 3.76 (dd, J = 8.2 and J = 16.4 Hz, 1H),
6.56 (m, 1H), 7.18-7.36 (m, 3H), 8.15 (d, J = 8.0 Hz, 2H), 8.33
(d, J = 7.6 Hz, 2H); 13C NMR (CDCl3), δ 23.42, 42.95, 48.08,
128.73, 129.67, 129.45, 129.87, 130.26, 132.65, 134.07, 135.42,
139.43, 170.45, 198.23. Anal. Calcd. for C17H14Cl2N2O4: C,
53.56; H, 3.70;; N, 7.35; Found: C, 53.4; H, 3.7; N, 7.2.
N-[3-(4-Methoxyphenyl)-1-(2-nitrophenyl)-3-oxopropyl]
Results and Discussion
In continuation of our ongoing research program on tung-
stosilicic acid,48 we wish to report a convenient and efficient
procedure for the synthesis of β-acetamido ketones in the pre-
sence of catalytic amounts of tungstosilicic acid supported on
SiO2 (Scheme 1).
Preparation of the silica supported 12-tungstosilicic acid.
The supported tungstosilicic acid catalyst were prepared by the
method of incipient wetness. In a typical procedure, a 600 mg
portion of acid was dissolved in deionized water (50 mL) and
impregnated drop-wise onto 1400 mg supports under constant
agitation. The resulting pastes were dried at 80 oC for 4 h and
then calcined at 170 oC for 4 h.49
FT-IR spectra can be used as a powerful technique for the
investigation of surface interaction between tungstosilicic acid
and inorganic support. Pure acid compound display infrared
bands at 980 (W=O), 925 (Si-O), 880 (W-Od-W) and 781 cm‒1
(W-Ob-W).50 In addition, a broad, intense band centered around
3450 cm‒1 (νO-H stretching) and a weak absorption at 1640 cm‒1
(δH2O bending) indicate the presence of water.
o
acetamide (Table 3, entry 26): mp 170 - 172 C; Rf = 0.45
However, small shifts of νW=Od (973 cm‒1) and νW-Oc-W
(790 cm‒1) vibrations were registered indicating interactions
of the support with the most external atoms Od and Oc of the
Keggin anion. Such effects are decreased with the increasing
coverage.
(n-hexane:ethyl acetate = 1:4); IR [(KBr) cm‒1]: 3290, 3080,
1675, 1648, 1587, 1520, 1448, 1250, 985, 820, 675, 598; 1H
NMR (400 MHz, CDCl3) δ 2.01(s, 3H), 3.59 (dd, J = 7.8 and
15.2 Hz, 1H), 3.61 (dd, J = 7.2 and 15.4 Hz, 1H), 5.93 (m, 1H),
6.93 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 6.2 Hz, 1H), 7.40 (t, J = 7.6
Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.94 (t,
J = 7.2 Hz, 2H); 13C NMR (CDCl3), δ 23.25, 41.70, 47.57, 55.54,
113.98, 124.97, 128.23, 129.60, 129.87, 130.72, 132.22, 133.45,
135.50, 138.31, 169.89, 198.58. Anal. Calcd. for C18H18N2O5:
C, 63.15; H, 5.30; N, 8.18; Found: C, 63.0; H, 5.2; N, 8.1.
N-[3-(4-Methoxyphenyl)-1-(2,4-dichlorophenyl)-3-oxopro-
pyl]acetamide (Table 3, entry 27): mp 188 - 190 oC; Rf = 0.55
(n-hexane:ethyl acetate = 1:4) ; IR [(KBr) cm‒1]: 3298, 3089,
1672, 1645, 1592, 1550, 1405, 1280, 1256, 1150, 990, 820, 668,
592; 1H NMR (400 MHz, CDCl3) δ 2.06 (s, 3H), 3.37 (dd, J =
5.6 and 16.4 Hz, 1H), 3.69 (dd, J = 5.6 and 16.8 Hz, 1H), 3.88
(s, 3H), 5.74 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.2,
1H), 7.20 (d, J = 8.0 Hz, 1H), 7.40 (m, J = 8.2 Hz, 2H), 7.88 (d,
J = 7.6 Hz, 2H); 13C NMR (CDCl3), δ 23.16, 26.97, 42.39, 46.94,
114.38, 123.87, 123.96, 126.56, 126.58, 129.31, 129.33, 129.60,
138.42, 146.23, 175.62, 198.87. Anal. Calcd. for C18H17Cl2NO3:
C, 59.03; H, 4.68; N, 3.82; Found: C, 58.9; H, 4.6; N, 3.9.
Effectof tungstosilicic acidloading onSiO2. For investiga-
tion of the effect of different amounts of H4SiW12O40 loading on
O
NHCOCH3
R
H4SiW12O40/SiO2
RCHO + R'COCH3 + CH3COCl
CH3CN, 80 o
C
R'
Scheme 1
Table 1. Effect of H4SiW12O40-SiO2 weight ratios in the synthesis of
N-(1,3-diphenyl-3-oxopropyl) acetamide from benzaldehyde and
acetophenone
Entry H4SiW12O40-SiO2 (wt %) Time (min) Yields (%)a
1
2
3
4
10
20
30
40
80
35
20
15
60
82
90
92
aIsolated yields

Silica Supported Tungstosilicic Acid
Bull. Korean Chem. Soc. 2010, Vol. 31, No. 12 3655
Table 2. Investigation of catalyst amount effect in the synthesis of
N-(1,3-diphenyl-3-oxopropyl) acetamide from benzaldehyde and
acetophenonea
Table 3. Synthesis of β-acetamido ketones in the presence of H4Si
W12O40-SiO2
Time
(min)
Yielda,b
(%)
Entry
R
R'
Supported
tungstosilicic acid
(mol %)
Amount of
catalyst (g)
Time
(min)
Yields
(%)b
Entry
1
1
2
3
4
5
6
7
8
C6H5-
3-NO2C6H4-
4-NO2C6H4-
2-NO2C6H4-
4-ClC6H4-
2-ClC6H4-
4-BrC6H4-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
20
60
50
45
30
25
25
35
40
45
30
20
30
35
50
35
50
50
30
40
40
25
40
35
50
40
35
50
30
120
90
80
82
90
90
90
90
87
87
86
89
92
90
85
83
80
80
76
85
92
75
78
75
85
87
84
90
75
80
25
0.025
0.26
85
50
2
3
4
5
0.05
0.075
0.1
0.52
0.78
1.04
1.3
60
35
20
20
78
85
90
92
C6H5-
C6H5-
0.125
a30% H4SiW12O40-SiO2 was used as catalyst. bIsolated yields.
4-BrC6H4-
4-BrC6H4-
4-BrC6H4-
4-BrC6H4-
4-BrC6H4-
4-BrC6H4-
4-BrC6H4-
4-BrC6H4-
4-NO2C6H4-
4-NO2C6H4-
4-NO2C6H4-
4-NO2C6H4-
4-NO2C6H4-
4-NO2C6H4-
4-NO2C6H4-
4-NO2C6H4-
4-NO2C6H4-
4-NO2C6H4-
4-CH3O-
9
3-NO2C6H4-
4-NO2C6H4-
4-ClC6H4-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
support in the synthesis of β-acetamido ketones, various weight
percents of acid were used. Table 1 shows differences in catal-
ytic activity among catalysts having 10 - 40 wt % of H4SiW12O40
on silica. Lowering the loading of the deposited tungstosilicic
acid causes the reduction of the catalytic activity. No improve-
ment in the reaction rates and yields was observed by increasing
the amount of acid on SiO2 from 30 to 40 wt %. Since 30 wt %
of H4SiW12O40-SiO2 was the best catalyst loading, it was used
to study the effect of various parameters on yields.
Effectof catalystconcentration. The catalyst concentration
was varied over a range of 0.025 - 0.125 g (0.26 - 1.3 mol % of
supported tungstosilicic acid) on the basis of the total volume
of the reaction mixture. Table 2 shows the effect of catalyst
concentration on the reaction of benzaldehyde and acetophe-
none. The yield of the corresponding β-acetamido ketones in-
creased with increasing of catalyst concentration from 0.26 to
1.04 mol %. Further addition of catalyst had no noticeable effect
on the yield. This was due to the fact that beyond a certain con-
centration, there exist an excess of catalyst sites over what is
actually required by the reactant molecules, and hence, the addi-
tional catalyst does not increase the rate of the reaction. There-
fore, in all further reactions 1.04 mol % was used for 30 wt %
of H4SiW12O40-SiO2.
2-ClC6H4-
4-BrC6H4-
2,4-Cl2C6H3-
2-Cl-6-F-C6H3-
C6H5-
3-NO2C6H4-
4-NO2C6H4-
4-ClC6H4-
4-BrC6H4-
4-FC6H4-
4-OCH3C6H4-
4-CH3C6H4-
2-OHC6H4-
2,6-Cl2C6H3-
2-NO2C6H4-
2,4-Cl2C6H3-
4-NO2C6H4-
2-OHC6H4-
CH3CH2CH2-
4-CH3O-
3-NO2C6H4-
3-NO2C6H4-
C6H5-
aAll products were characterized by 1H NMR, 13C NMR and IR spectro-
scopy and compared with those reported in the literature.31, 41,42 bIsolated
yields.
Synthesis of β-acetamido ketones catalyzed by supported
tungstosilicic acid. The results from the reactions of aryl alde-
hydes, aryl methyl ketones and acetyl chloride in the presence
of optimized H4SiW12O40-SiO2 in acetonitrile at 80 oC are shown
in Table 3. The experimental procedure for this reaction requires
no inert atmosphere. Both aromatic aldehydes and acetophe-
nones bearing either activating or deactivating groups under-
went transformation well to the corresponding β-acetamido
ketones, without the formation of any side products, in high to
excellent yields (Entries 1-29). All reactions were completed
within 20 - 60 min. It is noteworthy that no acetylation of aroma-
tic hydroxyl groups were observed under the reaction conditions
and the corresponding β-acetamido ketones were isolated in
good yields (Table 3, entries 24 and 29). We observed that ali-
phatic aldehydes react under these conditions, but produce the
corresponding product in low yields (Table 3, entry 30).
To use of H4SiW12O40-SiO2 in large scale synthesis especially
in chemical laboratory, a typical reaction was performed for
synthesis of 1 with tenfold amounts of reactants and catalyst
with respect to one mentioned in the experimental section. The
result showed the yield of 85% in this condition which is com-
CH3
+
+
O
OCOCH3
Cl
CH3COCl, H+
OCOCH3
N
O
O
R1
R1
H
R1
H
H
R1
O
CH3
NCCH3
CH3
CH3
O
CH3
O
O
O
N
H2O
HN
N
CH3
O
R1
H+
+
H3C
O
R2
R1
R2
R1
OH
CH2
O
R2
CH3
R2
Scheme 2
parable with one in Table 3.
The plausible mechanism for the formation of β-acetamido
ketones is shown in Scheme 2. The presence of acetyl chloride
is necessary for the transformation and the desired product in
its absence was not prepared even after 3 h. The mechanism may
involve α-chloroacetate from aldehyde and acetyl chloride. On
further reaction with acetonitrile it affords the corresponding
α-acetoxyamides which will react with the enolate form of the

3656 Bull. Korean Chem. Soc. 2010, Vol. 31, No. 12
Masoud Nasr-Esfahani et al.
using H4SiW12O40-SiO2 as catalyst. The catalyst can be easily
prepared and can be handled safely. Moreover, non-hygroscopic
and inexpensive characteristics for this transformation are other
advantages of this procedure. The simple experimental proce-
dure combined with the easy workup and good to excellent yields
of products are salient features of the presented method.
Table 4. Synthesis of some β-acetamido ketones in the presence of
H4SiW12O40
H4SiW12O40 H4SiW12O40-SiO2
Time Yieldsa Time Yields
Entry
Product
(min) (%)
(min)
(%)
CH3COHN
O
Acknowledgments. We are thankful to Yasouj University for
partial support of this work.
1
2
100
140
55
60
20
90
CH3COHN
O
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35
50
35
90
76
85
Cl
Cl
OCH3
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amide.
To achieve the reaction efficiency of recovered catalyst, the
reaction mixture of 1 was filtered and washed with hot aceto-
nitrile twice to give recovered silica supported tungstosilicic
acid. The recovered catalyst was used again for the synthesis
of 1 that led to the yield of 84%. The recovered catalyst can be
reused at least four times without noticeable losing activity.
Effect of unsupported acid in synthesis of β-acetamido ke-
tones. As shown in Table 4, in the presence of tungstosilicic
acid without supporting on SiO2, the synthesis of β-acetamido
ketones were performed in longer time with reduced yields in
comparison with supported one. For example, in presence of
H4SiW12O40-SiO2,the reaction of benzaldehyde and acetophe-
none (entry 1) was completed in 20 min, while by using of un-
supported catalyst this reaction was carried out in 100 min with
50% yield. This results show that supporting of tungstosilicic
acid on SiO2 accelerates catalytic strength of this catalyst.
Effect of SiO2 in synthesis of β-acetamido ketones. For in-
vestigation of the probable effect of SiO2 as catalyst in the syn-
thesis of β-acetamido ketones, various weight percents of sili-
cagel were used. In the synthesis of N-(1,3-diphenyl-3-oxo-
propyl) acetamide from benzaldehyde and acetophenone in the
presence of SiO2, the reaction was carried out in 12 h in 20%
yield while in the presence of H4SiW12O40-SiO2, the reaction of
benzaldehyde and acetophenone was completed in 20 min and
by using of unsupported catalyst, this reaction was carried out in
100 min with 55% yield (Table 4). These results show that both
supported and unsupported H4SiW12O40 accelerate rate of re-
action versus SiO2 alone.
Conclusion
We have reported an efficient, inexpensive and straightfor-
ward procedure for one-pot synthesis of β-acetamido ketones

Silica Supported Tungstosilicic Acid
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