One-pot four-component Dakin-West synthesis of β-acetamido ketones catalyzed by a vanadium-substituted heteropolyacid

Article abstract of DOI:10.1016/S1872-2067(11)60379-3

The multicomponent condensation of an aryl aldehyde, acetyl chloride, acetonitrile, and enolizable ketone as one-pot synthesis of β-acetamido ketones in high yields was investigated using commercial, non-corrosive, and environmentally benign Keggin and We

Full text of DOI:10.1016/S1872-2067(11)60379-3

CHINESE JOURNAL OF CATALYSIS
Volume 33, Issue 6, 2012
Online English edition of the Chinese language journal
Cite this article as: Chin. J. Catal., 2012, 33: 923–932.
ARTICLE
One-Pot Four-Component Dakin-West Synthesis of
ꢀ-Acetamido Ketones Catalyzed by a Vanadium-Substituted
Heteropolyacid
Reza TAYEBEE*, Shima TIZABI
Department of Chemistry, School of Sciences, Hakim Sabzevari University, Sabzevar 96179-76487, Iran
Abstract: The multicomponent condensation of an aryl aldehyde, acetyl chloride, acetonitrile, and enolizable ketone as one-pot synthesis of
ꢀ-acetamido ketones in high yields was investigated using commercial, non-corrosive, and environmentally benign Keggin and
Wells-Dawson heteropolyacid catalysts. The best catalyst was H5PW10V2O40. The methodology used simple experimental conditions, and
the short reaction times and high yields indicate it is a useful strategy for the large scale synthesis of ꢀ-acetamido ketones.
Key words: homogeneous catalysis; heteropolyacid; Keggin; Wells-Dawson; Dakin-West; ꢀ-acetamido ketone
Acetamido ketone derivatives are versatile intermediates in
the synthesis of important biological and pharmacological
organic compounds such as the natural nucleoside antibiotics
nikkomycins, neopolyoxins, and several antibiotic drugs [1–4].
The best known route for the synthesis of these important
compounds is the Dakin-West reaction [5,6]. A simple and
direct method for the synthesis of a ꢀ-acetamido ketone was
reported by Bhatia et al. [7] in 1994, which involved the
one-pot multicomponent coupling condensation of an enoliz-
able ketone, aldehyde, and acetonitrile in the presence of acetyl
chloride.
Synthetic strategies based on one-pot multicomponent reac-
tions have emerged as an efficient and powerful tool in syn-
thetic organic chemistry, especially in drug discovery processes
[8]. In the last decade, multicomponent synthetic procedures
have been considered for a broad range of synthetic routes
[9–11]. These efficient and economic reactions have even been
used with pharmacologically relevant templates for combina-
torial and parallel synthesis [12,13]. Multicomponent reactions
allow more than two building blocks to be combined in a
practical, time-saving one-pot operation, and give complex
structures by the simultaneous formation of two or more bonds
[14].
[15], montmorillonite K10 clay [16], BiCl3 [17], silica sulfuric
acid [18], transition metal and main group triflates, BF3, CuCl2,
BiCl3, LaCl3, LiClO4, InCl3 [19], heteropolyacids [20], and
solid acid Hꢀ-zeolite [21]. Although these methods are valu-
able, most of them suffer from one or more of the disadvan-
tages of employing expensive catalysts, high temperature, long
reaction times or harsh reaction conditions, and tedious work
up. Hence, the development of new catalysts with more effi-
ciency is still in demand. The designing of new catalysts and
exploring their catalytic activities have profound effects in the
efficiency of a wide range of organic syntheses and more
economical and environmentally friendly chemistry [22,23].
Here, we developed strong super-acidic vanadium
(V)-substituted Keggin and Wells-Dawson heteropolyacids,
notably H5PW10V2O40, as catalysts for the efficient and facile
synthesis of ꢀ-acetamido ketones through the one-pot con-
densation of an aryl aldehyde, acetophenone, acetyl chloride,
and acetonitrile (Scheme 1).
1 Experimental
1.1 Preparation of heteropolyacids
Earlier reports on the synthesis of ꢀ-acetamido ketones
through multicomponent reactions used catalysts such as CoCl2
1.1.1 Preparation of 10-molybdo-2- vanadophosphoric-
acid H5PMo10V2O40·34H2O [24,25]
Received 7 December 2011. Accepted 19 January 2012.
*Corresponding author. Tel: +98-571-4410310; Fax: +98-571-4410300; E-mail: rtayebee@yahoo.com
Copyright © 2012, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier BV. All rights reserved.
DOI: 10.1016/S1872-2067(11)60379-3

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 923–932
CH3
H
R
O
H3C
O
O
C
C
C
NH
O
C
O
C
H5PW10V2O40
80 oC, CH3CN
Cl
+
+
H3C
R
Scheme 1. Synthesis of ꢀ-acetamido ketones through one-pot condensation of an aryl aldehyde, acetophenone, acetyl chloride, and acetonitrile.
Sodium metavanadate (12.2 g, 100 mmol) was dissolved by
boiling in 50 ml of water and then mixed with Na2HPO4 (3.55
g, 25 mmol) in 50 ml water. After the solution was cooled, 5 ml
(17 mol/L, 85 mmol) of concentrated sulfuric acid was added
until the solution developed a red color. Then, 60.5 g (250
mmol) of Na2MoO4·32H2O was dissolved in 100 ml of water
and added to the red solution with vigorous stirring, followed
by the slow addition of concentrated sulfuric acid (42 ml, 17
mol/L, 714 mmol). The hot solution was allowed to cool at
room temperature. The 10-molybdo-2-vanadophosphoricacid
was extracted with 500 ml of diethyl ether. Air was passed
through the heteropoly etherate (bottom layer) to free it from
ether. The remaining solid residue was dissolved in water and
then allowed to crystallize. The large red crystals formed were
filtered, washed with water, and air-dried. The characterization
data, calcd (observed), were: P, 1.32 (1.37); Mo, 40.82 (40.61);
V, 4.33 (4.40); H2O, 26.05 (26.18). FT-IR (KBr, cmꢀ1): 1060
(s), 962 (vs), 915 (sh), 870 (m), 770 (vs).
added to the vigorously stirred solution. The desired yellow
potassium salt was precipitated by the addition of solid potas-
sium chloride (50 g). The product was filtered off, washed with
saturated potassium chloride solution, and air dried (yield =
100 g (84%)). The characterization data, calcd (observed),
were: K, 6.45 (6.27); Si, 0.93 (1.08); Mo, 6.33 (6.12); V, 1.68
(1.76); W, 54.58 (54.40); H2O, 8.90 (9.01). FT-IR (KBr, cm–1):
1007 (w), 960 (m), 912 (s), 874 (sh), 770 (vs).
1.1.4 Preparation of potassium 9-tungsto-3-vanadosilicate
K7[ꢀ-SiV3W9O40]·10H2O [27]
Sodium vanadate (1.9 g, 15.5 mmol) was dissolved in 300
ml of water. Na10[ꢁ-SiW9O34]·18H2O (145 g, 52 mmol) was
added to the stirred solution, followed by the addition of 185 ml
of 6 mol/L sulfuric acid. Then, the solution was maintained
under stirring for 45 min. The pH was adjusted to be between 6
and 7 by the addition of solid potassium carbonate. An orange
potassium salt (~100 g) was precipitated by the addition of
solid potassium chloride (80 g) and re-crystallized in water.
The characterization data, calcd (observed), were: K, 9.34
(9.12); Si, 0.96 (1.12); V, 5.16 (5.28); W, 56.48 (56.73); H2O,
6.14 (6.32). FT-IR(KBr, cm–1): 1004 (w), 960 (s), 900 (vs), 805
(vs), 740 (vs).
1.1.2 Preparation of 10-tungsto-2-vanadophosphoricacid
H5PW10V2O40·30H2O [25,26]
Sodium metavanadate (NaVO3, 12.2 g, 100 mmol) was
dissolved in 50 ml of boiling water and mixed with a 50 ml
aqueous solution of di-sodium hydrogen phosphate (Na2HPO4,
3.55g, 25 mmol). After the resulting solution was cooled to
room temperature, concentrated sulfuric acid (5 ml, 17 mol/L,
85 mmol) was added to give a red solution. Then, 100 ml
aqueous solution of sodium tungstate dihydrate
(Na2WO4·2H2O, 82.5 g, 250 mmol) was added to the red so-
lution with vigorous stirring, followed by the slow addition of
concentrated sulfuric acid (42 ml, 17 mol/L, 714 mmol). Ex-
traction of the solution with diethyl ether (500 ml) followed by
evaporation in air afforded orange-red crystals of
H5PW10V2O40 (yield, 74%). The characterization data, calcd
(observed), were: P, 0.98 (1.05); W, 58.24 (58.12); V, 3.22
(3.16); H2O, 17.12 (17.26). FT-IR (KBr, cm–1): 1070 (s), 980
(vs), 885 (s), 788 (vs).
1.1.5 Preparation of potassium 9-tungsto-3-molybdo-
silicate K4[ꢀ-SiMo3W9O40]·5H2O [27]
Sodium molybdate (8 g, 33 mmol) was dissolved in 70 ml of
water. A 30 ml portion of 4 M HCl was added to the stirred
solution. Na10[ꢁ-SiW9O34]·18H2O (30 g, 10.8 mmol) was
quickly added. The yellow potassium salt, K4[ꢁ-SiMo3W9O40],
was precipitated by the addition of solid potassium chloride (14
g) to the stirred solution (yield = 25 g (80%). The characteri-
zation data, calcd (observed), were: K, 5.47 (5.63); Si, 1.01
(1.14); Mo, 10.07 (10.24); W, 57.89 (57.33); H2O, 3.14 (3.23).
FT-IR (KBr, cm–1): 1012 (w), 958 (m), 918 (s), 888 (vw), 868
(vw), 775 (vs).
1.1.3 Preparation of potassium 9-tungsto-2-molybdo-1-
vanadosilicate K5[ꢀ-SiMo2VW9O40]·10H2O [27]
1.1.6 Preparation of the acids H4+x[ꢀ-SiMo3-xVxW9O40]
(x = 0, 1, 3) [27]
Sodium vanadate (4.8 g, 40 mmol) was dissolved in 230 ml
of water. This solution was acidified by 4 mol/L HCl (45 ml).
Solid K8SiMo2W9O39·20H2O (120 g, 40 mmol) was slowly
The potassium salt (15 g, 5 mmol) of each compound was
dissolved in 65 ml of water and placed in a separatory funnel.
Then, diethyl ether was added, followed by the slow addition of

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 923–932
concentrated hydrochloric acid (55, 85, or 100 ml for x = 0, 1,
7.58 (d, J = 9.1 Hz, 5H), 7.76 (d, J = 9.1 Hz, 5H); IR (KBr,
cmꢂ1): 3252, 3046, 1667, 1624, 1574, 1288, 1082, 878, 819.
ꢀ-Acetamido-ꢀ-(4-chlorophenyl)propiophenone. 1H NMR
(CDCl3, 200 MHz): ꢀ 2.00 (s, 3H), 3.40 (dd, J = 6.9 and 9.9 Hz,
1H), 3.71 (dd, J = 6.9 and 9.9 Hz, 1H), 5.54 (m, 1H), 7.02 (m,
5H), 7.45 (m, 3H), 7.84 (d, J = 9.1 Hz, 2H); IR (KBr, cmꢂ1):
3265, 3082,1678, 1642, 1556, 1245, 1104, 887, 823, 683.
or 3, respectively). The heavy phase was collected and diethyl
ether was evaporated under vacuum. The resulting solid was
dissolved in a minimum amount of water. Finally, the desired
heteropolyacid was slowly crystallized at room temperature.
1.1.7 Preparation of Preyssler K12Na2[NaP5W30O110] and
its acidic form H14[NaP5W30O110] [28]
ꢀ-Acetamido-ꢀ-(3-nitrophenyl)propiophenone.
1HNMR
(200 MHz, CDCl3): ꢀ 1.87 (s, 3H), 3.11 (d, J = 15.9 Hz, 1H),
3.52 (d, J = 12.1 Hz, 1H), 5.50 (s, 1H), 7.30 (m, 5H), 7.80 (d, J
= 6.2 Hz, 2H), 8.00 (d, J = 6.2 Hz, 2H); IR (KBr, cmꢂ1): 3290,
3024, 2245, 1680, 1649, 1542, 1440, 1215, 987, 750, 680, 545.
ꢀ-Acetamido-ꢀ-(2-hydroxyphenyl)propiophenone. 1H NMR
(200 MHz, CDCl3): ꢀ 2.00 (s, 3H), 3.49 (d, J = 7.2 Hz, 1H),
3.68 (d, J = 7.1 Hz, 1H), 6.87 (s, 1H), 7.50–7.72 (m, 5H), 7.95
(d, J = 5.9 Hz, 2H), 8.23 (d, J = 5.2 Hz, 2H); IR (KBr, cmꢂ1):
3286, 2845, 1679, 1638, 1595, 1501, 1446, 1341, 1289, 851,
747, 681, 588.
Ortho-phosphoric acid 90% (75 ml, 1.2 mol) was slowly
added to 50 ml of an aqueous solution of Na2WO4·2H2O (99 g,
0.3 mol) at 45 oC, and the resulting mixture was refluxed for 5
h. The solution obtained was diluted with 15 ml of water. Then,
powdered KCl (22.5 g, 0.32 mol) was slowly added to the
vigorously stirred solution over 35 min at room temperature.
The pale green impure precipitate was filtered and washed with
CH3COOK (0.1 mol/L). The white needle-like crystals of
potassium salt of the Preyssler’s anion were re-crystallized
from hot water. The free acid was prepared by passing a solu-
tion of 11.4 g potassium salt in 20 ml of water through a col-
umn (50 cm×1 cm) of Dowex 50WX8 in the H form. The
evaporation of the eluent to dryness in vacuum resulted in
ꢀ-Acetamido-ꢀ-(4-nitrophenyl)propiophenone. 1H NMR
(200 MHz, CDCl3): ꢀ 2.01 (s, 3H, CH3), 3.38 (dd, J = 5.6 and
17.4 Hz, 1H, CH2), 3.85 (dd, J = 7.1 and 17.4 Hz, 1H, CH2),
5.60 (m, 1H, methyne H ), 7.19ꢂ7.54 (m,7H, Ar-H), 7.87 (d, J
= 7.7 Hz, 2H, Ar-H), 9.18 (br, 1H, NH); IR (KBr, cmꢂ1):
3285,1682, 1648,1520,1350, 1300, 751.
H14[NaP5W30O110].
The
characterization
data
for
K12Na2[NaP5W30O110]·15H2O, calcd (observed), were: K, 5.69
(5.81); Na, 0.84 (0.71); P, 1.88 (1.74); W, 66.95 (66.83); H2O,
3.28 (3.35). FT-IR (KBr, cm–1): 1160 (s), 1070 (m), 1010 (w),
980 (vw), 920 (vs), 890 (vs), 760 (vs). The characterization
data for H14[NaP5W30O110]·58H2O, calcd (observed), were: Na,
0.27 (0.32); P, 1.82 (1.90); W, 64.8 (64.92); H2O, 12.27 (12.40).
ꢀ-Acetamido-ꢀ-(4-methoxyphenyl)propiophenone.
1H
NMR (200 MHz, CDCl3): ꢀ 2.09 (s, 3H), 2.47 (s, 3H), 3.51 (dd,
J = 7.1 and 10.0 Hz, 1H), 3.84 (dd, J = 7.1 and 10.0 Hz, 1H),
5.58 (m, 1H), 7.39 (s, 1H), 7.52 (m, 5H), 7.96 (m, 4H); IR
(KBr, cmꢂ1): 3263, 3051, 1672, 1630, 1581, 1290, 1081, 878,
817.
1.2 General procedure for the synthesis of ꢁ-acetamido
ketones
2 Results and discussion
A mixture of aromatic aldehyde (1 mmol), acetophenone (1
mmol), and acetyl chloride (2 mmol) in acetonitrile (4 ml) was
treated with a catalytic amount of the desired heteropolyacid at
80 oC. The progress of the reaction was monitored by TLC. The
work up procedure of this reaction was very simple. After
completion of the reaction, the mixture was filtered to separate
the catalyst. The solid crude product was washed with petro-
leum ether and filtered. The pure product was obtained, if
needed, by re-crystallization from an ethanol-water mixture.
Silica gel 60 (70–230 mesh) was used for column chromatog-
raphy. Infrared spectra were run on a 8700 Shimadzu Fourier
2.1 Introducing the Keggin H5PW10V2O40 framework,
effect of structure on reactivity
Phosphotungstic (molybdic) acids are well recognized ef-
fective catalysts in many acid catalyzed reactions. They consist
of large anions whose structure is referred to as the primary
structure. Several cations and water molecules form an ar-
rangement with the anions to form the secondary structure [30].
The [P(Mo,W)12O40]3– anions have the well-known Keggin
structure composed of a central tetrahedral PO4 surrounded by
12 edge-sharing metal-oxygen MoO6. Although other ele-
ments, such as silicon, can be used as the central atom, phos-
phorus has been the most preferred element and it leads to the
most stable anion in the heteropoly compounds.
It is well recognized that a vanadyl cation can be added as a
monovalent substituent in the heteropolyacid structure through
the replacement of the protons [20]. Although, vanadium does
not have an important effect on the structure of the acid, it
strongly influences physicochemical properties such as hydra-
tion extent, redox and catalytic capability of the Keggin com-
1
transform spectrophotometer. H and 13C NMR spectra were
recorded on a Bruker AVANCE 200-MHz instrument using
TMS as an internal reference. All products were identified by
comparing their NMR and IR data with those reported in the
literature. Spectral data for selected ꢀ-acetamido ketones
[7,20,29] are listed as follows.
1
ꢀ-Acetamido-ꢀ-(phenyl)propiophenone. H NMR (CDCl3,
200 MHz): ꢀ 2.03 (s, 3H), 3.34 (dd, J = 6.6 and 9.7 Hz, 1H),
3.67 (dd, J = 6.6 and 9.7 Hz, 1H), 5.60 (m, 1H), 7.32 (s, 1H),

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 923–932
pound.
First, the catalytic efficiency of different heteropolyacids in
H5SiW9Mo2VO40, Wells-Dawson H6P2Mo18O62, and Preyssler
H14NaP5W30O110 were less effective and led to lower conver-
sions (47%ꢂ54%) after 3ꢂ4 h. Surprisingly, the vana-
dium-substituted Keggin-type H5PW10V2O40 showed a higher
activity than the Keggin heteropolyacid, H3PW12O40, which has
the highest Brönsted acidity. Moreover, the results confirmed
that tungsten-containing heteropolyacids, H6P2W18O62 and
H5PW10V2O40, were preferred over their molybdenum ana-
logues, H6P2Mo18O62 and H5PMo10V2O40, for the synthesis of
ꢀ-acetamido-ꢀ-(4-chlorophenyl)propiophenone. It is difficult
to offer an exact explanation for the different catalytic activity
patterns observed for these two structural types of heter-
opolyacids since there is a complex relationship between the
activity, structure, and solubility of the polyanion in the reac-
tion medium. By changing the constituent elements of the
polyanion (both hetero and addenda atoms), the acid strength
of heteropolyacid as well as its catalytic activity and solubility
were varied in a wide range [31]. In the case of vana-
dium-substituted heteropolyacids, the vanadium atom can
the four-component condensation of para-chlorobenzaldehyde
with acetophenone and acetyl chloride in refluxing acetonitril
was studied (Table 1). Keggin H5PW10V2O40 and
H5PMo10V2O40 were active catalysts due to their bifunctional
nature originating from their strong acidic protons and the
presence of the vanadium transition metal ion as an effective
electron acceptor resource. H5PW10V2O40 gave the best cata-
lytic activity and led to 88% conversion after 0.5 h, while the
other heteropolyacids such as Keggin H3PW12O40,
V-containing
silico(phospho)tungstic(molybdic)acids
H7SiW9V3O40 and H5PMo10V2O40, and Wells-Dawson
H6P2W18O62 showed comparable activity and produced
77%ꢂ86% yields in 3 h. These results demonstrated the higher
catalytic efficiency of the vanadium-containing catalysts over
the others. As shown in Table 1, the heteropolyacid catalysts
without the vanadium component showed less efficiency.
Mixed metal substituted heteropolyacids such as Keggin
Table 1 Synthesis of ꢀ-acetamido-ꢀ-(4-chlorophenyl)propiophenone in the presence of various heteropolyacids in refluxing acetonitrile
CH3
H
O
H3C
O
O C
C
NH
C
O
C
O
C
Heteropolyacid
80 oC, CH3CN
+
+
H3C
Cl
Cl
Cl
Entry
1
2
3
4
5
6
7
8
Heteropolyacid
Amount (mol%)
Time (h)
0.5
3
3
3
3
3
3.5
4
4
10
1
3
0.4
2
0.2
0.5
0.8
1
6
3
Temperature (oC)
Yield* (%)
88
Selectivity (%)
100
H5PW10V2O40
H7SiW9V3O40
H3PW12O40
2.5
2.5
2.5
2.5
2.5
2.5
0.7
2.5
2.5
—
0.5
0.5
5
5
10
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
50
25
80
80
80
80
80
80
80
80
80
86
82
82
77
53
49
54
47
<15
65
63
90
88
93
92
60
42
89
91
88
85
55
26
28
<15
<15
100
100
100
H6P2W18O62
H5PMo10V2O40
H6P2Mo18O62
H14NaP5W30O110
H5SiW9Mo2VO40
2Na2O·P2O5·12WO3
—
>98
>95
>90
>90
>90
<50
>95
>95
100
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
H5PW10V2O40
H7SiW9V3O40
H5PW10V2O40
H7SiW9V3O40
H5PW10V2O40
H7SiW9V3O40
H5PW10V2O40
H5PW10V2O40
ZnO
ZnO(nano)
CuO(nano)
ZrCl4
ZrOCl2
ZrO2
100
100
100
10
2.5
2.5
50
10
10
20
20
20
20
>95
>70
>90
>90
>90
>95
>90
>80
>50
>50
>50
3
5
7
3
5
4
6
KH2PO4
L-prolin
SiO2
20
20
Reaction conditions: aromatic aldehyde 1 mmol, acetophenone 1 mmol, acetyl chloride 2 mmol, acetonitrile 4 ml. *Isolated yields.

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 923–932
occupy both anionic and cationic positions in the heteropoly-
2.4 Effect of the nitrilating agent
anion structure and, subsequently, affects the catalytic activity.
It has been demonstrated that the nitrilating agent is a critical
parameter in the four-component condensation reaction.
Hence, the effect of changing the nitrilating agent from CH3CN
to PhCN was investigated (Scheme 2). Acetonitrile was more
efficient than PhCN and led to 88% ꢀ-acetamido-ꢀ-
(4-chlorophenyl)propiophenone after 0.5 h, while phenyl cya-
nide afforded only 48% yield after 4 h. The optimum amount of
acetyl chloride was also studied. 2 equiv. of acetyl chloride was
the best. Increasing the volume of acetyl chloride to 4 equiv.
resulted in diminishing conversion from 88% to 62% after 0.5
h. Lower amounts of acetyl chloride also led to a decrease in
conversion.
2.2 Effect of H5PW10V2O40 and H7SiW9V3O40
concentrations
First, the four-component coupling condensation of ben-
zaldehyde, acetophenone, and acetyl chloride was performed in
acetonitrile in the absence of a catalyst. The reaction was inef-
ficient, and no reaction occurred even after a prolonged reac-
tion time (10 h), indicating that the reaction was indeed a het-
eropolyacid catalyzed reaction (Table 1, entry 10).
The catalytic activity can be influenced by the parameters
such as the kind and amount of the employed catalyst, solvent
system, and temperature. To establish the optimal reaction
condition, a set of experiments were conducted by changing the
catalyst amount, quantity of acetyl chloride, and temperature.
Initially, different amount of H5PW10V2O40 and H7SiW9V3O40
were used (Table 1, entries 1, 2, 11ꢂ16). The best condition to
prepare the ꢀ-acetamido ketones was achieved when 2.5 mol%
of H5PW10V2O40 was used. 4-Chlorobenzaldehyde led to 88%
product after 0.5 h (entry 1), while a higher amount of catalyst
(10 mol%) resulted in 93% conversion in the short time of 0.2 h
(entry 15). Employing smaller amounts of the catalyst (0.5
mol%) diminished the product yield to 65% after 1 h. The same
reactivity pattern was observed for H7SiW9V3O40, but this
catalyst was ~3ꢂ6 times (depending on catalyst amount) less
efficient than H5PW10V2O40 and led to a maximum conversion
of ~90% only after clearly longer times.
2.5 Comparison of the catalytic activity of H5PW10V2O40
and H7SiW9V3O40 with other catalysts
A comparison of the catalytic efficiency of the two examined
vanadium substituted heteropolyacids with some selected
catalysts is given in Table 1, entries 19–27. Clearly, the heter-
opolyacids (2.5 mol%) gave excellent activity and led to the
highest conversion among the catalysts in relatively short times
(entries 1 and 2). The Zr family (ZrCl4, ZrOCl2, andZrO2) gave
moderate activity and 26%–85% conversion with 20 mol% of
catalyst in 3–7 h (entries 22–24). Another distinct feature ap-
pears when the catalytic activity of zinc and copper oxides in
the bulk and nano-sized forms are compared (entries 19–21).
50 mol% of bulk ZnO led to 89% of conversion after 6 h,
while almost the same conversion was achieved with only 10
mol% nano-sized zinc oxide after 3 h. Furthermore, 10 mol%
CuO(nano) gave good catalytic activity and ꢀ-acetamido-ꢀ-(4-
chlorophenyl)propiophenone in 88% yield after 3 h. Other
catalysts such as SiO2, L-prolin, and KH2PO4 were inefficient,
even at high concentrations. These catalysts resulted in < 30%
of conversion after prolonged times (entries 25–27).
2.3 Effect of temperature
The effect of temperature was monitored by carrying out the
model reaction in the presence of 2.5 mol% H5PW10V2O40 in
acetonitrile at different temperatures (Table 1, entries 1, 17, and
18). The yield% was increased when the reaction temperature
was elevated from 25 to 80 oC. Therefore, the reflux tempera-
ture of acetonitrile, 80 oC, was selected for all the reactions.
2.6 Comparing reactivity of acetophenone with other
CH3
O C
NH
O
CH3CN, 80 oC
H5PW10V2O40 (2.5 mol%)
C
H
O
H3C
O
C
C
(0.5 h, 88%)
Cl
+
CH3
NH
O
C
O
C
O
C
Cl
PhCN, 80 oC
H3C
Cl
H5PW10V2O40 (2.5 mol%)
(4 h, 48%)
Cl
Scheme 2. Effect of nitrilating agent on the preparation of ꢀ-acetamido-ꢀ-(4-chlorophenyl)propiophenone.

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 923–932
ketones
Table 2 Synthesis of ꢀ-acetamido-ꢀ-(4-chlorophenyl) ketones in the
presence of H5PW10V2O40 in refluxing acetonitrile
In addition, the reactivity of acetophenone was compared
Carbonyl
compound
Time Yield Selectivity
with other ketones such as cyclohexanone, ethyl methyl ke-
tone, and acetone. The last three ketones gave unsatisfactory
results in the reaction with benzaldehyde using the reaction
conditions here (Table 2).
Product
CH3
(h)
(%)
(%)
O
C
O
H3C
O
NH
O
C
C
0.5 88
100
2.7 Synthesis of different ꢁ-acetamido-ꢁ-
(aryl)propiophenones catalyzed by H5PW10V2O40
Cl
CH3
C
O
After optimizing the reaction conditions, the present meth-
odology was extended to various substituted aromatic alde-
hydes (Table 3). The reactions were catalyzed well and the
reaction rates as well as the yields were satisfactory. The con-
version generally gave the desired product in high yields
(69%–97%) within 30–160 min. Aromatic aldehydes contain-
ing either electron-donating or electron-withdrawing groups
underwent the conversion smoothly. Several functional groups
such as halogen (Cl, Br) and NO2 moieties were found to be
stable under the reaction conditions. In the case of the aromatic
aldehyde, the electron-withdrawing group on the phenyl ring
promoted the reaction. The electron-releasing methoxy group
retarded the reaction rate and led to 74% yield for the corre-
sponding product after 100 min. It is noteworthy that no ace-
tylation of an aromatic hydroxyl group was detected when
salicylaldehyde (Table 3, entry 2) was used, and the corre-
sponding ꢀ-acetamido ketone was isolated in a good yield
(69%).
NH
O
3
4
5
20
50
n.d.
n.d.
Cl
CH3
O
C
NH O
CH3
O
C
<15
<15
CH2CH3
CH2CH3
Cl
CH3
O
C
NH O
O
C
CH3
H3C
CH3
Cl
Reaction conditions: catalyst 2.5 mol%, aromatic aldehyde 1 mmol, car-
bonyl compound 1 mmol, acetyl chloride 2 mmol, acetonitrile 4 ml, 80
oC.
Table 3 Synthesis of different ꢀ-acoetamido-ꢀ-(aryl)propiophenones in the presence of H5PW10V2O40 in refluxing acetonitrile
Melting point (oC)
Entry
1
Aldehyde
Time (min)
100
Yield (%)
74
Selectivity (%)
100
Found
Reported
H
OMe
C
114–116
115–117 [41]
O
H
C
2
3
160
30
69
77
>95
100
129–131
186–188
130–132 [20]
188–190 [42]
O
OH
C
H
H
O
NO2
C
4
5
40
30
80
88
100
100
103–105
144–146
101–103 [20]
144–146 [20]
O
H
Cl
C
O
H
C
6
45
79
100
109–111
110–112 [20]
O
O2N
H
C
7
8
40
45
81
97
100
100
101–103
148–150
100–103 [36]
150–151 [42]
O
Br
H
O2N
C
O
Reaction conditions: catalyst 2.5 mol%, aldehyde 1 mmol, PhCOCH3 1 mmol, acetyl chloride 2 mmol, acetonitrile 4 ml, 80 oC.

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 923–932
Table 4 Comparison of the catalytic efficiency of H5PW10V2O40 with
some different catalysts
80
60
40
20
0
Amount
(mol%)
2.5
Time
(h)
0.5
12
5
30
30
30
30
30
30
7
Yield
(%)
88
83
87
60
82
78
19
Catalyst
Ref.
H5PW10V2O40
ZrOCl2·8H2O
ZrCl4
Zn(OTf)2
Sc(OTf)3
BF3.OEt2
InCl3
CuCl2
this work
[37]
[37]
[19]
[19]
[19]
[19]
[19]
[19]
15
20
10
10
100
100
100
100
2 g
79
59
80
LiClO4
Montmorillonite K-10
1
2
3
4
5
6
7
Cylce
[16]
Fig. 1. Reusability of the catalyst.
2.8 Comparison of the catalytic efficiency of
H5PW10V2O40 with other reported catalysts
brations in the Keggin polyanions. Interestingly, the charac-
teristic bands of the Keggin ion for vanadium(V)-containing
heteropolyacid were shifted to lower wavenumbers with re-
spect to H3PW12O40. This shift was due to the influence of
vanadium (V) on the M–O bond and indicated that changes
occurred in the structure symmetry [34]. This shift suggested
that vanadium(V) has entered into the primary structure of the
Keggin anion of the H5PW10V2O40 catalyst. Moreover, a
shoulder in the P–O stretching vibration was noticed for the
H5PW10V2O40. The splitting of the P–Od band was reported for
a sample with the presence of vanadium(V) in the Keggin
structure. It is known that the introduction of a metal other than
W into the Keggin ion induces a decrease in the W–Ot
stretching frequency and a possible splitting of the P–Od band.
This splitting also suggested the incorporation of V into the
Keggin ion [35].
The FT-IR spectra of the recycled catalyst H5PW10V2O40
after catalytic reaction was checked and the four characteristic
peaks mentioned above were observed (Fig. 3). The FT-IR
spectra of the fresh and reused catalysts showed no change in
the primary Keggin anion even after repeated use. Thus, it was
shown that the Keggin structure was intact under the reaction
conditions here.
The superiority of the present method over previously re-
ported methodologies can be seen by comparing the results
obtained for the vanadium-substituted heteropolyacid,
H5PW10V2O40, with some previously reported catalysts (Table
4). The reaction of benzaldehyde, acetyl chloride, and aceto-
phenone in acetonitrile was chosen as the model reaction to
afford the corresponding ꢀ-acetamido-ꢀ-phenylpropiophenone.
The comparison was based on the amount of the catalyst, re-
action time, and percentage yield. Clearly, H5PW10V2O40 was
the best among the catalysts compared.
2.9 Stability and reusability of H5PW10V2O40
The stability and reusability of a catalyst are very important
parameters for industrial use. To establish the reusability of
H5PW10V2O40, the catalyst was washed with dichloromethane
and recycled. The recovered catalyst was reused seven times
without considerable loss of activity. The results of the first run
and subsequent recycles were almost constant in yields (Fig.
1). Thus, the reaction can be carried out with recovered or fresh
catalyst with equal efficacy.
The stability of the heteropolyacid H5PW10V2O40 was also
investigated by studying the stability of its primary structure
after recycling. The primary structure of H5PW10V2O40 was
identified by the characterization of its FT-IR absorption bands
[25,32]. As mentioned previously, Keggin-type H5PW10V2O40
consists of a PO4 tetrahedron surrounded by four M3O13 groups
formed by edge-sharing octahedra (Fig. 2). These groups are
connected to each other by corner-sharing oxygens [33], and
this arrangement gives rise to four types of oxygen bands be-
tween 1200 and 700 cm–1, which is a fingerprint region for
Keggin compounds. These characteristic IR bands appear at
1065 cm–1 (P–O in central tetrahedral), 947 cm–1 (terminal
W=O), 846 and 784 cm–1, broad, due to (W–Ob–W) and
(W–Oc–W), respectively, associated with the asymmetric vi-
Fig. 2. Structure of Keggin PM12O403– [30].

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 923–932
formation of ꢁ-chloroacetate as intermediate (I). Then, this
intermediate reacts with acetonitrile to afford the correspond-
ing ꢁ-acetoxy amide, which further combines with the enolate
form of acetophenone to afford the imidate ester and, finally,
the amide product. The protonation of the aldehyde activates
the carbony group for nucleophillic attack. Moreover, it can be
suggested that the V–O–M and V=O centers would be the
active sites of the vanadium-substituted heteropolyacids, which
participate in the activation of aldehyde carbonyl group.
Therefore, the heteropolyacid not only functioned as a Brön-
sted acid but also as a Lewis acid in the reaction mechanism.
The role of substituents in the enolizable ketone and alde-
hydes on the efficiency and yield was studied in detail. In the
case of the enolizable ketone, electron-withdrawing groups in
the para position enhanced the rate of reaction and yield
compared to electron-donating groups. This behavior was
attributed to the promoting enolization of the active methylene
group to facilitate the reaction, resulting in higher yield and
less reaction time. The same argument can be used for the poor
reactivity of cyclohexanol, acetone, and ethyl methyl ketone.
In the case of the aldehydes, electron-withdrawing groups in
the para position promoted the reaction, while elec-
(2)
(1)
4000 3600 3200 2800 2400 2000 1600 1200 800 400
Wavenumber (cmꢀ1)
Fig. 3. FT-IR spectra of fresh (1) and recycled catalyst after the 7th
run (2).
2.10 Reaction pathway
It is not exactly clear how H5PW10V2O40 catalyzes the reac-
tion, so we used previously reported mechanisms [20,36–40] to
suggest the reaction pathway in Scheme 3. The mechanism
involves acylation of the aldehyde with acetyl chloride and
H
+O
C
+
O
H /HPA
H
O
C
H C
3
Cl
O
C
C
CH
(I)
3
+
O
O
C
-
Cl
CH
3
O
H C
Cl
C
3
R
H
C
H
Cl
CH
C
3
R
CH
C
3
R
-
+
OH
O
C
N
-Cl
-H
O
NCCH
O
C
HN
3
tautomerism
Ph
C
H
Ph
C
2
H C
3
H C
3
H
2
C
O
+
R
C
O
C
R
+
O
O
H
H
N
CH
3
N
C
CH
3
C
C
-
-
hydrolysis
Cl
Cl
CH
C
3
O
C
R
R
+
CH
3
O
H
N
acetate migration
O
C
C
C
H
CH
C
Ph
3
CH
2
3
R
C
CH
C
3
O
N
O
C
+OH
O
N
C+H
C
CH
C
C
-
CH
3
CH
+
O
3
3
O
N
C
-
O
Cl
Cl
C
acetophenone
R
C
H
Ph
R
2
OH
C
O
C
R
H C
Ph
H C
CH
2
3
3
Scheme 3. Reaction pathway for the one-pot condensation of an aryl aldehyde, acetophenone, acetyl chloride, and acetonitrile.

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 923–932
CH3
O C
O
O
C
CHCl3, CH3(CO)Cl
H
O
O
H5PW10V2O40 (2.5 mol%)
C
Cl
CH3CN
H5PW10V2O40 (2.5 mol%)
No reaction
Cl
+
H3C
C
CH3CN, (COCl)2
No reaction
H5PW10V2O40 (2.5 mol%)
CH3
O C
CH3CN, CH3(CO)Cl
H5PW10V2O40 (2.5 mol%)
NH
O
C
Cl
Scheme 4. Some Mechanistic information on the heteropolyacid catalyzed synthesis of ꢀ-acetamido-ꢀ-(4-chlorophenyl)propiophenone.
tron-releasing substituents were detrimental to the reaction.
This was confirmed by the observation that electron-releasing
groups such as CH3, OCH3, and N(CH3)2 at the para position of
the aldehydes retarded the reaction.
also as a nitrogen donor.
3 Conclusions
Further FT-IR characterization of the reaction mixture led
to some important mechanistic information for the multicom-
ponent reaction according to the schemes 3 and 4 as follows.
(1) No ꢀ-acetamido ketone was observed when a mixture of
benzaldehyde, acetophenone, acetic anhydride and heter-
opolyacid catalyst in acetonitrile were reacted even after a
prolonged time.
(2) The reaction of 4-chlorobenzaldehyde with acetophe-
none in acetonitrile failed to provide the desired product in the
absence of acetyl chloride. This clearly indicated the key role
of acetyl chloride in the reaction.
(3) Using oxalyl chloride as a source of chloride ion, in-
stead of acetyl chloride, in the reaction of 4-chlorobenzalde-
hyde with acetophenone in acetonitrile was also unsuccessful.
This observation clearly demonstrated that the chloride ion
did not contribute to the condensation reaction.
(4) The reaction of 4-chlorobenzaldehyde, acetophenone,
and acetyl chloride in chloroform, instead of acetonitrile, led
to the formation of the corresponding ꢀ-acetoxy ketone. This
product was consequently converted to the corresponding
ꢀ-acetamido ketone by further treatment with acetonitrile.
(5) As described in 2.4 (Scheme 2), acetyl chloride was not
incorporated into the final product and acetonitrile itself is the
N-donor and nucleophile. Using benzonitrile instead of ace-
tonitrile gave the generation of benzamide. This observation
clearly confirmed that nitrile acted not only as a solvent but
This paper described a convenient and efficient process for
the synthesis of ꢀ-acetamido ketones through the
four-component coupling of aromatic aldehydes, enolisable
ketone, and acetyl chloride in acetonitrile using vanadium(V)-
containing heteropolyacids, especially H5PW10V2O40, as cheap,
commercial, non-corrosive, and environmentally benign cata-
lysts. The present methodology offers attractive features such
as simple procedure combined with easy workup, relatively
short reaction times, and high yields, and would have wide
scopes in organic synthesis. This protocol is recommended as a
useful and attractive strategy for the large scale synthesis of
ꢀ-acetamido ketones.
Acknowledgements
Partial financial support from the Research Council of
Sabzevar Tarbiat Moallem University is greatly appreciated.
Special thanks to Vahid Tayebee for English editing of the
manuscript.
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