Zr(HSO4)4/SiO2: An effective heterogeneous alternative for one-pot synthesis of β-acetamido ketones

Article abstract of DOI:10.1007/BF03245864

In a one-pot procedure, enolizable ketones reacted with aromatic aldehydes, acetyl chloride and acetonitrile at room temperature in the presence of Zr(HSO₄)₄/SiO₂ to furnish the corresponding β-acetamido ketones in improve

Full text of DOI:10.1007/BF03245864

J. Iran. Chem. Soc., Vol. 7, No. 1, March 2010, pp. 95-99.
JOURNAL OF THE
Iranian
Chemical Society
Zr(HSO4)4/SiO2: An Effective Heterogeneous Alternative for One-Pot Synthesis of
ꢀ-Acetamido Ketones
B.F. Mirjalilia,*, A. Bamonirib, M.A. Karimi Zarchia and H. Emtiazia
aDepartment of Chemistry, College of Science, Yazd University, 89195-741, Yazd, Iran
bDepartment of Chemistry, College of Science, University of Kashan, Kashan, Iran
(Received 6 April 2008, Accepted 30 January 2009)
In a one-pot procedure, enolizable ketones reacted with aromatic aldehydes, acetyl chloride and acetonitrile at room
temperature in the presence of Zr(HSO4)4/SiO2 to furnish the corresponding ꢀ-acetamido ketones in improved yields.
Keywords: Zr(HSO4)4/SiO2, ꢀ-Acetamido ketones, One-pot method, Multi-component reaction, Room temperature
EXPERIMENTAL
INTRODUCTION
Chemical
ꢀ-Acetamido ketones are valuable building blocks for the
preparation of ꢀ-amino ketones or ꢀ-amino alcohols such as
antibiotic nikkomycins [1,2] and neopolyoxines [3]. ꢁ-
acetamido ketones in Dakin-West reaction [4] and ꢀ-
acetamido ketones in Iqbal route are obtained [5,6]. Iqbal
route is based on one-pot reaction of aromatic aldehydes,
enolizable ketones and acetonitrile in the presence of the
acetyl chloride and catalytic amount of an acid. Many catalysts
such as CeCl3.7H2O [7], silica sulfuric acid [8], H6P2W18O62
[9], K5CoW12O40.3H2O [10], ZnO [11], sulfated zirconia [12],
FeCl3 [13], some heteropoly acids [14-16], silica supported
H3PW12O40 [17], nano ZnO [18], sulfamic acid [19], Sc(OTf)3
[20], SnCl2.2H2O [21], Zeolite Hꢀ [22], ZrOCl2.8H2O [23] and
Nafion-H [24] have been applied in this one-pot reaction. With
reference to solid acid utilization in organic synthesis [25-34],
herein, we wish to report the application of Zr(HSO4)4/SiO2,
an alternative protocol, for the synthesis of ꢀ-acetamido
ketones [32-35].
Chemicals were purchased from Fluka, Merck and Aldrich
chemicals companies. Using the previously reported
procedure, Zr(HSO4)4 was synthesized according to the
literature [23]. The products were characterized by their
spectral data (IR and 1H NMR) in some cases, and comparison
with authentic samples.
Preparation of Silica-Supported Zr(HSO4)4
A mixture of 0.6 g of Zr(HSO4)4 and 0.4 g of preheated
silica gel was ground into fine particles. A suspension of this
mixture and 0.5 ml of HCl 0.5 M was stirred for 20 min at
room temperature. The suspension was allowed to heat at
about 80-90 ºC until the obtained solid was almost dry which
in turn was further dried and calcinated in a domestic
microwave oven for 20 min in power 100.
General Procedure for One-Pot Synthesis of ꢀ-
Acetamido Ketones Using Zr(HSO4)4/SiO2
Enolizable ketone (1 mmol), aromatic aldehyde (1 mmol),
acetyl chloride (0.3 ml), acetonitrile (1 ml) and 60%
*Corresponding author. E-mail: fmirjalili@yazduni.ac.ir

Mirjalili et al.
Zr(HSO4)4/SiO2 (0.04 g, 0.05 mmol) were placed in a round
7.1 (sbr, 1H), 7.2 (m, 2H), 7.4 (d, J = 7.6, 1H), 7.6 (m, 3H),
7.9 (d, J = 8 Hz, 2H). 13C NMR (CDCl3, 100 MHz): ꢁ 24.27,
42.88, 49.17, 128.28, 128.73, 129.46, 130.0, 130.18, 131.09,
133.59, 135.86, 139.13, 141.27, 173, 196. IR (KBr, cm-1)
3292, 1688, 1653, 1552, 1353, 1200, 814, 753.
bottom flask. The materials were mixed at an ambient
temperature. The progress of the reaction was followed by
TLC (eluent:n-hexane:ethylacetate). After completion of the
reaction, crushed ice (40 ml) was added to the reaction
mixture and stirred. The oily solid was isolated and washed
with diethyl ether to remove any residual starting materials.
The crude mixture was solidified from ethanol and water
mixture. The pure product was obtained by recrystalization
from ethyl acetate and n-hexane or column chromatography
(ethyl acetate:n-hexane as eluent).
RESULS AND DISCUSSION
In order to utilize Zr(HSO4)4 as a catalyst in the synthesis
of ꢀ-acetamido ketones, the reaction of 4-methyl benzaldehyde
and 4-nitro acetophenone was examined in the presence of
several mmol of acetyl chloride, acetonitrile and catalysts
(Table 1).
Selected Spectroscopic Data
ꢀ-Acetamido-ꢀ-(2-chloro)-4-chloropropiophenone:
1H NMR (CDCl3, 400 MHz): ꢁ 2.1 (s, 3H), 3.5 (dd, J = 16.8
and 5.6 Hz, 1H), 3.8 (dd, J = 16.8 and 6 Hz, 1H), 5.8 (sbr, 1H),
Then, various aromatic aldehydes and ketones were
transformed to the corresponding ꢀ-acetamido ketones in the
presence of Zr(HSO4)4 as catalyst without the formation of any
Table 1. Optimization of the Reaction Conditions for One-Pot Reaction of 4-Methyl
benzaldehyde (1 mmol) and 4-Nitro Acetophenone (1 mmol)
CH3COHN
O
O
CHO
+
catalyst
CH3
CH3CN, CH3COCl
r.t., 4 h
CH3
NO2
CH3
NO2
Acetylchloride Acetonitrile
Yield
(%)
74
81
94
69
46
95
70
60
80
60
81
94
95
65
95
20
Entry
Catalyst (mmol)
(ml)
0.3
0.3
0.3
1.0
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
(ml)
0.3
0.7
1.0
0.3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1
2
3
4
5
6
7
8
Zr(HSO4)4 (0.08)
Zr(HSO4)4 (0.08)
Zr(HSO4)4 (0.08)
Zr(HSO4)4 (0.08)
Zr(HSO4)4 (0.06)
Zr(HSO4)4 (0.1)
Al(HSO4)3 (0.08)
ZrCl4 (0.08)
9
NaHSO4 (0.08)
H2SO4(0.08)
10
11
12
13
14
15
16
40% Zr(HSO4)4/SiO2 (0.033)
60% Zr(HSO4)4/SiO2 (0.05)
80% Zr(HSO4)4/SiO2 (0.06)
60% Zr(HSO4)4/SiO2 (0.0375)
60% Zr(HSO4)4/SiO2 (0.075)
-
96

Zr(HSO4)4/SiO2: An Effective Heterogeneous Alternative
side products with improved yields (Table 2).
and acetonitrile in the presence of catalyst failed to generate
any ꢀ-acetamido ketones. In the absence of acethyl chloride or
benzoyl chlorid, the reaction failed to provide the desired
product, obviously indicating that they play a necessary role in
this reaction, although not involved in the final product. When
benzyl cyanide or phenyl cyanide was used instead of
acetonitrile, the corresponding ꢀ-amido ketones such as ꢀ-
phenylacetamido ketone or ꢀ-benzamido ketone were
Acetylation of an aromatic hydroxyl group was observed
while using p-hydroxy benzaldehyde or vanillin. 4-
dimethylamino benzaldehyde, however, was inert to the
present reaction conditions. The preparative efficiency of this
one-pot synthesis was further checked by scaling-up (5 folds)
of the reaction of benzaldehyde with acetophenone and other
ingredients which proceeded with 90% yield.
Previously, three types of mechanisms for the Iqbal
procedure of ꢀ-acetamido ketone formation have been
proposed [6,7,9,11,18,19]. In some cases [7,18,19], ꢀ-acetoxy
ketone was offered as an intermediate product that converted
into ꢀ-acetamido ketone with acetonitrile. In our investigation,
when the reaction was not subjected to acetonitrile, no ꢀ-
acetoxy ketone was formed and only crossed aldol
condensation reaction occurred. Meanwhile, in the preparation
of ꢀ-acetamido ketones, no ꢀ-acetoxy ketones were obtained
as by-product. Besides, a mixture of chalcone, acetyl chloride
obtained. Note that neither
a
mixture of 4-methyl
benzaldehyde, 4-nitro acetophenone, acetic anhydride and
acetonitrile in the presence of Zr(HSO4)4/SiO2, nor a mixture
of 4-methyl benzaldehyde acylal, 4-nitro acetophenone and
Zr(HSO4)4/SiO2 in acetonitrile could produce any of the
corresponding ꢀ-acetamido ketones (Scheme 1).
CONCLUSIONS
In sum, catalytic activity of Zr(HSO4)4/SiO2 as a non-
Table 2. One-Pot Condensation of Aldehydes, Ketones, Acetyl Chloride and Acetonitrile to Give the
a
Corresponding ꢀ-Acetamido Ketones Catalyzed by Zr(HSO4)4/SiO2
O
CH3COHN
O
CHO
60% SiO2-Zr(HSO4)4
R4
+
R4
CH3
CH3CN, CH3COCl,
r.t., 2-6.5 h
R1
R3
R3
R1
R2
R2
(1)
(2)
(3)
Entry
Product (3)
R1,R2,R3 = H, R4 = Ph
R1,R2,R3 = H, R4 = 4-NO2-C6H4
R1 = Cl, R2,R3 = H, R4 = Ph
Time
Ref.
Yield
(%)b
96
87
70
81
85
67
94
68
80
93
88
m.p.
(°C)
104-105
97-98
135-136
129-130
89-91
(h)
3.0
4.0
2.5
2.5
3.0
6.5
3.0
3.5
2.0
2.0
2.0
3.0
1
2
3
4
5
6
7
8
[17]
[12]
[8]
R2 = NO2, R1,R3 = H, R4 = Ph
[9]
R1 = H, R2 = OCH3, R3 = OCOCH3, R4 = Ph
R1,R2 = H, R3 = CH3, R4 = 4-Cl-C6H4
R1,R2 = H, R3 = CH3, R4 = 4-NO2-C6H4
R1,R2 = H, R3 = CO2CH3, R4 = Ph
R1,R3 = H, R2 = OCH3, R4 = Ph
R1,R3 = H, R2 = NO2, R4 = 4-NO2-C6H4
R1,R3 = H, R2 = NO2, R4 = 4-Cl-C6H4
R2,R3 = H, R1 = Cl, R4 = 4-Cl-C6H4
[23]
[11]
[15]
[24]
[20]
[17]
[11]
-
-
84-85
156-158
87-89
105-106
145-146
168-169
9
10
11
12
75
aMolar ratio of aldehyde (mmol):ketone (mmol):acetyl chloride (ml) :acetonitrile (ml):60% Zr(HSO4)4/
SiO2(g)[mmol] equal to 1:1:0.3:1:0.04[0.05]. bIsolated yield.
97

Mirjalili et al.
O
O
RCOHN
Zr(HSO4)4
R=Ph
R=PhCH2 75%
73%
/SiO2
RCN, CH3COCl
r.t., 4 h
CH3
NO2
NO2
CH3COHN
Zr(HSO4)4/SiO2
O
CH3CN, PhCOCl
r.t., 72 h
80%
CH3
CH3
Zr(HSO4)4 /SiO2
CH3CN, r.t., 4 h
No Reaction
O
NO2
+
CH3COO
O
CHO
Zr(HSO )
4 4/SiO2
+
CH3COCl, r.t., 4 h
CH3
CH3
42%
H
CH3
NO2
NO2
0%
OAc
OAc
Zr(HSO4)4
/SiO2
+
NO2
COCH3
Ac2O, CH3CN
r.t., 4 h
CH3
85%
100%
Scheme 1
corrosive, easily producible and cheap material has been
studied for the synthesis of ꢀ-acetamido ketones. A mild
reaction condition, a simple experimental procedure, an easy
work-up and improved yields of products are some major
features of this reported method.
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Financial support for this work by the Research Affairs of
Yazd University is gratefully acknowledged.
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