Simple and new method for the synthesis of β-acetamido ketones on a solid surface

Article abstract of DOI:10.1080/00397911.2010.492459

Borax/POCl₃(BPO) was found to be an efficient reagent for the preparation of various β-acetamido ketones by a one-pot reaction of aryl aldehydes, enolisable ketones, acetyl chloride, and acetonitrile in a solvent-free medium. The present methodology offers several advantages, such as a cheaper process, good to excellent yields, simple procedure, short reaction times, and easy workup.

Full text of DOI:10.1080/00397911.2010.492459

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Simple and New Method for the
Synthesis of β-Acetamido Ketones on a
Solid Surface
Khodayar Gholivand a , Hadi Jafari b & Hadi Adibi c
a Department of Chemistry , Tarbiat Modares University , Tehran ,
Iran
b Department of Chemistry , Islamic Azad University–Sanandaj
Branch , Kurdistan , Iran
c Faculty of Pharmacy , Department of Medicinal Chemistry,
Kermanshah University of Medical Sciences , Kermanshah , Iran
Published online: 29 Apr 2011.
To cite this article: Khodayar Gholivand , Hadi Jafari & Hadi Adibi (2011) Simple and New Method
for the Synthesis of β-Acetamido Ketones on a Solid Surface, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:12, 1786-1793,
DOI: 10.1080/00397911.2010.492459
To link to this article: http://dx.doi.org/10.1080/00397911.2010.492459
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Synthetic Communications1, 41: 1786–1793, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.492459
SIMPLE AND NEW METHOD FOR THE SYNTHESIS OF
b-ACETAMIDO KETONES ON A SOLID SURFACE
Khodayar Gholivand,1 Hadi Jafari,2 and Hadi Adibi3
1Department of Chemistry, Tarbiat Modares University, Tehran, Iran
2Department of Chemistry, Islamic Azad University–Sanandaj Branch,
Kurdistan, Iran
3Faculty of Pharmacy, Department of Medicinal Chemistry, Kermanshah
University of Medical Sciences, Kermanshah, Iran
GRAPHICAL ABSTRACT
Abstract Borax/POCl3(BPO) was found to be an efficient reagent for the preparation of
various b-acetamido ketones by a one-pot reaction of aryl aldehydes, enolisable ketones,
acetyl chloride, and acetonitrile in a solvent-free medium. The present methodology offers
several advantages, such as a cheaper process, good to excellent yields, simple procedure,
short reaction times, and easy workup.
Keywords b-Acetamido ketones; borax; Dakin–West; multicomponent reactions; solid
surface
INTRODUCTION
Multicomponent reactions (MCRs) are of increasing importance in organic
and medicinal chemistry.[1–3] The strategies of MCRs offer significant advantages
over conventional linear-type syntheses for their high degree of atom economy, con-
vergence, ease of execution, and broad application. MCRs are particularly useful to
generate diverse chemical libraries of ‘‘druglike’’ molecules for biological screen-
ing.[4,5] In such reactions, three or more reactants come together in a single reaction
vessel to form new products that contain portions of all the components. As one of
the mostly studied MCRs, discovered in 1912, the Mannich reaction is an aminoalk-
ylation reaction of aldehyde (Fig. 1)[6] and is a very useful method for the prep-
aration of b-amino compounds.
Received March 17, 2010.
Address correspondence to Khodayar Gholivand, Department of Chemistry, Tarbiat Modares
University, P.O. Box 14115-175, Tehran, Iran. E-mail: gholi_kh@modares.ac.ir
1786

b-ACETAMIDO KETONES
1787
Figure 1.
b-Acetamido ketones are versatile intermediates, in that their skeletons exist in
a number of biologically or pharmacologically active compounds.[7,8] They could
easily be converted to 1,3-amino alcohols,[9] which are utilized for the synthesis of
several antibiotics.[10] b-Acetamido ketones are usually prepared through acylation
of b-aminoketones,[11] Michael addition to a,b-unsaturated ketones,[12] or photo-
isomerization of phthalimides.[13] Dakin et al. first reported the preparation of this
kind of compound by the Dakin–West reaction in 1928, which is the condensation
between an a-amino acid and acetic anhydride in the presence of a base, providing
acetamido ketones.[14]
Some catalysts, including montmorillonite K10 Clay,[15] SiO2–H2SO4,[16] tri-
flate salts,[17] zeolite,[18] iodine,[19] BiCl3 generated in situ from BiOCl and acetyl
chloride,[20] ZrOCl2 Á 8H2O,[21] iron(III) chloride,[22] CeCl3 Á 7H2O,[23] heteropolya-
cids,[24,25] ZnO,[26] polianiline salts,[27] selectfluor,[28] and TMSCl,[29] have been
employed for the synthesis of b-acetamido carbonyl compounds. While offering
some advantages, all of these methods suffer from different drawbacks such as the
use of expensive reagents, long reaction times, harsh reaction conditions, and tedious
workup procedures.
Surface-mediated solid-phase reactions are of growing interest,[30] because of
their ease of setup and workup, mild reaction conditions, rate of the reaction, selec-
tivity, good yields, lack of solvent, and the low cost of the reactions in comparison
with their homogeneous counterparts.
This article describes a facile synthesis of b-acetamido ketones. It was
found that borax (anhydrous)–supported POCl3 can catalyze the preparation of b-
acetamido ketones by a one-pot reaction of aryl aldehydes, enolisable ketones, acetyl
chloride, and acetonitrile in solvent-free conditions (Fig. 2). It is interesting to note
that the reaction was not observed in the presence of POCl3 and borax separately.
To find the optimal conditions, the synthesis of b-acetamido-b-phenyl propio-
phenone was used as a model reaction. A mixture of benzaldehyde (3 mmol), aceto-
phenone (3 mmol), acetyl chloride (0.6 ml), and acetonitrile (10 ml) was stirred under
various reaction conditions at 80 ꢀC (Table 1). In the absence of the catalyst,
b-acetamido-b-phenyl propiophenone was obtained in a trace amount after 10 h,
Figure 2.

1788
K. GHOLIVAND, H. JAFARI, AND H. ADIBI
Table 1. Preparation of b-acetamido-b-phenyl propiophenone from benzaldehyde (3 mmol) and aceto-
phenone (3 mmol) in the presence of acetyl chloride (0.6 mL) and acetonitrile (10 mL) in various conditions
at 80 ꢀC
Entry
Catalyst (g)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
No catalyst
Borax (0.3)
POCl3 (0.3)
BPO (0.05)
BPO (0.1)
BPO (0.2)
BPO (0.3)
10
5
Trace
25
5
5
45
3
0.5
0.5
0.5
89
88
90
aIsolated yields.
Table 2. Preparation of b-acetamido-b-phenyl propiophenone from benzaldehyde (3 mmol) and
acetophenone (3 mmol) in the presence of acetyl chloride (0.6 mL), acetonitrile (10 mL), and BPO (0.1 g)
at different temperatures
Entry
Temperature (ꢀC)
Time (h)
Yielda (%)
1
2
3
4
25
45
60
80
5
45
67
88
89
1.5
0.5
0.5
aIsolated yields.
while good results were obtained in the presence of BPO after 0.5 h (Table 1, entries
5–7). Using an optimized amount of catalyst, we found that 0.1 g of BPO could effec-
tively catalyze the model reaction at 80 ꢀC. With inclusion of 0.05 g BPO, the reaction
took a longer time. No significant impact on the yield was observed when the amount
of BPO was increased to 0.3 g. (Table 1, entries 6 and 7). The effect of temperature
was studied by carrying out the model reaction in the presence of BPO (0.1 g) at room
temperature (25 ꢀC), 45 ꢀC, 60 ꢀC, and 80 ꢀC. It was observed (Table 2, entries 1–3)
that the yield was increased as the reaction temperature was raised, but above
60 ꢀC temperature has no effect on the yield and time of the reaction.
To evaluate the efficiency of this methodology, we used several other aromatic
aldehydes and acetophenone derivatives having electron-donating as well as
electron-withdrawing substituents to obtain the corresponding b-acetamido ketones
under the optimized reaction conditions (Table 3). In general, electron-donating sub-
stituents furnished faster reaction rates, affording b-acetamido ketones in good
yields (Table 3, entries 5, 7, and 17). On the other hand, electron-withdrawing sub-
stituents decreased the rate of the reaction, and moderate yields of b-acetamido
ketones were obtained (Table 3, entries 11–15).
EXPERIMENTAL
All compounds were known, and their physical and spectroscopic data were
compared with those of authentic samples and found to be identical.

b-ACETAMIDO KETONES
1789
Table 3. One-pot condensation of aryl aldehydes, aryl ketones, acetyl chloride, and acetonitrile to give the
corresponding b-acetamido ketones catalyzed by BPO
Mp
Time
(min)
Yielda
(%)
Entry
1
R1
H
R2
H
Product
Found Reported
30
40
88
85
102–103 103–105[29]
2
3
2-Cl
H
H
134–136 135–137[29]
4-NO2
65
70
80
87
146–147 148–149[15]
4
3-NO2
H
112–114 112–115[15]
5
6
7
8
9
4-OMe
4-Cl
H
H
H
30
40
25
30
40
90
78
86
75
82
109–112 110–112[29]
143–145 146–148[29]
4-
OMe
128–131
130[21]
H
4-Cl
178–180 177–178[31]
H
4-NO2
99–101 101–103[32]
(Continued )

1790
K. GHOLIVAND, H. JAFARI, AND H. ADIBI
Table 3. Continued
Mp
Time
(min)
Yielda
(%)
Entry
10
R1
R2
Product
Found Reported
4-OM 4-NO2
45
77
86–88
87–89[15]
11
12
13
14
15
16
4-Cl 4-NO2
40
50
50
60
45
40
82
77
74
78
81
86
193–196 192–195[32]
140–142 141–143[16]
137–139 137–138[31]
186–188 187–188[13]
147–148 147–149[29]
4-Cl
4-Br
4-Cl
4-Cl
4-NO2 4-NO2
4-Br
H
4-CH3 4-NO2
83–84
83–85[15]
17
4-CH3
H
30
78
111–113 112–114[29]
aIsolated yields.
Preparation of BPO
A mixture of POCl3 (3 g) and anhydrous borax (2 g) were combined in a mortar
and pestle by grinding them together until a fine, homogeneous powder was obtained
(15–20 min).

b-ACETAMIDO KETONES
1791
Table 4. Comparison of the results for the preparation of b-acetamido ketones (Table 2, entry 1) using
multicomponent reactions with some other catalysts
Catalyst
Time (h)
Temperature (ꢀC)
Yield (%) [Ref.]
BPO
0.5
7
60
70
80
r.t
r.t
80
r.t
88 [Table 3]
80[15]
Montmorillonite K-10
Silica sulfuric acid
Sc(OTf)3
1.08
30
5
91[16]
82[17]
ZrOCl2 Á 8H2O
ZnO
90[21]
6
30
90[33]
BF3 Á OEt2
78[17]
Synthesis of b-Acetamido Ketone: General Procedure
A mixture of ketone (3 mmol), aldehyde (3 mmol), and acetyl chloride (0.6 mL)
in acetonitrile (10 mL) in the presence of BPO (0.1 g) was heated at 60 ꢀC. The
progress of reaction was monitored by thin-layer chromatography (TLC). After
completion of the reaction, the mixture was filtered to separate the catalyst, and then
the solvent was evaporated to dryness under reduced pressure. The pure products
could be obtained by recrystallization from a mixture of ethanol and water.
CONCLUSION
In conclusion, we have developed a simple methodology for the one-pot syn-
thesis of b-acetamido ketones by coupling four components (viz. benzaldehydes,
acetophenones, acetyl chloride, and acetonitrile), catalyzed by BPO. The major
advantages of the present protocol over existing methods can be seen by comparing
our results with those of some recently reported procedures, as shown in Table 4.
Good yields of the products, short reaction times, mild reaction conditions, and
the ease of workup procedure make this protocol complementary to the existing
methods. Studies for the application of this method as catalyst for several reactions
are under investigation in our laboratory.
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