One-pot, four-component reaction of aryl aldehydes, aryl ketones, phosphorus trichloride, and acetonitrile catalyzed by acetyl chloride: Synthesis of β-acetamido ketones

Article abstract of DOI:10.1080/00397910701767064

The one-pot, four-component reaction of aryl aldehydes, aryl ketones, phosphorus trichloride, and acetonitrile, catalyzed by acetyl chloride, affords β-acetamido ketones in good to excellent yields. Silicaphosphine (silphos), [P(Cl)3-n(SiO2)n], can also b

Full text of DOI:10.1080/00397910701767064

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One‐Pot, Four‐Component Reaction of
Aryl Aldehydes, Aryl Ketones, Phosphorus
Trichloride, and Acetonitrile Catalyzed by
Acetyl Chloride: Synthesis of β‐Acetamido
Ketones
Mohammad Anary‐Abbasinejad a & Azimeh Saidipoor a
a Department of Chemistry, Islamic Azad University, Yazd, Iran
Published online: 28 Jan 2008.
To cite this article: Mohammad Anary‐Abbasinejad & Azimeh Saidipoor (2008): One‐Pot, Four‐Component
Reaction of Aryl Aldehydes, Aryl Ketones, Phosphorus Trichloride, and Acetonitrile Catalyzed by Acetyl
Chloride: Synthesis of β‐Acetamido Ketones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:3, 354-360
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Synthetic Communicationsw, 38: 354–360, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701767064
One-Pot, Four-Component Reaction of Aryl
Aldehydes, Aryl Ketones, Phosphorus
Trichloride, and Acetonitrile Catalyzed by
Acetyl Chloride: Synthesis of b-Acetamido
Ketones
Mohammad Anary-Abbasinejad and Azimeh Saidipoor
Department of Chemistry, Islamic Azad University, Yazd, Iran
Abstract: The one-pot, four-component reaction of aryl aldehydes, aryl ketones, phos-
phorus trichloride, and acetonitrile, catalyzed by acetyl chloride, affords b-acetamido
ketones in good to excellent yields. Silicaphosphine (silphos), [P(Cl)3-n(SiO2)n], can
also be used effectively as a solid-supported reagent instead of phosphorus trichloride.
Keywords: b-acetamido ketones, Dakin–West reaction, phosphorus trichloride,
silicaphosphine, silphos
During the past few years, multicomponent reactions (MCRs) have proved to
be remarkably successful in generating molecular complexity in a single-
synthetic-step operation.[1] These processes consist of two or more synthetic
steps, which are performed without isolation of any intermediates, thus
reducing time and saving both energy and raw materials. MCRs are
powerful tools in modern drug-discovery processes and allow fast,
automated, and high-throughput generation of organic compounds.[2] Further-
more, a field of increasing interest is the synthesis of useful synthetic building
Received in the U.K. February 28, 2007
Address correspondence to Mohammad Anary-Abbasinejad, Department of
Chemistry, Islamic Azad University, Yazd Branch, P. O. Box 89195 155, Yazd,
Iran. E-mail: mohammadanary@yahoo.com
354

Synthesis of b-Acetamido Ketones
355
blocks via MCR chemistry. For this reason, the discovery of novel MCRs is of
interest.[3–5]
The Dakin–West reaction is the best known route for the synthesis of
b-acetamido ketones.[6,7] These compounds are versatile intermediates, in
that their skeletons exist in a number of biologically or pharmacologically
important compounds.[8,9] A few catalysts have already been applied for the
synthesis of b-acetamido ketones using this method, including different tran-
sition-metal triflates, BF3, CuCl2, BiCl3, LaCl3, LiClO4, InCl3,[10] CoCl2,[11]
montmorillonite K-10 clay,[12] H2SO4/SiO2,[13] heteropoly acids,[14]
[16]
BiOCl,[15] ZrOCl2 8H2O,
and silica sulfuric acid.[17] The role of these
.
acidic catalysts has been reported to be activation of the carbonyl group of
the aldehyde toward the addition of acetonitrile[11,12] or toward the attack of
the enole of aryl ketone.[10] Having in mind that phosphorus trichloride is
capable of accepting the electron pair of oxygen and activating the carbonyl
group toward the nucleopholic attacks, we decided to investigate the
reaction of aryl aldehydes, aryl ketones, acetonitrile, and acetyl chloride in
the presence of this compound as catalyst. We started our investigation by
carrying out the reaction of 4-chlorobenzaldehyde, acetophenone, acetylchlor-
ide, and acetonitrile. Thus, a mixture of 3 mmol of 4-chlorobenzaldehyde,
3 mmol of acetophenone, 3 mmol of phosphorus trichloride, and 3 mmol of
acetyl chloride was stirred in boiling acetonitrile as solvent for 60 min. The
reaction progress was monitored by thin-layer chromatography (TLC). After
the workup of the reaction, we obtained the desired b-acetamido ketones 3
in 90% yield. The structure of the product was deduced by comparison of
1
its H and 13C NMR and IR spectra with those of authentic compounds.[12]
To obtain the best reagent ratio and reaction condition, we carried out this
reaction with different amounts of acetyl chloride and phosphorus trichloride.
The obtained results are shown in Table 1. As indicated in Table 1, no reaction
was observed in the absence of acetyl chloride or phosphorus trichloride
Table 1. Four-component reaction between 4-chlorobenzaldehyde, aceto-
phenone, phosphorus trichloride, and acetonitrile catalyzed by acetyl chloride
CH3COCl
amount (mol%)
PCl3 amount
(mol%)
Entry
Time (min)
Yield (%)
a
1
2
3
4
5
6
0
100
10
100
0
240
240
60
—
a
—
100
100
110
110
73b
85b
90b
75b,c
20
20
60
60
20
300
aOnly starting materials were obtained after the workup of the reaction.
bIsolated yield.
cThe reaction is carried out at room temperature.

356
M. Anary-Abbasinejad and A. Saidipoor
Table 2. One-pot condensation of aryl aldehydes, aryl ketones, phosphorus trichlo-
ride (or silphos), and acetonitryl to give the corresponding b-acetamido ketones
Yield (%)b
(PClc3/silphosd)
Entry
1
Ar
Ar0
Producta
C6H5
C6H5
C6H5
C6H5
90/93
2
3
3-NO2C6H4
4-NO2C6H4
93/90
88/85
4
5
6
4-ClC6H4
C6H5
C6H5
C6H5
90/85
90/85
85/90
2-ClC6H4
4-CH3OC6H4
7
8
C6H5
4-NO2C6H4
4-BrC6H4
4-ClC6H4
94/95
92/90
89/83
93/88
C6H5
9
C6H5
10
4-NO2C6H4
4-NO2C6H4
(continued)

Synthesis of b-Acetamido Ketones
Table 2. Continued
357
Yield (%)b
(PClc3/silphosd)
Entry
11
Ar
Ar0
Producta
3-NO2C6H4
4-NO2C6H4
91/88
12
4-NO2C6H4
4-BrC6H4
90/93
13
14
3-NO2C6H4
4-FC6H4
4-BrC6H4
88/84
87/92
4-NO2C6H4
15
16
17
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
88/90
92/94
89/90
4-CH3C6H4
4-CH3OC6H4
18
19
4-ClC6H4
4-FC6H4
4-BrC6H4
4-ClC6H4
90/85
89/83
20
CH3CH2
4-NO2C6H4
22/31
1
aAll products were characterized by comparing their H NMR, 13C NMR, and IR
spectra with reported compounds.[11,12]
bIsolated yield.
cAll reactions were carried out in 15 mL, of boiling acetonitryl for 1 h with starting
material ratio of PCl3–aldehyde–ketone–CH3COCl ¼ 3.3:3:3:0.6.
dAll reactions were carried out in 15 mL of boiling acetonitryl for 1 h with 1.8 g of
silphos, 3 mmol of aldehyde, 3 mmol of ketone, and 0.6 mmol of CH3COCl.

358
M. Anary-Abbasinejad and A. Saidipoor
(entries 1 and 2). However, acetyl chloride can be used in catalytic amounts
(Table 1, entry 4). In all of the previously reported investigations on four-
component Dakin–West reaction, acetyl chloride has been used in excess
amounts (usually 3–4 equivalents).[13–17] Contrary to our expectation,
when we used phosphorus trichloride in catalytic amounts, we could only
obtain the desired Dakin–West products in low yields, and the major
isolated compounds were the starting aldehyde and ketone. The best amount
of phosphorus trichloride was found to be 1.1 equivalents. Considering
these observations, we can say that in this reaction phosphorus trichloride
acts as a reagent and acetyl chloride is catalyst.
To investigate the scope of this method for synthesizing b-acetamido
ketones, we carried out the reaction with different aryl aldehydes and aryl
ketones. The results are summarized in Table 2. Several functional groups
such as nitro, chloro, bromo, and methoxy were compatible with this
procedure. Aliphatic aldehydes can also be used, but the yield is low
(Table 2, entry 20).
Being successful in carrying out the reaction with phosphorus trichloride,
we decided to investigate the effectiveness of the newly introduced silicapho-
sphine (silphos), [P(Cl)3-n(SiO2)n], as a solid-supported reagent to synthesize
b-acetamido ketones. The introduction of supported reagents for bringing
about various chemical transformations has provided an attractive option for
organic synthesis.[18] Such reagents not only modify the reactivity but also
may impart product selectivity, enhanced reaction rates, cleaner reaction
products, and operational simplicity.[19,20] Silphos has been recently intro-
duced as an efficient reagent or catalyst for some organic transformations,
including halogenation of alcohols,[21] formylation and acetylation of
alcohols and amines,[22] and conversion of epoxides to alkenes or
b-bromoformates.[23]
To investigate the effectiveness of silphos, we first carried out its reaction
with 4-chloro benzaldehyde and acetophenone in the presence of acetyl
chloride in acetonitrile as solvent. Silphos was easily prepared by the
reaction of phosphorus trichloride and silica gel as reported in the litera-
ture.[21] The reaction was carried out by stirring a mixture of 4-chlorobenzal-
dehyde, acetophenone, acetyl chloride, and silphos in boiling acetonitrile. The
reaction was completed after an hour in refluxing acetonitrile as indicated by
thin-layer chromatography (TLC), and the product was obtained in 93% yield.
The amount of silphos and acetyl chloride was optimized for this reaction. The
best result was obtained by using 0.6 g of silphos with 1 mmol each of
p-chlorobenzaldehyde and acetophenone and 0.2 mmol of acetyl chloride in
15 mL of refluxing acetonitrile. This optimized condition was used for the
reaction of other aldehydes and ketones. Aromatic aldehydes or acetophe-
nones both with electron-withdrawing and electron-releasing groups
underwent smooth transformation to the corresponding b-acetamido ketones
in high to excellent yields (Table 2). However, no product was isolated in
the absence of silphos or acetyl chloride.

Synthesis of b-Acetamido Ketones
359
Scheme 1.
Although we did not investigate the reaction mechanism, one reasonable
possibility is shown in Scheme 1.
In conclusion, we have developed a one-pot, four-component reaction of
phosphorus trichloride, aryl aldehydes, aryl ketones, and acetonitrile for
synthesis of b-acetamido ketones by the Dakin–West reaction. The reaction
can also be carried out with simply prepared and filterable silphos instead
of harder-to-handle phosphorus trichloride. The advantages of this method
are easily available starting materials, short reaction times, easy and clean
workup, and excellent yields.
GENERAL PROCEDURE FOR PREPARATION OF
b-ACETAMIDO KETONES
A solution of aryl aldehyde (3 mmol), aryl ketone (3 mmol), phosphorus tri-
chloride (3.3 mmol), and acetyl chloride (0.6 mmol) in acetonitrile (15 mL)
was stirred at reflux temperature for an hour. The mixture was poured into
50 mL of ice water (when silphos was used, the reaction mixture was
filtered into ice water, and the mass on filtering paper was washed with

360
M. Anary-Abbasinejad and A. Saidipoor
30 mL of 1:1 mixture of acetonitrile/water into ice water). The solid product
was filtered, washed with ice water, and recrystallized from ethyl acetate/n-
hexane to give the pure product. All products were identified by comparing
their melting point and their NMR and IR values with those of authentic
samples.[12,13]
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