A modified procedure for the Dakin-West reaction: An efficient and convenient method for a one-pot synthesis of β-acetamido ketones using silica sulfuric acid as catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.01.149

A one-pot, four-component condensation of an aryl aldehyde, an aryl ketone, acetyl chloride and acetonitrile in the presence of silica sulfuric acid as an active, inexpensive, recoverable and recyclable catalyst is disclosed for the synthesis of β-acetami

Full text of DOI:10.1016/j.tetlet.2005.01.149

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2105–2108
A modified procedure for the Dakin–West reaction: an efficient
and convenient method for a one-pot synthesis of
b-acetamido ketones using silica sulfuric acid as catalyst
Mohammd M. Khodaei,* Ahmad R. Khosropour* and Peyman Fattahpour
Department of Chemistry, Faculty of Science, Razi University, Kermanshah 67149, Iran
Received 15 November 2004; revised 18 January 2005; accepted 25 January 2005
Abstract—A one-pot, four-component condensation of an aryl aldehyde, an aryl ketone, acetyl chloride and acetonitrile in the pres-
ence of silica sulfuric acid as an active, inexpensive, recoverable and recyclable catalyst is disclosed for the synthesis of b-acetamido
ketones.
Ó 2005 Elsevier Ltd. All rights reserved.
During the last few years, multi-component reactions
(MCRs) have proved to be remarkably successful in
generating molecular complexity in a single synthetic
operation.1 These processes consist of two or more syn-
thetic steps, which are performed without isolation of
any intermediates thus reducing time and saving both
energy and raw materials. MCRs are powerful tools in
the modern drug discovery process and allow fast, auto-
mated and high throughput generation of organic com-
pounds.2 Furthermore, a field of increasing interest is
the synthesis of useful synthetic building blocks via
MCR chemistry. For this reason, the discovery of novel
MCRs is of interest.3–5
is valuable, the time for the completion of this transfor-
mation is long (7 h). Therefore, the introduction of new
and efficient methods for this multi-component reaction
is still necessary. Towards this goal, and in continuation
of our investigations on the synthesis of b-enaminones11
and MCRs,12 we were prompted to explore new meth-
ods for this useful transformation.
In recent years, heterogeneous catalysts have gained
importance due to environmental and economic consid-
erations.13 Among these, the application of silica sulfu-
ric acid as a stable and efficient heterogeneous catalyst
in organic synthesis has been widely studied.14 This cat-
alyst is important from an environmental point of view,
because it produces little waste. It also has excellent
activity and selectivity even on an industrial scale and
in most cases can be recovered from reaction mixtures
and reused.
b-Acetamido ketones are versatile intermediates in that
their skeletons exist in a number of biologically or phar-
macologically important compounds.6,7 The best known
route for the synthesis of these compounds is the Dakin–
West reaction,8 which involves the condensation of an a-
amino acid with acetic anhydride in the presence of a
base via an intermediate azalactone to give the a-acet-
amido ketones.9 Iqbal et al. proposed another procedure
for the formation of these compounds through the con-
Now, we report an efficient and convenient procedure
for the synthesis of b-acetamido ketones using silica sul-
furic acid as catalyst (Scheme 1).
densation of an aryl aldehyde, acetophenone and acetyl
10a
chloride in acetonitrile in the presence of CoCl2
or
montmorillonite K-10 clay.10b Although, this method
Ar
NHCOCH3
Silica Sulfuric Acid
ArCHO + Ar'COCH3+CH3COCl
CH3CN, 80 o
C
O
Keywords: b-Acetamido ketones; Benzaldehydes; Acetophenones;
One-pot synthesis; Silica sulfuric acid; Catalyst; Dakin–West reaction.
1
2
Ar'
*
Corresponding authors. Tel./fax: +98 831 4274559; e-mail addresses:
mmkhoda@razi.ac.ir; arkhosropour@razi.ac.ir
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.149

2106
M. M. Khodaei et al. / Tetrahedron Letters 46 (2005) 2105–2108
Table 1. One-pot condensation of aryl aldehydes, aryl ketones, acetyl chloride and acetonitrile to give the corresponding b-acetamido ketones
catalyzed by silica sulfuric acid
Entry
1
Ar
Ar0
Producta
Time (min)
65
Yield %b
CH3CONH
O
O
C6H5
C6H5
91
CH3CONH
2
3
4
5
6
7
3-NO2C6H4
4-NO2C6H4
4-ClC6H4
2-ClC6H4
4-CH3OC6H4
C6H5
C6H5
120
110
70
80
82
89
93
84
90
NO2
CH3CONH
O
C6H5
O2N
CH3CONH
O
C6H5
Cl
CH3CONH
O
C6H5
95
Cl
CH3CONH
O
C6H5
80
CH3O
CH3CONH
O
4-NO2C6H4
90
NO2
CH3CONH
O
O
8
9
C6H5
4-BrC6H4
4-ClC6H4
80
70
93
90
Br
CH3CONH
C6H5
Cl
CH3CONH
O
10
4-NO2C6H4
4-NO2C6H4
100
75
O2N
NO2
CH3CONH
O
11
12
3-NO2C6H4
4-NO2C6H4
100
90
82
92
NO2
O2N
O2N
CH3CONH
O
4-NO2C6H4
4-BrC6H4
Br

M. M. Khodaei et al. / Tetrahedron Letters 46 (2005) 2105–2108
2107
Table 1 (continued)
Entry
Ar
Ar0
Producta
Time (min)
Yield %b
CH3CONH
O
13
14
3-NO2C6H4
4-BrC6H4
90
89
Br
O2N
CH3CONH
O
4-FC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-BrC6H4
90
70
80
87
70
88
94
87
91
72
30
NO2
F
CH3CONH
O
15
16
17
18
19
20
21
22
4-ClC6H4
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
4-FC6H4
NO2
Cl
CH3CONH
O
100
65
NO2
H3C
H3CO
Cl
CH3CONH
O
NO2
CH3CONH
O
O
60
Br
CH3CONH
CH3CONH
4-ClC6H4
100
65
Cl
F
O
4-ClC6H4
2-HOC6H4
CH3CH2
4-ClC6H4
Cl
Cl
CH3CONH
O
4-BrC6H4
70
Br
OH
CH3CONH
CH3CH2
O
4-NO2C6H4
120
NO2
a All products were characterized by 1H NMR, 13C NMR and IR spectroscopy.
b Isolated yields.
The experimental procedure for this reaction is remark-
ably simple and requires no inert atmosphere.15 We
started our investigation using aryl aldehydes and aryl
ketones as substrates. The reaction was carried out by
stirring an aryl aldehyde, an aryl methyl ketone and ace-
tyl chloride with silica sulfuric acid in acetonitrile at
80 °C. The results obtained are summarized in Table
1. All the products were characterized by 1H or 13C
NMRs spectroscopic data.
Aromatic aldehydes or acetophenones both with activ-
ating and deactivating groups underwent smooth

2108
M. M. Khodaei et al. / Tetrahedron Letters 46 (2005) 2105–2108
+
References and notes
O
CH3COCl, H+
OCOCH3
OCOCH3
H
R
1. (a) Eilbracht, P.; Schimdt, A. Chem. Rev. 1999, 99, 3329;
(b) Ugi, I. Pure Appl. Chem. 2001, 77, 187; (c) Bagley, M.
C.; Cale, J. W.; Bower, J. Chem. Commun. 2002, 1682; (d)
Dallinger, D.; Gorobets, N. Y.; Kappe, C. O. Org. Lett.
2003, 5, 1205; (e) Bora, U.; Saikia, A.; Boruah, R. C. Org.
Lett. 2003, 5, 435.
Cl
H
R
R
H
NCCH3
CH3
CH3
+
2. Weber, L. Curr. Med. Chem. 2002, 9, 1241.
N
O
N
O
3. Ugi, I.; Werner, B.; Do¨mling, A. Molecules 2003, 8, 53.
4. Do¨mling, A. Curr. Opin. Chem. Biol. 2000, 4, 318.
5. Weber, L. Drug Discovery Today 2002, 7, 143.
6. Casimir, J. R.; Turetta, C.; Ettouati, L.; Paris, J. Tetra-
hedron Lett. 1995, 36, 4797.
+
O
O
R
CH3
R
CH3
7. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.;
McCarthy, J. R.; Mitchell, D. J. Org. Chem. 2003, 68,
2623.
8. Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 745.
9. Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91.
10. (a) Bhatia, B.; Reddy, M. M.; Iqbal, J. J. Chem. Res. (S)
1994, 713; (b) Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org.
Chem. 2003, 68, 5735.
O
CH3
CH3
O
H3C
CH3
O
N
O
N
O
Product
R1
R
+
R
HO
R'
H2C
11. (a) Khodaei, M. M.; Khosropour, A. R.; Kookhazadeh,
M. Synlett 2004, 1980; (b) Khosropour, A. R.; Khodaei,
M. M.; Kookhazadeh, M. Tetrahedron Lett. 2004, 45,
1725.
Scheme 2.
12. (a) Khodaei, M. M.; Khosropour, A. R.; Beygzadeh, M.
Synth. Commun. 2004, 34, 1551; (b) Khosropour, A. R.;
Khodaei, M. M. Chem. Lett. 2004, 33, 1378; (c) Khodaei,
M. M.; Khosropour, A. R.; Hoseini Jomor, S. J. J. Chem.
Res. (S) 2003, 638.
13. (a) Samajdar, S.; Becker, F. R.; Naik, P. K. Tetrahedron
Lett. 2000, 41, 8017; (b) Bahulayan, D.; Narayan, G.;
Sreekumar, V.; Lalithambika, M. Synth. Commun. 2002, 32,
3565; (c) Srinivas, K. V. N. S.; Das, B. Synlett 2004, 1715.
14. (a) Zolfigol, M. A.; Bamoniri, A. Synlett 2002, 1621; (b)
Zolfigol, M. A.; Shirini, F.; Choghamarani, A. G.;
Mohammadpoor-Baltork, I. Green Chem. 2002, 4, 562;
(c) Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Bodaghi Fard,
M. A. Tetrahedron Lett. 2003, 44, 2889.
15. The general procedure is as follows: a solution of the aryl
aldehyde (1 mmol), aryl ketone (1 mmol), acetyl chloride
(0.3 mL) and acetonitrile (2 mL) in the presence of silica
sulfuric acid (0.3 g, equal to 0.78 mmol H+) was heated at
80 °C, with stirring for 60–120 min. The progress of the
reaction was followed by TLC. After completion of the
reaction, the mixture was filtered and the filtrate 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 product. Most of the
compounds prepared are known.10b The spectral data of
some representative b-acetamido ketones are given below.
b-Acetamido-b-(4-chlorophenyl)propiophenone (Table
1, entry 4): mp 146–148 °C, IR (NaCl, cmꢀ1) 3280, 3072,
1680, 1641, 1542, 1283, 1088, 892, 812, 690, 1H NMR
(CDCl3, 200 MHz) d 2.10 (s, 3H), 3.49 (dd, J = 7.8 and
10.9 Hz, 1H), 3.83 (dd, J = 7.8 and 10.9 Hz, 1H), 5.62 (m,
1H), 7.18 (m, 5H), 7.51 (m, 3H), 7.94 (d, J = 9.1 Hz, 2H),
13C NMR (CDCl3, 50 MHz) d 23.8, 43.4, 49.7, 128.4,
128.5, 129.1, 129.2, 133.5, 134.1, 136.8, 140.1, 170.0, 198.7.
b-Acetamido-b-(4-chlorophenyl)-4-chloropropiophenone
(Table 1, entry 20): mp 141–143 °C, IR (NaCl, cmꢀ1) 3264,
3056, 1670, 1635, 1584, 1292, 1088, 885, 825, 1H NMR
(CDCl3, 200 MHz) d 2.08 (s, 3H), 3.40 (dd, J = 7.3 and
10.9 Hz, 1H), 3.82 (dd, J = 7.3 and 10.9 Hz, 1H), 5.57 (m,
1H), 7.32 (s, 1H), 7.47 (d, J = 9.1 Hz, 4H), 7.90 (d,
J = 9.1 Hz, 4H), 13C NMR (CDCl3, 50 MHz) d 23.5, 43.6,
49. 9, 128.4, 129.3, 129.5, 129.9, 133.8, 135.1, 139. 7, 140.6,
170.5, 197.3.
transformation to the corresponding b-acetamido
ketones, without the formation of any side products,
in high to excellent yields and in relatively short reaction
times (<120 min). However, the synthesis could not be
achieved in the absence of the catalyst.
Several functional groups such as nitro chloro, bromo,
hydroxyl and methoxy were compatible with this proce-
dure (Table 1, entries 2–21). Interestingly, we found that
no acetylation of an aromatic hydroxyl group was
observed under the reaction conditions and the
corresponding b-acetamido ketone was isolated in an
excellent yield (Table 1, entry 21). We found that
aliphatic aldehydes react under these conditions, but
produce the corresponding b-acetamido ketones in low
yields (Table 1, entry 22). The catalyst can be easily
prepared and can be handled safely. It can also be
recovered and reused at least five times without losing
activity.
We propose a reaction mechanism based on IqbalÕs
suggestion10a for the formation of b-acetamido
ketones in Scheme 2. The presence of acetyl chloride is
necessary for the transformation and the reaction in
its absence gave none of the desired product even after
2 h.
In conclusion, we have developed a simple methodology
for the one-pot synthesis of b-acetamido ketones by cou-
pling four components, viz benzaldehydes, acetophe-
nones, acetyl chloride and acetonitrile catalyzed by the
reusable solid acid, silica sulfuric acid.
Acknowledgements
The authors thank the Razi University Research Coun-
cil for financial assistance.