CeCl3·7H2O: an efficient and reusable catalyst for the preparation of β-acetamido carbonyl compounds by multi-component reactions (MCRs)

Article abstract of DOI:10.1016/j.tetlet.2006.09.041

A convenient method for the preparation of β-acetamido carbonyl compounds is described by multi-component reactions of aromatic aldehydes, enolizable ketones or β-keto esters and acetonitrile in the presence of acetyl chloride and 10 mol % CeCl₃

Full text of DOI:10.1016/j.tetlet.2006.09.041

Tetrahedron Letters 47 (2006) 8137–8141
CeCl Æ7H O: an efficient and reusable catalyst for the
3
2
preparation of b-acetamido carbonyl compounds by
multi-component reactions (MCRs)
*
Abu T. Khan, Lokman H. Choudhury, Tasneem Parvin and Md. Asif Ali
Indian Institute of Technology Guwahati, Department of Chemistry, Guwahati 781 039, India
Received 1 August 2006; revised 28 August 2006; accepted 7 September 2006
Available online 4 October 2006
Abstract—A convenient method for the preparation of b-acetamido carbonyl compounds is described by multi-component reactions
of aromatic aldehydes, enolizable ketones or b-keto esters and acetonitrile in the presence of acetyl chloride and 10 mol %
CeCl Æ7H O at room temperature.
3
2
ꢀ
2006 Elsevier Ltd. All rights reserved.
After the discovery of multi-component reactions
amido carbonyl compounds has attracted much atten-
tion in organic synthesis. Conventionally, this class of
compounds is prepared by the Dakin–West reaction,
the condensation of an a-amino acid with acetic anhyd-
ride in the presence of a base provides the a-acetamido
ketones through an intermediate azalactone.6 Iqbal
et al. developed a route using aromatic aldehydes, enol-
izable ketones or b-keto esters and acetonitrile in the
1
(
MCRs) in 1850 by Strecker, the concept has stimu-
5
lated substantial interest in organic chemistry because
it provides useful product(s) in a single step by the cre-
ation of several new bonds in one pot. In drug discovery
as well as ‘Green Chemistry’, MCRs are the preferred
techniques due to high throughput synthesis of
compounds in a cost- and time effective manner.
presence of acetyl chloride and a catalytic amount of a
7
b-Acetamido carbonyl compounds are valuable building
Lewis acid catalyst such as CoCl or Montmorillonite
2
8
blocks for a number of biologically and pharmaceuti-
K-10 clay. Although these methods are valuable some
2
cally important compounds, examples being for the
drawbacks remain such as a requirement for either
a long reaction time or harsh reaction conditions, or
the reaction has to be carried out under an inert
3
preparation of 1,3-amino alcohols, antibiotic nikko-
4
mycins or neopolyoxines. Thus, the synthesis of b-acet-
O
NHCOCH3
O
CeCl3 7H O (10 mol%)
R
2
+
RCHO
CH COCl, CH CN,
3
3
rt, 86-98%
R = benzylic
AcHN
O
O
AcHN
O
O
CHO
O
O
CeCl3 7H O (10 mol%)
2
+
+
R1
CH3COCl, CH3CN,
rt, 76-84%
1
R1
R
X
X
X
syn
anti
Scheme 1.
*
0
Corresponding author. Tel.: +91 361 2582305; fax: +91 361 2582349; e-mail: atk@iitg.ernet.in
040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.041

8
138
A. T. Khan et al. / Tetrahedron Letters 47 (2006) 8137–8141
O catalyzed multi-component
Table 1. Optimization of the CeCl
reaction
3
Æ7H
2
atmosphere. Recently, other methods have also been
9
reported involving Cu(OTf) /Sc(OTf) , silica sulfuric
2
3
1
0
11
12
acid, BiOCl and ZrOCl Æ8H O. However, most of
O
O
NHCOCH3
2 2
CHO
these methods also employ either expensive catalysts
or long reaction times or harsh reaction conditions. In
continuation of our effort towards the development of
newer and ‘greener’ synthetic methodologies, we set
out to find out a simple and improved protocol for the
preparation of b-acetamido carbonyl compounds using
a readily available, cheap and non-toxic catalyst.
Catalyst (x mol%)
CH COCl, CH CN, rt
3
3
Cl
Cl
1
3
a
Entry
Catalyst CeCl
mol %
3
Æ7H
2
O
Time (h)
Yield (%)
1
2
3
4
0
5
10
10
24
15
6
15
87
98
b
CeCl Æ7H O is a relatively cheap, water, air-stable and
24
0
3
2
1
4
non-toxic reagent.
Due to the hardness of the
a
Crude yields.
b
cerium cation, it is able to activate carbonyl functional-
Reaction was carried out in the absence of acetyl chloride.
3 2
Table 2. CeCl Æ7H O catalyzed multi-component reaction for the preparation of b-acetamido ketones
O
O
NHCOCH3
X
CHO
CeCl3 7H O (10 mol %)
2
CH COCl, CH CN, rt
3
3
X
a
b
Entry
1
b-Acetamido ketones
Time (h)
7
Yield (%)
O
NHAc
96
O
NHAc
2
7
92
95
CH3
O
NHAc
3
4
6
6
Br
NHAc
NHAc
NHAc
O
O
O
c
98
Cl
5
6
12
11
96
86
NO2
O N
2
O
NHAc
7
10
90
NO2
NHAc
O
O
8
9
6
6
89
96
OMe
NHAc
OMe
OMe

A. T. Khan et al. / Tetrahedron Letters 47 (2006) 8137–8141
8139
Table 2 (continued)
a
b
Entry
b-Acetamido ketones
Time (h)
5
Yield (%)
O
NHAc
10
93
OMe
OMe
OMe
NHAc
1
1
1
2
6
8
94
76
O
O
AcHN
Ph
Ph
NHAc
O
a
b
c
1
All the products were characterized by IR and H NMR spectroscopy as well as by elemental analysis.
Yields after work-up.
The catalyst was recovered and reused in subsequent reactions three times without losing any significant activity affording 91%, 88%, and 85%
yields, respectively.
ities for nucleophilic attack and has been used as a Lewis
sponding b-acetamido keto esters were obtained in good
yields with moderate to good diastereoselectivities.
Similarly, ethyl benzoylacetate afforded the correspond-
ing products (Table 3, entries 6–8) in excellent yields
with good diastereoselectivity. Interestingly, the major
products obtained using methyl acetoacetate (Table 3,
entries 1–5) were the anti isomers, whereas ethyl benzo-
ylacetate afforded mainly the syn isomers (Table 3,
entries 6–8).
1
5
acid for several transformations. Herein, we report a
mild and efficient protocol for the preparation of b-
acetamido carbonyl compounds by four-component
reactions of an aromatic aldehyde, acetonitrile, an
enolizable ketone or b-keto ester and acetyl chloride,
catalyzed by CeCl Æ7H O at room temperature (Scheme
3
2
1
).
To find the optimal conditions, a mixture of 4-chloro-
benzaldehyde (2 mmol), acetophenone (2 mmol), acetyl
chloride (3 mmol) and acetonitrile (5 mL) was stirred
under various reaction conditions (Table 1). In the
absence of the catalyst, the product b-acetamido ketone
was obtained in 15% yield only after 24 h. Even with the
inclusion of 5 mol % CeCl Æ7H O, the transformation
took a long time, however, using 10 mol % catalyst
furnished the b-acetamido carbonyl compound in an
excellent yield (Table 1).
The generality and superiority of the present protocol
over existing methods can be seen by comparing our re-
sults with those of some recently reported procedures, as
shown in Table 4. The reaction of benzaldehyde with
acetophenone for the preparation of b-acetamido-b-
(phenyl)-propiophenone (Table 2, entry 1) was chosen
as a model reaction and the comparison is in terms of
mol % of the catalysts used, reaction time, and reaction
conditions and percentage yields.
3
2
After optimization,16 a variety of other aromatic alde-
hydes having electron-donating as well as electron-with-
drawing substituents were shown to undergo the
reaction smoothly giving the desired products in good
yields. The results are summarized in Table 2. All the
products were fully characterized by spectroscopic
methods and compared with the authentic spectra. Aro-
matic aldehydes containing a nitro substituent took
longer reaction times (entries 5–7). The a,b-unsaturated
aldehyde, cinnamaldehyde, also reacted under the same
experimental conditions (entry 11), as did terephthal-
aldehyde on treatment with 2 equiv of acetophenone
and the other reactants (entry 12).
Noting that the reaction proceeds with only 15% yield
even after 24 h in the absence of a catalyst, we believe
that the cerium chloride activates the aldehyde group
for nucleophilic attack as well as facilitating enolization.
We were interested to determine whether a chalcone
intermediate (by aldol condensation) is involved. Thus,
a mixture of chalcone (2 mmol), acetyl chloride
(3 mmol) and acetonitrile (5 mL) was stirred at room
temperature for 6 h, but no b-acetamido ketone was
formed.
In conclusion, we have revealed a simple, efficient and
‘greener’ protocol for the preparation of b-acetamido
carbonyl compounds using CeCl Æ7H O as a reusable
3
2
To explore the further applicability of Ce(III)-catalyzed
multi-component reactions, a variety of aromatic alde-
hydes (Table 3, entries 1–5) were treated with methyl
acetoacetate and acetyl chloride in the presence of
catalyst (Scheme 2). The salient features of this protocol
include operational simplicity, high yields of the
products, avoidance of column chromatography, ready
availability, low toxicity, moisture compatibility and
reusability of the catalyst.
1
0 mol % of catalyst at room temperature and the corre-

8140
A. T. Khan et al. / Tetrahedron Letters 47 (2006) 8137–8141
Table 3. CeCl
3
Æ7H
2
O catalyzed multi-component reaction for the preparation of b-acetamido keto esters
AcHN
O
AcHN
O
O
CHO
O
O
2
CeCl3 7H O (10 mol%)
.
R
2
2
R
1
2
+
R
R
CH COCl, CH CN, rt
1
3
3
1
O
R
X
X
R
a
b
Entry
1
Product
Yield (%)
76
syn:anti
AcHN
O
25:75
OMe
O
O
AcHN
O
2
3
OMe
84
78
24:76
5:95
Cl
AcHN
O
O
OMe
OMe
MeO
MeO
O
AcHN
4
5
83
81
7:93
O
OMe
AcHN
O
MeO
MeO
OMe
10:90
O
OMe
AcHN
O
6
7
OEt
Ph
81
84
90:10
72:28
O
AcHN
O
OEt
O N
O
Ph
2
AcHN
O
OEt
Ph
8
83
70:30
MeO
O
OMe
a
Yields after work-up.
b
1
The syn:anti ratio was determined from H NMR measurements of the crude reaction mixture.
Table 4. Comparison of the results for the preparation of b-acetamido ketone (Table 2, entry 1) using multi-component reactions with other
catalysts
Catalyst
mol %
Reaction time
Reaction temperature (ꢁC)
Yield (%)
1
1
9
1
0
Silica sulfuric acid
ZrOCl Æ8H O
2 2
78
20
10
20
10
65 min
5 h
30 h
7 h
80
rt
rt
rt
rt
91
90
82
92
96
2
Sc(OTf)
BiOCl
3
1
CeCl
3
Æ7H
2
O
7 h

A. T. Khan et al. / Tetrahedron Letters 47 (2006) 8137–8141
8141
Ce3+
13. (a) Khan, A. T.; Ghosh, S.; Choudhury, L. H. Eur. J. Org.
Chem. 2006, 2226–2231; (b) Khan, A. T.; Choudhury, L.
H.; Ghosh, S. J. Mol. Catal. A: Chem. 2006, 255, 230–235;
(c) Khan, A. T.; Goswami, P.; Choudhury, L. H.
Tetrahedron Lett. 2006, 47, 2751–2754; (d) Khan, A. T.;
Parvin, T.; Choudhury, L. H. Synthesis 2006, 2497–2502.
O
O
O
O
OAc
H
CH COCl
3
X
X
1
4. Bartoli, G.; Marcantoni, E.; Sambri, L. Synlett 2003,
101–2116.
CH CN
3
2
1
5. (a) Bose, D. S.; Kumar, R. K. Tetrahedron Lett. 2006, 47,
813–816; (b) Khodaei, M. M.; Khosropour, A. R.;
Kookhazadeh, M. Synlett 2004, 1980–1984; (c) Yadav, J.
S.; Reddy, B. V. S.; Sathaiah, K.; Vishnumurthy, P.
Synlett 2005, 2811–2813.
NHAc
O
N=CCH3
H O
2
X
X
1
6. Typical procedure: A mixture of aromatic aldehyde
3 2
Scheme 2. A plausible mechanism for the CeCl Æ7H O catalyzed multi-
component reaction for the preparation of b-acetamido carbonyl
compounds.
(2 mmol), acetophenone or b-keto ester (2 mmol), acetyl
chloride (3 mmol) and CeCl Æ7H O (75 mg, 10 mol %) in
3 2
acetonitrile (5 mL) was stirred at room temperature. After
completion of the reaction (monitored by TLC), the
reaction mixture was poured into 50 mL of ice water. On
solidification, it was filtered, washed with ice water and
recrystallized from ethyl acetate/hexane to give the pure
b-acetamido ketone. For all the substrates in Table 3, the
reactions were stirred for 12 h, then 50 mL of water was
added. The mixture was extracted with ethyl acetate
Acknowledgements
L.H.C. thanks CSIR for financial support and the
authors thank the Director, IIT Guwahati, for provid-
ing the general facilities to carry out the work. We are
grateful to the referee for valuable suggestions and
comments.
(
(
3 · 20 mL), the extracts were washed with water
3 · 20 mL), dried over Na SO and the solvent was
2
4
removed using a rotary evaporator. The crude mixture
was recrystallized from ethyl acetate/hexane and the solid
product (mixture of diastereomers) was isolated. For the
recovery of the catalyst, the aqueous layer was evaporated
under reduced pressure, and the residue reused in
subsequent reactions without losing any significant activ-
ity. The spectral data of some representative b-acetamido
carbonyl compounds are given below.
References and notes
1
2
. Strecker, A. Liebigs Ann. Chem. 1850, 75, 27–45.
. Casimir, J. R.; Turetta, C.; Ettouati, L.; Paris, J. Tetra-
hedron Lett. 1995, 36, 4797–4800.
3
4
. (a) Barluenga, J.; Viado, A. L.; Aguilar, E.; Fustero, S.;
Olano, B. . J. Org. Chem. 1993, 58, 5972–5975; (b) Enders,
D.; Moser, M.; Geibel, G.; Laufer, M. C. Synthesis 2004,
b-Acetamido-b-(3,4,5-trimethoxyphenyl)propiophenone
(entry 10, Table 2): Solid; mp: 159 ꢁC. IR (KBr): 3277,
À1
1
1687, 1647, 1592, 1560, 1126, 1002 cm
.
H NMR
2
040–2046.
3
(400 MHz, CDCl ): d 2.03 (s, 3H), 3.38 (dd, J = 5.2 Hz,
. (a) Kobinata, K.; Uramoto, M.; Nishii, M.; Kusakabe, H.;
Nakamura, G.; Isono, K. Agric. Biol. Chem. 1980, 44,
J = 16.4 Hz, 1H), 3.70 (dd, J = 5.2, 16.8 Hz, 1H), 3.77
(s, 3H), 3.79 (s, 6H), 5.45 (m, 1H), 6.52 (s, 2H), 6.67 (br,
d, J = 6.8 Hz, 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.55 (t,
1
709–1711; (b) Daehn, U.; Hagenmaier, H.; Hoehne, H.;
Koenig, W. A.; Wolf, G.; Zaehner, H. Arch. Microbiol.
976, 107, 249–256.
1
3
J = 6.4 Hz, 1H), 7.88 (d, J = 7.6 Hz, 2H). C NMR
1
(100 MHz, CDCl ): d 23.59, 43.28, 50.58, 56.18 (2C),
3
5
6
7
. Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 745–757.
. Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91–109.
. Rao, I. N.; Prabhakaran, E. N.; Das, S. K.; Iqbal, J. J.
Org. Chem. 2003, 68, 4079–4082, and references therein.
. Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003,
60.78, 103.77, 103.89, 127.97 (3C), 128.59 (3C), 133.43
(2C), 136.56, 153.11, 169.21, 198.51. Anal. Calcd for
C H O N (357.40): C, 67.21; H, 6.49; N, 3.92; found C,
20 23 5
67.29; H, 6.42; N 3.82. Ethyl 2-benzoyl-3-acetamido-3-(p-
nitrophenyl)propionate (entry 7, Table 3): (mixture of
diastereomers) data for the major isomer: IR (KBr): 3303,
8
9
6
8, 5735–5738.
À1
1
. Pandey, G.; Singh, R. P.; Garg, A.; Singh, V. K.
1724, 1688, 1649, 1540, 1521, 1348, 1298, 1173 cm . H
NMR (400 MHz, CDCl ): d 1.22 (t, J = 6.8 Hz, 3H), 2.09
Tetrahedron Lett. 2005, 46, 2137–2140.
3
1
1
1
0. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P.
Tetrahedron Lett. 2005, 46, 2105–2108.
1. Ghosh, R.; Maiti, S.; Chakraborty, A. Synlett 2005, 115–
(s, 3H), 4.18 (q, J = 6.8 Hz, 2H), 4.98 (d, J = 4.4 Hz, 1H),
5.97 (dd, J = 4.4, 9.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H),
7.50 (d, J = 8.8 Hz, 3H), 7.57 (t, J = 7.2 Hz, 1H), 7.79
(d,J = 7.2 Hz, 2H), 8.10 (d, J = 8.8 Hz, 2H). Anal. Calcd
1
18.
2. Ghosh, R.; Maiti, S.; Chakraborty, A.; Chakraborty, S.;
for C20
20 2 6
H N O (384.39): C, 62.50; H, 5.24; N, 7.29; found
Mukherjee, A. K. Tetrahedron 2006, 62, 4059–4064.
C, 62.38; H, 5.18; N, 7.36.