Facile one-pot multicomponent synthesis of β-acetamido ketones with Amberlyst-15 as heterogeneous catalyst

Article abstract of DOI:10.1002/hlca.200690279

The one-pot multicomponent coupling of an aromatic aldehyde, an enolizable ketone or keto ester, acetonitrile, and acetyl chloride at room temperature in the presence of Amberlyst-15 as catalyst affords β-acetamido ketones in high yields. The inexpensive catalyst works under heterogeneous conditions and can be readily reused.

Full text of DOI:10.1002/hlca.200690279

Helvetica Chimica Acta – Vol. 89 (2006)
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Facile One-Pot Multicomponent Synthesis of b-Acetamido Ketones with
Amberlyst-15 as Heterogeneous Catalyst1)
by Biswanath Das* and Kongara Ravinder Reddy
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500007, India
(phone: +91-40-7193434; fax: +91-40-7160512; e-mail: biswanathdas@yahoo.com)
The one-pot multicomponent coupling of an aromatic aldehyde, an enolizable ketone or keto ester,
acetonitrile, and acetyl chloride at room temperature in the presence of Amberlyst-15 as catalyst affords
b-acetamido ketones in high yields. The inexpensive catalyst works under heterogeneous conditions and
can be readily reused.
Introduction. – b-Acetamido ketones are useful intermediates in different organic
syntheses due to their polyfunctional nature and presence in several bioactive com-
pounds [1]. They can be converted into 3-amino alcohols, which may be applied for
the synthesis of various important antibiotics [2]. The multicomponent synthesis of
b-acetamido ketones was originally proposed by Iqbal and co-workers [3], who used
a coupling reaction catalyzed by Lewis acids such as CoCl2 [3a–c], polyaniline-sup-
ported [Co(OAc)2] [3d], or Montmorillonite K-10 clay [3e]. This approach is valuable,
but the first catalyst requires long reaction times (7 d) at room temperature, and the
other two systems only work at elevated temperature (70–808).
In continuation of our work [4] on the development of useful synthetic methodol-
ogies, we herein report that Amberlyst-15 efficiently catalyzes the one-pot coupling
between aromatic aldehydes, enolizable ketones or keto esters, and both acetyl chloride
(AcCl) and acetonitrile (MeCN) at room temparature to form b-acetamido ketones
(see Table).
Results and Discussion. – A series of b-acetamido ketones 1 were prepared from
various aromatic aldehydes 2 and acetophenones 3a–h (R5 =H; Table). The conversion
generally furnished the desired product in high yield (78–90%) within 5–7 h. When the
propiophenones 3i–k (R5 =Me) or the b-keto esters 3l–o were used as substrates, the
reaction yielded a mixture of the anti- and syn-adducts, as suggested by 1H-NMR spec-
troscopy. In the case of the propiophenones, the diastereoselectivity was high, the anti-
configured adduct being the major product. Aromatic aldehydes containing either elec-
tron-donating or -withdrawing groups underwent the conversion smoothly. Several
functional groups such as halogen (Cl, Br), NO2, ester, and ether moieties were
1
)
Part 99 in the series ꢀStudies on Novel Synthetic Methodologiesꢁ, IICT Communication No. 061124.
ꢂ 2006 Verlag Helvetica Chimica Acta AG, Zürich

3110
Helvetica Chimica Acta – Vol. 89 (2006)
found to be stable under the reaction conditions. The structures of the products were
1
readily established from their H-NMR, MS, and elemental-analysis data.
Table. Synthesis of the b-Acetamido Ketones 3
Series
Substituents
Time [h]
Yield [%]a)
anti/synb)
R1
R2
R3
R4
R5
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
H
H
H
NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-BrÀC6H4
4-NO2ÀC6H4
C6H5
C6H5
C6H5
Me
Me
Me
C6H5
H
H
H
H
H
H
H
H
6.089
6.25
5.5086
5.75
6.078
5.090
6.25
6.081
7.083
6.25
6.5082
6.088
5.25
5.5088
5.75
Me
MeO
H
H
NO2
H
MeO
Me
MeO
NO2
H
NO2
Cl
Cl
85
85
79
Me
Me
Me
MeOOC
MeOOC
EtOOC
EtOOC
87:13
89
91:9
56 :44
87
79 :21
d
c
)
62 :38
c
66 :34
87
)
73 :27
a) Isolated yield after chromatographic purification. b) Diastereoisomer ratio according to 1H-NMR anal-
ysis. c) The anti isomer was obtained in pure form by crystallization from hexane/AcOEt.
Amberlyst-15 is a commercially available, inexpensive, solid, nonhazardous, heter-
ogeneous acid catalyst and can be easily recovered by filtration. We found that the
recovered catalyst can be readily re-used at least three times, basically without loss
in catalytic efficiency. For example, in the reaction leading to 1a, the repeated use of
the catalyst gave rise to yields of 89, 85, and 84%. In the absence of the catalyst, no reac-
tion took place.
In conclusion, we have developed a simple, mild, and efficient method for the multi-
component synthesis of b-acetamido ketones using Amberlyst-15 as a reusable catalyst.
The authors thank UGC (New Delhi, India) for financial support.
Experimental Part
General Synthetic Procedure. To a mixture of the aldehyde 2 (1 mmol), the ketone 3 (1 mmol), and
AcCl (1 mmol) in MeCN (5 ml), Amberlyst-15 (200 mg) was added. The mixture was stirred at r.t., and
the reaction was monitored by TLC. After completion of the reaction (ca. 5–7 h), the mixture was

Helvetica Chimica Acta – Vol. 89 (2006)
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poured on H2O (10ml) and filtered to recover the catalyst. The org. portion was removed from the fil-
trate, and the remaining mass was extracted with AcOEt (3”10ml). The extract was concentrated, and
the residue was subjected to column chromatography (SiO2; hexane/AcOEt) to afford the pure product
1. When keto esters (instead of ketones) were used, the reaction was conducted under N2 atmosphere.
The anal. data of some representative products are given below.
N-(3-Oxo-1,3-diphenylpropyl)acetamide (1a). 1H-NMR (200 MHz, CDCl3): 7.87 (d, J=8.0, 2 H);
7.56–7.12 (m, 9 H); 5.50( m, 1 H); 3.66 (dd, J=17.0, 4.5, 1 H); 3.31 (dd, J=17.0, 5.3, 1 H); 1.89 (s,
3 H). FAB-MS: 268 ([M+H]+). Anal. calc. for C17H17NO2: C 76.40, H 6.37, N 5.24; found: C 76.32, H
6.31, N 5.29.
N-[1-(3-Nitrophenyl)-3-oxo-3-phenylpropyl]acetamide (1e). 1H-NMR (200 MHz, CDCl3): 8.21 (br. s,
1 H); 8.10( d, J=8.0, 1 H); 7.92 (d, J=8.0, 2 H); 7.72–7.44 (m, 5 H); 7.01 (d, J=8.5, 1 H); 5.64 (m, 1 H);
3.81 (dd, J=17.0, 4.4, 1 H); 3.48 (dd, J=17.0, 5.2, 1 H); 2.07 (s, 3 H). FAB-MS: 313 ([M+H]+). Anal.
calc. for C17H16N2O4: C 65.39, H 5.13, N 8.97; found: C 65.48, H 5.21, N 8.91.
1
N-[2-Methyl-1-(4-nitrophenyl)-3-oxo-3-phenylpropyl]acetamide (1k). H-NMR (200 MHz, CDCl3):
8.22 (d, J=8.0, 2 H); 7.91 (d, J=8.0, 2 H); 7.67–7.50 (m, 5 H); 6.08 (d, J=8.0, 1 H); 5.41 (t, J=8.2,
1 H); 4.10( m, 1 H); 2.01 (s, 3 H); 1.21 (d, J=7.0, 3 H). FAB-MS: 327 ([M+H]+). Anal. calc. for:
C18H18N2O4: C 66.26, H 5.52, N 8.59; found: C 66.38, H 5.59, N 8.51.
1
Ethyl 2-[(Acetylamino)(4-chlorophenyl)methyl]-3-oxobutanoate (1n). H-NMR (200 MHz, CDCl3):
7.36–7.22 (m, 4 H); 6.98 (d, J=8.9, 1 H); 5.69 (dd, J=8.9, 5.9, 1 H); 4.21 (q, J=7.02 H); 4.01 ( d, J=5.9,
1 H); 2.19 (s, 3 H); 2.04 (s, 3 H); 1.28 (d, J=7.0, 3 H). FAB-MS: 312 ([M+H]+). Anal. calc. for
C15H18ClNO4: C 57.79, H 5.78, N 4.49; found: C 57.70, H 5.84, N 4.41.
REFERENCES
[1] J. R. Casimir, C. Turetta, L. Ettouati, J. Paris, Tetrahedron Lett. 1995, 36, 4797; A. G. Goodfrey, D. A.
Brooks, L. A. Hay, M. Peters, J. R. Mc Carthy, D. Mitchell, J. Org. Chem. 2003, 68, 2623.
[2] K. Kobinata, M. Uramoto, M. Nishii, H. Kusakabe, G. Nakamura, K. Isono, Agric. Biol. Chem. 1980,
44, 1709.
[3] a) B. Bhatia, M. M. Reddy, J. Iqbal, J. Chem. Soc., Chem. Commun. 1994, 713; b) M. Mukhopad-
hyay, B. Bhatia, J. Iqbal, Tetrahedron Lett. 1997, 38, 1083; c) I. N. Rao, E. N. Prabhakaran, S. K. Das,
J. Iqbal, J. Org. Chem. 2003, 68, 4079; d) E. N. Prabhakaran, J. Iqbal, J. Org. Chem. 1999, 64, 3339; e)
D. Bahulayan, S. K. Das, J. Iqbal., J. Org. Chem. 2003, 68, 5735.
[4] B. Das, J. Banarjee, R. Ramu, R. Pal, N. Ravindranath, C. Ramesh, Tetrahedron Lett. 2003, 44, 5465;
B. Das, J. Banarjee, Chem. Lett. 2004, 33, 960; B. Das, M. R. Reddy, H. Holla, R. Ramu, K. Venka-
teswarlu, J. Chem. Res. 2005, 793; B. Das, P. Thirupathi, I. Mahender,V. S. Reddy, Y. K. Rao, J. Mol.
Catal., A 2006, 247, 233.
ReceivedAugust 24, 2006