Supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sulphate on silica gel as an economical and efficient catalyst for the one-pot preparation of ?-acetamido ketones via a four-component condensation reaction

Article abstract of DOI:10.1007/s12039-013-0538-z

An efficient, one-pot, four-component condensation of aldehydes, acetophenone (or propiophenone), acetyl chloride and acetonitrile in the presence of catalytic amounts of L-pyrrolidine-2-carboxylic acid-4-hydrogen sulphate (supported on silica gel), a gre

Full text of DOI:10.1007/s12039-013-0538-z

c
J. Chem. Sci. Vol. 126, No. 1, January 2014, pp. 103–109. ꢀ Indian Academy of Sciences.
Supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sulphate on silica
gel as an economical and efficient catalyst for the one-pot preparation
of β-acetamido ketones via a four-component condensation reaction
ARASH GHORBANI-CHOGHAMARANI∗ and PARISA ZAMANI
Department of Chemistry, Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran
e-mail: arashghch58@yahoo.com; a.ghorbani@mail.ilam.ac.ir
MS received 18 April 2013; revised 9 September 2013; accepted 18 September 2013
Abstract. An efficient, one-pot, four-component condensation of aldehydes, acetophenone (or propiophe-
none), acetyl chloride and acetonitrile in the presence of catalytic amounts of L-pyrrolidine-2-carboxylic acid-
4-hydrogen sulphate (supported on silica gel), a green and non-toxic catalyst, is described for the preparation
of β-acetamido ketones in good to excellent yields.
Keywords. β-Acetamido ketones; L-pyrrolidine-2-carboxylic acid-4-hydrogen sulphate; one-pot;
four-component; catalyst.
1. Introduction
HClO4-SiO2,12 CeCl3,13 ZnO,14 cyanuric chloride,15
Amberlyst-15,16 and POCl3/borax,17 have also been
used. Although these methods are valuable, most of
them employ expensive catalysts, long reaction times or
harsh reaction conditions.
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 intermediate 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
2. Experimental
Chemicals were purchased from Fluka, Merck and
Aldrich chemical companies. The known products were
characterized by comparison of their spectral (1H NMR,
and 13CNMR) and physical data with those of authentic
samples. Unknown compounds were identified by their
1H and 13CNMR spectra and elemental analysis.
β-Acetamido ketones are versatile intermediates in
that their skeletons exist in a number of biologically
or pharmacologically important compounds.6 The best
known route for the synthesis of these compounds
is the Dakin–West reaction,7 which involves the con-
densation of an amino acid with acetic anhydride in
the presence of a base via an intermediate azalactone
to give the acetamido ketones.8 Bhatia et al.9 pro-
posed another procedure for the formation of these
compounds through the condensation of an aryl alde-
hyde, acetophenone, and acetyl chloride in acetoni-
trile in the presence of CoCl2 or montmorillonite K-10
clay.10 Other catalysts such as heteropolyacids,11
2.1 General procedure for the synthesis of
β-acetamido ketones
Supported L-pyrrolidine-2-carboxylic acid-4-hydrogen
sulphate on silica gel (0.274 g) was added to the mixture
of aryl aldehyde (1 mmol), aryl ketone (1 mmol), acetyl
chloride (0.3 mL) and acetonitrile (reagent as well as
solvent) (3 mL). The reaction mixture was heated under
reflux conditions and stirred for appropriate time (reac-
tion progress was monitored by TLC). After completion
of the reaction, the reaction mixture was filtered off and
the solvent (acetonitrile) was evaporated. For further
purification and separation of diastereomers, the crude
product was dissolved in dichloromethane and purified
by P-TLC (n-hexane/acetone, 8/2).
∗For correspondence
103

104
Arash Ghorbani-Choghamarani and Parisa Zamani
143, 135.4, 134.2, 133.69, 129.5, 129, 128.2, 128.2,
2.2 Representative NMR Data
122.5, 122.7, 54.6, 45.2, 23.2, 14.1 ppm.
Anal. Calcd for C18H18N2O4: C, 66.25; H, 5.56; N,
8.58. Found: C, 65.49; H, 5.84; N, 8.30.
2.2a N-(1-(naphthalen-2-yl)-3-oxo-3-phenylpropyl)
acetamide: Mp: 114–117◦C; 1H NMR (400 MHZ,
CDCl3): δ = 7.93 (d, 2H, J= 7.2 HZ), 7.8 (t, 4H,
J = 8 HZ), 7.58 (t, 1H, J = 6.8 HZ), 7.47 (t, 6H,
J = 6.8 HZ), 6.81 (d, 1H, J = 7.6 HZ), 5.76–5.74 (m,
1H), 3.87 (dd, 1H, J = 12, 4.8 HZ), 3.56 (dd, 1H,
J = 10.8, 6 HZ), 2.08 (s, 3H) ppm.
2.2f N-(-2-methyl-1-(naphthalen-2-yl)-3-oxo-3-phenyl-
propyl)acetamide (anti-isomer): Mp: 177–179◦C;
1H NMR (400 MHZ, CDCl3): δ = 7.8–7.68 (m, 7H),
7.53–7.36 (m, 6H), 5.58 (dd, J = 8.8, 4 HZ, 1H), 4.26–
4.23 (m, 1H), 2.17 (s, 3H), 1.47 (d, J = 7.2 HZ, 3H)
ppm; 13C NMR (100 MHZ, CDCl3): δ = 205.2, 170.1,
138.5, 136.3, 133.6, 133.2, 132.6, 128.7, 128.4, 128.21,
128, 127.5, 126.1, 125.8, 125.2, 124.6, 55.9, 44.4, 29.7,
23.5, 16.9 ppm.
2.2b N-(1-(4-bromophenyl)-2-methyl-3-oxo-3-phenyl-
propyl)acetamide (anti-isomer): Mp: 156–159◦C;
1H NMR (400 MHZ, CDCl3): δ = 7.79 (d, J = 7.6 HZ,
2H), 7.59–7.55 (m, 2H), 7.45–7.41 (m, 2H), 7.36 (d,
J = 8.4 HZ, 2H), 7.15 (d, J = 8.4 HZ, 2H), 5.35–5.33
(m, 1H), 4.09–4.05 (m, 1H), 2.12 (s, 3H), 1. 37 (d,
J = 7.2 HZ, 3H) ppm; 13C NMR (100 MHZ, CDCl3):
δ = 204.9, 170.1, 140.2, 136.1, 133.8, 131.6, 128.8,
128.2, 128.1, 121.1, 55.2, 44.2, 23.4, 16.8 ppm.
Anal. Calcd for C22H21NO2: C, 79.73; H, 6.39; N,
4.23. Found: C, 77.82; H, 6.34; N, 4.15.
2.2g N-(-2-methyl-1-(naphthalen-2-yl)-3-oxo-3-phenyl-
propyl)acetamide (syn-isomer): Mp: 196–198◦C;
1H NMR (400 MHZ, CDCl3): δ = 7.95 (d, J = 4 HZ,
2H), 7.8–7.77 (m, 4H), 7.58–7.45 (m, 6H), 6.31 (m,
1H), 5.69 (t, J = 7.6 HZ, 1H), 4.24–4.19 (m, 1H),
2.02 (s, 3H), 1.28 (d, J = 6.8 HZ, 3H) ppm; 13C NMR
(100 MHZ, CDCl3): δ = 201.9, 169.7, 137.8, 136.3,
133.3, 133.2, 132.3, 128.8, 128.5, 128.2, 127.9, 127.6,
126.3, 126, 125.8, 125, 54.9, 45.6, 23.3, 13.6 ppm.
Anal. Calcd for C22H21NO2: C, 79.73; H, 6.39; N,
4.23. Found: C, 78.42; H, 6.88; N, 3.96.
Anal. Calcd for C18H18BrNO2: C, 60.01; H, 5.04; N,
3.82. Found: C, 60.68; H, 4.86; N, 3.89.
2.2c N-(1-(4-bromophenyl)-2-methyl-3-oxo-3-phenyl-
propyl)acetamide (syn-isomer): Mp: 146–147◦C;
1H NMR (400 MHZ, CDCl3): δ = 7.9–7.88 (m, 2H),
7.59–7.22 (m, 7H), 6.57 (m, 1H), 5.46–5.44 (m, 1H),
4.08–4.04 (m, 1H), 1.99 (s, 3H), 1.25 (d, J = 7.2 HZ,
3H) ppm; 13C NMR (100 MHZ, CDCl3): δ = 201.7,
169.7, 139.6, 136.1, 133.5, 131.7, 128.9, 128.8, 128.18,
121.4, 54.5, 45.2, 23.3, 13.8 ppm.
2.2h N-(-1-(4-fluorophenyl)-2-methyl-3-oxo-3-phenyl-
Anal. Calcd for C18H18BrNO2: C, 60.01; H, 5.04; N,
3.82. Found: C, 63.05; H, 5.39; N, 4.04.
1
propyl)acetamide (anti-isomer): Mp: 128–132◦C; H
NMR (400 MHZ, CDCl3): δ = 7.78 (d, J = 7.2 HZ,
2H), 7.59–7.53 (m, 2H), 7.42 (t, J = 8 HZ, 2H), 7.29–
7.22 (m, 2H) 6.92 (t, J = 8.8 HZ, 2H), 5.36 (dd, J = 4,
8.8 HZ, 1H), 4.11–4.07 (m, 1H), 2.1 (s, 3H), 1.38 (d,
J = 7.2 HZ, 3H) ppm; 13C NMR (100 MHZ, CDCl3):
δ = 205, 170, 163, 160.6, 136.9, 136.9, 136.3, 133.7,
128.8, 128.2, 128, 128, 115.4, 115.2, 55.2, 44.5, 23.4,
16.7 ppm.
2.2d N-(2-methyl-1-(3-nitrophenyl)-3-oxo-3-phenyl-
propyl)acetamide (anti-isomer): Mp: 142–146◦C;
1H NMR (400 MHZ, CDCl3): δ = 8.03–8.22 (m,
2H), 7.81–7.29 (m, 8H), 5.50 (m, 1H), 4.16 (m, 1H),
2.16–2.1 (s, 3H), 1.46–1.30 (m, 3H) ppm; 13C NMR
(100 MHZ, CDCl3): δ = 204.2, 170.4, 148.3, 143.4,
135.8, 134, 132.8, 129.5, 128.9, 128.2, 128.2, 122.3,
121.4, 55.2, 44.3, 23.3, 16.8 ppm.
Anal. Calcd for C18H18FNO2: C, 72.22; H, 6.06; N,
4.68. Found: C, 71.42; H, 6.20; N, 4.55.
Anal. Calcd for C18H18N2O4: C, 66.25; H, 5.56; N,
8.58. Found: C, 65.81; H, 5.51; N, 7.79.
2.2i N-(-1-(4-fluorophenyl)-2-methyl-3-oxo-3-phenyl-
propyl)acetamide (syn-isomer): Mp: 107–111◦C;
2.2e N-(2-methyl-1-(3-nitrophenyl)-3-oxo-3-phenyl- 1H NMR (400 MHZ, CDCl3): δ = 7.91 (d, J = 7.2 HZ,
propyl)acetamide (syn-isomer): Mp: 128–133◦C; 2H), 7.59 (t, J = 7.6 HZ, 1H), 7.48 (t, J = 8 HZ, 2H),
1H NMR (400 MHZ, CDCl3): δ = 8.25 (s, 1H), 8.1 7.33–7.29 (m, 2H), 6.99 (t, J = 8.8 HZ, 2H), 6.07–6.05
(d, J = 6.8 HZ, 1H), 7.9 (d, J = 7.6 HZ, 2H), 7.74 (d, (m, J = 7.6 HZ, 1H), 5.44 (t, J = 7.6 HZ, 1H), 4.09–
J = 7.6 HZ, 1H), 7.6–7.57 (m, 2H), 7.49–7.43 (m, 3H), 4.02 (m, 1H), 2.01 (s, 3H), 1.24 (d, J = 7.2 HZ, 3H)
6.69 (m, 1H), 5.54 (t, J = 7.6 HZ, 1H), 4.16–4.09 (m, ppm; 13C NMR (100 MHZ, CDCl3): δ = 201.8,169.6,
1H), 2.05 (s, 3H), 1.29 (d, J = 6.8 HZ, 3H) ppm; 13C 163.2, 160.8, 136.2, 136.2, 133.42, 128.9, 128.7, 128.6,
NMR (100 MHZ, CDCl3): δ = 201.4, 170.1, 148.3, 111.6, 115.4, 54.5, 45.4, 29.7, 23.4,13.7 ppm.

Preparation of β-acetamido ketones
105
Anal. Calcd for C18H18FNO2: C, 72.22; H, 6.06; N,
4.68. Found: C, 70.75; H, 6.11; N, 4.65.
Table 1. Preparation of 3-(acetoxyamino)-3-(4-chlorophenyl)-
1-phenylpropan-1-one from p-chlorobenzaldehyde and ace-
tophenone in the presence of acetyl chloride and acetonitrile
catalysed by L-pyrrolidine-2-carboxylic acid-4-hydrogen
sulphate (supported on silica gel) under reflux conditions.
3. Results and discussion
Entry
Catalyst (mol %)
Time (h)
Yield(%)a
In order to improve above mentioned drawbacks,
we decide to introduce a new, simple, mild and
effective procedure for the one-pot synthesis of β-
acetamido ketones via four-component condensation
reaction between aldehydes, enolizable ketones, acetyl
chloride and acetonitrile in the presence of supported L-
pyrrolidine-2-carboxylic acid-4-hydrogen sulphate on
silica gel (which has been prepared according to
our previously reported procedure)18 as catalyst under
reflux conditions (scheme 1).
1
2
3
4
5
6
7
0
10
20
30
40
50
65
4
4
4
4
4
4
4
0
16
33
40
55
69
90
aIsolated yield
In this study, we wish to report a convenient and effi-
cient procedure for synthesis of β-acetamido ketones
using L-pyrrolidine-2-carboxylic acid-4-hydrogen sul-
phate (supported on silica gel) as catalyst.
Initially, in order to find appropriate amount of cata-
lyst, p-chlorobenzaldehyde (1 mmol), acetophenone
(1 mmol), acetyl chloride (0.3 mL) and acetonitrile
(3 mL) was subjected to condensation under reflux con-
ditions in the presence of different amounts of sup-
ported L-pyrrolidine-2-carboxylic acid-4-hydrogen sul-
phate on silica gel (scheme 2 and table 1).
100
90
80
70
60
50
40
30
20
10
0
10
20
30
40
50
65
catalyst (mol%)
Also, the results of the preparation of 3-
(acetoxyamino)-3-(4-chlorophenyl)-1-phenylpropan-1-
one as a function of the amounts of catalyst is shown
in figure 1. By optimizing the reaction conditions, it
was found that 65 mol% of L-pyrrolidine-2-carboxylic
acid-4-hydrogen sulphate (supported on silica gel) was
enough for completion of the reaction.
Figure 1. Preparation of 3-(acetoxyamino)-3-(4-chloro-
phenyl)-1-phenylpropan-1-one as a function of the catalyst
amount.
With the optimal reaction conditions in hand, we
have explored the generality of this catalyst-mediated
β-acetamido ketone synthesis with various aldehydes
and enolizable ketones. The results are summarized in
table 2.
Results from the reactions of aryl aldehydes, aryl
ketones and acetyl chloride in presence of optimized
catalyst in acetonitrile under reflux conditions are
shown in table 2. The electronic features and position of
the substituent on the aromatic ring of aldehyde had no
significant effect on the outcome of reaction. Also, both
HO3SO
COOH/SiO2
O
O
N
H
O
(Cat.)
NH
O
+
Ar
H
CH3CN, CH3COCl
R
Ar
reflux
R
R= H, CH3
Scheme 1. Synthesis of β-acetamido ketones.
HO3SO
COOH/SiO2
N
H
O
NHAc
O
O
(Cat.)
H
+
CH3CN, CH3COCl
reflux
Cl
Cl
Scheme 2. Effect of catalyst on the outcome of the reaction.

106
Arash Ghorbani-Choghamarani and Parisa Zamani
Table 2. Preparation of β-acetamido ketones from aldehydes and enolizable ketones
in the presence of acetyl chloride and acetonitrile catalysed by L-pyrrolidine-2-
carboxylic acid-4-hydrogen sulphate (supported on silica gel) under reflux conditions.
Entry
Product
Time (h)
Yield (%)a
syn/anti (%)
O
NH O
1
4
90
–
NO2
a
O
NH O
2
4
78
–
O2N
b
NH O
c
O
O
O
O
O
O
3
4
5
6
7
8
9
4
24
6
90
–
–
–
–
–
–
–
Cl
Cl
Cl
Cl
Cl
Br
F
NH O
c
0b
NH O
c
0c
NH O
c
6
0d
NH O
c
6
26e
71
65
NH O
4
d
O
NH O
4
e

Preparation of β-acetamido ketones
107
Table 2. (Continued).
Entry
Product
Time (h)
4
Yield (%)a
syn/anti (%)
O
NH O
10
11
12
61
55
70
–
f
Me
O
NH O
4
4
–
–
g
O
O
NH O
h
NH O
13
14
4
4
80
68
52:48
47:53
NO2
i
O
NH O
O2N
j
O
O
NH O
15
16
17
4
4
4
75
98
80
44:56
42:58
42:58
Cl
k
NH O
l
Br
F
O
NH O
m
O
NH O
18
4
68
55:45
Me
n

108
Arash Ghorbani-Choghamarani and Parisa Zamani
Table 2. (Continued).
Entry
Product
Time (h)
Yield (%)a
syn/anti (%)
O
NH O
19
4
67
50:50
o
O
NH O
20
4
98
34:66
p
aIsolated yield.
bIn the absence of catalyst.
cIn the presence of SiO2.
dIn the presence of 4-hydroxy-L-proline.
eIn the presence of catalyst without SiO2.
aromatic aldehydes and ketones bearing either electron- determined by 1H NMR spectroscopy of the crude pro-
donating or electron-withdrawing groups afforded the duct). The results show that the amount of syn-isomer
β-acetamido ketones without the formation of any side is nearly close to the anti-isomer. Also, in table 2 entries
products, in good to excellent yields.
13 and 18, showed that the syn-diastereomer is slightly
Given the successful delineating of described pro- larger than anti-diastereomer. However, in the previ-
cedure, we were encouraged to consider the stereo- ous reports, the products were obtained as a mixture
chemistry of obtained product with propiophenone. As of syn and anti isomers favouring anti-isomer or rarely
shown in table 2, reaction of this ketone with differ- syn-isomer.
ent aldehydes catalysed by L-pyrrolidine-2-carboxylic
In order to investigate the role of catalyst for
acid-4-hydrogen sulphate (supported on silica gel), the preparation of β-acetamido ketones, one of the reac-
reaction yielded a mixture of the anti- and syn-isomers tions was designed in the absence of supported L-
(scheme 3). The catalyst that was used in this project pyrrolidine-2-carboxylic acid-4-hydrogen sulphate on
was increased amount of syn-isomer compared with the silica gel; in the presence of L-pyrrolidine-2-carboxylic
previously reported studies.9,19,20 Also, we were able to acid-4-hydrogen sulphate without silica gel, SiO2 and
separate the two diastereomers from each other by P- 4-hydroxy-L-proline were designed. Surprisingly, we
TLC and measure the proportion of each isomer (entries have observed no product in the absence of catalyst or in
13–20, table 2), (the ratio of syn/anti diastereomers was the presence of silica gel or 4-hydroxy-L-proline. Also,
HO3SO
O
NH
O
/SiO
COOH
2
O
1
N
H
Ar
O
2
syn
3(i-p)
(Cat.)
+
Ar
H
CH3CN, CH3COCl
+
reflux
O
NH
O
Ar
anti
4(i-p)
Scheme 3. Diasteroselectivity on the synthesis of β-acetamido ketones.

Preparation of β-acetamido ketones
109
HO3SO
Acknowledgement
Financial support for this study by the Research Affairs
of Ilam University, Ilam, Iran is acknowledged.
COOH
N
H
H
H
O
O
O
+
R
Ar
H
Ar
H
Ar
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4. Conclusion
In conclusion, we have reported an efficient, inexpen-
sive and straightforward procedure for one-pot syn-
thesis of β-acetamido ketones using supported L-
pyrrolidine-2-carboxylic acid-4-hydrogen sulphate on
silica gel as catalyst. The important features provided
by this procedure are the use of effective, non-toxic
and cost-effective catalyst and increasing the amount of
syn-isomer.
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Supplementary information
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The supplementary information for compounds g, i, j,
o and m can be seen in the website (www.ias.ac.in/
chemsci).