An efficient and simple one-pot synthesis of β-acetamido ketones catalyzed by ytterbium triflate in ionic liquid

Article abstract of DOI:10.1071/CH08557

Ytterbium triflate immobilized in the ionic liquid [bmim][BF₄] catalyzes the three-component coupling of aromatic aldehydes, enolizable ketones, and acetonitrile in the presence of acetyl chloride at room temperature to afford -acetamido ketones in good yields. The catalyst can be recovered and recycled for subsequent reactions without any appreciable loss of efficiency.

Full text of DOI:10.1071/CH08557

RESEARCH FRONT
Rapid Communication
CSIRO PUBLISHING
Aust. J. Chem. 2009, 62, 322–327
www.publish.csiro.au/journals/ajc
An Efficient and Simple One-Pot Synthesis of β-Acetamido
Ketones Catalyzed by Ytterbium Triflate in Ionic Liquid
Anil Kumar,A,B M. Sudershan Rao,A Israr Ahmad,A and Bharti KhungarA
AChemistry Group, Birla Institute of Technology and Science, Pilani 333 031, India.
BCorresponding author. Email: anilkumar@bits-pilani.ac.in
Ytterbium triflate immobilized in the ionic liquid [bmim][BF4] catalyzes the three-component coupling of aromatic
aldehydes, enolizable ketones, and acetonitrile in the presence of acetyl chloride at room temperature to afford β-acetamido
ketones in good yields. The catalyst can be recovered and recycled for subsequent reactions without any appreciable loss
of efficiency.
Manuscript received: 18 December 2008.
Final version: 4 March 2009.
Introduction
gradually emerged as a novel environmentally benign alterna-
tive to traditional organic solvents.[6] They have unique chemical
and physical properties, such as excellent chemical and thermal
stability and non-flammability, good solvating ability, ease of
recyclability, and their potential to enhance reaction rates and
selectivity. These properties of ionic liquids can be tuned by
changing the alkyl chains or anions and these solvents have been
termed ‘designer solvents’.[2] Their non-volatile nature without
anydetectablevapourpressuregivesthemsignificantadvantages
in minimizing solvent consumption and addresses the problem
of emission of volatile organic solvents into the atmosphere and
thus makes these solvents an attractive alternative to classical
organic solvents. Because of these special properties, ionic liq-
uids have been investigated extensively as solvents or catalysts
for many important organic reactions.[7]
Rare earth metal triflates have emerged as new type of Lewis
acids in organic synthesis.[8] These catalysts when immobi-
lized in ionic liquids can be easily recovered from the reaction
mixture and reused, showing their potential as a safe and envi-
ronmentally benign catalyst.[9] Ytterbium triflate (ytterbium(iii)
trifluoromethanesulfonate, Yb(OTf)3) has been found to act as
an effective but mild Lewis acid catalyst in various organic
transformations.[10]
β-Acetamido ketones are important intermediates for the syn-
thesis of 1,3-amino alcohols and β-amino acids, as well as for
the synthesis of various biologically and medicinally impor-
tant compounds.[1] Because of this, synthesis of these com-
pounds has gained great attention in organic chemistry. Iqbal
et al. first reported the one-pot multicomponent reaction for
the formation of these compounds through the condensa-
tion of an aryl aldehyde, acetophenone, and acetyl chloride
using CoCl2 or montmorillonite K-10 clay[3] as catalysts
[2]
in acetonitrile. Since then, several catalysts such as Cu(OTf)2
and Sc(OTf)3,[4a] silica-supported sulfuric acid,[4b,c] BiOCl,[4d]
ZrOCl2·8H2O,[4e] ZnO,[4f] H6P2W18O62,[4g] H3PW12O40,[4h,i]
CeCl3·7H2O,[4j] Amberlyst-15,[4k] SiCl4–ZnCl2,[4l] lanthanum
triflate,[4m] silica-supported NaHSO4,[4n] I2,[4o] FeCl3,[4p]
SnCl2·2H2O,[4q] K5CoW12O40·3H2O,[4r] supported heteropoly
acids,[4s] sulfated zirconia,[4t] Mg(HSO4)2,[4u] and para-
Toluenesulfonicacid(pTSA)[4v] havebeenemployedaseffective
catalysts for the synthesis of β-acetamido carbonyl compounds.
These methods are quite useful; however, most of the conven-
tional Lewis acids used in these methods are prone to fast
hydrolysis and consequent deactivation. In some of the meth-
ods, the catalysts are used in stoichiometric amounts and are
destroyed in the workup and cannot be recovered or reused.
Moreover, many of these methods encounter some limita-
tions, such as requirement of expensive catalysts, low yields,
prolonged reaction time, harsh reaction conditions, high tem-
perature, tedious workup procedures and co-occurrence of side
reactions. Therefore, development of better methods for the
one-pot synthesis of β-acetamido carbonyl compounds in terms
of high yield, shorter reaction time, environmentally benign
design, operationalsimplicity, andreusabilityofcatalystremains
desirable.
In continuation of our endeavour in green synthesis and using
ionic liquids as a recyclable, ecofriendly reaction medium and
Yb(OTf)3 as a mild and efficient Lewis acid,[11] herein we report
the results of the synthesis of β-acetamido ketones from corre-
sponding ketones, aldehydes, acetonitrile, and acetyl chloride
using 20 mol-% of ytterbium triflate as a catalyst in ionic liquid
(Scheme 1).
O
O
O
O
HN
CH3
Green chemistry has emerged as a discipline that perme-
ates all aspects of synthetic chemistry. There are a variety of
approaches for the development of greener protocols, which
reflect the enormity and complexity of this field. Alterna-
tive reaction media are some of the ways to make a protocol
greener.[5] In this regard, over the past decade, ionic liquids have
Catalyst
H
ϩ
CH3COCl, CH3CN
Solvent, r.t.
RЈ
R
RЈ
R
1
2
3
Scheme 1.
© CSIRO 2009
10.1071/CH08557
0004-9425/09/040322

RESEARCH FRONT
Synthesis of β-Acetamido Ketones
323
Table 1. Effect of catalyst on the synthesis of β-acetamido ketone in
[bmim][BF4]
Table 2. Effect of solvents on the synthesis of β-acetamido ketone
catalyzed by Yb(OTf)3
Reaction conditions: 4-chlorobenzaldehyde (1.33 mmol), acetophenone
(1.33 mmol), [bmim][BF4] (2.0 mL), CH3COCl (2.0 mmol), CH3CN
(6.65 mmol), and catalyst (20 mol-%)
Reaction conditions: acetophenone (1.33 mmol), 4-chlorobenzaldehyde
(1.33 mmol), [bmim][BF4] (2 mL), CH3COCl (2 mmol), CH3CN
(6.65 mmol), and Yb(OTf)3 (20 mol-%)
Serial no.
Catalyst
Time [h]
Yield [%]A
Serial no.
Solvent
Time [h]
Yield [%]A
B
1
2
3
4
5
6
7
8
No catalyst
BF3·Et2O
Montmorillonite K10
MgO
48
24
30
24
24
24
24
24
30
30
30
10
10
10
10
10
10
10
–
1
2
3
4
5
6
7
8
9
10
[bmim][BF4]
[bmim][PF6]
[bmim][Br]
DCM
Toluene
DMSO
DMF
EtOH
H2O
PEG-400
10
10
10
12
12
12
12
24
24
24
75
72
58
20
30
20
15
30
25
B
–
B
FeCl3·6H2O
–
B
AlCl3
–
–
B
ZnCl2
p-TSA
Dowex
B
20
B
–
–
B
9
–
–
–
B
B
10
11
12
13
14
15
16
17
18
Amberlyst-XAD-16
Amberlite-15
In(OTf)3
Yb(OTf)3
Y(OTf)3
La(OTf)3
Sc(OTf)3
Zn(OTf)2
Ba(OTf)2
–
B
AIsolated yield.
BNo product formed.
65
76C
60
10
55
63
50
δ 5.55–5.51 ppm for one proton corresponding to the proton at
the β-CH group and two double doublets at δ 3.74 and 3.42 ppm,
each for one proton, corresponding to the two protons at the
AIsolated yield.
BNo product formation was observed.
1
α-CH2 group in the H NMR spectrum. In Fourier-transform
(FT)-IR, it showed two peaks at 1685 and 1645 cm−1 for the
carbonyl and acetamide groups, respectively.
CYields were 78, 75, 76, 60, and 20% when 50, 30, 30, 10, and 5 mol-%
catalyst were used, respectively.
All aromatic aldehydes and enolizable ketones gave good
yields of β-acetamido ketone (3a–o). However, it is notewor-
thy to mention that aldehydes with electron-withdrawing groups
gave better yields compared with aldehydes with electron-
releasing groups (Table 3, entries 2–5), whereas ketones contain-
ing electron-releasing groups resulted in higher yields compared
with ketones with electron-withdrawing groups (entries 1 and 3,
Table 3). It is expected that the reaction mechanism is similar
to the previously reported acid-catalyzed mechanism.[3,4b] The
enhanced rate of reaction in ionic liquid may be due to stabi-
lization of the charged species formed as intermediates and due
to the enhanced nucleophilicity of acetonitrile in ionic liquid.
Similar effects of ionic liquid has been reported for fluorination
by nucleophilic substitution,[12] nucleophilic substitution of acti-
vated aryl halides with secondary amines[13a,b] and the reactivity
of anionic nucleophiles in ionic liquids.[14]
Finally, the feasibility of reuse and recycling of the ytterbium
triflate was examined through a series of sequential reactions
of 4-chlorobenzaldehyde, acetophenone, and acetyl chloride in
the presence of acetonitrile as a model reaction to give 3b. In
a typical reaction, the catalyst was recovered by extracting the
product with diethyl ether, leaving behind Yb(OTf)3 immobi-
lized in ionic liquid. The recovered catalyst was reused for five
cycles.The reaction proceeded smoothly with a yield of 76–72%
and, thus, the catalyst can be used several times with negligible
loss of catalytic activity and there is no need of regeneration of
the catalyst (Table 4, runs 1–5).
Result and Discussion
At first, the three-component condensation reaction of 4-
chlorobenzaldehyde, acetophenone, and acetyl chloride was
performed in the presence of acetonitrile using a catalytic
amount of several Lewis acids in [bmim][BF4] ionic liquid
(Table 1). In the absence of the catalyst, no product forma-
tion was observed even after 48 h (Table 1, entry 1). Yb(OTf)3
was found to be the most useful catalyst among all the catalysts
used under these conditions, giving the highest yield of N-(3-
oxo-1,3-diphenylpropyl)acetamide (3b) in 76% yield (Table 1,
entry 13).
Next, we also examined the effect of different solvents such
as DCM, toluene, DMSO, DMF, ethanol, polyethylene gly-
col (PEG)-400 and water on a model reaction using Yb(OTf)3
as the catalyst of choice. It was found that the catalytic effi-
ciency ofYb(OTf)3 dropped to give product in very low yield in
DCM, toluene, DMSO, and DMF, whereas in ethanol, water, and
PEG-400, no product formation was observed (Table 2, entries
4–10).Among the different ionic liquids used, [bmim][BF4] was
found to give highest yield. Therefore, we selected the ionic
liquid [bmim][BF4] as solvent and Yb(OTf)3 as the catalyst of
choice for the one-pot reaction of ketones, aldehydes, and acetyl
chloride in the presence of acetonitrile to give corresponding
β-acetamido ketones.
To generalize the method, we performed the reaction of
variety of enolizable ketones and aldehydes at room temper-
ature in [bmim][BF4] using Yb(OTf)3 as catalyst. As shown in
Table 3, in all cases, good yields of the β-acetamido ketones were
obtained, emphasizing the generality of our methodology. The
β-acetamido ketones were characterized by IR, H NMR, and
mass spectroscopic data. For example, N-(1-(4-chlorophenyl)-
3-oxo-3-phenylpropyl)acetamide (3b) showed a multiplet at
Conclusions
In summary, we have described Yb(OTf)3 immobilized in ionic
liquid as an effective and reusable catalyst for the one-pot syn-
thesis of β-acetamido ketones by three-component coupling at
room temperature. Simplicity, good yield of products, efficiency,
reusability of the catalyst, and clean reaction conditions are the
salient features of the present method.
1

RESEARCH FRONT
324
A. Kumar et al.
Table 3. Synthesis of β-acetamido ketones catalyzed by Yb(OTf)3 in ionic liquid at room temperature
Entry
Product
Structure
Time [h]
Mp [◦C] (Lit. mp)
Yield [%]A
CH3
O
HN
O
1
3a
10
102 (101–103)[4i]
70
CH3
O
HN
O
2
3
4
5
3b
3c
3d
3e
8
6
148 (146–148)[4b]
140 (148–149)[3]
75
80
65
68
Cl
CH3
O
HN
O
NO2
CH3
O
O
HN
10
12
89–90 (110–112)[4u]
102–103 (110–112)[4v]
CH3
CH3
O
O
HN
OMe
CH3
O
HN
O
6
7
3f
12
6
120
65
75
Cl
OMe
CH3
O
O
HN
3g
148–150
NO2
Cl
CH3
O
O
HN
8
9
3h
3i
6
140 (141–143)[4b]
78
68
Cl
Cl
Cl
CH3
O
HN
O
10
118–120 (116–118)[4u]
NO2
CH3
O
O
O
HN
10
3j
6
128
70
68
NO2
MeO
MeO
CH3
O
HN
11
12
3k
3l
10
6
108–110
CH3
CH3
O
HN
O
130 (135–137)[4u]
78
NO2
(Continued)

RESEARCH FRONT
Synthesis of β-Acetamido Ketones
325
Table 3. (Continued)
Entry
13
Product
Structure
Time [h]
Mp [◦C] (Lit. mp)
125–126
Yield [%]A
CH3
O
HN
O
3m
3n
3o
10
12
12
65
MeO
OMe
O
O
HN
CH3
14
15
200–202 (192–194)[3]
50
40
NO2
O
O
HN
CH3
186–189
Cl
AIsolated yield of pure product.
1H NMR, IR, and mass spectroscopic (electrospray ioniza-
tion) data of β-acetamido ketones (3a–o) are given below.
3a: δH (CDCl3, 400 MHz) 7.90 (d, J 7.41, 2H), 7.54 (t, J 7.38,
1H), 7.46–7.42 (m, 2H), 7.34–7.21 (m, 5H), 6.73 (d, J 7.92, 1H,
NH), 5.59–5.54 (m, 1H), 3.76 (dd, J 16.88 and 5.16, 1H), 3.44
(dd, J 16.92 and 6.12, 1H), 2.02 (s, 3H). νmax(KBr)/cm−1 3280,
1693, 1643. m/z (ESI) 268 [M + H+].
Table 4. Reuse studies ofYb(OTf)3 immobilized in ionic liquid for the
synthesis of 3b
Run
Yield [%]A
1
76
2
75
3
73
4
74
5
72
AYield of pure isolated product.
3b: δH (CDCl3, 400 MHz) 7.89 (d, J 7.32, 2H), 7.60–7.56 (m,
1H), 7.45 (t, J 8.0, 2H), 7.27 (s, 4H), 6.79 (d, J 8.08, 1H, NH),
5.55–5.51 (m, 1H), 3.74 (dd, J 17.16 and 5.0, 1H), 3.42 (dd, J
17.12 and 5.88, 1H), 2.04 (s, 3H). νmax(KBr)/cm−1 3288, 1685,
1645. m/z (ESI) 302 [M + H+].
Experimental
Melting points were measured using a Buchi R-535 appara-
1
tus and are uncorrected. The H NMR spectra were recorded
on a Brucker Heaven Avance 11 400 (400 MHz) spectrophoto-
meter using TMS as internal standard and CDCl3 as solvent
and the chemical shifts are expressed in ppm. The IR spectra
were recorded using KBr pellets on a Shimadzu Prestige-
3c: δH (CDCl3, 400 MHz) 8.15 (d, J 7.83, 2H), 7.88 (d, J 7.24,
2H), 7.62–7.45 (m, 5H), 6.97 (d, J 8.24, 1H, NH), 5.68–5.63 (m,
1H), 3.81 (dd, J 17.64 and 4.88, 1H), 3.50 (dd, J 17.6 and 5.44,
1H), 2.09 (s, 3H). νmax(KBr)/cm−1 3287, 685, 1645. m/z (ESI)
313 [M + H+].
21 FTIR spectrophotometer and νmax are expressed in cm−1
.
All the metal triflates, 1-methylimidazole, and bromobutane
werepurchasedfromSigma–Aldrich.Aldehydes, ketones, acetyl
chloride, acetonitrile, and other reagents were purchased from
Merck and SRL India. All the reagents were of analytical grade
and obtained through commercial sources and were used as such.
The products were purified by column chromatography using sil-
ica gel (60–120 mesh). The required ionic liquid [bmim][BF4]
was prepared according to the reported procedure by reaction
of 1-methylimidazole with 1-bromobutane followed by anion
substitution with sodium tetrafluoroborate in dry acetone.[11a]
3d: δH (CDCl3, 400 MHz) 7.90 (d, J 7.40, 2H), 7.56 (t, J
7.40, 1H), 7.46 (t, J 7.88, 2H), 7.21 (d, J 8.12, 2H), 7.11 (d, J
8.0, 2H), 6.61 (d, J 7.88, 1H, NH), 5.55–5.50 (m, 1H), 3.75 (dd,
J 16.84 and 5.08, 1H), 3.43 (dd, J 16.80 and 6.28, 1H), 2.29 (s,
H), 2.01 (s, 3H). νmax(KBr)/cm−1 3292, 1682, 1643. m/z (ESI)
282 [M + H+].
3e: δH (CDCl3, 400 MHz) 7.90 (d, J 7.60, 2H), 7.55 (t, J 7.44,
1H), 7.43 (t, J 7.46, 2H), 7.26 (d, J 7.92, 2H), 6.83 (d, J 8.68,
2H), 6.63 (d, J 7.96, 1H, NH), 5.52–5.47 (m, 1H), 3.76 (s, 3H),
3.73 (dd, J 17.08 and 5.32, 1H), 3.41 (dd, J 16.76 and 6.4, 1H),
2.0 (s, 3H). νmax(KBr)/cm−1 3304, 1688, 1657. m/z (ESI) 298
[M + H+].
General Experimental Procedure
3f : δH (CDCl3, 400 MHz) 7.90 (d, J 8.64, 2H), 7.41 (d, J
8.64, 2H), 7.24 (d, J 8.72, 2H), 6.74 (d, J 8.76, 2H), 6.53 (d,
J 7.88, 1H, NH), 5.49–5.44 (m, 1H), 3.76 (s, 3H), 3.72 (dd, J
16.40 and 5.24), 3.35 (dd, J 16.52 and 6.72, 1H), 2.09 (s, 3H).
νmax(KBr)/cm−1 3304, 1693, 1587. m/z (ESI) 332 [M + H+].
3g: δH (CDCl3, 400 MHz) 8.21 (s, 1H), 8.09 (d, J 7.72, 1H),
7.85 (d, J 8.68, 2H), 7.71 (d, J 7.68, 1H), 7.50 (t, J 7.96, 1H),
7.44 (d, J 8.68, 2H), 6.87 (d, J 8.20, 1H, NH), 5.67–5.63 (m,
1H), 3.78 (dd, 1H, J 17.60 and 5.04), 3.48 (dd, J 17.60 and 5.60,
1H), 2.09 (s, 3H). νmax(KBr)/cm−1 3298, 1686, 1643. m/z (ESI)
347 [M + H+].
Ketone (1.33 mmol) and aldehyde (1.33 mmol) were dissolved
in ionic liquid [bmim][BF4] (2 mL), and to this, acetyl chloride
(2.0 mmol), acetonitrile (6.65 mmol), andYb(OTf)3 (20 mol-%)
were added. The reaction mixture was then stirred at room tem-
perature for the appropriate time. After this time, the reaction
mixture was extracted with diethyl ether (3 × 5 mL). The com-
bined organic phase was concentrated under reduced pressure
and the crude residue was treated with ethyl acetate/hexane to
afford the product as a precipitate. The precipitate was passed
through a bed of silica gel. All products were characterized by
mp, 1H NMR, IR, and mass spectroscopic data.

RESEARCH FRONT
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A. Kumar et al.
3h: δH (CDCl3, 400 MHz) 7.84 (d, J 9.12, 2H), 7.44 (d, J 8.68,
2H), 7.29–7.24 (m, 4H), 6.63 (d, J 8.04, 1H, NH), 5.52–5.50 (m,
1H), 3.73 (dd, J 17.08 and 4.92, 1H), 3.39 (dd, J 17.04 and 6.08,
1H), 2.04 (s, 3H). νmax(KBr)/cm−1 3269, 1678, 1633. m/z (ESI)
336 [M + H+].
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3j: δH (CDCl3, 400 MHz) 8.25 (s, 1H), 8.06 (d, J 7.44, 1H),
7.88 (d, J 8.96, 2H), 7.70 (d, J 7.72, 1H), 7.46 (t, J 8.0, 1H), 7.16
(d, J 8.20, 1H, NH), 6.91 (d, J 8.96, 2H), 5.63 (m, 1H), 3.86 (s,
3H), 3.73 (dd, J 17.28 and 5.16, 1H), 3.43 (dd, J 17.28 and 5.48,
1H), 2.06 (s, 3H). νmax(KBr)/cm−1 3244, 3186, 1658, 1597. m/z
(ESI) 343 [M + H+].
3k: δH (CDCl3, 400 MHz) 7.90 (d, J 8.92, 2H), 7.21 (d, J 8.08,
2H), 7.10 (d, J 7.92, 2H), 6.92 (d, J 8.96, 2H), 6.72 (d, J 8.20,
1H, NH), 5.52–5.47 (m, 1H), 3.86 (s, 3H), 3.68 (dd, J 16.56 and
5.16, 1H), 3.35 (dd, J 16.52 and 6.16, 1H), 2.29 (s, 3H), 2.01 (s,
3H). νmax(KBr)/cm−1 3304, 1688, 1643, 1598. m/z (ESI) 312
[M + H+].
3l: δH (CDCl3, 400 MHz) 8.41 (s, 1H), 8.23 (d, J 7.8, 1H),
7.89 (dd, J 7.8, 3.24, 2H), 7.72 (d, J 7.8, 1H), 7.60 (td, J 7.4,
1.32, 1H), 7.51–7.44 (m, 3H), 6.96 (d, J 8.24, 1H, NH), 5.66 (m,
1H), 3.80 (dd, J 17.56 and 4.96, 1H), 3.52 (dd, J 17.56 and 5.52,
1H), 2.08 (s, 3H). νmax(KBr)/cm−1 3286, 1689, 1647, 1630. m/z
(ESI) 313 [M + H+].
3m: δH (CDCl3, 400 MHz) 7.91 (d, J 8.8, 2H), 7.23 (d, J 8.7,
2H), 6.91 (d, J 8.7, 2H), 6.83 (d, J 8.8, 2H), 6.69 (d, J 8.1, 1H,
NH), 5.5 (m, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 3.69 (dd, 1H, J
16.48 and 5.04), 3.34 (dd, 1H, J 16.48 and 6.28), 2.01 (s, 3H).
νmax(KBr)/cm−1 3269, 1678, 1633. m/z (ESI) 328 [M + H+].
3n: δH (CDCl3, 400 MHz) 8.35–8.21 (m, 2H), 7.81–7.65 (m,
2H), 6.51 (d, J 7.84, 1H, NH), 5.45 (m, 1H), 2.25–1.91 (m, 9H),
1.85 (s, 3H). νmax(KBr)/cm−1 3431, 2929, 1672, 1628. m/z (ESI)
291 [M + H+].
3o: δH (CDCl3, 400 MHz) 7.38 (d, J 8.64, 2H), 7.26 (d, J
8.64, 2H), 6.49 (d, J 7.79, 1H, NH), 5.51 (m, 1H), 2.06 (s, 3H),
2.05–1.78 (m, 9H). νmax(KBr)/cm−1 3433, 2926, 1689, 1646,
1550. m/z (ESI) 280 [M + H+].
(u) B. Das, M. Krishnaiah, K. Lazminarayana, K. R. Reddy,
J. Mol. Catal. Chem. 2007, 270, 284. doi:10.1016/J.MOLCATA.
2007.02.014
Acknowledgements
The authors thank the Council of Scientific and Industrial Research (CSIR),
New Delhi, for financial support (Project no. 01(2214)/08/EMR-II), and
I. Ahmad thanks Birla Institute of Technology and Science, Pilani, for insti-
tutional fellowships. We are also thankful to Mr Avtar Singh at The Sophis-
ticated Analytical Instrumentation Facility, Panjab University, Chandigarh,
Punjab, for recording the 1H NMR spectra of the samples.
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