One-pot synthesis of β-amido ketones using bronsted acidic ionic liquid as an efficient and reusable catalyst

Article abstract of DOI:10.1139/V08-173

An efficient protocol was developed for one-pot condensation of an aldehyde, ketone, acetyl chloride, and nitriles catalyzed by a stable and reusable 1-methyl-imidazolium hydrogen sulfate ([Hmim][HSO₄]) as a Bronsted acidic ionic liquid. The sy

Full text of DOI:10.1139/V08-173

401
One-pot synthesis of b-amido ketones using
Brønsted acidic ionic liquid as an efficient and
reusable catalyst
Krishna M. Deshmukh, Ziyauddin S. Qureshi, Nitin S. Nandurkar, and
Bhalchandra M. Bhanage
Abstract: An efficient protocol was developed for one-pot condensation of an aldehyde, ketone, acetyl chloride, and ni-
triles catalyzed by a stable and reusable 1-methyl-imidazolium hydrogen sulfate ([Hmim][HSO4]) as a Brønsted acidic
ionic liquid. The system tolerated a variety of functional groups affording the corresponding b-amido ketones in moderate
to good yields under milder operating conditions.
Key words: ionic liquids, multicomponent reactions, b-amido ketones, one-pot synthesis.
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Resume : On a developpe un protocole efficace pour la condensation monotope d’un aldehyde, d’une cetone, du chlorure
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d’acetyle et de nitriles, catalysee par un liquide ionique stable et reutilisable, le sulfate acide de 1-methyl-imidazolium
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[Hmim][HSO4] qui agit comme acide de Brønsted. Le systeme tolere une grande variete de groupements fonctionnels
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conduisant a la formation des b-amidocetones correspondantes avec des rendements allant de moderes a bons, dans les
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conditions d’operation les plus douces.
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Mots-cles : liquides ioniques, reactions a plusieurs composantes, b-amidocetones, synthese monotope.
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[Traduit par la Redaction]
Introduction
In recent years, application of ionic liquids have gained
considerable interest in the context of green synthesis.
Although ionic liquids were initially introduced as an alter-
native green reaction media, today they have marched far
beyond this border for their significant role in controlling
the reaction as a catalyst. Among various ionic liquids de-
veloped to date, Brønsted acidic ionic liquids have emerged
as a most promising alternative for a wide variety of acid
catalyzed reactions.16–24
b-Amido ketones constitute an important class of com-
pounds having biological and medicinal properties.1,2 They
are used as precursors for the synthesis of 1,3-amino
alcohol present in antibiotic drug such as nikkomycines or
neopolyoxines.3,4 Traditionally, these compounds are synthe-
sized by a Dakin–West reaction, which involves the conden-
sation of an a-amino acid with acetic anhydride in the
presence of a base.5 Iqbal and co-workers proposed a multi-
component route for the synthesis of b-acetamido ketones
via condensation of an aldehyde, enolizable ketones, acetyl
Results and discussion
6
chloride, and acetonitrile using CoCl2 and Montmorillonite
We herein report an efficient protocol for one-pot conden-
sation of an aldehyde, ketone, acetyl chloride, and nitriles cat-
alyzed by a stable and reusable Brønsted acidic ionic liquid,
1-methyl-imidazolium hydrogen sulfate ([Hmim][HSO4]).
The system tolerated a variety of functional groups afford-
ing corresponding b-amido ketones in moderate to good
yields under milder operation conditions (Scheme 1).
Initially, condensation of benzaldehyde, acetophenone,
acetyl chloride, and acetonitrile were chosen as model reac-
tion and the role of the different ionic liquids as a catalyst
and it’s loading on the reaction system was investigated
(Table 1, entries 1–4). The influence of various 1-methyl-
imidazolium based ionic liquids, such as 1-butyl-3-methyl-
imidazolium hydrogen sulfate ([C4mim][HSO4]), 1-methyl-
imidazolium hydrogen sulfate ([Hmim][HSO4]), 1-methyl-
imidazolium tetraflouroacetate ([Hmim][Tfa]), and 1-
methyl-imidazolium nitrate ([Hmim][NO3]), were studied.
Out of various ionic liquids screened, the [Hmim][HSO4]
ionic liquid was found to be the most effective, providing
good yield of the desired product. The effect of catalyst
K107 as the catalysts. Subsequently, other groups extended
these methodologies by exploring various Lewis or Brønsted
acid catalysts such as FeCl3Á6H2O,8 ZrOCl2Á8H2O,9 silica
sulfuric acid,10,11SiCl4-ZnCl2,12 heteropoly acid,13 ZnO,14
and BiCl3 generated from BiOCl.15 Inspite of their potential
applications, these methodologies face disadvantages like
the requirement of harsh reaction conditions, use of expen-
sive and moisture sensitive Lewis acid catalysts, and ele-
vated temperatures.
Received 1 August 2008. Accepted 24 October 2008. Published
on the NRC Research Press Web site at canjchem.nrc.ca on
18 December 2008.
K.M. Deshmukh, Z.S. Qureshi, N.S. Nandurkar, and
B.M. Bhanage.1 Department of Chemistry, Institute of Chemical
Technology, University of Mumbai, N. Parekh Marg, Matunga,
Mumbai 400 019, India.
1Corresponding author (e-mail:
bhalchandra_bhanage@yahoo.com).
Can. J. Chem. 87: 401–405 (2009)
doi:10.1139/V08-173
Published by NRC Research Press

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Can. J. Chem. Vol. 87, 2009
Table 1. Effect of catalysts and catalyst loading on the conden-
sation of benzaldehyde, acetophenone, acetyl chloride, and
acetonitrile.
Scheme 1. Synthesis of b-amido ketones using ionic liquid as cata-
lyst.
Catalyst loading
(mol %)
Entry
Catalyst
Yield (%)a
1
[C4mim][HSO4]
[Hmim][HSO4]
[Hmim][Tfa]
[Hmim][NO3]
[Hmim][HSO4]
[Hmim][HSO4]
[Hmim]HSO4]
[Hmim][HSO4]
[Hmim][HSO4]
[Hmim][HSO4]
40
40
40
40
10
20
30
50
60
2b
3
75, 73, 71
66
36
50
54
63
72
70
62
4
5
6
7
8
9
10
loading on the reaction system was also investigated and
40 mol% [Hmim][HSO4] was found to be the most effective
in providing a higher yield. (Table 1, entries 5–10).
60
100
Since [Hmim][HSO4] was one of the most effective func-
tional ionic liquids, it was selected to investigate the possibility
of recyclability. After the completion of the reaction, the reac-
tion mixture was evaporated under reduced pressure to obtain a
residue. The residue was dissolved in ethyl acetate to obtain
two phases; the ionic liquid phase was separated by decanta-
tion of ethyl acetate. The ionic liquid phase was then washed
with diethyl ether (3 Â 5 mL) and was evaporated under re-
duced pressure at 80 8C for 1 h to remove the redundant mixed
solvent and it was then used for further recyclability test.
It can be seen from Table 1, entry 2, that there was no
obvious change on the recovered catalyst (88%–95%) and
excellent yield was obtained. After recycling three times,
[Hmim][HSO4] was still stable enough and had less impact
on the catalytic activity. The purity of the recycled ionic
Note: Reaction conditions: benzaldehyde (1 mmol); acetophenone
(1 mmol); acetyl chloride (0.3 mL); acetonitrile (4 mL); reaction time:
10 h at RT.
aIsolated yields.
bRecyclability of the catalyst tested up to three cycles.
Scheme 2. Mechanism for the synthesis of b-amido ketones.
1
liquid was confirmed using H NMR and it was the same as
that used for the first run. This indicated that [Hmim][HSO4]
was a highly efficient and recyclable catalyst for synthesis
of b-amido ketones.
Thus, using [Hmim][HSO4] as the best catalyst, the con-
densation of various aldehydes, ketones, and nitriles with
different steric and electronic properties were investigated
(Table 2, entries 1–22). The condensation of benzaldehyde,
acetophenone, acetyl chloride, and nitriles provided a 75%
yield of the desired product. Aldehydes with electron-donat-
ing (CH3, OCH3) and electron-withdrawing substituents
(NO2, Cl, Br, F) were also investigated and found to provide
good yields (50%–84%) under the present conditions. Sub-
stituted acetophenones having activating and deactivating
groups were found to be compatible and provided good
yields of the desired products (Table 2, entries 2–4, 10–13,
16, 17, 21, 22). To show the generality of the protocol, the
effect of aliphatic and aromatic nitriles, such as acetonitrile,
benzonitrile, and phenylacetonitrile were also investigated.
The reaction of benzonitrile require longer reaction times,
up to 24 h and the probable reason for this may be the steric
factor as well as low nucleophilicity of benzonitrile (Table 2,
entries 14–17).
The reaction of acetonitrile and phenylacetonitrile were
found to proceed smoothly under the present conditions,
providing good yields of the desired products. Thus, the pro-
tocol is general in nature and tolerates a wide range of func-
tional groups. A plausible reaction mechanism for the
present reaction may proceed as depicted in Scheme 2. The
yield of b-amido ketones depends upon the ionic liquid
chosen, as shown in Table 1. It can be seen that
[Hmim][NO3] gives a lower yield of the product as com-
pared to [Hmim][HSO4] and [C4mim][HSO4], which sug-
gests that the counter anion also plays a catalytic role in the
reaction (Scheme 2). The counter anion protonates the ke-
tone by a donating proton.
In summary, [Hmim][HSO4] is a reusable and moisture sta-
ble Brønsted acidic ionic liquid, reported as an efficient cata-
lyst for the synthesis of a wide range of b-amido ketone under
mild operating conditions. The system tolerates a wide range
of functional groups affording the desired products in good to
excellent yields. Further work is in progress to broaden the
scope of ionic liquids to various other organic transformations.
Experimental section
The chemicals and solvents were supplied by Sigma-
Aldrich, Fluka, and S.D. Fine-chem Ltd. companies and
used without further purification
Synthesis of ionic liquids
In this study, the ionic liquids used were synthesized
according to the procedure reported in the literature22–24 and
1
were characterized by H NMR.
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Deshmukh et al.
403
Table 2. One-pot condensation of aldehyde, ketone, acetyl chloride, and nitriles to give the corre-
sponding b-amido ketone catalyzed by [Hmim][HSO4].
Synthesis of b-amido ketones using [Hmim][HSO4] as the
catalyst
mixture of solvents (ethyl acetate–hexane) to get the pure
product. All compounds are known compounds and were
characterized by using IR and H NMR.
1
To a stirred suspension of [Hmim] [HSO4] (40 mol %)
in acetonitrile (4 mL) were added benzaldehyde (1 mmol),
acetophenone (1 mmol), and acetyl chloride (0.3 mL). The
reaction mixture was stirred at ambient temperature for
10 h. After the completion of the reaction, crushed ice
(30 mL) was added to the reaction mixture and stirred
thoroughly. On solidification, the products were filtered
off and dried to get the corresponding b-amido ketone.
The solid product obtained was recrystallized from the
Selected spectroscopic data
1
Characterization of ionic liquids using H NMR
1-Butyl-3-methyl-imidazolium hydrogen sulfate
([C4mim][HSO4])
1H NMR (400 MHz, CDCl3, ppm) d: 0.91 (t, J = 7.5 Hz,
Published by NRC Research Press

404
Can. J. Chem. Vol. 87, 2009
Table 2 (concluded).
1
3H), 1.25 (m, J = 7.4 Hz, 2H), 1.75 (m, J = 7.4 Hz, 2H), 2.5
(s, 3H), 4.18 (t, J = 7.0 Hz, 2H), 7.70 (m, 2H), 7.79 (s, 1H),
9.25 (s, 1H).
Characterization of b-amido ketones using H NMR and
FT-IR
N-[3-Oxo-1,3-diphenyl-propyl] acetamide (Table 2, entry 1)
IR (KBr, cm–1) n: 3284, 3058, 2925, 1690, 1646, 1540,
1225, 988, 618. H NMR (200 MHz, CDCl3, ppm) d: 2.03
(s, 3H), 3.40 (dd, J = 6.0, 16.9 Hz, 1H), 3.76 (dd, J = 6.0,
16.9 Hz, 1H), 5.57 (m, 1H), 6.70 (br d, J = 7.5 Hz, 1H),
7.22–7.61 (m, 8H), 7.91 (d, J = 7.5 Hz, 2H).
1-Methyl-imidazolium hydrogen sulfate ([Hmim][HSO4])
IR (KBr, cm–1) n: 3265, 3145, 2846, 1550, 1480,
1186, 1058, 883, 618. 1H NMR (400 MHz, CDCl3,
ppm) d: 3.86 (s, 3H), 7.67 (m, 3H), 9.07 (s, 1H), 14.5
(br, s, 1H).
1
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Deshmukh et al.
405
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2006.02.037.
N-[1-(4-Fluorophenyl)-3-oxo-3-phenyl-propyl] acetamide
(Table 2, entry 7)
IR (KBr, cm–1) n: 3283, 3083, 1686, 1635, 1574, 1372,
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2007.06.128.
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1
1298, 990, 895. H NMR (200 MHz, CDCl3, ppm) d: 2.01
(s, 3H), 3.45 (dd, J = 6.0, 16.9 Hz, 1H), 3.75 (dd, J = 6.0,
16.9 Hz, 1H), 5.50 (m, 1H), 6.72 (brs, 1H), 7.01 (t, 2H),
7.40 (m, 5H), 7.83 (d, J = 7.5 Hz, 2H).
N-[1-(4-Methoxyphenyl)-3-oxo-3-(4-methylphenyl) propyl]-
2-phenylacetamide (Table 2, entry 22)
IR (KBr, cm–1) n: 3333, 2955, 1689, 1640, 1515, 1247,
1
1184, 1032, 822, 733. H NMR (200 MHz, CDCl3, ppm) d:
2.32 (s, 3H), 3.22 (dd, J = 5.5, 16.6 Hz, 1H), 3.45 (dd, J =
5.5, 16.6 Hz, 1H), 3.51 (s, 2H), 3.68 (s, 3H), 5.39 (m, 1H),
6.49 (brs, 1H), 7.03 (d, J = 7.5 Hz, 2H), 7.13–7.28 (m, 9H),
7.69 (d, J = 7.8 Hz, 2H).
Acknowledgments
Financial assistance from the Indira Gandhi Center for
Atomic Research (IGCAR) is kindly acknowledged.
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