Lewis acidic ionic liquids for the synthesis of electrophilic alkenes via the Knoevenagel condensation

Article abstract of DOI:10.1016/S0040-4039(01)02341-3

1-Butyl-3-methylimidazolium chloroaluminate, [bmim]Cl·AlCl₃, N = 0.67 and 1-butylpyridinium chloroaluminate, [bpy]Cl·AlCl₃, N = 0.67 ionic liquids were found to work well as the Lewis acid catalyst and solvent in the Knoevenagel condensations of benzaldehyde and substituted benzaldehydes with diethyl malonate to give benzylidene malonates. The benzylidene malonates subsequently underwent Michael additions with diethyl malonate. The extent of Michael product formed during the reaction was found to vary with the Lewis acidity and the molar proportion of ionic liquid. The influence of Lewis acidity of the ionic liquid on the Knoevenagel and Michael products is demonstrated. In the case of 2-hydroxyarylaldehydes, the reactions led to the formation of 3-ethoxycarbonyl coumarins under ambient conditions.

Full text of DOI:10.1016/S0040-4039(01)02341-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1127–1130
Lewis acidic ionic liquids for the synthesis of electrophilic
alkenes via the Knoevenagel condensation
Jitendra R. Harjani, Susheel J. Nara and Manikrao M. Salunkhe*
Department of Chemistry, The Institute of Science, 15-Madam Cama Road, Mumbai 400 032, India
Received 27 October 2001; revised 24 November 2001; accepted 7 December 2001
Abstract—1-Butyl-3-methylimidazolium chloroaluminate, [bmim]Cl·AlCl3, N=0.67 and 1-butylpyridinium chloroaluminate,
[bpy]Cl·AlCl3, N=0.67 ionic liquids were found to work well as the Lewis acid catalyst and solvent in the Knoevenagel
condensations of benzaldehyde and substituted benzaldehydes with diethyl malonate to give benzylidene malonates. The
benzylidene malonates subsequently underwent Michael additions with diethyl malonate. The extent of Michael product formed
during the reaction was found to vary with the Lewis acidity and the molar proportion of ionic liquid. The influence of Lewis
acidity of the ionic liquid on the Knoevenagel and Michael products is demonstrated. In the case of 2-hydroxyarylaldehydes, the
reactions led to the formation of 3-ethoxycarbonyl coumarins under ambient conditions. © 2002 Elsevier Science Ltd. All rights
reserved.
Ever since the ionic liquids came into the spotlight
during the last decade, rigorous and consistent efforts
in this area have paved the way for alternative and new
synthetic strategies in the realm of synthetic organic
chemistry. The pioneering work of Seddon and others
have unravelled several remarkable properties of ionic
liquids that can be ably exploited in tackling problems
encountered in synthetically useful reactions.1 Their
unprecedented ability to solvate a broad spectrum of
substrates of organic and inorganic nature has widened
the horizon of their applicability. Infinitesimally small
vapour pressure, recyclability without any diminution
in the desirable properties (except in the case of
chloroaluminate ionic liquids), high thermal stability
and ease of handling are the features possessed by these
liquids. The hallmark of such liquids is our ability to
alter their properties2 as desired, by manipulating their
structure with respect to the choice of organic cation,
anion and side chain attached to the organic cation. All
these properties have bestowed entirety to these liquids
for their application in developing environmentally
benign chemical technologies.
The Knoevenagel reaction is well known for its
immense potential in the synthesis of electrophilic
olefins from active methylene and carbonyl com-
pounds.3 More than a century old now, a wide array of
catalysts have been employed to accomplish this reac-
tion, each affording variable yields of olefins. The reac-
tion is catalysed by weak bases under homogenous
conditions.3 However, the past decade has witnessed a
rapid emergence of heterogeneous catalysts comprising
of mainly inorganic materials such as clays, zeolites,
etc. owing to their environmentally benign properties,
which have been aptly employed in this reaction.4
Apart from these properties, the feature which encour-
aged their application in Knoevenagel reaction is that
most of them are ditopic in nature, containing both
acidic and basic sites, while others are solely acidic or
basic. Some Lewis acid catalysts have also been
Scheme 1. Reaction of benzaldehyde and substituted benzaldehydes with diethyl malonate in the Lewis acidic [bmim] Cl·xAlCl3
and [bpy]Cl·xAlCl3 ionic liquids.
* Corresponding author. Tel.: 91-22-2816750; fax: 91-22-2816750; e-mail: mmsalunkhe@hotmail.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02341-3

1128
J. R. Harjani et al. / Tetrahedron Letters 43 (2002) 1127–1130
exploited for this reaction.5 Chloroaluminate based
ionic liquids have been the focal point of our investiga-
tions owing to their variable Lewis acidity. We have
exploited the acidity of these liquids in Fries
rearrangements6a and Friedel–Crafts sulphonylations.6b
In continuation of our ongoing research program of
exploration of newer reactions and their mechanistic
investigations in these ionic liquids, we thought it
would be worthwhile to investigate the Knoevenagel
reaction in these liquids. We herein report for the first
time Knoevenagel condensations of benzaldehyde and
substituted benzaldehydes with diethyl malonate in
Lewis acidic 1-butyl-3-methylimidazolium chloroalumi-
nate, [bmim]Cl·xAlCl3 and 1-butylpyridinium chloro-
aluminate, [bpy]Cl·xAlCl3 ionic liquids (Scheme 1).
Knoevenagel and Michael can become competitive to
give different ratios of the two products. The ratio of
Knoevenagel to Michael product (K/M) was found to
be higher when the molar ratio of aldehyde, diethyl
malonate and ionic liquid was 1.0:1.0:0.5, respectively,
in most of the cases (Table 1) except in the case of
4-methoxybenzaldehyde. The presence of an electron-
donating group at the 4-position decreases its reactivity
towards the Knoevenagel reaction and consequently a
significant amount of the Michael product was
observed in this case. Hence, the influence of parame-
ters such as the molar proportion and the Lewis acidity
of the ionic liquid on conversion and K/M ratio of such
a substrate is expected to be more pronounced. Obvi-
ously, 4-methoxybenzaldehyde was the substrate of
choice for these studies. As the molar proportion of
ionic liquid was increased progressively while, the
molar ratio of aldehyde to diethyl malonate was main-
tained at 1.0:1.0, the extent of conversion and the K/M
ratio increased, as illustrated in Table 2. Thus, a higher
molar proportion of ionic liquid favours the Knoeve-
nagel product.
Lewis acidity of such ionic liquids is a function of the
apparent mole fraction of AlCl3, N present in the
liquid. We initially investigated the Knoevenagel con-
densation in [bmim]Cl·AlCl3, N=0.67. Several experi-
ments with substituted benzaldehydes gave us almost
quantitative conversions7 (Table 1) when the aldehyde,
diethyl malonate and ionic liquid were taken in the
molar ratio of 1.0:1.0:0.5, respectively. However, apart
from the major product, i.e. the Knoevenagel product,
some other products were also detected on GC in all
the cases. The Knoevenagel product, benzylidene mal-
onate, which happens to be an excellent Michael
acceptor8 underwent subsequent Michael addition with
diethyl malonate and give the Michael adduct. Once
benzylidene malonate is formed, the two reactions,
The Lewis acidity of these liquids varies as an apparent
mole fraction of AlCl3. This feature of ionic liquids
allowed us to monitor the influence of the Lewis acidity
on the extent of conversion and on the K/M ratio. The
expected trend of increase in conversion with increase
in Lewis acidity was observed as illustrated in Table 3.
However, the ratio K/M falls off as the Lewis acidity of
the liquid increases.
Table 1. Reactions of benzaldehyde and substituted benzaldehydes with diethyl malonate in the Lewis acidic [bmim]Cl·AlCl3,
N=0.67 and [bpy]Cl·AlCl3, N=0.67 ionic liquids

J. R. Harjani et al. / Tetrahedron Letters 43 (2002) 1127–1130
1129
Table 2. Influence of the molar proportion of
[bmim]Cl·AlCl3, N=0.67 on the extent of conversion and
K/M ratio in the reactions of 4-methoxybenzaldehyde with
diethyl malonate
In addition, [bpy]Cl·AlCl3, N=0.67 was also employed
for these reactions. The conversions in this ionic liquid
were relatively less in comparison to [bmim]Cl·AlCl3,
N=0.67; consequently, the proportion of Michael
product in this liquid is improved in most of the cases.
This feature is in accordance with the results obtained
in [bmim]Cl·AlCl3, N=0.67 ionic liquid at lower molar
proportions (Table 1). Thus, [bpy]Cl·AlCl3, N=0.67
offers a relatively less reactive environment which fos-
ters relatively low K/M product ratios in almost all the
cases. However, the substrates (entries 6 and 7) which
exhibited a lower K/M ratio in [bmim]Cl·AlCl3, N=
0.67, showed higher selectivities for the Knoevenagel
product, i.e. a higher K/M ratio in [bpy]Cl·AlCl3, N=
0.67.
Molar proportion of
Conversion (%) K/M ratio
[bmim]Cl·AlCl3, N=0.67
0.5
1.0
1.5
71
74
80
1.8
49.0
49.0
Table 3. Influence of Lewis acidity on the extent of con-
version and K/M ratio in the reactions of 4-methoxybenz-
aldehyde with diethyl malonate in [bmim]Cl·xAlCl3
N
x
Conversion (%)
K/M ratio
We also investigated Knoevenagel condensations of
ketones with diethyl malonate. No reactions were
observed in the cases of acyclic and cyclic ketones,
under the conditions in which aldehydes gave almost
quantitative conversions.9 However, 2-cyclohexen-1-one
spontaneously underwent the Michael reaction with
diethyl malonate exclusively with no Knoevenagel con-
densation at all, yielding the Michael adduct character-
ised by 1H NMR and MS m/z 256 (M+) in almost
quantitative yield. This observation prompted us to
investigate the Michael addition of diethyl malonate
with 1,3-diphenyl-2-propen-1-one, which at room tem-
perature furnished the corresponding Michael adduct.
Detailed investigations concerning Michael additions in
these liquids are currently in progress.
0.50
0.55
0.59
0.63
0.67
1.00
1.25
1.50
1.75
2.00
–
–
22
41
57
71
4.3
3.0
2.4
1.8
Scheme 2. Coumarin synthesis via Knoevenagel condensa-
tions of 2-hydroxybenzaldehydes with diethyl malonate in the
Lewis acidic [bmim]Cl·AlCl3, N=0.67.
In the case of 2-hydroxybenzaldehyde, the Knoevenagel
condensation and transesterification led to the forma-
tion of 3-ethoxycarbonyl coumarin. To generalise the
procedure and to demonstrate the ability of these liq-
uids to catalyse the coumarin synthesis, various 2-
hydroxyarylaldehydes were subjected to condensations
with diethyl malonate9 (Scheme 2), the results are sum-
marised in Table 4. The substrates exhibited enhanced
reactivity to such an extent that the reactions took
barely a few minutes, furnishing 3-ethoxycarbonyl cou-
marins in good yields.
Table 4. Synthesis of 3-ethoxycarbonyl coumarins via
Knoevenagel condensations of 2-hydroxyarylaldehydes
with diethyl malonate in the Lewis acidic [bmim]Cl·AlCl3,
N=0.67
In conclusion, the two ionic liquids [bmim]Cl·AlCl3,
N=0.67 and [bpy]Cl·AlCl3, N=0.67 served as an alter-
native media that catalysed Knoevenagel and Michael
reactions, two synthetically useful reactions involving
CꢀC bond formation. The synthesis of coumarins via
Knoevenagel route is also demonstrated in these liq-
uids. Considerable control over various products in
these reactions can be exercised by variation of the
parameters associated with the ionic liquid. The experi-
mental procedure9 is simple and timesaving, avoiding
cumbersome water removal steps.
References
1. Review: Welton, T. Chem. Rev. 1999, 99, 2071.
2. Review: Wasserscheid, P.; Keim, W. Angew. Chem., Int.
Ed. Engl. 2000, 39, 3772.

1130
J. R. Harjani et al. / Tetrahedron Letters 43 (2002) 1127–1130
3. Jones, G. Organic Reactions; Wiley: New York, 1967; Vol.
XV, p. 204.
8. Bergmann, E. D.; Ginsburg, D.; Pappo, R. Organic Reac-
tions; Wiley: New York, 1959; Vol. X, p. 179.
9. Experimental procedure: In a typical experimental proce-
dure, to the weighed quantity of ionic liquid,
[bmim]Cl·AlCl3, N=0.50–0.67 or [bpy]Cl·AlCl3 N=0.67,
an aldehyde and diethyl malonate were added in the molar
ratio of 0.5:1.0:1.0 on a 5 mmol scale with respect to the
aldehyde, unless otherwise stated in the text. All additions
were carried out in an inert atmosphere glove box. The
reaction commenced instantaneously making the reaction
mixture highly viscous. The reaction was quenched after 5
min with 6N HCl in cold conditions. The product was
extracted with ethyl acetate (3×10 mL). The combined
organic extracts were dried using anhydrous sodium sul-
phate, evaporated under reduced pressure and assayed on
GC. The crude products were chromatographed using
silica gel column chromatography to yield pure com-
pounds that were characterised by IR, NMR, MS and
physical constants.
4. Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. J. Org. Chem.
1999, 64, 1033 and references cited therein.
5. (a) Green, B.; Crane, R. I.; Khaidem, I. S.; Leighton, R.
S.; Newaz, S. S.; Smyser, T. E. J. Org. Chem. 1985, 50,
640; (b) Rao, P. S.; Venkataratnam, R. V. Tetrahedron
Lett. 1991, 32, 5821.
6. (a) Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Tetra-
hedron Lett. 2001, 42, 1979; (b) Nara, S. J.; Harjani, J. R.;
Salunkhe, M. M. J. Org. Chem. 2001, 66, 8616.
7. Conversions in all cases were monitored with respect to
the decay of an aldehyde on GC. Nucon 5700 chro-
matograph equipped with FID was employed for the
analysis. The detector temperature was maintained at
270°C. The column was programmed with an initial tem-
perature of 140°C and was increased thereafter to 270°C at
the rate of 10°C min−1. The column used was liquid phase
ov-17 (length 6%).