Ionic liquid as catalyst and reaction medium - A simple, efficient and green procedure for Knoevenagel condensation of aliphatic and aromatic carbonyl compounds using a task-specific basic ionic liquid

Article abstract of DOI:10.1002/ejoc.200600335

The basic ionic liquid 1-butyl-3-methylimidazolium hydroxide, [bmIm]OH, efficiently catalyzes Knoevenagel condensation without requirement of any organic solvent. A wide range of aliphatic and aromatic aldehydes and ketones easily undergo condensations with diethyl malonate, malononitrile, ethyl cyanoacetate, malonic acid and ethyl acetoacetate. The reactions proceed at room temperature and are very fast (10-30 min). However, the most significant feature of this methodology is the condensation of aliphatic aldehyde with diethyl malonate, which is not very easy to achieve by conventional reagents, and was not addressed adequately in literature providing a general and convenient procedure. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600335

FULL PAPER
DOI: 10.1002/ejoc.200600335
Ionic Liquid as Catalyst and Reaction Medium – A Simple, Efficient and
Green Procedure for Knoevenagel Condensation of Aliphatic and Aromatic
Carbonyl Compounds Using a Task-Specific Basic Ionic Liquid
[a]
[a]
Brindaban C. Ranu* and Ranjan Jana
Keywords: Ionic liquid / Green chemistry / Catalysis / Knoevenagel condensation / Carbonyl compounds
The basic ionic liquid 1-butyl-3-methylimidazolium hydrox-
ide, [bmIm]OH, efficiently catalyzes Knoevenagel condensa-
tion without requirement of any organic solvent. A wide
range of aliphatic and aromatic aldehydes and ketones easily
undergo condensations with diethyl malonate, malononitrile,
ethyl cyanoacetate, malonic acid and ethyl acetoacetate. The
reactions proceed at room temperature and are very fast (10–
30 min). However, the most significant feature of this meth-
odology is the condensation of aliphatic aldehyde with di-
ethyl malonate, which is not very easy to achieve by conven-
tional reagents, and was not addressed adequately in litera-
ture providing a general and convenient procedure.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
though reactions of aromatic aldehydes are very facile and
were addressed in all the procedures, condensation of ali-
phatic aldehydes are difficult to achieve and were not ade-
quately covered. Although there are isolated examples of
condensation of aliphatic aldehydes with malonic esters as
one of the steps in course of synthesis of target com-
During last decade ionic liquids have emerged as very
potential green alternatives to volatile and hazardous or-
ganic solvents, and are being used as efficient and recyclable
[
1]
reaction media for a variety of important reactions. How-
ever, we envisioned ionic liquids as far more potential than
being employed as only reaction media, and thus initiated
an investigation to explore their capability as effective cata-
[5n]
pounds, the reactions are not very fast and high yielding.
[5a,5o,5p]
A couple of reports
also addressed a few reactions,
however, these lack general applicability. In addition, the
[
2]
[3]
lysts and reagents for chemical transformations.
[5a]
reactions are very slow (22–70 h), and the reaction condi-
The Knoevenagel condensation is a very useful reaction
and has been widely employed for carbon–carbon bond for-
mation in organic synthesis.[ This reaction is usually cata-
lyzed by a base, an acid, or a heterogeneous neutral sup-
port. Among many other procedures a few using titanium
tions also vary with each substrate. This prompted us to
develop a convenient method for this useful transformation
4]
[2,3]
utilizing our recent expertise on ionic liquids.
Recently,
design of task specific ionic liquid has attracted much atten-
[1m,1n]
tion.
We also introduced the task-specific ionic liquid
[
5a]
tetrachloride, 1,5,7-triazabicyclo[4.4.0]dec-5-ene immobi-
1
-butyl-3-methylimidazolium hydroxide, [bmIm]OH, with a
[5b]
[5c]
lized in MCM-41,
modified Mg-Al hydrotalcite,
[2h]
remarkable effect on Michael addition
and as a part of
[
5d]
[5e]
MgO,
rare-earth exchanged NaY zeolite,
USY zeo-
this program we report here an excellent catalytic efficiency
of [bmIm]OH for Knoevenagel condensations, particularly
for reactions of aliphatic aldehydes with diethyl malonate
[
5f]
[5g]
[5h]
[5i]
lite, aluminium oxide, water, high pressure, ethyl-
[
5j]
enediammonium diacetate in ionic liquid, Lewis acidic
[
5k]
glycine in ionic acid,[5l] hy-
ionic liquid, [bpy]Cl·AlCl ,
3
(Scheme 1).
drotalcites in ionic liquid[
5m]
may be mentioned.
During the course of our investigations, on another pro-
ject we need to make Knoevenagel condensation products
of aliphatic aldehydes with malonic esters. We tried several
[
6]
[5g]
conventional reagents like piperidine, Al O , glycine in
[
2
3
[
5l]
bmIm]BF4 without any useful result within a reasonable
time (24 h). Our literature search then revealed, that al-
[
a] Department of Organic Chemistry, Indian Association for the
Cultivation of Science, Jadavpur,
Kolkata 700 032, India
Fax: +91-33-2473 2805
E-mail: ocbcr@iacs.res.in
Scheme 1.
Eur. J. Org. Chem. 2006, 3767–3770
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3767

B. C. Ranu, R. Jana
Table 1. Knoevenagel condensation catalyzed by [bmlm]OH.
FULL PAPER
Results and Discussion
The experimental procedure is very simple. A mixture of
aldehyde (5 mmol), diethyl malonate (or other active meth-
ylene compound) (5 mmol) and [bmIm]OH (20 mol-%) was
stirred at room temperature for a certain period of time as
required to complete the reaction (TLC). The product was
isolated by direct distillation of the reaction mixture under
reduced pressure. In case of small-scale reactions or any
compound, which is not thermally stable, the product may
be isolated by extraction with ethyl acetate followed by us-
ual work-up and chromatography. The ionic liquid remain-
ing in the reaction flask after being washed with ethyl ace-
tate and dried at 80 °C under vacuum for 3–4 h was recy-
cled in subsequent runs.
A wide range of aliphatic and aromatic aldehydes and
ketones underwent condensations with a variety of active
methylene compounds – such as diethyl malonate, ethyl cya-
noacetate, malononitrile, malonic acid, ethyl acetoacetate –
by this procedure to provide the corresponding Knoevena-
gel products. The results are summarized in Table 1. The
ketones are found to be less reactive than aldehydes. Het-
eroaromatic aldehydes such as thiophenyl, pyridinyl and
furfuryl aldehydes (Entries 28–31) also underwent smooth
reactions. The condensations of aliphatic aldehydes with
malonic acids were accomplished with moderate yields. The
α,β-unsaturated aldehyde produced the corresponding
product without any difficulty. It was also observed that the
reaction of aliphatic aldehydes with diethyl malonate, which
are easily achieved by [bmim]OH, did not proceed at all
under the catalysis of [bmIm]BF or [bmIm]Br. This shows
4
the vital role of the hydroxy counterion of this task-specific
ionic liquid in this transformation.
When an aromatic o-hydroxy aldehyde was condensed
with diethyl malonate or ethyl acetoacetate by this pro-
cedure, the corresponding coumarin was obtained in one-
pot in very high yields. Several aldehydes were found to
undergo this reaction without any difficulty. The results are
reported in Table 2.
All these reactions are, in general very fast and clean.
The isolated yields of products are also quite high. The
1
13
products are of high purity ( H and C NMR) irrespective
of whether they are obtained by direct distillation or solvent
extraction. The products, α,β-unsaturated esters are found
to be trans (except a couple of reactions as in Entries 25
and 30, where cis isomers are also formed) as obtained in
[
5c,5f,5j,5r]
other procedures.
The products are easily identified
1
13
by spectroscopic data (IR, H NMR and C NMR).
It has been found that the residual ionic liquid may be
recycled for five runs without any loss of efficiency. After
five runs 50% fresh ionic liquid was mixed with it to main-
[
18]
tain equal efficiency. Although there are a few reports of
side reactions due to carbene formation of imidazolium-
based ionic liquids under strong bases, we did not encoun-
ter such side reactions while using [bmIm]OH under the
present procedure. This is possibly due to the faster reac-
tions (10–30 min) of aldehydes with active methylene com-
pounds.
[
a] Yields refer to those of pure isolated products characterized by
1
13
IR and H and C NMR spectroscopic data.
3768
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3767–3770

Ionic Liquid as Catalyst and Reaction Medium for Knoevenagel Condensations
Table 2. Synthesis of coumarins by Knoevenagel condensation.
10.5 Hz, 1 H), 4.19–4.33 (m, 4 H), 2.65–2.73 (m, 1 H), 1.25–1.36
FULL PAPER
1
3
(
m, 6 H), 1.07 (d, J = 6.5 Hz, 6 H) ppm. C NMR: δ = 165.5,
1
64.0, 154.6, 126.5, 61.1, 61.0, 29.2, 21.6 (2 C), 14.0, 13.9 ppm.
[
5a]
These values are in good agreement with the reported ones.
When the reaction was carried out with 1 mmol or smaller amounts
the product was isolated by extraction with ethyl acetate followed
by column chromatography over silica gel. In a few cases where the
products were prone to decomposition under distillation condition,
solvent extraction process was followed. The residual ionic liquid
was washed with small amount of ethyl acetate, dried under vac-
uum at 80 °C for 4 h and recycled.
This procedure is followed for condensations of all substrates listed
in Table 1 and synthesis of coumarins is listed in Table 2. All the
products except four (entries 3,6,13,30 in Table 1) are known com-
pounds (references in Table 1, Table 2) and were identified by com-
parison of their spectroscopic data with those reported. The new
compounds were properly characterized by their spectroscopic data
[
a] Yields refer to isolated pure products unless otherwise stated.
1
13
Conclusions
(IR, H and C NMR) and elemental analysis. These values are
reported below.
In conclusion, the present procedure using the task-spe-
cific basic ionic liquid [bmIm]OH provides a very efficient
and convenient methodology for Knoevenagel condensa-
tion of aliphatic and aromatic carbonyl compounds with
a variety of active methylene compounds. The significant
2
-Butylidenemalononitrile: (Entry 3, Table 1). Yellowish liquid. IR:
–
1 1
ν˜ = 2237, 1604 cm . H NMR: δ = 7.35 (t, J = 7.9 Hz, 1 H), 2.54–
.61 (m, 2 H), 1.54–1.71 (m, 2 H), 1.01 (t, J = 7.4 Hz, 3 H) ppm.
2
13
C NMR: δ = 169.5, 111.9, 110.3, 89.7, 34.4, 20.8, 13.3 ppm.
C H N (120.15): calcd. C 69.97, H 6.71, N 23.32; found C 69.72,
7 8 2
advantages offered by this methodology are: (a) general ap- H 6.75, N 23.25.
plicability to a large number of substrates (33) with very
2
-Butylidenemalonic Acid: (Entry 6, Table 1). Low-melting solid.
facile reaction of aliphatic aldehydes with diethyl malonate,
which is difficult to achieve by other methods, (b) mild reac-
–1 1
IR: ν˜ = 3071 (broad), 1690, 1643 cm . H NMR: δ = 9.8 (broad,
H), 7.85 (t, J = 7.5 Hz, 1 H), 2.72–2.84 (m, 2 H), 1.51–1.66 (m,
2
1
3
tion conditions (room temperature), (c) clean and fast (7– 2 H), 0.99 (t, J = 7.5 Hz, 3 H) ppm. C NMR: δ = 169.4, 168.0,
4
0 min) reaction, (d) high isolated yields of products, and 165.7, 121.3, 33.0, 21.7, 13.8 ppm. C H O (158.15): calcd. C
7
10
4
(
e) reusability of catalyst and cost-effectiveness. Another at- 53.16, H 6.37; found C 53.02, H 6.24.
tractive feature of this methodology is the use of ionic li-
quid as catalyst as well as reaction medium primarily avoid-
2
-Octylidenemalononitrile: (Entry 13, Table 1). Viscous liquid. IR:
–1
1
ν˜ = 2237, 1647, 1608, 1465 cm . H NMR: δ = 7.34 (t, J = 7.8 Hz,
ing hazardous organic solvent in the whole procedure in 1 H), 2.55–2.62 (m, 2 H), 1.47–1.54 (m, 2 H), 1.18–1.33 (m, 8 H),
1
3
contrast to the reported procedures using ionic liquids to- 0.87–0.91 (m, 3 H) ppm. C NMR: δ = 169.7, 111.9, 111.2, 89.5,
gether with additional catalysts[
5j,5i,5m]
16
2
and organic solvents 32.6, 31.3, 29.0, 28.5, 27.3, 22.4, 13.8 ppm. C11
H
N
(176.26):
calcd. C 74.96, H 9.15, N 15.89; found C 74.72, H 9.21, N 15.68.
in the process. Thus, we believe that this simple and green
procedure will be a practical alternative to the existing pro- Ethyl 2-Acetyl-3-(furan-2-yl)acrylate: (Entry 30, Table 1). Yellowish
–
1 1
cedures to cater the need of academia as well as industries. liquid. IR: ν˜ = 1720, 1660, 1625, 1211 cm . H NMR: δ = 7.47 (s,
1
4
H), 7.31 (s, 1 H), 6.71 (d, J = 3.5 Hz, 1 H), 6.43–6.44 (m, 1 H),
.23 (q, J = 7.0 Hz, 2 H), 2.43 (s, 3 H), 1.27 (t, J = 7.3 Hz, 3 H)
1
3
ppm. C NMR: δ = 201.9, 164.3, 149.0, 146.2, 129.5, 125.8, 117.6,
Experimental Section
1
5
12.5, 61.5, 26.3, 13.9 ppm. C11
.81; found C 63.28, H 5.75.
12 4
H O (208.21): calcd. C 63.45, H
General: NMR spectra were recorded with a Bruker DPX-300 in-
1
13
strument at 300 MHz for H and 75 MHz for C NMR in CDCl
3
solutions. IR spectra were measured with a FT-8300 Shimadzu
spectrometer (neat for liquids and KBr pellet for solids). All liquid Acknowledgments
substrates were distilled before use. [bmIm]OH was prepared fol-
lowing our earlier procedure.[ This ionic liquid is considerably
2h]
This work has enjoyed the support from CSIR, New Delhi [Grant
No. 01(1936)/04]. R.J. is also thankful to CSIR for his fellowship.
stable under ambient conditions and can be used in reactions with-
out any difficulty as reported by us
[2h]
and another group re-
[
19]
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3769

B. C. Ranu, R. Jana
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Received: April 15, 2006
Published Online: June 19, 2006
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Eur. J. Org. Chem. 2006, 3767–3770